Patient-reported outcome (PRO) results from the AGITG DOCTOR trial: a randomised phase 2 trial of tailored neoadjuvant therapy for resectable oesophageal adenocarcinoma.

BACKGROUND: AGITG DOCTOR was a randomised phase 2 trial of pre-operative cisplatin, 5 fluorouracil (CF) followed by docetaxel (D) with or without radiotherapy (RT) based on poor early response to CF, detected via PET, for resectable oesophageal adenocarcinoma. This study describes PROs over 2 years. METHODS: Participants (N = 116) completed the EORTC QLQ-C30 and oesophageal module (QLQ-OES18) before chemotherapy (baseline), before surgery, six and 12 weeks post-surgery and three-monthly until 2 years. We plotted PROs over time and calculated the percentage of participants per treatment group whose post-surgery score was within 10 points (threshold for clinically relevant change) of their baseline score, for each PRO scale. We examined the relationship between Grade 3+ adverse events (AEs) and PROs. This analysis included four groups: CF responders, non-responders randomised to DCF, non-responders randomised to DCF + RT, and "others" who were not randomised. RESULTS: Global QOL was clinically similar between groups from 6 weeks post-surgery. All groups had poorer functional and higher symptom scores during active treatment and shortly after surgery, particularly the DCF and DCF + RT groups. DCF + RT reported a clinically significant difference (-13points) in mean overall health/QOL between baseline and pre-surgery. Similar proportions of patients across groups scored +/- 10 points of baseline scores within 2 years for most PRO domains. Instance of grade 3+ AEs were not related to PROs at baseline or 2 years. CONCLUSIONS: By 2 years, similar proportions of patients scored within 10 points of baseline for most PRO domains, with the exception of pain and insomnia for the DCF + RT group. Non-responders randomised to DCF or DCF + RT experienced additional short-term burden compared to CF responders, reflecting the longer duration of neoadjuvant treatment and additional toxicity. This should be weighed against clinical benefits reported in AGITG DOCTOR. This data will inform communication of the trajectory of treatment options for early CF non-responders. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR), ACTRN12609000665235 . Registered 31 July 2009.

New SnO2/MgAl-layered double hydroxide composites as photocatalysts for cationic dyes bleaching.

A new type of nanocomposite containing SnO(2) has been obtained by wet impregnation of dehydrated Mg/Al-hydrotalcite-type compounds with ethanolic solutions of SnCl(4).2H(2)O. Tin chloride hydrolysis was achieved using NaOH or NH(4)OH aqueous solutions, at pH around 9, followed by the conversion into corresponding hydroxides through calcinations. The powder X-ray diffraction (PXRD) and UV-Vis diffuse reflectance (UV-DR) methods confirmed the structure of as-synthesized solids. The chemical composition and morphology of the synthesized materials were investigated by energy dispersive X-ray analysis (EDX), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The as-synthesized materials were used for photocatalytic studies showing a good activity for methylene blue decolourization, which varies with SnO(2) content and used as a hydrolysing agent. The proposed mechanism is based on the shifting of flat band potential of SnO(2) due to the interaction with Mg/Al-LDH, this being energetically favourable to the formation of hydroxyl radicals responsible for methylene blue degradation.

Salvage definitive chemo-radiotherapy for locally recurrent oesophageal carcinoma after primary surgery: retrospective review.

To determine the overall survival and gastrointestinal toxicity for patients treated with salvage definitive chemo-radiotherapy after primary surgery for locoregional relapse of oesophageal carcinoma. A retrospective review of 525 patients who had a resection for oesophageal or oesophagogastric carcinoma at Princess Alexandra Hospital identified 14 patients treated with salvage definitive radiotherapy or chemo-radiotherapy, following localized recurrence of their disease. We analysed the patient and treatment characteristics to determine the median overall survival as the primary end point. Gastrointestinal toxicity was examined to determine if increased toxicity occurred when the stomach was irradiated within the intrathoracic radiotherapy field. The median overall survival for patients treated with curative intent using salvage definitive chemo-radiotherapy was 16 months and the 2-year overall survival is 21%. One patient is in clinical remission more than 5 years after therapy. Age <60 years old and nodal recurrence were favourable prognostic factors. Treatment compliance was 93% with only one patient unable to complete the intended schedule. Fourteen per cent of patients experienced grade 3 or 4 gastrointestinal toxicity. Salvage definitive chemo-radiotherapy should be considered for good performance status patients with oesophageal carcinoma who have a locoregional relapse after primary surgery. The schedule is tolerable with low toxicity and an acceptable median survival.

