Head-and-neck squamous cell carcinoma (HNSCC) is one of the most common malignancies globally, and the number of elderly patients diagnosed with HNSCC is increasing. However, as elderly HNSCC ...patients are underrepresented in clinical trials, current clinical decision making for this cohort largely lacks clinical evidence.
Elderly patients (≥65 years) with HNSCC undergoing (chemo)radiotherapy from 2010 to 2018 at Freiburg University Medical Center were assessed for patterns of care, locoregional control (LRC), progression-free (PFS) and overall survival (OS) regarding definitive and adjuvant treatments. Acute and late therapy-associated toxicities were quantified according to CTCAE v5.0.
Two hundred forty-six patients were included in this analysis, of whom 166 received definitive and 80 adjuvant treatment. Two-year rates for OS, PFS and LRC were 56.9, 44.9 and 75.5%, respectively. Survival differed significantly between age groups with an OS of 40 and 22 months and a PFS of 23 and 12 months for patients aged 65-74 or ≥ 75 years, respectively (p < 0.05). Concomitant chemotherapy resulted in improved OS in patients aged 65-74 years compared to radiotherapy alone (p < 0.05) for definitive treatments, while patients ≥75 years did not benefit (p = 0.904). For adjuvant chemoradiotherapy, a trend towards superior OS rates was observed for patients aged 65-74 years (p = 0.151). Low performance status (HR = 2.584, 95% CI 1.561-4.274; p < 0.001) and smoking (HR = 1.960, 95% CI 1.109-3.464, p < 0.05) were the strongest independent prognostic factor in the multivariate analysis for decreased OS. One hundred thirty-eight patients (56.1%) experienced acute grade 3/4 and 45 patients (19.9%) chronic grade 3 toxicities.
Radiotherapy is a feasible treatment modality for elderly HNSCC patients. The relatively low OS compared to high LRC may reflect age and comorbidities. Concomitant chemotherapy should be critically discussed in elderly HNSCC patients.
Brain insults are a major cause of acute mortality and chronic morbidity. Given the largely ineffective current therapeutic strategies, the development of new and efficient therapeutic interventions ...is clearly needed. A series of previous investigations has shown that the noble and anesthetic gas xenon, which has low-affinity antagonistic properties at the N-methyl-D-aspartate (NMDA) receptor, also exhibits potentially neuroprotective properties with no proven adverse side effects. Surprisingly and in contrast with most drugs that are being developed as therapeutic agents, the dose-response neuroprotective effect of xenon has been poorly studied, although this effect could be of major critical importance for its clinical development as a neuroprotectant. Here we show, using ex vivo and in vivo models of excitotoxic insults and transient brain ischemia, that xenon, administered at subanesthetic doses, offers global neuroprotection from reduction of neurotransmitter release induced by ischemia, a critical event known to be involved in excitotoxicity, to reduction of subsequent cell injury and neuronal death. Maximal neuroprotection was obtained with xenon at 50 vol%, a concentration at which xenon further exhibited significant neuroprotective effects in vivo even when administered up to 4 h after intrastriatal NMDA injection and up to at least 2 h after induction of transient brain ischemia.--David, H. N., Haelewyn, B., Rouillon, C., Lecoq, M., Chazalviel, L., Apiou, G., Risso, J.-J., Lemaire, M., Abraini, J. H. Neuroprotective effects of xenon: a therapeutic window of opportunity in rats subjected to transient cerebral ischemia.
Xylans are polysaccharides that are naturally abundant in agricultural by-products, such as cereal brans and straws. Microbial degradation of arabinoxylan is facilitated by extracellular esterases ...that remove acetyl, feruloyl, and p-coumaroyl decorations. The bacterium Ruminiclostridium cellulolyticum possesses the Xua (xylan utilization associated) system, which is responsible for importing and intracellularly degrading arabinoxylodextrins. This system includes an arabinoxylodextrins importer, four intracellular glycosyl hydrolases, and two intracellular esterases, XuaH and XuaJ which are encoded at the end of the gene cluster.
