Safety and effectiveness of indirect radiofrequency ablation (closure FAST) of incompetent great saphenous veins with Type I aneurysms: Long-term results radiofrequency ablation for saphenous aneurysms.

BACKGROUND: Assess the safety and effectiveness of indirect radiofrequency ablation (RFA, Closure FAST) for the treatment of incompetent great saphenous veins (GSVs) with type 1 aneurysms. METHODS: This was a retrospective analysis performed in three centers (2007-2021). All patients presenting with saphenous aneurysms close to the junction (within 2 cm) were included. They were treated with RFA. Phlebectomies and/or sclerotherapy were performed during the same treatment session. Duplex ultrasound (DUS) was performed early after the procedure and then, more than a year later. RESULTS: Eight patients (11 limbs) were included between June 2007 and May 2021 with a median diameter of the GSV aneurysm 21 mm (IQR 17.2-23.4). No severe adverse events occurred apart from one endovenous heat-induced thrombosis (EHIT) class III (9.1%). After more than a year (mean 7.2 ± 4.2, median 8 years), none of the aneurysms was present on DUS and the truncal obliteration rate was 100%. CONCLUSION: RFA appears to be a safe and effective treatment for patients presenting with incompetent saphenous veins with the type 1 aneurysm.

Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: usefulness of the individual patient data meta-analysis.

BACKGROUND: Chemotherapy (CT) combined with radiotherapy is the standard treatment of 'limited-stage' small-cell lung cancer. However, controversy persists over the optimal timing of thoracic radiotherapy and CT. MATERIALS AND METHODS: We carried out a meta-analysis of individual patient data in randomized trials comparing earlier versus later radiotherapy, or shorter versus longer radiotherapy duration, as defined in each trial. We combined the results from trials using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival. RESULTS: Twelve trials with 2668 patients were eligible. Data from nine trials comprising 2305 patients were available for analysis. The median follow-up was 10 years. When all trials were analysed together, 'earlier or shorter' versus 'later or longer' thoracic radiotherapy did not affect overall survival. However, the HR for overall survival was significantly in favour of 'earlier or shorter' radiotherapy among trials with a similar proportion of patients who were compliant with CT (defined as having received 100% or more of the planned CT cycles) in both arms (HR 0.79, 95% CI 0.69-0.91), and in favour of 'later or longer' radiotherapy among trials with different rates of CT compliance (HR 1.19, 1.05-1.34, interaction test, P < 0.0001). The absolute gain between 'earlier or shorter' versus 'later or longer' thoracic radiotherapy in 5-year overall survival for similar and for different CT compliance trials was 7.7% (95% CI 2.6-12.8%) and -2.2% (-5.8% to 1.4%), respectively. However, 'earlier or shorter' thoracic radiotherapy was associated with a higher incidence of severe acute oesophagitis than 'later or longer' radiotherapy. CONCLUSION: 'Earlier or shorter' delivery of thoracic radiotherapy with planned CT significantly improves 5-year overall survival at the expense of more acute toxicity, especially oesophagitis.

Comparison of gemcitabine and carboplatin versus cisplatin and etoposide for patients with poor-prognosis small cell lung cancer.

