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Biomedical subjects

A G Robertson

Publications and source records attributed to A G Robertson.

At least 19 recordsLinked to original sources
PubMed2001

The accuracy of head and neck carcinoma sentinel lymph node biopsy in the clinically N0 neck.

BACKGROUND: Sentinel lymph node (SLN) biopsy originally was described as a means of identifying lymph node metastases in malignant melanoma and breast carcinoma. The use of SLN biopsy in patients with oral and oropharyngeal squamous cell carcinoma and clinically N0 necks was investigated to determine whether the pathology of the SLN reflected that of the neck. METHODS: Patients undergoing elective neck dissections for head and neck squamous cell carcinoma accessible to injection were enrolled into our study. Sentinel lymph node biopsy was performed after blue dye and radiocolloid injection. Preoperative lymphoscintigraphy and the perioperative use of a gamma probe identified radioactive SLNs; visualization of blue stained lymphatics identified blue SLNs. A neck dissection completed the surgical procedure, and the pathology of the SLN was compared with that of the remaining neck dissection. RESULTS: Sentinel lymph node biopsy was performed on 40 cases with clinically N0 necks. Twenty were pathologically clear of tumor and 20 contained subclinical metastases. SLNs were found in 17 necks with pathologic disease and contained metastases in 16. The sentinel lymph node was the only lymph node containing tumor in 12 of 16. CONCLUSIONS: The SLN, in head and neck carcinomas accessible to injection without anesthesia, is an accurate reflector of the status of the regional lymph nodes, when found in patients with early tumors. Sentinel lymph nodes may be found in clinically unpredictable sites, and SLN biopsy may aid in identifying the clinically N0 patient with early lymph node disease. If SLNs cannot be located in the neck, an elective lymph node dissection should be considered.

Adult↗
PubMed2001

Identification and structure of the nerve growth factor binding site on TrkA.

Nerve growth factor (NGF) is involved in the development and maintenance of the nervous system and has been implicated as a possible therapeutic target molecule in a number of neurodegenerative diseases, especially Alzheimer's disease. NGF binds with high affinity to the extracellular region of a tyrosine kinase receptor, TrkA, which comprises three leucine-rich motifs (LRMs), flanked by two cysteine-rich clusters, followed by two immunoglobulin-like (Ig-like) domains. We have expressed the second Ig-like domain as a recombinant protein in E. coli and demonstrate that NGF binds to this domain with similar affinity to the native receptor. This domain (TrkAIg(2)) has the ability to sequester NGF in vitro, preventing NGF-induced neurite outgrowth, and in vivo, inhibiting NGF-induced plasma extravasation. We also present the three-dimensional structure of the TrkAIg(2) domain in a new crystal form, refined to 2.0 A resolution.

Animals↗
PubMed2001

Recombinant human nerve growth factor for clinical trials: protein expression, purification, stability and characterisation of binding to infusion pumps.

Nerve growth factor (NGF) has been suggested to be of therapeutic benefit to patients with Alzheimer's disease. One of the early changes in this disease is a loss of cholinergic function within the brain, and NGF is able to rescue cholinergic neurons both in vitro and in vivo. We describe the production of recombinant human beta-NGF (rhNGF), using baculovirus infection of insect cells; its purification, formulation and subsequent stability for use in clinical trials. Tests were also carried out to monitor release of protein from infusion pumps and catheters for intracerebroventricular administration (icv). Initial problems with non-specific binding were overcome using a blocking formula.

Animals↗
PubMed2001

Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5.

