Immune checkpoint blockade (ICB) has revolutionised the treatment of solid tumours, yet most patients do not derive a clinical benefit. Resistance to ICB is often contingent on the tumour ...microenvironment (TME) and modulating aspects of this immunosuppressive milieu is a goal of combination treatment approaches. Radiation has been used for over a century in the management of cancer with more than half of all cancer patients receiving radiotherapy. Here, we outline the rationale behind combining radiotherapy with ICB, a potential synergy through mutually beneficial remodelling of the TME. We discuss the pleiotropic effects radiation has on the TME including immunogenic cell death, activation of cytosolic DNA sensors, remodelling the stroma and vasculature, and paradoxical infiltration of both anti-tumour and suppressive immune cell populations. These events depend on the radiation dose and fractionation and optimising these parameters will be key to develop safe and effective combination regimens. Finally, we highlight ongoing efforts that combine radiation, immunotherapy and inhibitors of DNA damage response, which can help achieve a favourable equilibrium between the immunogenic and tolerogenic effects of radiation on the immune microenvironment.
•Radiotherapy exhibits immunogenic effects and has the potential to stimulate abscopal effects.•The release of DAMPs is stimulated by radiotherapy resulting in immunogenic cell death.•Radiotherapy upregulates signals in the TME promoting CD8+ T cell mediated killing.•TME remodelling following radiotherapy depends on dose and fractionation.•Hypofractionation with ICB demonstrates promising robust immunogenicity in preclinical studies.
Background
The impact of cardiorespiratory comorbidity on operative outcomes after esophagectomy remains controversial. This study investigated the effect of cardiorespiratory comorbidity on ...postoperative complications for patients treated for esophageal or gastroesophageal junction cancer.
Patients and Methods
A European multicenter cohort study from five high-volume esophageal cancer centers including patients treated between 2010 and 2017 was conducted. The effect of cardiorespiratory comorbidity and respiratory function upon postoperative outcomes was assessed.
Results
In total 1590 patients from five centers were included; 274 (17.2%) had respiratory comorbidity, and 468 (29.4%) had cardiac comorbidity. Respiratory comorbidity was associated with increased risk of overall postoperative complications, anastomotic leak, pulmonary complications, pneumonia, increased Clavien–Dindo score, and critical care and hospital length of stay. After neoadjuvant chemoradiotherapy, respiratory comorbidity was associated with increased risk of anastomotic leak odds ratio (OR) 1.83, 95% confidence interval (CI) 1.11–3.04, pneumonia (OR 1.65, 95% CI 1.10–2.47), and any pulmonary complication (OR 1.52, 95% CI 1.04–2.22), an effect which was not observed following neoadjuvant chemotherapy or surgery alone. Cardiac comorbidity was associated with increased risk of cardiovascular and pulmonary complications, respiratory failure, and Clavien–Dindo score ≥ IIIa. Among all patients, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio > 70% was associated with reduced risk of overall postoperative complications, cardiovascular complications, atrial fibrillation, pulmonary complications, and pneumonia.
Conclusions
The results of this study suggest that cardiorespiratory comorbidity and impaired pulmonary function are associated with increased risk of postoperative complications after esophagectomy performed in high-volume European centers. Given the observed interaction with neoadjuvant approach, these data indicate a potentially modifiable index of perioperative risk.
Neoadjuvant therapy is increasingly the standard of care in the management of locally advanced adenocarcinoma of the oesophagus and junction (AEG). In randomised controlled trials (RCTs), the MAGIC ...regimen of pre- and postoperative chemotherapy, and the CROSS regimen of preoperative chemotherapy combined with radiation, were superior to surgery only in RCTs that included AEG but were not powered on this cohort. No completed RCT has directly compared neoadjuvant or perioperative chemotherapy and neoadjuvant chemoradiation. The Neo-AEGIS trial, uniquely powered on AEG, and including comprehensive modern staging, compares both these regimens.
This open label, multicentre, phase III RCT randomises patients (cT2-3, N0-3, M0) in a 1:1 fashion to receive CROSS protocol (Carboplatin and Paclitaxel with concurrent radiotherapy, 41.4Gy/23Fr, over 5 weeks). The power calculation is a 10% difference in favour of CROSS, powered at 80%, two-sided alpha level of 0.05, requiring 540 patients to be evaluable, 594 to be recruited if a 10% dropout is included (297 in each group). The primary endpoint is overall survival, with a minimum 3-year follow up. Secondary endpoints include: disease free survival, recurrence rates, clinical and pathological response rates, toxicities of induction regimens, post-operative pathology and tumour regression grade, operative in-hospital complications, and health-related quality of life. The trial also affords opportunities for establishing a bio-resource of pre-treatment and resected tumour, and translational research.
This RCT directly compares two established treatment regimens, and addresses whether radiation therapy positively impacts on overall survival compared with a standard perioperative chemotherapy regimen Sponsor: Irish Clinical Research Group (ICORG).
