•HPV-driven cancers have significantly better survival than traditional head and neck cancers.•Current treatments are reassessed to develop less toxic strategies with good oncological ...outcomes.•Treatment de-escalation raises issues such as patient selection and the benefit/risk balance.•Rigorously constructed trials leading to specific management for HPV-driven OPSCCs are mandatory.
HPV-driven oropharyngeal cancers have significantly better survival rates than tobacco and alcohol induced head and neck cancers. As HPV-positive patients are younger, healthier and far more likely to survive their disease, long-term treatment side effects are becoming a major issue. This has led the scientific and medical community to reassess the current treatment protocols in order to develop less toxic strategies while maintaining good oncological outcomes. In this article, we discuss the ongoing treatment de-escalation trials and highlight the issues raised by these studies.
Evaluate the prognostic and predictive impact of HPV-associated p16-expression and assess the combined prognostic impact of p16 and smoking on altered fractionated radiotherapy (AFRT) for ...oropharyngeal cancer (OPC) within the frames of the update of the Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH).
Patients with OPC, known tumor p16-status and smoking history were identified from the MARCH update, resulting in a dataset of 815 patients from four randomized trials (RTOG9003, DAHANCA6&7, RTOG0129, ARTSCAN). Analysis was performed using a Cox model stratified by trial and adjusted on gender, age, T-stage, N-stage, type of radiotherapy fractionation, p16, smoking. Primary endpoint was progression-free survival (PFS).
In total, 465 patients (57%) had p16-positive tumors and 350 (43%) p16-negative. Compared to p16-negative, p16-positive patients had significantly better PFS (HR = 0.42 95% CI: 0.34–0.51, 28.9% absolute increase at 10 years) and OS (HR = 0.40 0.32–0.49, 32.1% absolute increase at 10 years). No interaction between p16-status and fractionation schedule was detected. Smoking negatively impacted outcome; in the p16-positive subgroup, never smokers had significantly better PFS than former/current smokers (HR = 0.49 0.33–0.75, 24.2% survival benefit at 10 years).
No predictive impact of p16-status on response to AFRT could be detected but the strong prognostic impact of p16-status was confirmed and especially p16-positive never smoking patients have superior outcome after RT.
Brachytherapy: An overview for clinicians Chargari, Cyrus; Deutsch, Eric; Blanchard, Pierre ...
CA: a cancer journal for clinicians,
September/October 2019, Letnik:
69, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Brachytherapy is a specific form of radiotherapy consisting of the precise placement of radioactive sources directly into or next to the tumor. This technique is indicated for patients affected by ...various types of cancers. It is an optimal tool for delivering very high doses to the tumor focally while minimizing the probability of normal tissue complications. Physicians from a wide range of specialties may be involved in either the referral to or the placement of brachytherapy. Many patients require brachytherapy as either primary treatment or as part of their oncologic care. On the basis of high‐level evidence from randomized controlled trials, brachytherapy is mainly indicated: 1) as standard in combination with chemoradiation in patients with locally advanced cervical cancer; 2) in surgically treated patients with uterine endometrial cancer for decreasing the risk of vaginal vault recurrence; 3) in patients with high‐risk prostate cancer to perform dose escalation and improve progression‐free survival; and 4) in patients with breast cancer as adjuvant, accelerated partial breast irradiation or to boost the tumor bed. In this review, the authors discuss the clinical relevance of brachytherapy with a focus on indications, levels of evidence, and results in the overall context of radiation use for patients with cancer.
The mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) pathway is a critical signaling component in the development of obesity-linked insulin resistance and operates a nutrient-sensing ...negative feedback loop toward the phosphatidylinositol 3-kinase (PI 3-kinase)/Akt pathway. Whereas acute treatment of insulin target cells with the mTOR complex 1 (mTORC1) inhibitor rapamycin prevents nutrient-induced insulin resistance, the chronic effect of rapamycin on insulin sensitivity and glucose metabolism in vivo remains elusive.
To assess the metabolic effects of chronic inhibition of the mTORC1/S6K1 pathway, rats were treated with rapamycin (2 mg/kg/day) or vehicle for 15 days before metabolic phenotyping.
Chronic rapamycin treatment reduced adiposity and fat cell number, which was associated with a coordinated downregulation of genes involved in both lipid uptake and output. Rapamycin treatment also promoted insulin resistance, severe glucose intolerance, and increased gluconeogenesis. The latter was associated with elevated expression of hepatic gluconeogenic master genes, PEPCK and G6Pase, and increased expression of the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) as well as enhanced nuclear recruitment of FoxO1, CRTC2, and CREB. These changes were observed despite normal activation of the insulin receptor substrate/PI 3-kinase/Akt axis in liver of rapamycin-treated rats, as expected from the blockade of the mTORC1/S6K1 negative feedback loop.
These findings unravel a novel mechanism by which mTORC1/S6K1 controls gluconeogenesis through modulation of several key transcriptional factors. The robust induction of the gluconeogenic program in liver of rapamycin-treated rats underlies the development of severe glucose intolerance even in the face of preserved hepatic insulin signaling to Akt and despite a modest reduction in adiposity.