BACKGROUND: The binding of neurotrophin ligands to their respective Trk cellular receptors initiates intracellular signals essential for the growth and survival of neurons. The site of neurotrophin binding has been located to the fifth extracellular domain of the Trk receptor, with this region regulating both the affinity and specificity of Trk receptor:neurotrophin interaction. Neurotrophin function has been implicated in a number of neurological disorders, including Alzheimer's disease and Parkinson's disease. RESULTS: We have determined the 2.7 A crystal structure of neurotrophin-4/5 bound to the neurotrophin binding domain of its high-affinity receptor TrkB (TrkB-d5). As previously seen in the interaction of nerve growth factor with TrkA, neurotrophin-4/5 forms a crosslink between two spatially distant receptor molecules. The contacts formed in the TrkB-d5:neurotrophin-4/5 complex can be divided into a conserved area similar to a region observed in the TrkA-d5:NGF complex and a second site-unique in each ligand-receptor pair-formed primarily by the ordering of the neurotrophin N terminus. CONCLUSIONS: Together, the structures of the TrkB-d5:NT-4/5 and TrkA-d5:NGF complexes confirm a consistent pattern of recognition in Trk receptor:neurotrophin complex formation. In both cases, the N terminus of the neurotrophin becomes ordered only on complex formation. This ordering appears to be directed largely by the receptor surface, with the resulting complementary surfaces providing the main determinant of receptor specificity. These features provide an explanation both for the limited crossreactivity observed between the range of neurotrophins and Trk receptors and for the high-affinity binding associated with respective ligand-receptor pairs.

Amino Acid Motifs↗
PubMed2001

Treatment of oral cancer: the need for defined protocols and specialist centres. variations in the treatment of oral cancer.

The authors of this study aimed to identify treatment philosophies for oral cancer within the west of Scotland and to investigate any survival differences associated with the various treatment options by means of a retrospective review of case notes and cancer registry data. All patients with squamous cancer of the tongue or floor of the mouth were identified from the West of Scotland Cancer Registry for the period 1984-1990. A total of 206 patients were available for study. Five different treatment protocols were identified: 5% of patients underwent biopsy only, 16% biopsy plus radiotherapy, 11% excisional biopsy, 25% radical surgery, and 42% radical surgery plus radiotherapy. Tumour staging by the TNM classification was an important factor that determined outcome. When adjusting for T stage and nodal involvement, there was a significant effect of treatment protocol on both the disease-free period (P < 0.001) and on survival (P < 0.001). The treatment options were used differently by individual clinicians and were related to stage of the disease. One hundred and forty-four (70%) of the patients were treated by a single combined head and neck unit based within the plastic surgery unit at Canniesburn Hospital. The remaining 62 were treated in 13 different units throughout the west of Scotland. For those not treated in the combined head and neck unit, the increased hazard for recurrence was 1.43 (95% confidence interval (CI) 1.01-2.02), and the increased hazard ratio for death was 1.48 (95% CI 1.06-2.06) when adjusting for tumour stage, and nodal involvement. Treatment philosophies for oral cancer have a significant effect on outcome. There is a need to develop clearly defined protocols based on staging and site of disease. We believe that treatment should be carried out within a multidisciplinary setting in a combined head and neck cancer unit.

Adult↗
PubMed2000

Identification of syntaxin 1A as a novel binding protein for presenilin-1.

Mutations in the presenilin 1 gene have been shown to result in Alzheimer's disease. Presenilin 1 is a multi-transmembrane protein with a large hydrophilic loop near the C-terminus. This region is required for known functions of presenilin 1. We have constrained this loop within the active site of the bacterial protein, thioredoxin, to mimic its native conformational state. This hybrid protein was used as bait in a yeast two hybrid screen in an attempt to identify presenilin binding proteins. By this method syntaxin 1A, a synaptic plasma membrane protein, was identified as a novel binding protein for presenilin 1. In vitro experiments confirm the two-hybrid results suggesting that PS1 binds syntaxin under physiological conditions.

Alzheimer Disease↗
PubMed2000

Natural history and patterns of recurrence of tongue tumours.

This retrospective study comprises 226 patients with squamous cell carcinoma of the tongue treated at Canniesburn Hospital, Glasgow between 1980 and 1996. The male:female ratio was 1.2:1 and the average age was 64 years. The ratio of anterior 2/3 to posterior 1/3 tongue lesions was 1.8:1. A total of 23% of patients were clinically staged as T1, 50% were T2 and 27% were T3/T4. At presentation 156 patients (69%) had a clinically negative neck, while 110 patients (49%) had a neck dissection at the time of treatment of the primary. A comparison between the clinical and pathological T and N stages highlighted the difficulties of clinical TNM staging with upstaging of the primary T stage in 21% of patients and downstaging in 6% and upstaging of neck disease in 36% and downstaging in 7.7%. The incidence of clinically occult disease in the neck was 41% including six patients (4.5%) with occult disease in the contralateral neck.