Microstructural and chemical transformation of thin Ti/Pd and TiDy/Pd bilayer films induced by vacuum annealing.

Using a combination of scanning electron microscopy, transmission electron microscopy (TEM), X-ray diffraction and X-ray photoelectron spectroscopy (XPS), we made a comparative study of the high-temperature annealing impact on thin titanium deuteride (TiD(y)) films covered by an ultrathin Pd layer, and on Ti/Pd bilayer films. The bilayer films were prepared under ultrahigh vacuum conditions and were in situ annealed using the same annealing procedure. It was found that the surface and the bulk morphology of both films undergo different annealing-induced transformations, leading to an extensive intermixing between the Ti and Pd layers and the formation of a new PdTi(2) bimetallic phase. Energy-filtered TEM imaging and energy-dispersive X-ray spectrometry analysis, as well as XPS depth profiling all provided evidence of a different distribution of Pd and Ti in the annealed TiD(y)/Pd film compared with the annealed Ti/Pd film. Our results show that thermal decomposition of TiD(y), as a consequence of annealing the TiD(y)/Pd film, modifies the intermixing process, thereby promoting Ti diffusion into the Pd-rich top layer of the TiD(y) film and thus providing a more likely path for the formation of the PdTi(2) phase than in an annealed Ti/Pd film.

Structural and chemical characterisation of titanium deuteride films covered by nanoscale evaporated palladium layers.

Thin titanium deuteride (TiD(y)) films, covered by an ultra-thin palladium layer, have been compared with the corresponding titanium and palladium films using a combination of scanning electron microscopy (SEM), transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). The TiD(y) layers were prepared under ultra-high vacuum (UHV) conditions by precisely controlled deuterium sorption at 298 K on a Ti film evaporated onto a Si(100) substrate. Both Ti and TiD(y) films were then covered in situ by a nanoscale Pd layer. It was found that a 10- to 12-nm-thick Pd layer protects the TiD(y) films efficiently against extensive air interaction. The morphology of both the surface and bulk Pd/TiD(y) (Ti) films have been observed using SEM and cross-sectional TEM analysis, respectively. A polycrystalline bulk morphology in both Ti and TiD(y) films accompanied by a fine-grained Pd surface was observed. High-magnification cross-sectional TEM images reveal the TiD(y) film to be plastically deformed leading to an increase in the roughness of the top Pd layer. Complex structures, including Moiré patterns, have been identified within the Pd/TiD(y) interface. The chemical nature of this interface has been analysed after partial sputtering of the Pd top layer using XPS. Besides TiD(y) and Pd, TiO and PdO were found to be the main chemical species in the interface region of the Pd/TiH(y) film. The XPS valence-band spectra of the Pd/TiD(y) interface reveal electronic features characteristic of a Pd-Ti bimetallic structure.

The triad of bilateral retinoblastoma, dysplastic naevus syndrome and multiple cutaneous malignant melanomas: a case report and review of the literature.

We report a case of a patient with the triad of retinoblastoma, dysplastic naevus syndrome (DNS) and multiple cutaneous melanomas. The combination of retinoblastoma and DNS is a significant risk factor for the development of cutaneous melanoma. This risk extends to family members. We recommend that survivors of (inherited) retinoblastoma and their relatives are closely screened for the presence of dysplastic naevi.

Metastatic lesions in the joint associated with acute inflammatory arthritis after dendritic cell immunotherapy for metastatic melanoma.