BACKGROUND: The combination of cisplatin and etoposide (PE) has been a standard treatment for patients with poor-prognosis small cell lung cancer (SCLC). This non-inferiority design trial aimed to determine whether the combination of gemcitabine and carboplatin (GC) results in similar survival but is less toxic with better quality of life. METHODS: Previously untreated patients with SCLC with extensive disease or limited stage with poor prognostic factors were randomly assigned to six 3-weekly cycles of GC or PE. RESULTS: 241 patients (121 GC, 120 PE) were recruited, of which 216 (90%) had died. There was no difference in overall survival (HR 1.01, 95% CI 0.77 to 1.32). Median survival with GC and PE was 8.0 and 8.1 months, respectively. Median progression-free survival was 5.9 months with GC and 6.3 months with PE. Grade 3 or 4 myelosuppressions were more frequent with GC (anaemia: 14% GC vs 2% PE; leucopenia: 32% GC vs 13% PE; thrombocytopenia: 22% GC vs 4% PE), but these were not associated with increased hospital admissions, infections or fatalities. Grade 2-3 alopecia (68% PE vs 17% GC) and nausea (43% PE vs 26% GC) were more frequent with PE. Patients given GC received more chemotherapy as outpatients (89% GC vs 66% PE of treatment cycles). In QoL questionnaires, more patients receiving PE reported being upset by hair loss (p = 0.004) and impaired cognitive functioning (p = 0.04). CONCLUSIONS: GC is as effective as PE in terms of overall survival and progression-free survival and has a toxicity profile more acceptable to patients. TRIAL REGISTRATION NUMBER: ISRCTN 39679215.

A very faint core-collapse supernova in M85.

An anomalous transient in the early Hubble-type (S0) galaxy Messier 85 (M85) in the Virgo cluster was discovered by Kulkarni et al. on 7 January 2006 that had very low luminosity (peak absolute R-band magnitude M(R) of about -12) that was constant over more than 80 days, red colour and narrow spectral lines, which seem inconsistent with those observed in any known class of transient events. Kulkarni et al. suggest an exotic stellar merger as the possible origin. An alternative explanation is that the transient in M85 was a type II-plateau supernova of extremely low luminosity, exploding in a lenticular galaxy with residual star-forming activity. This intriguing transient might be the faintest supernova that has ever been discovered.

Mechanism of transcriptional regulation by the Escherichia coli nitric oxide sensor NorR.

Nitric oxide (NO) is a highly reactive water-soluble gas encountered by bacteria endogenously as an intermediate of denitrification and exogenously as one of the radical species deployed by macrophages against invading pathogens. Bacteria therefore require a mechanism to detoxify NO. Escherichia coli flavorubredoxin and its associated oxidoreductase, encoded by the norV and norW genes respectively, reduces NO to nitrous oxide under anaerobic conditions. Transcription of the norVW genes is activated in response to NO by the sigma(54)-dependent regulator NorR, a member of the prokaryotic enhancer binding protein family. NorR binds co-operatively to three enhancer sites to regulate transcription of both norVW and the divergently transcribed norR gene. In the present paper, we show that disruption of any one of the three GT-(N(7))-AC NorR binding sites in the norR-norVW intergenic region prevents both activation of norVW expression and autogenous repression of the norR promoter by NorR. We have recently demonstrated that the N-terminal GAF (cGMP-specific and -stimulated phosphodiesterases, Anabaena adenylate cyclases and Escherichia coli FhlA) domain of NorR contains a non-haem mononuclear iron centre and senses NO by formation of a mono-nitrosyl iron complex. Site-directed mutagenesis has identified candidate protein ligands to the ferrous iron centre in the GAF domain.

Nitric oxide-sensing mechanisms in Escherichia coli.

Exposure of Escherichia coli to nitric oxide (NO) or nitrosating agents causes significant changes in patterns of gene expression. Three recent studies have used microarrays to analyse the response of the E. coli transcriptome to NO and nitrosative stress. Drawing on the array data, I review our current understanding of the E. coli regulatory systems that are involved.

Assessment of quality of life in the supportive care setting of the big lung trial in non-small-cell lung cancer.