Adult↗
PubMed2000

A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer.

An E1B 55 kDa gene-deleted adenovirus, Onyx-015, which reportedly selectively replicates in and lyses p53-deficient cells, was administered by a single intratumoral injection to a total of 22 patients with recurrent head and neck cancer. The objectives of this Phase I study were to determine the safety, feasibility, and efficacy of this therapy and determine any correlation to p53 status. Six cohorts were investigated with a dose escalation from 10(7)-10(11) plaque-forming units. Toxicity was assessed using NCIC criteria. Tumor response was assessed by clinical and radiological measurement. Blood samples were taken to detect adenovirus DNA and neutralizing antibody to adenovirus. Tumor biopsies were taken to detect adenovirus by in situ hybridization. Treatment was well tolerated, with the main toxicity being grade 1/2 flu-like symptoms. Dose-limiting toxicity was not reached at the highest dose of 10(11) plaque-forming units. Twenty-one of the 22 patients treated showed an increase in neutralizing antibody to adenovirus. In situ hybridization showed viral replication in 4 of 22 patients treated, all of whom had mutant p53 tumors. Using conventional response criteria, no objective responses were observed. However, magnetic resonance imaging scans were suggestive of tumor necrosis at the site of viral injection in five patients, three of whom were classified using nonconventional criteria as partial responders, and two of whom were classified using nonconventional criteria as minor responders. Of these five cases, four had mutant p53 tumors. The response duration for the three partial responders was 4, 8, and 12 weeks. An additional eight patients had stable disease in the injected tumors lasting from 4-8 weeks. These preliminary results show that intratumoral administration of Onyx-015 is feasible, well tolerated, and associated with biological activity. Further investigation of Onyx-015, particularly with a more frequent injection protocol and in combination with systemic chemotherapy, is warranted.

Adenovirus E1B Proteins↗
PubMed1999

Improved survival for patients with clinically T1/T2, N0 tongue tumors undergoing a prophylactic neck dissection.

BACKGROUND: Prophylactic surgical treatment of the neck in "early tongue tumors" is a controversial issue. METHODS: From a database of 226 patients with squamous cell carcinoma of the tongue treated at Canniesburn Hospital, Glasgow, U.K., between 1980 and 1996, a total of 137 patients with a minimum follow up of 24 months or until death were clinically identified as being T1/T2, N0 (UICC) when first seen. These patients were divided into three groups according to the management of the neck; 53 patients did not have a neck dissection at any time (NKD0), 47 patients underwent a synchronous neck dissection at the time of treatment of the primary (NKDS), and 37 patients subsequently required a metachronous neck dissection when lymph node metastasis became clinically apparent (NKDM). These three groups were compared with respect to age, sex, site, duration of symptoms, previous treatment (if any), initial treatment protocol, resection margin, type of neck dissection (if any), loco-regional recurrence, systemic escape, number of positive lymph nodes, and presence of extracapsular spread. Disease-related survival was calculated using Kaplan-Meier survival curves with logrank test and chi-square statistical analysis. RESULTS: The pT stage was upgraded to T3/4 in 3/53 patients (6%) of the NKD0 group, 11/47 patients (23%) of the NKDS group, and 2/37 patients (5%) of the NKDM group (p < 0.001). The 5-year determinate survival rates for the three groups were: NKD0 59.7%, NKDS 80.5%, NKDM 44.8%, and (NKD0 + NKDM) 53.6% with a statistically significant improvement in survival for NKDS vs NKDM (logrank 10.58, p = 0.001) and for NKDS vs (NKD0 + NKDM) (logrank 6.06, p = 0.014). The incidences of positive nodes in the NKDS and NKDM groups were 18/47 patients (38%) and 32/37 patients (86%) respectively. Neck positive patients in the NKDM group had a significantly greater number of positive nodes in comparison with N positive patients in the NKDS group (chi trend, p = 0.001), a higher incidence of extracapsular spread, 30/32 vs 9/18 (chi test, p < 0. 0001), and decreased survival. The incidence of occult cervical metastasis for the whole group was 41%. CONCLUSION: Patients with clinical T1/2, N0 tongue tumors who underwent a synchronous neck dissection had an improved survival outcome even though as a group they had a higher incidence of occult metastasis, relatively more T2 lesions, a worse pT stage, and had more posterior third lesions requiring more difficult initial surgery. Tongue tumors have a high incidence of subclinical nodal disease, which is less curable when it presents clinically. The information gleaned from the nodal status allows a more informed plan of adjuvant therapy.

