Factors affecting duration of gastrostomy tube retention in survivors following treatment for head and neck cancer.

BACKGROUND: Many patients treated for head and neck cancer require nutritional support, which is often delivered using a gastrostomy tube. It is difficult to predict which patients will retain their gastrostomy tube in the long term. This study aimed to identify the factors which affect the duration of gastrostomy tube retention. METHOD: In this retrospective study, 151 consecutive patients from one centre were audited. All patients had a mucosal tumour of the head and neck, and underwent gastrostomy tube insertion between 2003 and 2007. RESULTS: There were near-complete data sets for 132 patients. The gastrostomy tube was retained in survivors (n = 66) for a mean of 21.3 months and in non-survivors (n = 66) for 11.9 months. Univariate analysis showed that co-morbidity was the only factor which significantly increased duration of gastrostomy tube retention in survivors (p = 0.041). CONCLUSION: Co-morbidity alone was associated with a significant increase in gastrostomy tube retention. It is suggested that co-morbidity be included as a variable in future relevant research. Co-morbidity should also be considered when counselling patients about their long-term function following cancer treatment. Gastrostomy tube retention is likely to be affected by many factors, with few single variables having importance independently.

Functional status after total laryngectomy: cross-sectional survey of 79 laryngectomees using the Performance Status Scale for Head and Neck Cancer.

INTRODUCTION: Total laryngectomy affects patients' post-operative speech and swallowing functions. We aimed to assess these outcomes. MATERIALS AND METHODS: Patients' normalcy of diet, ability to eat in public and speech comprehensibility were assessed using the Performance Status Scale for Head and Neck Cancer, in a cross-sectional survey of disease-free laryngectomees. RESULTS AND ANALYSIS: Seventy-nine laryngectomees (72 men and seven women), with a mean age of 64 years (range 37 to 96), were included. Mean scores were 81.6 (standard deviation 29.2) for normalcy of diet, 77.8 (standard deviation 30.2) for eating in public and 65.2 (standard deviation 23.5) for speech. Normalcy of diet achieved higher scores within six months of laryngectomy and remained stable. There was a statistically significant difference between scores for the speech and public eating domains, comparing patients less and more than six months post-laryngectomy. This trend was maintained beyond 12 months. CONCLUSIONS: In post-laryngectomy patients, Performance Status Scale for Head and Neck Cancer scores improved over time, especially those for the speech and public eating domains, reflecting increasing confidence in social interactions and familiarity with surgical voice restoration.

The 2-week rule for suspected head and neck cancer in the United Kingdom: referral patterns, diagnostic efficacy of the guidelines and compliance.

A retrospective audit of 1079 2-week referrals between 1 January 2004 and 31 December 2006 was undertaken. The aims of this audit were to assess compliance of referrals with Department of Health (DoH) guidelines; the effectiveness of the 2-week referral route in detecting head and neck cancers, and to determine whether this route identified more early stage cancers. Of 1079 2-week referrals, 71.5% conformed to DoH criteria. DoH guidelines were found to have a high sensitivity of 83.9% (75.5-89.7%, 95% CI) for head and neck cancer, but a low positive predictive value of 12.8% (10.5-15.3%) and a specificity of 30.0% (27.2-33.1%). Only 10.9% of 2-week referrals were diagnosed with a head and neck cancer. The cancer detection rate was higher amongst referrals that conformed to DoH guidelines (12.8%) compared to those that did not 6.2%. This was statistically significant (Chi square, p<0.01). The guidelines had a positive likelihood ratio of 1.20 (1.1-1.3), suggesting that there is a minimal increase in the likelihood of head and neck cancer when DoH guidelines are correctly applied. The diagnostic odds ratio (DOR) of the DoH referral criteria is 2.21. Most head and neck cancers were diagnosed via routine referral routes, 2-week referrals contributing to only 21.4% of all head and neck cancers diagnosed during the study period. The 2-week referral route did not identify more early stage cancers.

Primary squamous cell carcinoma of the thyroid gland: a case report and role of radiotherapy.

