A for stage III and IV squamous carcinoma of the head and neck: a Trans-Tasman Radiation Oncology Group Study

Purpose: The aims of this randomized controlled trial were to determine whether there were differences in the disease-free survival (DFS) and toxicity between conventional radiotherapy (CRT) and a continuous 3 week accelerated radiotherapy regimen (ART) in stage III and IV squamous cell carcinoma of the oral cavity, oropharynx, larynx and hypopharynx. Patients and methods: Patients from 14 centres throughout Australia and New Zealand were randomly assigned to either CRT, using a single 2 Gy/day to a dose of 70 Gy in 35 fractions in 49 days or to ART, using 1.8 Gy twice a day to a dose of 59.4 Gy in 33 fractions in 24 days. Treatment allocation was stratified for site and stage. The accrual began in 1991 and the trial was closed in 1998 when the target of 350 patients was reached. Results: The median potential follow-up time was 53 months (range, 14-101). The DFS at 5 years was 41% (95% CI, 33-50%) for ART and 35% (95% CI, 27-43%) for CRT (P = 0.323) and the hazard ratio was 0.87 in favour of ART (95% CI, 0.66-1.15). The 5-year disease-specific survival rates were 40% for CRT and 46% for ART (P = 0.398) and the loco-regional control was 47% for CRT vs. 52% for ART (P = 0.300). The respective hazard ratios were 0.88 (95% CI, 0.65-1.2) and 0.85 (0.62-1.16), favouring the accelerated arm. In the ART arm, confluent mucositis was more severe (94 vs. 71%; P < 0.001) and peaked about 3 weeks earlier than in the CRT arm, but healing appeared complete in all cases. There were statistically significant reductions in the probability of grade 2 or greater late soft tissue effects over time in the ART arm (P < 0.05), except for the mucous membrane where late effects were similar in both arms. Conclusions: Differences in DFS, disease-specific survival and loco-regional control have not been demonstrated. ART resulted in more acute mucosal toxicity, but this did not result in greater prolongation of the treatment time compared with the CRT arm. There were less late effects in the ART arm, with the exception of late mucosal effects. This trial has confirmed that tumour cell repopulation occurs during conventionally fractionated radiotherapy for head and neck cancer. However, it has also provided additional evidence that overall improvements in the therapeutic ratio using accelerated fractionation strategies are seriously constrained by the need to limit total doses to levels that do not exceed acute mucosal tolerance. The accelerated schedule tested has been shown in this trial to be an acceptable alternative to conventionally fractionated irradiation to 70 Gy. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

Early Australian experience with infliximab, a chimeric antibody against tumour necrosis factor-alpha, in the treatment of Crohn's disease: is its efficacy augmented by steroid-sparing immunosuppressive therapy?

Background: Tumour necrosis factor-alpha (TNF-alpha) plays an important role in the pathology of Crohn's disease. Infliximab, a chimeric antibody against TNF-alpha, has been shown in controlled clinical trials to be effective in two-thirds of patients with refractory or fistulating Crohn's disease. The factors that determine a clinical response in some patients but not others are unknown. Aims: To document the early Australian experience with infliximab treatment for Crohn's disease and to identify factors that may determine a beneficial clinical response. Methods: Gastroenterologists known to have used infliximab for Crohn's disease according to a compassionate use protocol were asked to complete a spreadsheet that included demographic information, Crohn's disease site, severity, other medical or surgical treatments and a global clinical assessment of Crohn's disease outcome, judged by participating physicians as complete and sustained (remission for the duration of the study), complete but unsustained (remission at 4 weeks but not for the whole study) or partial clinical improvement (sustained or unsustained). Results: Fifty-seven patients were able to be evaluated, with a median follow-up time of 16.4 (4-70) weeks, including 23 patients with fistulae. There were 21 adverse events, including four serious events. Fifty-one patients (89%) had a positive clinical response for a median duration (range) of 11 (2-70) weeks. Thirty patients (52%) had a remission at 4 weeks, 10 of whom had remission for longer than 12 weeks. Forty-two per cent of fistulae closed. Sustained remission (P = 0.065), remission at 4 weeks (P = 0.033) and a positive clinical response of any sort (P = 0.004) were more likely in patients on immunosuppressive therapy, despite there being more smelters in this group. Conclusion: This review of the first Australian experience with infliximab corroborates the reported speed and efficacy of this treatment for Crohn's disease. The excellent response appears enhanced by the concomitant use of conventional steroid-sparing immunosuppressive therapy.