Adult↗
PubMed1999

A suggested method for sentinel node biopsy in squamous cell carcinoma of the head and neck.

BACKGROUND: Debate continues over the management of the N0 neck in head and neck malignancy. Therefore, the possibility of performing sentinel node biopsy in these patients was investigated to formulate a method for the procedure. METHODS: Patients undergoing prophylactic or therapeutic neck dissections were injected with either Patent Blue V dye alone or with blue dye and 99m-Tc labeled Albures. The latter group underwent preoperative lymphoscintigraphy. During surgery, blue stained lymphatics were followed to blue nodes, and a neoprobe was used to identify radioactive nodes. RESULTS: In 5 of 13 patients receiving blue dye, a blue node was identified, but none contained tumor. Metastases were identified in other neck nodes in 3 of 5. Sentinel nodes were identified in 15 of 16 patients receiving dye, and Albures. Sentinel node biopsy was accurate in 7 of 7 necks containing impalpable metastases when all nodes had been evaluated after dissection. DISCUSSION: Sentinel node biopsy using blue dye and radiocolloid may prove to be a reliable technique in the N0 neck and warrants further investigation.

Biopsy↗
PubMed1999

Interstitial iridium-192 implantation for recurrent and/or locally advanced head and neck cancer.

We report our experience with the use of interstitial iridium-192 implantation in the management of patients with recurrent and locally advanced squamous cell carcinoma of the head and neck. Between June 1992 and July 1998 this technique was employed in the management of two groups of patients: (1) a primary group, comprising 42 patients who had presented for the first time with advanced head and neck disease, and had therefore not undergone any previous treatment; and (2) a salvage group of 16 patients with recurrent disease previously treated with external beam radiotherapy (four received therapy to the neck, one to the cheek, eight to the tongue and three to the floor of the mouth). The follow-up in each group was short, ranging from 3 to 56 months. The overall response in the primary group was 38/42 (90%). A complete response was achieved in 35/42 (83%). In the salvage group, the overall response was 13/16 (81%); 4/16 (25%) showed a complete response and 9/16 (56%) a partial response. The estimated percentage surviving at 1 year for patients with primary disease is 70% (95% confidence interval (CI) 54-86). For those receiving salvage therapy the estimated percentage surviving at 1 year is 45% (95% CI 19-71).

Adult↗
PubMed1998

Molecular characterization of benzyl alcohol dehydrogenase and benzaldehyde dehydrogenase II of Acinetobacter calcoaceticus.

The nucleotide sequences of xylB and xylC from Acinetobacter calcoaceticus, the genes encoding benzyl alcohol dehydrogenase and benzaldehyde dehydrogenase II, were determined. The complete nucleotide sequence indicates that these two genes form part of an operon and this was supported by heterologous expression and physiological studies. Benzaldehyde dehydrogenase II is a 51654 Da protein with 484 amino acids per subunit and it is typical of other prokaryotic and eukaryotic aldehyde dehydrogenases. Benzyl alcohol dehydrogenase has a subunit Mr of 38923 consisting of 370 amino acids, it stereospecifically transfers the proR hydride of NADH, and it is a member of the family of zinc-dependent long-chain alcohol dehydrogenases. The enzyme appears to be more similar to animal and higher-plant alcohol dehydrogenases than it is to most other microbial alcohol dehydrogenases. Residue His-51 of zinc-dependent alcohol dehydrogenases is thought to be necessary as a general base for catalysis in this category of alcohol dehydrogenases. However, this residue was found to be replaced in benzyl alcohol dehydrogenase from A. calcoaceticus by an isoleucine, and the introduction of a histidine residue in this position did not alter the kinetic coefficients, pH optimum or substrate specificity of the enzyme. Other workers have shown that His-51 is also absent from the TOL-plasmid-encoded benzyl alcohol dehydrogenase of Pseudomonas putida and so these two closely related enzymes presumably have a catalytic mechanism that differs from that of the archetypal zinc-dependent alcohol dehydrogenases.