Genetic studies demonstrate that the genes xuaH and xuaJ are part of the xua operon, which covers xuaABCDD'EFGHIJ. This operon forms a functional unit regulated by the two-component system XuaSR. The esterases encoded at the end of the cluster have been further characterized: XuaJ is an acetyl esterase active on model substrates, while XuaH is a xylan feruloyl- and p-coumaryl-esterase. This latter is active on oligosaccharides derived from wheat bran and wheat straw. Modelling studies indicate that XuaH has the potential to interact with arabinoxylobiose acylated with mono- or diferulate. The intracellular esterases XuaH and XuaJ are believed to allow the cell to fully utilize the complex acylated arabinoxylo-dextrins imported into the cytoplasm during growth on wheat bran or straw.
This study reports for the first time that a cytosolic feruloyl esterase is part of an intracellular arabinoxylo-dextrin import and degradation system, completing its cytosolic enzymatic arsenal. This system represents a new pathway for processing highly-decorated arabinoxylo-dextrins, which could provide a competitive advantage to the cell and may have interesting biotechnological applications.
•The survival score stratifies elderly HNSCC patients in 3 prognostic groups.•The score is based on performance status, comorbidity burden and baseline CRP level.•The score for elderly HNSCC patients ...having radiotherapy was externally validated.•The developed nomogram predicts 2- and 4-year overall survival of this cohort.
To establish a clinically feasible prognostic score and nomogram based on easily accessible clinical data that will aid decision-making in elderly head-and-neck squamous cell carcinoma (HNSCC) patients undergoing (chemo)radiotherapy.
284 elderly HNSCC patients (≥65 years) undergoing curative (chemo)radiotherapy were included for the development of a score predicting overall survival (OS) based on the beta regression coefficients from significant parameters in a multivariate Cox regression analysis with p < 0.1 as inclusion criterion. A second, external cohort of 217 elderly HNSCC patients receiving (chemo)radiotherapy was used for validation. Using the aggregated data (n = 501), a nomogram was developed to predict 2- and 4-year OS.
Karnofsky Performance Status (HR = 2.654; p < 0.001), Charlson Comorbidity Index (HR = 2.598; p < 0.001) and baseline C-reactive protein (CRP) level (HR = 1.634; p = 0.068) were prognostic for OS in the multivariate analysis. An OS score based on beta regression coefficients was created, in which reduced performance status, increased comorbidity burden and increased CRP levels were included, leading to 3 distinct survival groups. The median OS for the 3 groups amounted to 107, 28 and 6 months, respectively (p < 0.001). The developed score was able to significantly differentiate between a favorable (median OS = 130 months), intermediate (29 months) and unfavorable prognosis (9 months) also in the external validation cohort (p = 0.005).
We propose a novel, validated prognostic score based on easily accessible clinical data allowing stratification between prognostic groups of elderly HNSCC patients receiving (chemo)radiotherapy. The derived nomogram for the prediction of 2-year and 4-year OS may aid decision-making for this vulnerable population.