Rapid radiation-induction of atm protein levels in situ

Ataxia-telangiectasia (A-T) is characterised by hypersensitivity to ionising radiation (IR), immunodeficiency, neurodegeneration and predisposition to malignancy. Mutations in the A-T gene (ATM) often result in reduced levels of ATM protein and/or compromise ATM function. IR induced DNA damage is known to rapidly upregulate ATM kinase activity/phosphorylation events in the control of cell cycle progression and other processes. Variable expression of ATM levels in different tissues and its upregulation during cellular proliferation indicate that the level of ATM is also regulated by mechanisms other than gene mutation. Here, we report on the IR induction of ATM protein levels within a number of different cell types and tissues. Induction had begun within 5 min and peaked within 2 h of exposure to 2 Gy of IR, suggesting a rapid post-translational mechanism. Low basal levels of ATM protein were more responsive to IR induction compared to high ATM levels in the same cell type. Irradiation of fresh skin biopsies led to an average three-fold increase in ATM levels while immunohistochemical analyses indicated low expressing cells within the basal layer with ten-fold increases in ATM levels following IR. ATM high expressing lymphoblastoid cell lines (LCLs) which were initially resistant to the radiation-induction of ATM levels also became responsive to IR after ATM antisense expression was used to reduce the basal levels of the protein. These results demonstrate that ATM is present in variable amounts in different tissue/cell types and where basal levels are low ATM levels can be rapidly induced by IR to saturable levels specific for different cell types. ATM radiation-induction is a sensitive and rapid radioprotective response that complements the IR mediated activation of ATM.

Outpatient cognitive behavioural therapy programme for alcohol dependence impact of naltrexone use on outcome

Objective: Cognitive-behavioural therapy (CBT) has been effectively used in the treatment of alcohol dependence. Clinical studies report that the anticraving drug naltrexone, is a useful adjunct to treatment. Currently, few data are available on the impact of adding this medication to programmes in more typical, outpatient, and rehabilitation settings. The objective of this study was to examine the impact on outcome of adding naltrexone to an established outpatient alcohol rehabilitation program which employed CBT. Method: Fifty patients participated in an established 12-week, outpatient, 'contract'-based alcohol abstinence programme which employed CBT. They also received naltrexone 50 mg orally daily (CBT + naltrexone). Outcomes were compared with 50 historical, matched controls, all of whom participated in the same programme without an anticraving medication (CBT alone). All patients met DSM-IV criteria for alcohol dependence. Results: Programme attendance across the eight treatment sessions was lower in the CBT alone group (p < 0.001). Relapse to alcohol use occurred sooner and more frequently in the CBT alone group (p < 0.001). Rehabilitation programme completion at 12 weeks was 88% (CBT + naltrexone) compared with 36% for (CBT alone) (p < 0.001). Alcohol abstinence at 12 weeks was 76% (CBT + naltrexone) compared with 18% (CBT alone) (p < 0.001). Conclusion: When employing the same outpatient rehabilitation programme and comparing outcomes using matched historical controls, the addition of naltrexone substantially improves programme attendance, programme completion and reported alcohol abstinence. In a typical outpatient programme, naltrexone addition was associated with significantly improved programme participation, better outcomes and was well tolerated.