A 47 year old man undergoing immunotherapy for metastatic melanoma with autologous dendritic cells pulsed with autologous tumour peptide and hepatitis B surface antigen developed acute left ankle arthritis. Gout and acute infection were excluded, and an autoimmune aetiology or occult metastasis were considered. The arthritis initially subsided with indomethacin, but the symptoms recurred 2 months later, and magnetic resonance imaging demonstrated metastatic melanoma of the left talus. Immunohistochemical staining of a cerebral metastatic deposit biopsied 1 week after the onset of arthritis demonstrated T-cell and macrophage infiltration of the tumour. In addition, the patient developed melanoma-specific delayed type hypersensitivity and cytotoxic T-cell responses after vaccination. Thus, the monoarthritis represented an 'appropriate' inflammatory response directed against metastatic melanoma.

Estimating the prevalence of diagnosed diabetes in a health district of Wales: the importance of using primary and secondary care sources of ascertainment with adjustment for death and migration.

AIMS: To determine diagnosed diabetic prevalence within our district (population 434398) in 1996 using data from two sources. METHODS: A general practice audit comprising data on patients with diabetes from 61 (82%) of 74 general practices was linked to a record linkage-derived patient index in which data from secondary care and other sources underwent a process of probability matching to identify records relating to the same patient and to flag those with diabetes. By linking this dataset to a mortality dataset, patients known to have died before 1996 could be excluded. Age and sex-stratified emigration rates were applied to those identified by the hospital dataset for each year from 1991 onwards. RESULTS: A total of 386988 residents (89.1%) were listed with a general practitioner participating in the audit, of whom 6050 patients were identified as having diabetes in 1996; a prevalence rate of 1.56%. From the hospital-based source, 7639 patients were identified who were alive in 1996, a period prevalence of 1.76%. By combining the two sources, and extrapolating the general practice audit to the population as a whole, a total of 10 530 patients were identified of whom 8735 were confirmed as still resident within South Glamorgan during 1996. This represented a period prevalence of between 2.01% to 2.42%. By applying age and sex-stratified migration rates to the diabetic population identified by hospital sources, a diagnosed diabetic population of 10,004 was identified, a prevalence of 2.3%. CONCLUSIONS: This study demonstrates that to calculate the true prevalence of diagnosed diabetes from health sources, it is necessary to use both primary and secondary care sources.

The prevalence of multiple diabetes-related complications.

AIMS: To determine the prevalence of the complications of diabetes and the interrelationship between them within a United Kingdom district health authority population. METHODS: Data extracted from a general practice diabetes audit were combined with data for patients with diabetes derived from a patient index constructed using record linkage techniques. RESULTS: A total of 10709 patients were identified as having diabetes (prevalence 2.47%). Coronary heart disease was present in 25.2%, cerebrovascular disease in 9.6%, complications of the 'diabetic foot' in 18.1%, retinopathy in 16.5% and nephropathy in 2.0%. Over a half of the patients (52.1%) had none of the studied complications, 30.2% had one, 12.7% had two, 4.1% had three, 0.8% had four and 0.1% had all five. All complications were related to both age and duration of diabetes but duration was particularly apparent for the microvascular complications (retinopathy and nephropathy). Macrovascular complications in the Type 2 diabetic population appear advanced in onset compared with Type 1. CONCLUSIONS: Multiple complications are apparent in almost one fifth of patients with diabetes. Macrovascular morbidity in Type 2 diabetes of early onset indicates that a targeted approach to treatment may prove most beneficial in both patient and health service terms.

Immature human monocyte-derived dendritic cells migrate rapidly to draining lymph nodes after intradermal injection for melanoma immunotherapy.

Injected antigen-loaded immature monocyte-derived dendritic cells (DCs) may be incapable of migrating from skin to draining lymph nodes for antigen presentation. The in vivo migratory capacity of intradermally administered immature monocyte-derived DCs was therefore investigated during a phase I/II clinical trial for metastatic melanoma. DCs cultured from adherent monocytes in the presence of autologous serum, granulocyte-macrophage colony stimulating factor and interleukin-4 were pulsed with antigen and labelled with technetium-99m hexamethylpropylene-amineoxime (99mTc-HMPAO) ex vivo, then injected intradermally. A 99mTc-HMPAO control containing an equivalent amount of radioactivity was injected into the opposite thigh. The pelvis was then imaged with a gamma camera. The DCs were characterized as immature by functional and phenotypic analysis. Labelled DCs travelled to the draining inguinal lymph nodes within 10 min, and the draining lymph nodes were clearly outlined up to 4 h after injection. Free NmTc outlined draining lymph nodes after 10 min but was cleared from the nodes within 1 h. Thus, immature human monocyte-derived DCs migrate rapidly to and remain in draining lymph nodes after intradermal injection for immunotherapy.