Primary squamous cell carcinoma is an extremely rare tumour of the thyroid gland. A case of an elderly lady who was diagnosed to have primary squamous cell carcinoma of the thyroid gland is presented and the role of radiotherapy is discussed.

Surgical treatment of chronic parotid sialadenitis.

OBJECTIVE: To review the results of surgical management of chronic parotid sialadenitis refractory to medical therapy, with particular respect to long-term symptom resolution and development of post-operative complications. METHODS: A retrospective review of parotidectomies performed for chronic intractable parotid sialadenitis. Information was collected about presentation, pre-operative investigations, surgical treatment, post-operative complications and outcome. RESULTS: 36 parotidectomies were performed for chronic sialadenitis between 1991 and 2002. Age at presentation was 56+/-9.6 years, with median symptom duration of 2.3 years. For patients with non-specific presentations, magnetic resonance imaging (MRI) was the most useful pre-operative investigation. Superficial parotidectomy with duct preservation was the main treatment with a 94 per cent success rate, and near-total parotidectomy was reserved for patients with extensive deep-lobe involvement. Duct ligation significantly increased the risk of transient facial palsy. There was a 56 per cent and 22 per cent incidence of temporary facial paresis and Frey's syndrome, respectively. CONCLUSIONS: Controversies exist regarding the optimal pre-operative investigation and surgical treatment of chronic parotid sialadenitis. We advocate magnetic resonance image (MRI) scanning for patients with non-specific symptoms of sialadenitis, and sialography in the presence of reasonable clinical suspicion. We propose superficial parotidectomy without parotid duct ligation as the standard of care, with near-total parotidectomy reserved for extensive deep-lobe disease.

Optimizing the assessment of quality of life after laryngeal cancer treatment.

Reports of the impact of larynx cancer treatment modality on quality of life are conflicting, in part due to varying study methodology. The aims of this study were to (1) provide preliminary comparisons of quality of life following radiotherapy or combination therapy; (2) evaluate a number of measures of quality of life and thereby (3) inform future prospective studies. Thirty-six laryngeal cancer patients, 24 following radiotherapy, 12 following radiotherapy and laryngectomy completed the Functional Assessment of Cancer Therapy (FACT) - General/Head and Neck subscale; Nottingham Health Profile (NHP); and the Hospital Anxiety and Depression scale (HAD), three to 12 months post-treatment. Results showed trends towards a less good quality of life in the combined therapy group over a wide range of outcomes, significant for the disease specific FACT head and neck subscale, NHP emotion (p = 0.04) and isolation (p = 0.027). To the authors' knowledge, however, this is the first demonstration of greater impact of laryngeal cancer on quality of life in younger subjects, who had lower scores among others on emotional wellbeing (p = 0.015) and anxiety (p = 0.035). Younger patients thus appear more likely to need more intensive support through treatment. Many of the physical and psychosocial domains derived from the three tools used were highly correlated. In other words, given the known high morbidity of the disease and its treatment, the selection of tools for head and neck quality of life assessment may be much less important than their universal application.

Crystal structures of MMP-1 and -13 reveal the structural basis for selectivity of collagenase inhibitors.

The X-ray crystal structures of the catalytic domain of human collagenase-3 (MMP-13) and collagenase-1 (MMP-1) with bound inhibitors provides a basis for understanding the selectivity profile of a novel series of matrix metalloprotease (MMP) inhibitors. Differences in the relative size and shape of the MMP S1' pockets suggest that this pocket is a critical determinant of MMP inhibitor selectivity. The collagenase-3 S1' pocket is long and open, easily accommodating large P1' groups, such as diphenylether. In contrast, the collagenase-1 S1' pocket must undergo a conformational change to accommodate comparable P1' groups. The selectivity of the diphenylether series of inhibitors for collagenase-3 is largely determined by their affinity for the preformed S1' pocket of collagenase-3, as compared to the induced fit in collagenase-1.

Understanding the P1' specificity of the matrix metalloproteinases: effect of S1' pocket mutations in matrilysin and stromelysin-1.