Quantitative analysis of the speed and accuracy of tongue movements in dysarthria subsequent to traumatic brain injury using electromagnetic articulography

It has been recognised that in order to study the displacement, timing and co-ordination of articulatory components (i.e., tongue. lips, jaw) in speech production it is desirable to obtain high-resolution movement data on multiple structures inside and outside the vocal tract. Until recently, with the exception of X-ray techniques such as cineradiography, the study 0. speech movements has been hindered by the inaccessibility of the oral cavity during speech. X-ray techniques are generally not used because of unacceptable radiation exposure. The aim of the present study was to demonstrate the use of a new physiological device, the electromagnetic articulograph, for assessing articulatory dysfunction subsequent to traumatic brain injury. The components of the device together with the measuring principle are described and data collected from a single case presented. A 19 year-old male who exhibited dysarthria subsequent to a traumatic brain injury was fitted wit 2 the electromagnetic articulograph (Carstens AG-100) and a kinematic analysis of his tongue movements during production of the lingual consonants it, s, k/ within single syllable words was performed. Examination of kinematic parameters including movemmt trajectories, velocity, and acceleration revealed differences in the speed and accuracy of his tongue movements compared to those produced by a non-neurologically impaired adult male. It was concluded that the articulograph is a useful device for diagnosing speed and accuracy disorders in tongue movements during speech and that the device has potential for incorporation into physiologically based rehabilitation programs as a real-time biofeedback instrument.

Combination therapy with tacrolimus and anti-thymocyte globulin for the treatment of steroid-resistant acute graft-versus-host disease developing during cyclosporine prophylaxis

We report our experience with the combination of anti-thymocyte globulin (ATGAM) and tacrolimus in the treatment of 20 patients with steroid refractory and dependent acute graft-versus-host disease (GVHD) transplanted between August 1996 and February 2000. All patients received cyclosporine-based GVHD prophylaxis. Thirteen patients developed a maximum of grade TV, five grade III and two grade II acute GVHD, with 15 patients being refractory to steroids and five dependent on steroids. Patients were treated with ATGAM (15 mg/kg for 5 d) and tacrolimus (0.025-0.1 mg/kg/d) in addition to continuation of their high-dose steroids and cessation of their cyclosporine. Within 28 d of treatment, we observed eight complete responses (CR), six partial responses (PR) and six with no response. Overall response (CR + PR) was predicted by GVHD severity. Infectious complications occurred in 80% of patients. The median survival was 86.5 d (range, 21-1081 d) with 35% of patients remaining alive, Survival following combination therapy was significantly more likely in men (P < 0.001), skin-only GVHD (P = 0.027), less severe GVHD (P = 0.048), and in responders to tacrolimus and ATGAM (P< 0.001). In conclusion, concurrent introduction of ATGAM and tacrolimus is a promising therapeutic combination for GVHD refractory to steroids and cyclosporine.

Ancient mitochondrial DNA and morphology elucidate an extinct island radiation of Indian Ocean giant tortoise (Cylindrapsis)

Ancient mitochondrial DNA sequences were used for investigating the evolution of an entire clade of extinct vertebrates, the endemic tortoises (Cylindraspis) of the Mascarene Islands in the Indian Ocean. Mitochondrial DNA corroborates morphological evidence that there were five species of tortoise with the following relationships: Cylindraspis triserrata ((Cylindraspis vosmaeri and Cylindraspis peltastes) (Cylindraspis inepta and Cylindraspis indica)). Phylogeny indicates that the ancestor of the group first colonized Mauritius where speciation produced C. triserrata and the ancestor of the other species including a second sympatric Mauritian form, C. inepta. A propagule derived from this lineage colonized Rodrigues 590 km to the east, where a second within-island speciation took place producing the sympatric C. vosmaeri and C. peltastes. A recent colonization of Réunion 150 km to the southwest produced C. indica. In the virtual absence of predators, the defensive features of the shells of Mascarene tortoises were largely dismantled, apparently in two stages. 'Saddlebacked' shells with high fronts evolved independently on all three islands. This and other features, such as a derived jaw structure and small body size, may be associated with niche differentiation in sympatric species and may represent a striking example of parallel differentiation in a large terrestrial vertebrate. The history of Mascarene tortoises contrasts with that of the Galápagos, where only a single species is present and surviving populations are genetically much more similar. However, they too show some reduction in anti-predator mechanisms and multiple development of populations with saddlebacked shells.