NCT01726452 . Protocol 10-14. Date of registration 06/11/2012.
Oesophagectomy remains the only curative intervention for oesophageal cancer, with defined nutritional and health-related quality of life (HR-QOL) consequences. It follows therefore that there is a ...significant risk of decline in physical wellbeing with oesophagectomy however this has been inadequately quantified. This study prospectively examines change in physical functioning and habitual physical activity participation, from pre-surgery through 6-months post-oesophagectomy.
Patients scheduled for oesophagectomy with curative intent were recruited. Key domains of physical functioning including exercise tolerance (six-minute walk test (6MWT)) and muscle strength (hand-grip strength), and habitual physical activity participation, including sedentary behaviour (accelerometry) were measured pre-surgery (T0) and repeated at 1-month (T1) and 6-months (T2) post-surgery. HR-QOL was measured using the EORTC-QOL C30.
Thirty-six participants were studied (mean age 62.4 (8.8) years, n = 26 male, n = 26 transthoracic oesophagectomy). Mean 6MWT distance decreased significantly from T0 to T1 (p = 0.006) and returned to T0 levels between T1 and T2 (p < 0.001). Percentage time spent sedentary increased throughout recovery (p < 0.001) and remained significantly higher at T2 in comparison to T0 (p = 0.003). In contrast, percentage time spent engaged in either light or moderate-to-vigorous intensity activity, all reduced significantly (p < 0.001 for both) and remained significantly lower at T2 in comparison to T0 (p = 0.009 and p = 0.01 respectively). Patients reported deficits in multiple domains of HR-QOL during recovery including global health status (p = 0.04), physical functioning (p < 0.001) and role functioning (p < 0.001). Role functioning remained a clinically important 33-points lower than pre-operative values at T2.
Habitual physical activity participation remains significantly impaired at 6-months post-oesophagectomy. Physical activity is a measurable and modifiable target for physical rehabilitation, which is closely aligned with patient-reported deficits in role functioning. Rehabilitation aimed at optimising physical health in oesophageal cancer survivorship is warranted.
Abstract Esophageal adenocarcinoma (EAC) is the eighth most common cancer worldwide, and approximately 15% of patients survive 5 years. Reflux disease (GERD) and Barrett’s esophagus (BE) are major ...risk factors for the development of EAC, and epidemiologic studies highlight a strong association with obesity. The immune, inflammatory and intracellular signaling changes resulting from chronic inflammation of the esophageal squamous epithelium are increasingly well characterized. In GERD and Barrett’s, an essential role for T-cells in the initiation of inflammation in the esophagus has been identified, and a balance between T-cell responses and phenotype may play an important role in disease progression. Obesity is a chronic low-grade inflammatory state, fueled by adipose tissue derived- inflammatory mediators such as IL-6, TNF-α and leptin, representing a novel area for targeted research. Additionally, reactive oxygen species (ROS) and receptor tyrosine kinase (RTK) activation may drive progression from esophagitis to EAC, and downstream signaling pathways employed by these molecules may be important. This review will explain the diverse range of mechanisms potentially driving and maintaining inflammation within the esophagus and explore both existing and future therapeutic strategies targeting the process.
A new radio census of neutron star X-ray binaries van den Eijnden, J; Degenaar, N; Russell, T D ...
Monthly notices of the Royal Astronomical Society,
11/2021, Volume:
507, Issue:
3
Journal Article
Peer reviewed
Open access
ABSTRACT
We report new radio observations of a sample of 36 neutron star (NS) X-ray binaries, more than doubling the sample in the literature observed at current-day sensitivities. These sources ...include 13 weakly magnetized (B < 1010 G) and 23 strongly magnetized (B ≥ 1010 G) NSs. 16 of the latter category reside in high-mass X-ray binaries, of which only two systems were radio-detected previously. We detect four weakly and nine strongly magnetized NSs; the latter are systematically radio fainter than the former and do not exceed LR ≈ 3 × 1028 erg s−1. In turn, we confirm the earlier finding that the weakly magnetized NSs are typically radio fainter than accreting stellar-mass black holes. While an unambiguous identification of the origin of radio emission in high-mass X-ray binaries is challenging, we find that in all but two detected sources (Vela X-1 and 4U 1700-37) the radio emission appears more likely attributable to a jet than the donor star wind. The strongly magnetized NS sample does not reveal a global correlation between X-ray and radio luminosity, which may be a result of sensitivity limits. Furthermore, we discuss the effect of NS spin and magnetic field on radio luminosity and jet power in our sample. No current model can account for all observed properties, necessitating the development and refinement of NS jet models to include magnetic field strengths up to 1013 G. Finally, we discuss jet quenching in soft states of NS low-mass X-ray binaries, the radio non-detections of all observed very-faint X-ray binaries in our sample, and future radio campaigns of accreting NSs.