IMPORTANCE: The optimal approach to the use of venoarterial extracorporeal membrane oxygenation (ECMO) during cardiogenic shock is uncertain. OBJECTIVE: To determine whether early use of moderate ...hypothermia (33-34 °C) compared with strict normothermia (36-37 °C) improves mortality in patients with cardiogenic shock receiving venoarterial ECMO. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of patients (who were eligible if they had been endotracheally intubated and were receiving venoarterial ECMO for cardiogenic shock for <6 hours) conducted in the intensive care units at 20 French cardiac shock care centers between October 2016 and July 2019. Of 786 eligible patients, 374 were randomized. Final follow-up occurred in November 2019. INTERVENTIONS: Early moderate hypothermia (33-34 °C; n = 168) for 24 hours or strict normothermia (36-37 °C; n = 166). MAIN OUTCOMES AND MEASURES: The primary outcome was mortality at 30 days. There were 31 secondary outcomes including mortality at days 7, 60, and 180; a composite outcome of death, heart transplant, escalation to left ventricular assist device implantation, or stroke at days 30, 60, and 180; and days without requiring a ventilator or kidney replacement therapy at days 30, 60, and 180. Adverse events included rates of severe bleeding, sepsis, and number of units of packed red blood cells transfused during venoarterial ECMO. RESULTS: Among the 374 patients who were randomized, 334 completed the trial (mean age, 58 SD, 12 years; 24% women) and were included in the primary analysis. At 30 days, 71 patients (42%) in the moderate hypothermia group had died vs 84 patients (51%) in the normothermia group (adjusted odds ratio, 0.71 95% CI, 0.45 to 1.13, P = .15; risk difference, −8.3% 95% CI, −16.3% to −0.3%). For the composite outcome of death, heart transplant, escalation to left ventricular assist device implantation, or stroke at day 30, the adjusted odds ratio was 0.57 (95% CI, 0.36 to 0.90; P = .02) for the moderate hypothermia group compared with the normothermia group and the risk difference was −12.7% (95% CI, −22.3% to −3.2%). Of the 31 secondary outcomes, 30 were inconclusive. The incidence of moderate or severe bleeding was 41% in the moderate hypothermia group vs 42% in the normothermia group. The incidence of infections was 52% in both groups. The incidence of bacteremia was 20% in the moderate hypothermia group vs 30% in the normothermia group. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial involving patients with refractory cardiogenic shock treated with venoarterial ECMO, early application of moderate hypothermia for 24 hours did not significantly increase survival compared with normothermia. However, because the 95% CI was wide and included a potentially important effect size, these findings should be considered inconclusive. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02754193
Temporary mechanical circulatory support as well as multidisciplinary team approach in a regional care organization might improve survival of cardiogenic shock. No study has evaluated the relative ...effect of each temporary mechanical circulatory support on mortality in the context of a regional network.
Prospective observational data were retrieved from patients consecutively admitted with cardiogenic shock to the intensive care units in 3 centers organized into a regional cardiac assistance network. Temporary mechanical circulatory support indication was decided by a heart team, based on the initial shock severity or if shock was refractory to medical treatment within 24 hours of admission. A propensity score for circulatory support use was used as an adjustment co-variable to emulate a target trial. The primary endpoint was in-hospital mortality.
Two hundred and forty-six patients were included in the study (median age: 59.5 years, 71.9% male): 121 received early mechanical assistance. The main etiologies were acute myocardial infraction (46.8%) and decompensated heart failure (27.2%). Patients who received early mechanical assistance had more severe conditions than other patients. Their crude in-hospital mortality was 38% and 22.4% in other patients but adjusted in-hospital mortality was not different (hazard ratio 0.91, 95% CI:0.65-1.26). Patients with mechanical assistance had a higher rate of complications than others with longer Intensive Care Unit and hospital stays.
In the conditions of a cardiac assistance regional network, in-hospital mortality was not improved by early mechanical assistance implantation. A high incidence of complications of temporary mechanical circulatory support may have jeopardized its potential benefit.
Transcription factors are recognized as the master regulators of gene expression. Interestingly, about 10% of the transcription factors described in mammals are up to date directly implicated in a ...very large number of human diseases. With the exception of ligand-inducible nuclear receptors, transcription factors have longtime been considered as "undruggable" targets for therapeutics. However, the significant breakthroughs in their protein biochemistry and interactions with DNA at the structural level, together with increasing needs for new targeted-approaches particularly in cancers, has changed this postulate and opened the way for targeting transcription factors. Along with a better knowledge of their specific DNA binding sequences by genome wide and high throughput sequencing assay, these informations make possible the potent targeting of the transcription factors by three approaches dependently of their mechanism of action. In this review, we discuss the different physicochemical interactions between the transcription factors and the DNA helix, and the protein/protein interactions within a transcription factor complex and their impacts on the DNA structure. In order to impair transcription factor activities, small molecules compounds can either act by direct interaction on the transcription factor, or by blocking the protein/protein interactions in a transcription complex, or by competing with the transcription factor itself and specifically targeting its cognate binding sequence. For this latter mode of transcription targeting, we pay special attention to the DNA intercalating, alkylating or groove binders for transcription factor/DNA binding modulation.