Laparoscopy in the management of diaphragmatic rupture due to blunt trauma.

BACKGROUND: Traumatic diaphragmatic rupture remains a diagnostic challenge often unrecognized until laparotomy in over 40% of patients and the diagnosis is delayed in a further 15%. This report describes four patients diagnosed at laparoscopy with a ruptured diaphragm. METHODS: One patient had a left diaphragmatic rupture amenable to laparoscopic repair in the emergency setting. Three patients underwent laparoscopy 2, 7 and 10 days after injury which revealed two right-sided and one extensive left-sided rupture, respectively; each required open repair. RESULTS: While laparoscopy is an excellent diagnostic tool, particularly in the delayed setting, repair is not possible for right-sided ruptures because of the liver bulk. CONCLUSIONS: Thoracoscopy in the instance of delayed presentation may offer the best chance for minimal-access diagnosis and treatment when there is suspicion of a right-sided diaphragmatic rupture.

Interruptions during general practice consultations--the patients' view.

BACKGROUND: Although most aspects of the consultation have been extensively reported there is very little information on the effects of interruptions on the consultation. OBJECTIVE: We wished to discover the patients' view of interruptions. METHODS: In this pilot study the sources and frequency of interruptions to the consultations of a single general practitioner were measured. The effects of interruptions on 102 patients whose consultations were interrupted were then ascertained using a simple questionnaire. RESULTS: The overall interruption rate was found to be 10.2%. The telephone was the commonest source of interruption, accounting for 50% of interruptions. Although most patients did not perceive the interruption as having an important effect on the consultation, 20% of patients did feel that the interruption had a bad effect on the consultation and 40% of patients felt it would have been better not to have been interrupted. A majority of patients (52%) did not feel that the reason for the interruption was important. Although most patients did not feel affected by the interruption, a significant minority (18%) of patients had a strongly negative emotional response to the interruption. CONCLUSIONS: In view of these findings the need for further work has been highlighted.

A novel approach to dual-acting thromboxane receptor antagonist/synthase inhibitors based on the link of 1,3-dioxane-thromboxane receptor antagonists and -thromboxane synthase inhibitors.

A new class of dual-acting racemic thromboxane receptor antagonist/thromboxane synthase inhibitors is reported, based on the novel approach of linking the known thromboxane synthase inhibitors (TXSI) dazoxiben (2) or isbogrel (11) (separately) to thromboxane receptor antagonists (TXRA) from the 1,3-dioxane series, such as ICI 192605 (10). Dual activity was observed in vitro with inhibition of human microsomal thromboxane synthase in the range IC50 = 0.01-1.0 microM and receptor antagonist activity by inhibition of U46619-induced human platelet aggregation in the range pA2 = 5.5-7.0. The in vitro results also showed that very large groups could be tolerated at the selected substitution positions of the TXRA and TXSI components. Oral activity was observed in ex vivo tests in both rats and dogs at a dose of 10 mg/kg. Thus, (E)-7-[4-[[4-[(2SR,4SR,5RS)-5-[(Z)-5-carboxypent -2-enyl]-4-(2- hydroxyphenyl)-1,3-dioxan-2-yl]-benzyl]oxy]phenyl]-7-(3-pyridyl)he pt-6- enoic acid (110) was both an antagonist (pA2 = 6.7) and a synthase inhibitor (IC50 = 0.02 microM). On oral dosing (10 mg/kg) to rats and dogs, 110 showed significant TXRA activity [concentration ratio > 64 (rat, 3 h) and > 59 +/- 11.3 (dog, 2 h) vs ex vivo U46619-induced platelet aggregation]. Inhibition of thromboxane synthase at the respective time points in these experiments was 81 +/- 4.4% (rat) and 69 +/- 4.8% (dog).