PURPOSE: The Big Lung Trial (BLT) was a large, pragmatic trial to evaluate the addition of chemotherapy to primary treatment (ie, surgery, radical radiotherapy, or supportive care) in non-small-cell lung cancer (NSCLC). In the supportive care group, there was a small but significant survival benefit in patients treated with chemotherapy compared with supportive care alone (no chemotherapy). A substudy was undertaken to evaluate the quality of life (QoL) implications of the treatment options. QoL was assessed using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires C30 (QLQ-C30) and LC17, and daily diary cards. PATIENTS AND METHODS: EORTC QLQ-C30 and LC17 were collected at 0, 6 to 8, 12, 18, and 24 weeks. Diary cards were completed during the first 12 weeks of the study. The primary end point was global QoL at 12 weeks. RESULTS: A total of 273 patients were randomly assigned: 138 to no chemotherapy and 135 to chemotherapy. There was no evidence of a large detrimental effect on QoL of chemotherapy. No statistically significant differences in global QoL or physical/emotional functioning, fatigue and dyspnea, and pain were detected at 12 weeks. Higher rates of palliative radiotherapy in the no chemotherapy arm may have lessened differences in QoL. Global QoL, role functioning, fatigue, appetite loss, and constipation were prognostic indicators of survival at 12 weeks. CONCLUSION: There were no important adverse effects of chemotherapy on QoL.

Estimation of the additional costs of chemotherapy for patients with advanced non-small cell lung cancer.

BACKGROUND: A large multicentre randomised trial, the Big Lung Trial, which in part compared supportive care with or without cisplatin-based chemotherapy in patients with advanced non-small cell lung cancer, provided an opportunity to evaluate the impact on the UK National Health Service of the costs incurred with the use of chemotherapy. METHODS: This costing study was based on the retrospective collection of resource use data from hospital records. Case notes from 194 patients (98 chemotherapy + supportive care (C), 96 supportive care alone (NoC)) were inspected in eight centres recruiting the largest numbers of patients into the Big Lung Trial. Quantities were multiplied by fixed unit costs to calculate a total cost for each patient. The main outcome measure was the total cost incurred by the use of secondary care resources (including investigations, chemotherapy, radiotherapy, surgical procedures, inpatient days, outpatient attendances, and hospice inpatient care) in the two groups. RESULTS: Patients randomised to receive cisplatin-based chemotherapy had an average of 3.4 more inpatient bed days than the mean of 11.9 days for patients randomised to supportive care alone, and more outpatient attendances. NoC patients were more likely to have received palliative radiotherapy. The mean total cost for C patients was 5355 sterling pound compared with 3595 sterling pound for the NoC group, difference 760 sterling pound (95% CI 781 sterling pound to 2742 sterling pound ). When split, the cost in the C group associated with the administration of chemotherapy was 1233 sterling pound and non-chemotherapy costs were 4122 sterling pound . CONCLUSION: The additional cost of chemotherapy was not offset by a reduction in subsequent costs (as the non-chemotherapy costs were similar), so the survival benefit of about 10 weeks observed in the C group was achieved with the cost of chemotherapy administration.

DNA binding properties of the Escherichia coli nitric oxide sensor NorR: towards an understanding of the regulation of flavorubredoxin expression.

Nitric oxide is an intermediate of denitrification, and is one of the radical species deployed by macrophages against invading pathogens, therefore bacterial responses to NO are of considerable importance. The Escherichia coli flavorubredoxin and its associated oxidoreductase reduce NO to nitrous oxide under anaerobic conditions, and are encoded by the norVW transcription unit. Expression of norVW requires the NO sensing regulatory protein NorR and is dependent on RNA polymerase containing the alternative sigma factor, sigma(54). We have purified NorR and shown that it binds to three sites in the norVW promoter region, located 75-140 bp upstream of the experimentally verified transcription start site. We have also identified two binding sites for the integration host factor, one between the NorR sites and the sigma(54)-RNA polymerase binding site, and a second downstream of the norVW transcription start site. Comparison of the norVW promoters of enteric bacteria along with known and putative NorR-regulated promoters from Vibrio, Ralstonia and Pseudomonas species suggests that NorR binding sites contain an invariant GT(N7)AC motif flanking an AT-rich central region. The identification of a consensus for NorR binding sites will help to elucidate additional members of the NorR regulon.