Acinetobacter calcoaceticus↗
PubMed1998

Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience.

PURPOSE: To report our experience in the use of interstitial iridium-192 implantation combined with external radiotherapy in anal cancer. METHODS AND MATERIALS: From 1984 to 1994, 79 patients with anal cancer were treated with radical intent using radiotherapy (plus chemotherapy) at Beatson Oncology Centre, Glasgow, Scotland. The mean and median age at presentation were 68 and 70 years, respectively (range 34-85) with a male-to-female ratio of 0.39. The histologic distribution was as follows: 48 squamous, 16 basaloid, 14 adenocarcinoma, and 1 basal cell carcinoma. The T stages were: 8 T1, 40 T2, 26 T3, and 5 T4 lesions. Twelve (15%) patients had nodal involvement at presentation. All patients underwent interstitial implantation using iridium-192 as part of the initial treatment. Seventy-six patients were treated with external radiotherapy followed by implant with a mean delay of 37 days after the end of radiotherapy. Twelve patients also received chemotherapy with 5-fluorouracil and mitomycin-C concurrently with external radiotherapy. Follow-up ranged from 6 to 123 months, with a median of 37 months. RESULTS: Seventy-nine patients were analyzed to assess local control, survival, and complications. A complete response rate of 91% (72 of 79) was achieved after planned radiation treatment. At the end of external radiotherapy, 29% (22 of 76) had achieved complete response, 58% (7 of 12) with chemotherapy and 23% (15 of 64) without it. Local control was achieved in 62 of 79 (78%) patients and 8 of 17 (47%) local failures were salvaged by abdominoperineal resection. Five patients developed inguinal node failure; four of these were salvaged. Overall, 10% of all patients developed distant metastasis as the first site of failure and 25% failed at any site after salvage therapy. Time to unsalvageable relapse was significantly different on comparing T stage (p = 0.005) and histology (p = 0.029) of tumor. Major complications requiring surgical intervention were seen in six (7.5%) patients. Anal function preservation with local control was possible in 56 of 79 (71%) patients. CONCLUSION: We report excellent results with radiotherapy in T1 and T2 lesions. The role of chemoradiotherapy as radical treatment of anal cancer should be defined in the context of locally advanced tumors.

Adenocarcinoma↗
PubMed1998

Similar decreases in local tumor control are calculated for treatment protraction and for interruptions in the radiotherapy of carcinoma of the larynx in four centers.

PURPOSE: Data on patients with cancer of the larynx are analyzed using statistical models to estimate the effect of gaps in the treatment time on the local control of the tumor. METHODS AND MATERIALS: Patients from four centers, Edinburgh, Glasgow, Manchester, and Toronto, with carcinoma of the larynx and treated by radiotherapy were followed up and the disease-free period recorded. In all centers the end point was control of the primary tumor after irradiation alone. The local control rates at > or = 2 years, Pc, were analyzed by log linear models, and Cox proportional hazard models were used to model the disease-free period. RESULTS: T stage, nodal involvement, and site of the tumor were important determinants of the disease-free interval, as was the radiation schedule used. Elongation of the treatment time by 1 day, or a gap of 1 day, was associated with a decrease in Pc of 0.68% per day for Pc = 0.80, with a 95% confidence interval of (0.28, 1.08)%. An increase of 5 days was associated with a 3.5% reduction in Pc from 0.80 to 0.77. At Pc = 0.60 an increase of 5 days was associated with an 7.9% decrease in Pc. The time factor in the Linear Quadratic model, gamma/alpha, was estimated as 0.89 Gy/day, 95% confidence interval (0.35, 1.43) Gy/day. CONCLUSIONS: Any gaps (public holidays are the majority) in the treatment schedule have the same deleterious effect on the disease free period as an increase in the prescribed treatment time. For a schedule, where dose and fraction number are specified, any gap in treatment is potentially damaging.