Assembly of TopBP1 biomolecular condensates triggers activation of the ataxia telangiectasia-mutated and Rad3-related (ATR)/Chk1 signaling pathway, which coordinates cell responses to impaired DNA ...replication. Here, we used optogenetics and reverse genetics to investigate the role of sequence-specific motifs in the formation and functions of TopBP1 condensates. We propose that BACH1/FANCJ is involved in the partitioning of BRCA1 within TopBP1 compartments. We show that Chk1 is activated at the interface of TopBP1 condensates and provide evidence that these structures arise at sites of DNA damage and in primary human fibroblasts. Chk1 phosphorylation depends on the integrity of a conserved arginine motif within TopBP1’s ATR activation domain (AAD). Its mutation uncouples Chk1 activation from TopBP1 condensation, revealing that optogenetically induced Chk1 phosphorylation triggers cell cycle checkpoints and slows down replication forks in the absence of DNA damage. Together with previous work, these data suggest that the intrinsically disordered AAD encodes distinct molecular steps in the ATR/Chk1 pathway.
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•BRCA1 is partitioned within TopBP1 condensates in a FANCJ-dependent manner•Chk1 is phosphorylated at the interfacial regions of TopBP1 biomolecular condensates•Optogenetic TopBP1 condensation system recapitulates this phenomenon•Light-activated Chk1 phosphorylation triggers cell cycle checkpoints without DNA damage
Egger et al. implement their previously proposed ATR/Chk1 activation model by dissociating the functions of ATR and Chk1. Using reverse genetics and optogenetics, they show that Chk1 is phosphorylated at the interface of TopBP1 biomolecular condensates, triggering cell cycle checkpoints and slowing down replication fork progression.
Purpose The role of adjuvant chemotherapy (AC) or induction chemotherapy (IC) in the treatment of locally advanced nasopharyngeal carcinoma is controversial. The individual patient data from the ...Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma database were used to compare all available treatments. Methods All randomized trials of radiotherapy (RT) with or without chemotherapy in nonmetastatic nasopharyngeal carcinoma were considered. Overall, 20 trials and 5,144 patients were included. Treatments were grouped into seven categories: RT alone (RT), IC followed by RT (IC-RT), RT followed by AC (RT-AC), IC followed by RT followed by AC (IC-RT-AC), concomitant chemoradiotherapy (CRT), IC followed by CRT (IC-CRT), and CRT followed by AC (CRT-AC). P-score was used to rank the treatments. Fixed- and random-effects frequentist network meta-analysis models were applied. Results The three treatments with the highest probability of benefit on overall survival (OS) were CRT-AC, followed by CRT and IC-CRT, with respective hazard ratios (HRs 95% CIs) compared with RT alone of 0.65 (0.56 to 0.75), 0.77 (0.64 to 0.92), and 0.81 (0.63 to 1.04). HRs (95% CIs) of CRT-AC compared with CRT for OS, progression-free survival (PFS), locoregional control, and distant control (DC) were, respectively, 0.85 (0.68 to 1.05), 0.81 (0.66 to 0.98), 0.70 (0.48 to 1.02), and 0.87 (0.61 to 1.25). IC-CRT ranked second for PFS and the best for DC. CRT never ranked first. HRs of CRT compared with IC-CRT for OS, PFS, locoregional control, and DC were, respectively, 0.95 (0.72 to 1.25), 1.13 (0.88 to 1.46), 1.05 (0.70 to 1.59), and 1.55 (0.94 to 2.56). Regimens with more chemotherapy were associated with increased risk of acute toxicity. Conclusion The addition of AC to CRT achieved the highest survival benefit and consistent improvement for all end points. The addition of IC to CRT achieved the highest effect on DC.
Abstract Background and purpose A constant relative biological effectiveness (RBE) is used for clinical proton therapy; however, experimental evidence indicates that RBE can vary. We analyzed ...pediatric ependymoma patients who received proton therapy to determine if areas of normal tissue damage indicated by post-treatment image changes were associated with increased biological dose effectiveness. Material and methods Fourteen of 34 children showed T2-FLAIR hyperintensity on post-treatment magnetic resonance (MR) images. We delineated regions of treatment-related change and calculated dose and linear energy transfer (LET) distributions with Monte Carlo. Voxel-level image change data were fit to a generalized linear model incorporating dose and LET. Cross-validation was used to determine model parameters and for receiver operating characteristic curve analysis. Tolerance dose (TD50 ; dose at which 50% of patients would experience toxicity) was interpolated from the model. Results Image changes showed dependence on increasing LET and dose. TD50 decreased with increasing LET, indicating an increase in biological dose effectiveness. The cross-validated area under the curve for the model was 0.91 (95% confidence interval 0.88–0.94). Conclusions Our correlation of changes on MR images after proton therapy with increased LET constitutes the first clinical evidence of variable proton biological effectiveness.
In France, before the pandemic, approximatively 480 ICU beds nationally remained closed because of the shortage of nurses. A high turnover of nurses is observed in French ICUs,11 undoubtedly due to ...the work conditions (frequent night shifts and weekend work), the absence of specific recognition as a critical care nurse (especially compared with numerous European countries), poor pay (remuneration below the French average wage4), and the absence of a professional critical care nurse educational program. Currently, French nurses develop critical care specific skills through on-the-job training. This approach is far from that recommended by the World Federation of Critical Care Nurses, back in 2005, which stressed that critically ill patients have very special needs and must be cared for by nurses with specialist skills, knowledge, and attitudes12 In France, the few courses for critical care nurses that exist are locally delivered and heterogeneous in their content and assessment. Since the beginning of the COVID-19 crisis, French critical care medical societies supported the positions and the claims of the critical care nurses. More than ever, they underlined the numerous skills ICU nurses possess and how unrecognized they are. In addition to highlighting the wide range of skills these nurses have, they stressed how these skills (or lack of them) may affect patient outcomes.
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