Matrilysin (MAT) prefers leucine over residues that have aromatic side chains at the P1' position of peptide and protein substrates, while stromelysin (HFS) has a broader specificity. The X-ray structures of these enzymes show that their respective S1' subsites differ primarily due to the amino acids present at positions 214 and 215. To examine the role that these residues play in determining P1' specificity, the amino acids at these positions in matrilysin have been replaced by those found in stromelysin (MAT: Y214L, MAT:A215V, and MAT:Y214L/A215V). The specificity and activity of MAT:A215V are similar to those of wild type matrilysin. Both MAT:Y214L and MAT:Y214L/A215V, however, have P1' specificities that are more similar to stromelysin than matrilysin. Specifically, these enzymes exhibit an 8- to 9-fold reduction in kcat/KM toward a peptide substrate with Leu in subsite P1' relative to wild type matrilysin. This is predominantly the result of an approximate 5-fold decrease in kcat. The KM values only partially increase toward the value observed for stromelysin. Studies of the pre-steady-state reaction of wild type and mutant matrilysin with substrates with Leu and Tyr residues in the P1' position confirm that the KM values for these reactions reflect KD values for substrate binding. Thus, replacement of a single tyrosine residue in the S1' pocket of matrilysin by leucine alters its P1' specificity to resemble that of stromelysin. In contrast, alteration of the S1' subsite of stromelysin (HFS:L214Y/V215A) to resemble matrilysin increases activity (i.e., higher kcat/KM) toward peptide substrates with both leucine and residues with aromatic side chains in the P1' position with only a partial increase in specificity for Leu. These increases in activity are the result of decreases in the KM values for these reactions.

Purification of human matrilysin produced in Escherichia coli and characterization using a new optimized fluorogenic peptide substrate.

Human promatrilysin (matrix metalloproteinase-7) has been produced in Escherichia coli as an N-terminal fusion protein with ubiquitin. The insoluble product was solubilized, refolded, and activated with amino-phenylmercuric acetate. Activation of the fusion protein demonstrated kinetics and intermediates that were very similar to those observed during activation of promatrilysin produced in Chinese Hamster Ovary (CHO) cells. Following activation, matrilysin was purified to > 95% homogeneity using a Sepharose-Pro-Leu-Gly-NHOH affinity column. The matrilysin purified by this procedure is indistinguishable from the enzyme purified from CHO cells with respect to the kinetic parameters for hydrolysis of a peptide substrate and the ability to obtain diffraction quality crystals in the presence of an inhibitor of the enzyme. Additionally, to facilitate detailed kinetic analyses of matrilysin, a new fluorogenic peptide substrate with the optimized sequence Dnp-Arg-Pro-Leu-Ala-Leu-Trp-Arg-Ser (Dnp, dinitrophenyl) has been synthesized. This peptide is the best substrate developed for matrilysin thus far with Km and kcat values of 26 microM and 5.0 s-1, respectively.

Occupational rhinitis--possible mechanisms of pathogenesis.

Occupational rhinitis has been a prescribed industrial disease in the UK since 1907. It has only relatively recently received significant attention from otorhinolaryngologists although numerous studies have been performed in the past by occupational and industrial health physicians. At the present time the precise mechanisms of pathogenesis are unclear and would appear to be multiple. Recently interest has arisen because of compensation claims. Diagnosis made on the basis of the clinical history is subject to two problems: firstly, there is difficulty in differentiating between occupational and nonoccupational rhinitis, and secondly, clinical histories can easily be feigned. Physical signs would be a more reliable indicator of occupational damage to the nasal mucosa if they differ from the signs normally found in allergic or vasomotor rhinitis. In a series of 100 shipyard workers dry atrophic nasal mucosa was found in 66 and septal ulceration in two. From their clinical histories 78 individuals complained of nasal obstruction, 28 of epistaxis, 42 of hyposmia, 10 of anosmia and 90 of rhinorrhoea. Possible pathogenesis is described.