Carcinoma↗
PubMed1998

Behavior of radial forearm skin flaps transplanted into the oral cavity.

Radial forearm skin flaps transplanted into the oral cavity in patients undergoing treatment for intra-oral tumors frequently acquire a gross appearance resembling that of buccal mucosa. This article reports studies of biopsies of the flaps in 53 patients, of which 21 showed changes at some stage in the follow-up period. The project aims to determine whether 1) the change in the epithelium to a mucosal form is genuine or reactive, 2) a creeping replacement of epidermis results from the surrounding buccal epithelium, 3) alterations in the epidermis could be associated with changes in the dermis, 4) the change is caused by radiotherapy. Examination of the biopsies by resin histology and transmission electron microscopy shows that the changes may be reversible: it suggests that they are reactive in nature, and related to the degree of dermal inflammation, rather than to the effect of radiotherapy. The dermis persists as such and is not replaced by buccal lamina propria.

Adult↗
PubMed1998

Effect of gap length and position on results of treatment of cancer of the larynx in Scotland by radiotherapy: a linear quadratic analysis.

PURPOSE: This paper reports on the analysis of the effect of the length and position of unplanned gaps in radiotherapy treatment schedules. MATERIALS AND METHODS: Data from an audit of the treatment of carcinoma of the larynx are used. They represent all newly diagnosed cases of glottic node-negative carcinoma of the larynx between 1986 and 1990, inclusive, in Scotland that were referred to one of the five Scottish Oncology Centres for primary radical radiotherapy treatment. The end-points are local control of cancer of the larynx in 5 years and the length of the disease-free period. The local control rates at > or =5 years, Pc were analyzed by log linear models and Cox proportional hazard models were used to model the disease-free period. RESULTS: Unplanned gaps in treatment are associated with poorer local control rates and an increased hazard of a local recurrence through their effect on extending the treatment time. A gap of 1 day is potentially damaging but the greatest effect is at treatment extensions of 3 or more days, where the hazard of a failure of local control is increased by a factor of 1.75 (95% confidence interval 1.20-2.55) compared to no gap. The time factor for the actual time was imprecisely estimated at 2.7 Gy/day with a standard error of 13.2 Gy/day. Among those cases who had exactly one gap resulting in a treatment extension of 1 day, there is no evidence that gap position influences local control (P = 0.17). The treatment extension as a result of the gap is more important than the position of the gap in the schedule. CONCLUSIONS: Gaps in the treatment schedule have a detrimental effect on the disease-free period. A gap has a slightly greater effect than an increase in the prescribed treatment time. Any gap in treatment is potentially damaging. The position of the gap in the schedule was shown to be not important.

Appointments and Schedules↗
PubMed1998

Early closure of a randomized trial: surgery and postoperative radiotherapy versus radiotherapy in the management of intra-oral tumours.

Tumours of the oral cavity/oropharynx occur relatively infrequently in the UK. The management of such lesions, especially the squamous cell carcinomas, is still a little controversial. Some centres advocate radiotherapy while others adopt surgery and radiotherapy. In an attempt to resolve the question of which approach gives the better results, a multicentre randomized trial was established to compare surgery plus postoperative radiotherapy with radical radiotherapy alone. It was anticipated that 350 patients would be required to give a statistically significant result, but, after 35 patients had been entered, the trial was closed prematurely with a marked difference in overall survival in favour of the combination arm (P = 0.0006). At this analysis, carried out 23 months after trial closure, the survival difference between the two arms remains statistically significant for all causes of mortality (P = 0.001; relative death rate = 0.24; 95% CI 0.10-0.59).

Adult↗