Lipid-lowering therapy following major cardiac events: progress and deficits

Objective: To assess hospital prescribing of lipid-lowering agents in a tertiary hospital, and examine continuation of, or changes to, such therapy in the 6-18 months following discharge. Design: Retrospective data extraction from the hospital records of patients admitted from October 1998 to April 1999. These patients and their general practitioners were then contacted to obtain information about ongoing management after discharge. Setting: Tertiary public hospital and community. Participants: 352 patients admitted to hospital with acute myocardial infarction or unstable angina, and their GPs. Main outcome measures: Percentage of eligible patients discharged on lipid-lowering therapy and percentage of patients continuing or starting such therapy 6-18 months after discharge. Results: 10% of inpatients with acute coronary syndromes did not have lipid-level estimations performed or arranged during admission. Documentation of lipid levels in discharge summaries was poor. Eighteen per cent of patients with a total serum cholesterol level greater than 5.5 mmol/L did not receive a discharge prescription for a cholesterol-lowering agent. Compliance with treatment on follow-up was 88% in the group discharged on treatment. However, at follow-up, 70% of patients discharged without therapy had not been commenced on lipid-lowering treatment by their GPs. Conclusions: Prescribing of lipid-lowering therapy for secondary prevention following acute coronary syndromes remains suboptimal. Commencing treatment in hospital is likely to result in continuing therapy in the community. Better communication of lipid-level results, treatment and treatment aims between hospitals and GPs might encourage optimal treatment practices.

A histone deacetylase inhibitor, azelaic bishydroxamic acid, shows cytotoxicity on Epstein-Barr virus-transformed B-cell lines - A potential therapy for posttransplant lymphoproliferative disease

Background. Posttransplant lymphoproliferative disease (PTLD), driven by the presence of Epstein-Barr virus (EBV), is becoming an increasingly important clinical problem after solid organ transplantation. The use of immunosuppressive therapy leads to the inhibition of the cytotoxic T cells that normally control the EBV latently infected B cells. The prognosis for many patients with PTLD is poor, and the optimal treatment strategy is not well defined. Method. This study investigates the use of a histone deacetylase inhibitor, azelaic bishydroxamic acid (ABRA), for its ability to effectively kill EBV-transformed lymphoblastoid cell lines. Results. In vitro treatment of lymphoblastoid cell lines with ABRA showed that they were effectively killed by low doses of the drug (ID50 2-5 mug/ml) within 48 hr. As well as being effective against polyclonal B-cell lines, ABHA was also shown to be toxic to seven of eight clonal Burkitt's lymphoma cell lines, indicating that the drug may also be useful in the treatment of late-occurring clonal PTLD. In addition, ABHA treatment did not induce EBV replication or affect EBV latent gene expression. Conclusion. These studies suggest that ABHA effectively kills both polyclonal and clonal B-cell lines and has potential in the treatment of PTLD.

Quantum interference in optical fields and atomic radiation

We discuss the connection between quantum interference effects in optical beams and radiation fields emitted from atomic systems. We illustrate this connection by a study of the first- and second-order correlation functions of optical fields and atomic dipole moments. We explore the role of correlations between the emitting systems and present examples of practical methods to implement two systems with non-orthogonal dipole moments. We also derive general conditions for quantum interference in a two-atom system and for a control of spontaneous emission. The relation between population trapping and dark states is also discussed. Moreover, we present quantum dressed-atom models of cancellation of spontaneous emission, amplification on dark transitions, fluorescence quenching and coherent population trapping.