HOXA9 (Homeobox A9) is a homeotic transcription factor known for more than two decades to be associated with leukemia. The expression of HOXA9 homeoprotein is associated with anterior-posterior ...patterning during embryonic development, and its expression is then abolished in most adult cells, with the exception of hematopoietic progenitor cells. The oncogenic function of HOXA9 was first assessed in human acute myeloid leukemia (AML), particularly in the mixed-phenotype associated lineage leukemia (MPAL) subtype. HOXA9 expression in AML is associated with aggressiveness and a poor prognosis. Since then, HOXA9 has been involved in other hematopoietic malignancies and an increasing number of solid tumors. Despite this, HOXA9 was for a long time not targeted to treat cancer, mainly since, as a transcription factor, it belongs to a class of protein long considered to be an "undruggable" target; however, things have now evolved. The aim of the present review is to focus on the different aspects of HOXA9 targeting that could be achieved through multiple ways: (1) indirectly, through the inhibition of its expression, a strategy acting principally at the epigenetic level; or (2) directly, through the inhibition of its transcription factor function by acting at either the protein/protein interaction or the protein/DNA interaction interfaces.
Systemic lupus erythematosus (SLE) is a complex clinical syndrome, elements of which remain poorly understood. Although recognized over 140 years ago when Kaposi recorded the systemic nature and ...manifestations of the disease, CNS involvement represents one of the least understood aspects of SLE. This knowledge gap remains despite the fact that up to 75% of adults and children with SLE will, at some point over the course of the disease and to different extents, experience the various disabling effects of neuropsychiatric SLE (NPSLE). Indeed, after decades of research, our understanding of the underlying pathophysiology of NPSLE, in particular, remains limited. Numerous factors contribute to the immune dysfunction that occurs in SLE, including genetic, environmental and hormonal influences, and the contributory or predisposing components that lead to neurological tropism of disease in some patients have not been clearly demonstrated. Features of NPSLE pathogenesis that might be directly linked to clinical manifestations have been identified; however, the complexity and variety of NPSLE symptoms and the clinical overlap with other psychiatric disorders continue to make accurate diagnosis difficult and time-consuming. Thus, efforts to define biomarkers of NPSLE are needed to improve prediction of disease outcomes and guide treatment. In this article, we review the manifestation and pathogenesis of NPSLE, focusing on the features that might aid identification of potential biomarkers.
Cardiac surgery-associated acute kidney injury (CS-AKI) affects up to 30% of patients, increasing morbidity and healthcare costs. This condition results from complex factors like ischemia-reperfusion ...injury and renal hemodynamic changes, often exacerbated by surgical procedures. Norepinephrine, commonly used in cardiac surgeries, may heighten the risk of CS-AKI. In contrast, vasopressin, a noncatecholaminergic agent, shows potential in preserving renal function by favorably affecting renal hemodynamic. Preliminary findings, suggest vasopressin could reduce the incidence of CS-AKI compared to norepinephrine. Additionally, vasopressin is linked to a lower incidence of postoperative atrial fibrillation, another factor contributing to longer hospital stays and higher costs. This study hypothesizes that vasopressin could effectively reduce CS-AKI occurrence and severity by optimizing renal perfusion during cardiac surgeries.
The NOVACC trial (NCT05568160) is a multicenter, randomized, double blinded superiority-controlled trial testing the superiority of vasopressin over norepinephrine in patients scheduled for cardiac surgery with cardiopulmonary bypass (CPB). The primary composite end point is the occurrence of acute kidney injury and death. The secondary end points are neurological, cardiologic, digestive, and vasopressor related complications at day 7, day 30, day 90, hospital and intensive care unit lengths of stay, medico-economic costs at day 90.
The NOVACC trial will assess the effectiveness of vasopressin in cardiac surgery with CPB in reducing acute kidney injury, mortality, and medical costs.
NCT05568160.
PDF