Detoxification of nitric oxide by the flavorubredoxin of Salmonella enterica serovar Typhimurium.

Salmonella possesses multiple enzymes that utilize NO as a substrate, and could therefore contribute to the organism's ability to resist nitrosative killing by macrophages. Flavorubredoxin is an oxygen-sensitive enzyme that reduces NO to nitrous oxide. The Salmonella enterica serovar Typhimurium norV gene encoding flavorubredoxin was disrupted and the NO sensitivity of the mutant was determined. The norV mutant showed a greater sensitivity to NO than wild-type S. Typhimurium, but did recover growth after a transient inhibition. The mutant phenotype suggests that multiple enzymes are employed by S. Typhimurium to detoxify NO under anaerobic conditions, one of which is flavorubredoxin.

Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group.

PURPOSE: This phase III randomized trial compared two chemotherapy regimens, gemcitabine plus carboplatin and mitomycin, ifosfamide, and cisplatin, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). The regimens were compared with regard to effects on survival, response rates, toxicity, and quality of life. PATIENTS AND METHODS: Eligible patients had previously untreated stage IIIB or IV NSCLC suitable for cisplatin-based chemotherapy. Randomly assigned patients were to receive four cycles, each at 3-week intervals, of carboplatin area under the curve of 5 on day 1 plus gemcitabine 1,200 mg/m(2) on days 1 and 8 (GCa) or mitomycin 6 mg/m(2), ifosfamide 3g/m(2), and cisplatin 50 mg/m(2) on day 1 (MIC). RESULTS: Between February 1999 and August 2001, 422 patients (GCa, n = 212; MIC, n = 210) were randomly assigned in the United Kingdom. The majority of patients received the intended four cycles (GCa, 64%; MIC, 61%). There was a significant survival advantage for GCa compared with MIC (hazard ratio, 0.76; 95% CI, 0.61 to 0. 93; P = .008). Median survival was 10 months with GCa and 7.6 months with MIC (difference, 2.4 months; 95% CI, 1.0 to 4.0), and 1-year survival was 40% with GCa and 30% with MIC (difference, 10%; 95% CI, 3% to 18%). Overall response rates were similar (42% for GCa v 41% for MIC; P = .84). More thrombocytopenia occurred with GCa (P = .03), but this was not associated with increased hospital admission or fatality. GCa caused less nausea, vomiting, constipation, and alopecia and was associated with fewer admissions for administration and better quality of life. CONCLUSION: In patients with advanced NSCLC, GCa chemotherapy was shown to be a better-tolerated treatment that conferred a survival advantage over MIC.

Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life.

BACKGROUND: In 1995 a meta-analysis of randomised trials investigating the value of adding chemotherapy to primary treatment for non-small cell lung cancer (NSCLC) suggested a small survival benefit for cisplatin-based chemotherapy in each of the primary treatment settings. However, the meta-analysis included many small trials and trials with differing eligibility criteria and chemotherapy regimens. METHODS: The aim of the Big Lung Trial was to confirm the survival benefits seen in the meta-analysis and to assess quality of life and cost in the supportive care setting. A total of 725 patients were randomised to receive supportive care alone (n = 361) or supportive care plus cisplatin-based chemotherapy (n = 364). RESULTS: 65% of patients allocated chemotherapy (C) received all three cycles of treatment and a further 27% received one or two cycles. 74% of patients allocated no chemotherapy (NoC) received thoracic radiotherapy compared with 47% of the C group. Patients allocated C had a significantly better survival than those allocated NoC: HR 0.77 (95% CI 0.66 to 0.89, p = 0.0006), median survival 8.0 months for the C group v 5.7 months for the NoC group, a difference of 9 weeks. There were 19 (5%) treatment related deaths in the C group. There was no evidence that any subgroup benefited more or less from chemotherapy. No significant differences were observed between the two groups in terms of the pre-defined primary and secondary quality of life end points, although large negative effects of chemotherapy were ruled out. The regimens used proved to be cost effective, the extra cost of chemotherapy being offset by longer survival. CONCLUSIONS: The survival benefit seen in this trial was entirely consistent with the NSCLC meta-analysis and subsequent similarly designed large trials. The information on quality of life and cost should enable patients and their clinicians to make more informed treatment choices.

