Summary Background Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare ...gefitinib with placebo in previously treated advanced oesophageal cancer. Methods For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0–2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179. Findings Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 3·73 months, 95% CI 3·23–4·50, for gefitinib vs 3·67 months, 95% CI 2·97–4·37, for placebo; hazard ratio HR 0·90, 95% CI 0·74–1·09, p=0·29). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference −8·61, 95% CI −14·49 to −2·73; n=227; p=0·004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (2·69, 95% CI −2·33 to 7·72, n=231, p=0·293), dysphagia (−3·18, 95% CI −8·36 to 2·00, n=231, p=0·228), and eating (−4·11, 95% CI −9·96 to 1·75, n=229, p=0·168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (1·57 months, 95% CI 1·23–1·90 in the gefitinib group vs 1·17 months, 95% CI 1·07–1·37 in the placebo group; HR 0·80, 95% CI 0·66–0·96, p=0·020). The most common toxicities were diarrhoea (36 16% of 224 patients on gefitinib vs six 3% of 225 on placebo) and skin toxicity (46 21% vs two 1%), both mostly grade 2. The commonest grade 3–4 toxicities were fatigue (24 11% vs 13 6% patients) and diarrhoea (13 6% vs two 1%). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0·023). Interpretation The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients. Funding Cancer Research UK.
A retrospective review.
To obtain an assessment of complication incidence using the largest known database of adult scoliosis and to determine whether the rate of complication depends on various ...clinical parameters.
The Scoliosis Research Society (SRS) morbidity and mortality database has previously been used to assess complication rates in adolescents undergoing scoliosis correction. To better understand complications in adults, degenerative and idiopathic adult scoliosis (AS) cases were studied.
The SRS morbidity and mortality database was queried to identify cases of AS from 2004 to 2007. Complications were identified and analyzed on the basis of patient type of scoliosis (degenerative vs. adult idiopathic), age, use of osteotomy, revision surgery status, and surgical approach. Age was stratified into less than or equal to 60 and greater than 60. Surgical approach was stratified into anterior only, posterior only, and combined anterior/posterior.
A total of 4980 cases of AS were submitted from 2004 to 2007. There were 521 patients with complications (10.5%), and a total of 669 complications (13.4%). The most common complications were dural tear 142 (2.9%), superficial wound infection 46 (0.9%), deep wound infection 73 (1.5%), implant complication 80 (1.6%), acute neurological deficits 49 (1.0%), delayed neurological deficits 41 (0.5%), epidural hematoma 12 (0.2%), wound hematoma 22 (0.4%), pulmonary embolus 12 (0.2%), and deep venous thrombosis 9 (0.2%). There were 17 deaths (0.3%). There were 2555 patients with degenerative and 2425 patients with adult idiopathic scoliosis. Complication rates in these two groups were not significantly different (11.0% and 9.9%, respectively, P = 0.20). Age was not associated with complication rate (P = 0.32). Significantly higher complication rates were identified in osteotomies, revision surgery, and/or combined anterior-posterior surgery (P = 0.0006, 0.006, and 0.03, respectively).
The overall complication rate for AS treatment is 13.4%. Complication rate is significantly higher when osteotomies, revision procedures, and combined anterior/posterior approaches are used. Complication rate is not influenced by scoliosis type or age.
Retrospective review of a prospectively collected, multicenter database.
To assess rates of new neurologic deficit (NND) associated with spine surgery.
NND is a potential complication of spine ...surgery, but previously reported rates are often limited by small sample size and single-surgeon experiences.
The Scoliosis Research Society morbidity and mortality database was queried for spinal surgery cases complicated by NND from 2004 to 2007, including nerve root deficit (NRD), cauda equina deficit (CED), and spinal cord deficit (SCD). Use of neuromonitoring was assessed. Recovery was stratified as complete, partial, or none. Rates of NND were stratified based on diagnosis, age (pediatric < 21; adult ≥ 21), and surgical parameters.
Of the 108,419 cases reported, NND was documented for 1064 (1.0%), including 662 NRDs, 74 CEDs, and 293 SCDs (deficit not specified for 35 cases). Rates of NND were calculated on the basis of diagnosis. Revision cases had a 41% higher rate of NND (1.25%) compared with primary cases (0.89%; P < 0.001). Pediatric cases had a 59% higher rate of NND (1.32%) compared with adult cases (0.83%; P < 0.001). The rate of NND for cases with implants was more than twice that for cases without implants (1.15% vs. 0.52%, P < 0.001). Neuromonitoring was used for 65% of cases, and for cases with new NRD, CED, and SCD, changes in neuromonitoring were reported in 11%, 8%, and 40%, respectively. The respective percentages of no recovery, partial, and complete recovery for NRD were 4.7%, 46.8%, and 47.1%, respectively; for CED were 9.6%, 45.2%, and 45.2%, respectively; and for SCD were 10.6%, 43%, and 45.7%, respectively.
Our data demonstrate that, even among skilled spinal deformity surgeons, new neurologic deficits are inherent potential complications of spine surgery. These data provide general benchmark rates for NND with spine surgery as a basis for patient counseling and for ongoing efforts to improve safety of care.