Cytomegalovirus protein substrates are not cleaved by the herpes simplex virus type 1 proteinase.

The herpesvirus maturational proteinase, assemblin, is made as a precursor that undergoes at least two autoproteolytic cleavages--one in a sequence toward its carboxyl end, called the maturational (M) site, and one in a sequence toward its midpoint, called the release (R) site. The M- and R-site sequences are both well conserved among the herpesvirus proteinase homologs, suggesting that the proteinase of one herpesvirus might be able to cleave the substrates of another. To test this possibility, we cloned and expressed in human cells the long (i.e., full-length open reading frame of proteinase gene) and short (i.e., proteolytic domain, assemblin) forms of the proteinase from human and simian cytomegalovirus (HCMV and SCMV, respectively) and from herpes simplex virus type 1 (HSV-1), as well as the genes for their respective assembly protein precursor substrates. Data from cotransfections of these proteinase genes with appropriate homologous and heterologous substrates showed that although the SCMV and HCMV enzymes cleaved the M-sites of the assembly protein substrates of all three viruses and an SCMV R-site substrate, the HSV-1 proteinase cleaved only its own substrate. This finding demonstrates that the substrate specificity properties of the HSV-1 enzyme differ from those of the two CMV enzymes.

Herpesvirus proteinase: site-directed mutagenesis used to study maturational, release, and inactivation cleavage sites of precursor and to identify a possible catalytic site serine and histidine.

The cytomegalovirus maturational proteinase is synthesized as a precursor that undergoes at least three processing cleavages. Two of these were predicted to be at highly conserved consensus sequences--one near the carboxyl end of the precursor, called the maturational (M) site, and the other near the middle of the precursor, called the release (R) site. A third less-well-conserved cleavage site, called the inactivation (I) site, was also identified near the middle of the human cytomegalovirus 28-kDa assemblin homolog. We have used site-directed mutagenesis to verify all three predicted sequences in the simian cytomegalovirus proteinase, and have shown that the proteinase precursor is active without cleavage at these sites. We have also shown that the P4 tyrosine and the P2 lysine of the R site were more sensitive to substitution than the other R- and M-site residues tested: substitution of alanine for P4 tyrosine at the R site severely reduced cleavage at that site but not at the M site, and substitution of asparagine for lysine at P2 of the R site reduced M-site cleavage and nearly eliminated I-site cleavage but had little effect on R-site cleavage. With the exception of P1' serine, all R-site mutations hindered I-site cleavage, suggesting a role for the carboxyl end of assemblin in I-site cleavage. Pulse-chase radiolabeling and site-directed mutagenesis indicated that assemblin is metabolically unstable and is degraded by cleavage at its I site. Fourteen amino acid substitutions were also made in assemblin, the enzymatic amino half of the proteinase precursor. Among those tested, only 2 amino acids were identified as essential for activity: the single absolutely conserved serine and one of the two absolutely conserved histidines. When the highly conserved glutamic acid (Glu22) was substituted, the proteinase was able to cleave at the M and I sites but not at the R site, suggesting either a direct (e.g., substrate recognition) or indirect (e.g., protein conformation) role for this residue in determining substrate specificity.

An assessment of the reproducibility of combined glottography in a clinical setting.

Although combined glottography has potential as a clinical tool, it has had limited use in the monitoring of laryngeal function before and after treatment. There is no data about the standardization nor reproducibility of the procedure. An indication of the reproducibility of combined glottography is paramount if changes in laryngeal function are to be measured accurately. Using a standardized technique, two complimentary studies examined the reproducibility of combined glottography within one sitting (Study 1) and over time (Study 2). The components of variance were analysed (ANOVA). In Study 1 the variance under controlled conditions for Open Quotient (OQ) and Speed Quotient (SQ) was only 13% and 18% respectively of the total, whilst in Study 2 the variance over time for OQ and SQ was 55% and 58% respectively. Under controlled conditions combined glottography is a reproducible technique.

A comparison of combined glottography in men and women.