Chemotherapy for patients with non-small cell lung cancer: the surgical setting of the Big Lung Trial.

OBJECTIVES: The non-small cell lung cancer (NSCLC) meta-analysis suggested a survival benefit for cisplatin-based chemotherapy when given in addition to surgery, radical radiotherapy or 'best supportive care'. However, it included many small trials and trials with differing eligibility criteria and chemotherapy regimens. The aim of the Big Lung Trial was therefore to run a large pragmatic trial to confirm the survival benefits seen in the meta-analysis. METHODS: In the surgery setting, a total of 381 patients were randomised to chemotherapy (C, 192 patients) or no chemotherapy (NoC, 189 patients). C was three 3-weekly cycles of cisplatin/vindesine, mitomycin/ifosfamide/cisplatin, mitomycin/vinblastine/cisplatin or vinorelbine/cisplatin. RESULTS: Chemotherapy was given before surgery in 3% of patients whilst 97% received adjuvant chemotherapy. Baseline characteristics were: median age 61 years, 69% male, 48% squamous cell, 93% WHO PS 0-1, 27% stage I, 38% stage II, and 34% stage III. Complete resection was achieved in approximately 95% of patients. In the C group, 13% received no chemotherapy, 21% one or two cycles, and 64% all three cycles of their prescribed chemotherapy (60% of the latter with no delays or modification). 30% had grade 3/4 toxicity, mainly haematological, nausea/vomiting and neutropenic fever, and six patients were reported as having a treatment-related death. 198 (52%) of patients have died, but there is currently no evidence of a benefit in overall survival to the C group: HR 1.02 (95% CI 0.77-1.35), P = 0.90). CONCLUSIONS: This trial has failed to observe a survival benefit with adjuvant chemotherapy following complete resection of stage I-III NSCLC. However, the hazard ratio and 95% confidence intervals are consistent with the previously reported meta-analysis and two large recently reported trials, which suggest a small survival benefit with cisplatin-based chemotherapy.

Characterization of the expression and activity of the periplasmic nitrate reductase of Paracoccus pantotrophus in chemostat cultures.

The periplasmic nitrate reductase (Nap) from Paracoccus pantotrophus has a role in cellular redox balancing. Previously, transcription from the nap promoter in P. pantotrophus was shown to be responsive to the oxidation state of the carbon substrate. During batch culture, expression was higher during growth on reduced substrates such as butyrate compared to more oxidized substrates such as succinate. In the present study the effect of growth rate on nap expression in succinate-, acetate- and butyrate-limited chemostat cultures was investigated. In all three cases transcription from the nap promoter and Nap enzyme activity showed a strong correlation. At the fastest growth rates tested for the three substrates nap expression and Nap activity were highest when growth occurred on the most reduced substrate (butyrate > acetate > succinate). However, in all three cases a bell-shaped pattern of expression was observed as a function of growth rate, with the highest levels of nap expression and Nap activity being observed at intermediate growth rates. This effect was most pronounced on succinate, where an approximately fivefold variation was observed, and at intermediate dilution rates nap expression and Nap activity were comparable on all three carbon substrates. Analysis of mRNA prepared from the succinate-grown cultures revealed that different transcription initiation start sites for the nap operon were utilized as the growth rate changed. This study establishes a new regulatory feature of nap expression in P. pantotrophus that occurs at the level of transcription in response to growth rate in carbon-limited cultures.

Surgery for nonsmall cell lung cancer: can improvements be made?