A fatal case of Japanese encephalitis (JE) occurred in northern Australia in early 2021. Sequence studies showed that the virus belonged to genotype IV (GIV), a genotype previously believed to be ...restricted to the Indonesian archipelago. This was the first locally acquired case of Japanese encephalitis virus (JEV) GIV to occur outside Indonesia, and the second confirmed fatal human case caused by a GIV virus. A closely related GIV JEV strain subsequently caused a widespread outbreak in eastern Australia in 2022 that was first detected by fetal death and abnormalities in commercial piggeries. Forty-two human cases also occurred with seven fatalities. This has been the first major outbreak of JEV in mainland Australia, and geographically the largest virgin soil outbreak recorded for JEV. This outbreak provides an opportunity to discuss and document the factors involved in the virus' spread and its ecology in a novel ecological milieu in which other flaviviruses, including members of the JE serological complex, also occur. The probable vertebrate hosts and mosquito vectors are discussed with respect to virus spread and its possible endemicity in Australia, and the need to develop a One Health approach to develop improved surveillance methods to rapidly detect future outbreak activity across a large geographical area containing a sparse human population. Understanding the spread of JEV in a novel ecological environment is relevant to the possible threat that JEV may pose in the future to other receptive geographic areas, such as the west coast of the United States, southern Europe or Africa.
Antibiotic resistance and associated genes are ubiquitous and ancient, with most genes that encode resistance in human pathogens having originated in bacteria from the natural environment (eg, ...β-lactamases and fluoroquinolones resistance genes, such as qnr). The rapid evolution and spread of "new" antibiotic resistance genes has been enhanced by modern human activity and its influence on the environmental resistome. This highlights the importance of including the role of the environmental vectors, such as bacterial genetic diversity within soil and water, in resistance risk management. We need to take more steps to decrease the spread of resistance genes in environmental bacteria into human pathogens, to decrease the spread of resistant bacteria to people and animals via foodstuffs, wastes and water, and to minimize the levels of antibiotics and antibiotic-resistant bacteria introduced into the environment. Reducing this risk must include improved management of waste containing antibiotic residues and antibiotic-resistant microorganisms.
•Carbon dioxide (CO2) levels are important in managing neurologic conditions.•Spreading depolarizations (SD) are a pathologic mechanism of cerebral cortex.•CO2 levels did not impact SD ...characteristics in normoxic or hypoxic rat brain.•Mean arterial pressure negatively correlated with SD duration.•The role of CO2 warrants investigation in conditions of acute focal brain injury.
Patients with traumatic brain injury are typically maintained at low-normal levels of arterial partial pressure of carbon dioxide (PaCO2) to counteract the risk of elevated intracranial pressure during intensive care. However, several studies suggest that management at hypercarbic levels may have therapeutic benefit. Here we examined the impact of CO2 levels on spreading depolarizations (SD), a mechanism and marker of acute lesion development in stroke and brain trauma. In an acute preparation of mechanically ventilated (30/70 O2/N2) female rats, SDs were evoked by cortical KCl application and monitored by electrophysiology and laser doppler flowmetry; CO2 levels were adjusted by ventilator settings and supplemental CO2. During 90 min of KCl application, rats were maintained at hypocapnia (end-tidal CO2 22 ± 2 mmHg) or hypercapnia (57 ± 4 mmHg) but did not differ significantly in arterial pH (7.31 ± 0.10 vs. 7.22 ± 0.08, p = 0.31) or other variables. Surprisingly, there was no difference between groups in the number of SDs recorded (10.7 ± 4.2 vs. 11.7 ± 3.1; n = 3 rats/group; p = 0.75) nor in SD durations (64 ± 27 vs. 69 ± 37 sec, p = 0.54). In separate experiments (n = 3), hypoxia was induced by decreasing inhaled O2 to 10% and single SDs were induced under interleaved conditions of hypo-, normo-, and hypercapnia. No differences in SD duration were observed. In both normoxia and hypoxia experiments, however, mean arterial pressures were negatively correlated with SD durations (normoxia R2 = −0.29; hypoxia R2 = −0.61, p’s < 0.001). Our results suggest that any therapeutic benefit of elevated CO2 therapy may be dependent on an acidic shift in pH or may only be observed in conditions of focal brain injury.
A better understanding is needed of how hydrological and biogeochemical processes control dissolved organic carbon (DOC) concentrations and dissolved organic matter (DOM) composition from headwaters ...downstream to large rivers. We examined a large DOM dataset from the National Water Information System of the US Geological Survey, which represents approximately 100 000 measurements of DOC concentration and DOM composition at many sites along rivers across the United States. Application of quantile regression revealed a tendency towards downstream spatial and temporal homogenization of DOC concentrations and a shift from dominance of aromatic DOM in headwaters to more aliphatic DOM downstream. The DOC concentration–discharge (C-Q) relationships at each site revealed a downstream tendency towards a slope of zero. We propose that despite complexities in river networks that have driven many revisions to the River Continuum Concept, rivers show a tendency towards chemostasis (C-Q slope of zero) because of a downstream shift from a dominance of hydrologic drivers that connect terrestrial DOM sources to streams in the headwaters towards a dominance of instream and near-stream biogeochemical processes that result in preferential losses of aromatic DOM and preferential gains of aliphatic DOM.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVETo prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.
METHODSAdults treated with ...brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory.
RESULTSOf 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04–9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ).
CONCLUSIONSAdjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low.
CLINICALTRIALS.GOV IDENTIFIERNCT00572195.
CLASSIFICATION OF EVIDENCEThis study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.
Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological ...transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories.
Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1.
Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