Psychological responses to malignant melanoma. An investigation of traumatic stress reactions to life-threatening illness.

A cross-sectional study of 95 individuals with malignant melanoma was conducted to investigate posttraumatic stress responses to a diagnosis of melanoma and to validate the use of the Impact of Event Scale (IES) as a measure of the response to the trauma of life-threatening disease. The diagnosis and progression of malignant disease are likely to present a range of acute and chronic trauma to the individual and the individual's family. The findings suggest that the IES is a reliable and valid measure of this distress, with scores varying according to disease progression and prognostic status of nonmetastatic disease patients. This indicates the importance of clinical attention to the specific symptoms that may best reflect the traumatic impact of life-threatening illness and its progression, and the applicability of posttraumatic stress syndromes in understanding the psychological distress of this clinical population.

Dual-acting thromboxane receptor antagonist/synthase inhibitors: synthesis and biological properties of [2-substituted-4-(3-pyridyl)-1,3-dioxan-5-yl] alkenoic acids.

The design, synthesis, and pharmacology of a new class of compounds possessing both thromboxane receptor antagonist and thromboxane synthase inhibitory properties are described. Replacement of the phenol group of the known thromboxane antagonist series 4(Z)-6-[(4RS,5SR)-4-(2-hydroxyphenyl)-1,3-dioxan-5-yl] hex-4-enoic acid by a 3-pyridyl group led to a series of compounds, 5, which were potent thromboxane synthase inhibitors and weak thromboxane antagonists. Further modifications at the dioxane C2 position led to compounds, 7, which were potent dual-acting agents. In the case of compound 7w, the dual activity was shown to reside almost exclusively in the (-)-enantiomer, 7x. Following oral dosing to rats and dogs, 7x (3 mg/kg) displayed significant dual activity over a period of at least 8 h.

Percutaneous fluoroscopic gastrostomy. A safe option?

OBJECTIVE: To assess the safety of percutaneous fluoroscopic gastrostomy (PFG) tube insertion for enteral nutrition. DESIGN AND SETTING: The records of 70 consecutive patients who had a PFG procedure at a tertiary referral hospital (Princess Alexandra Hospital) were analysed retrospectively. MAIN OUTCOME MEASURE: Incidence of morbidity and mortality from PFG. RESULTS: Sixty-nine of 70 procedures were successfully performed. There were two deaths secondary to aspiration pneumonia and a morbidity rate of 13%. These figures are comparable with results from other series. CONCLUSION: PFG is a safe, effective procedure for enteral nutrition.

Videothoracoscopic primary repair of early distal oesophageal perforation.

Distal oesophageal perforation following dilation of oesophageal strictures or achalasia is usually recognized soon after the event. Treatment of two patients with perforation resulting from vigorous achalasia, diagnosed within hours of the procedure, was approached by videothoracoscopic exposure and successful primary repair was achieved in both instances. Details relating to patient preparation and operative technique are presented. Both patients recovered, with normal diet being tolerated by the seventh day after surgery, were discharged on day eight and 10 and returned to normal activities within 3 weeks of surgery. The technique presented is apparently well suited to distal oesophageal perforations diagnosed early, when primary closure can be achieved safely, and significantly improves patient recovery after this often iatrogenic injury.

Plasma concentrations of bupivacaine after wound infiltration of an 0.5% solution after inguinal herniorrhaphy: a preliminary study.

After routine inguinal herniorrhaphy we gave 12 patients a wound infiltration regimen of bolus doses of 20 ml of 0.5% bupivacaine via a catheter within the wound and rectally administered indomethacin (100 mg). Peak venous plasma bupivacaine concentrations ranged from 0.07 mg.l-1 to 1.14 mg.l-1 (mean (SD) 0.47 (0.33) mg.l-1), and occurred at between 0.25 and 2 h after the first dose. Plasma concentrations were well below the toxic threshold of 4 mg.l-1 and there was no accumulation. The regimen provided satisfactory analgesia. There were no wound infections nor signs of toxicity.