Low-dose spiral computed tomography (CT) for the earlier detection of lung cancer is at the stage of producing hypothesis-generating studies. These studies have shown that more cancers are found at a favourable stage (IA) in prevalence screening but that the fewer numbers found in incidence screening tend to have a slightly worse stage. Randomised controlled trials will be necessary to resolve the place of spiral CT screening. The role of neo-adjuvant chemotherapy before surgery in nonsmall cell lung cancer looks less promising than suggested by earlier studies and the place of adjuvant chemotherapy following surgery appears to be unhelpful, although results of some large, randomised international studies are still awaited. Radical radiotherapy is a poor alternative to surgery in resectable patients who refuse or are unfit for surgery and postoperative radiotherapy is detrimental. Positron emission tomography scanning offers a genuine opportunity to identify occult disease and improve staging prior to surgery and therefore save futile thoracotomies in approximately 20% of patients otherwise apparently suitable for resection.

Some factors affecting cerebral tissue saturation during obstructive sleep apnoea.

Measurement of cerebral tissue saturation during obstructive sleep apnoea (OSA) may provide additional information to conventional peripheral oxygen saturation. Thirteen subjects with OSA (mean apnoea/hypopnoea index 65.7+/-27.9) were monitored using full polysomnography and monitoring of near-infrared cerebral tissue oxygenation index (TOI). One-thousand and thirty-six apnoeas and hypopnoeas were analysed, in terms of duration, sleep stage, arterial oxygen saturation (Sa,O2) dip, minimum Sa,O2, TOI dip and minimum TOI. Cerebral TOI is a measure of cerebral tissue saturation of haemoglobin with oxygen, calculated using near-infrared spatially resolved spectroscopy, which has been shown to have a high specificity for intracranial changes. Decreases in cerebral oxygenation were observed during apnoeas and hypopnoeas. Baseline TOI ranged from 50.1-73.0% and mean apnoea/hypopnoea related TOI dips ranged from 1.43-6.85%. Mean Sa,O2 dips varied from 3.8-21.7%. In regression analysis, factors significantly predicting the magnitude of the TOI dip were Sa,O2 dip, minimum Sa,O2, apnoea duration and rapid eye movement sleep stage. The effect of apnoea duration and sleep stage remained significant after Sa,O2 was included in the regression equation. Near-infrared spectroscopy provides a noninvasive technique for monitoring cerebral tissue saturation during obstructive sleep apnoea.

Mandibular advancement splints and continuous positive airway pressure in patients with obstructive sleep apnoea: a randomized cross-over trial.

This prospective, randomized, cross-over trial was designed to compare the efficacy of a mandibular advancement splint (MAS) with that of nasal continuous positive airway pressure (nCPAP) in patients with obstructive sleep apnoea (OSA). Twenty-four patients (20 males and four females) with mild to moderate OSA (AHI between 10 and 49 events per hour) were enrolled in the study. Each patient used both MAS and nCPAP, with the initial therapy being allocated at random. Treatment periods lasted for two months with a two-week wash-out interval between. Polysomnography was performed prior to the study and after each clinical intervention. Patient and partner questionnaires were used to assess changes in general health and daytime somnolence. The AHI decreased from 22.2 to 3.1 using nCPAP, and to 8.0 using the MAS (P < 0.001 for both devices) and there was no statistically significant difference between the two treatments. The Epworth Sleepiness Score (ESS) fell from 13.4 to 8.1 with nCPAP, and to 9.2 with MAS (P < 0.001), again with no differences between the use of MAS or nCPAP. The questionnaire data showed an improvement in general health scores (P < 0.001) after both treatments, but daytime sleepiness only improved significantly using nCPAP (P < 0.001). Despite this, 17 out of the 21 subjects who completed both arms of the study preferred the MAS. The splints were well tolerated and their efficacy suggests that the MAS may be a suitable alternative to nCPAP in the management of patients with mild or moderate OSA.