Out-patient combined glottography has shown potential in the assessment of the vocal cord cycle in laryngeal abnormality. We compared this technique in men and women with normal laryngeal function, to evaluate the influence of patient sex on the results. Ten adult men were compared with 10 age matched women. The open quotient was significantly greater in women. This indicates the woman's glottis is open for a greater proportion of the glottic cycle, as a result of the anatomical and physiological differences of the larynx between the sexes. Analyses are made of the glottic cycle differences which may account, in part, for the different quality of the female voice. Interpretation of results using this technique must take account of the patient's sex.

Acute isolated sphenoid sinusitis: a disease with complications.

A case of acute isolated sphenoid sinusitis is described in a twelve year old boy who presented with ophthalmic complications. The literature is reviewed to emphasize the potential dangers of this condition.

A herpesvirus maturational proteinase, assemblin: identification of its gene, putative active site domain, and cleavage site.

A herpesvirus proteinase activity has been identified and partially characterized by using the cloned enzyme and substrate genes in transient transfection assays. Evidence is presented that the proteinase gene of cytomegalovirus strain Colburn encodes a 590-amino acid protein whose N-terminal 249 residues contain the proteolytic activity and two domains that are highly conserved in the homologous protein of other herpesviruses. Insertion of a short amino acid sequence between these domains abolished proteinase activity, suggesting that this region constitutes part or all of the enzyme active site. Plasma desorption mass spectrometry was used to identify the C terminus of the mature assembly protein as alanine, enabling the recognition of a consensus proteinase cleavage sequence of V/L-X-A decreases S/V, near the C-terminal end of all herpesvirus assembly protein homologs. Interestingly, the proteinase and its substrate, the assembly protein precursor, are encoded by opposite halves of the same open reading frame.

Cytomegalovirus assembly protein nested gene family: four 3'-coterminal transcripts encode four in-frame, overlapping proteins.

The genomic region encoding the assembly protein of simian cytomegalovirus (CMV) strain Colburn has been cloned, sequenced, and found to be organized as a nested set of four in-frame, 3'-coterminal genes, each with its own TATA promoter element and translational start codon, and all using a single 3' polyadenylation signal. The 3' end of the longest open reading frame (1.770 bp) was identical to the 930-bp sequence coding for the assembly protein precursor, as determined from a cDNA clone. The assembly protein coding region of human CMV strain AD169 was similarly organized, suggesting that both viral genomes could give rise to four independently transcribed 3'-coterminal RNAs coding for four overlapping, in-frame, carboxy-coterminal proteins. These predictions were tested and confirmed. Four mRNAs corresponding in size and sequence to those predicted were identified in both human and simian CMV-infected cells by using transcript-specific antisense oligonucleotide probes in Northern (RNA blot) assays. The 5' ends of the three largest of these Colburn transcripts were determined by S1 nuclease protection assays and found to map between the anticipated TATA sequences and corresponding translational start codons. The four predicted overlapping proteins were identified by immunoassays in lysates of simian and human CMV-infected cells by using an antiserum specific for the carboxyl end of the assembly protein precursor. The structural relationship of both sets of proteins was verified by comparing their peptide patterns following protein cleavage at tryptophan residues by N-chlorosuccinimide. The similar organization of the homologous coding regions in other herpesviruses into at least two nested, in-frame, 3'-coterminal genes is discussed.

Cytomegalovirus homologs of cellular G protein-coupled receptor genes are transcribed.

The genome of human cytomegalovirus (HCMV) contains three genes with homology to cellular G protein-coupled receptors (GCRs). Evidence is presented here that all three HCMV GCR genes are transcribed during infection, that they are transcribed as two sets of 3'-coterminal mRNAs, and that their transcription is restricted to the late phase of infection.

Early inappropriate secretion of antidiuretic hormone after trans-sphenoidal pituitary adenomectomy.

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a rare but life-threatening complication of trans-sphenoidal pituitary adenomectomy. It has previously only been described as a late phenomenon. We report an early presentation within the first week. The pathophysiology, clinical features and treatment are discussed.