Background
Cardiopulmonary exercise testing (CPX) can objectively measure fitness and oxygen uptake at anaerobic threshold. The relationship between fitness and postoperative outcomes after upper ...gastro-intestinal surgery is unclear. The aim of the present review is to assess the prognostic ability of CPX in predicting postoperative outcome associated with oesophagogastric surgery.
Methods
Relevant studies were identified through a systematic search of EMBASE, Medline, CINAHL, Cochrane Library, and Web of Science to July 2019. The eligibility criteria for studies included prognostic studies of upper gastro-intestinal surgery among adult populations using a preoperative CPX and measurement of postoperative outcome (mortality or morbidity or length of stay). Risk of bias was assessed using the QUIPS Quality in Prognostic Studies validated tool.
Results
Thirteen papers with a total of 1735 participants were included in data extraction. A total of 7 studies examined the association between CPX variables and postoperative mortality. Patients undergoing gastro-intestinal surgery with lower anaerobic threshold values were found to have an increased risk of postoperative mortality. Similarly, a lower rate of oxygen consumption was found to be associated with higher mortality. There was conflicting evidence regarding the association between CPX variables and postoperative morbidity. The evidence did not demonstrate any association between preoperative CPX variables and hospital length of stay.
Conclusion
Studies report an association between CPX variables and postoperative mortality; however, there is conflicting evidence regarding the association between CPX variables and postoperative morbidity.
Background
Up to 40 per cent of patients undergoing oesophagectomy develop pneumonia. The aim of this study was to assess whether preoperative inspiratory muscle training (IMT) reduces the rate of ...pneumonia after oesophagectomy.
Methods
Patients with oesophageal cancer were randomized to a home‐based IMT programme before surgery or usual care. IMT included the use of a flow‐resistive inspiratory loading device, and patients were instructed to train twice a day at high intensity (more than 60 per cent of maximum inspiratory muscle strength) for 2 weeks or longer until surgery. The primary outcome was postoperative pneumonia; secondary outcomes were inspiratory muscle function, lung function, postoperative complications, duration of mechanical ventilation, length of hospital stay and physical functioning.
Results
Postoperative pneumonia was diagnosed in 47 (39·2 per cent) of 120 patients in the IMT group and in 43 (35·5 per cent) of 121 patients in the control group (relative risk 1·10, 95 per cent c.i. 0·79 to 1·53; P = 0·561). There was no statistically significant difference in postoperative outcomes between the groups. Mean(s.d.) maximal inspiratory muscle strength increased from 76·2(26·4) to 89·0(29·4) cmH2O (P < 0·001) in the intervention group and from 74·0(30·2) to 80·0(30·1) cmH2O in the control group (P < 0·001). Preoperative inspiratory muscle endurance increased from 4 min 14 s to 7 min 17 s in the intervention group (P < 0·001) and from 4 min 20 s to 5 min 5 s in the control group (P = 0·007). The increases were highest in the intervention group (P < 0·050).
Conclusion
Despite an increase in preoperative inspiratory muscle function, home‐based preoperative IMT did not lead to a decreased rate of pneumonia after oesophagectomy. Registration number: NCT01893008 (https://www.clinicaltrials.gov).
Increased muscle function, no better outcome
The incidence of esophageal adenocarcinoma has increased significantly in the western world over the last 20 yr. Most cases arise in a background of chronic gastroesophageal reflux, and specialized ...intestinal metaplasia in Barrett's esophagus is frequently an antecedent phenotype or evident in association with adenocarcinoma. The molecular events that characterize the pathway from inflammation to metaplasia to dysplasia and adenocarcinoma are poorly understood.
To examine the expression of the proinflammatory cytokines IL-8 and IL-1beta along the esophagitis, metaplasia, dysplasia, and adenocarcinoma pathway, and to correlate this with histological changes and expression of the transcription factor NF-kappaB.
Fresh biopsy specimens were collected from patients with reflux esophagitis (n=15), Barrett's esophagus (n=35), Barrett's adjacent to adenocarcinoma (n=8), and esophageal adenocarcinoma (n=35). IL-8 and IL-1beta expression were measured using enzyme-linked immunosorbent assay. NF-kappaB expression was measured by electrophoretic mobility shift assay.
Elevated expression of NF-kappaB was found in 2 (13%) out of 15 patients with reflux esophagitis, 21 (60%) out of 35 patients with Barrett's esophagus, and 28 (80%) out of 35 patients with esophageal adenocarcinoma. All 5 patients with Barrett's esophagus and high-grade dysplasia showed elevated expression of NF-kappaB. IL-8 and IL-1beta were significantly increased in esophagitis, Barrett's, and adenocarcinoma compared with squamous epithelium, and in adenocarcinoma compared with all other groups. There was a stepwise increase in the expression of IL-8, IL-1beta, and NF-kappaB from normal through Barrett's epithelium to adenocarcinoma in eight cases of esophageal adenocarcinoma. The levels of both IL-8 and IL-1beta in adenocarcinoma patients correlated with stage of disease. Patients with adenocarcinoma who were NF-kappaB positive had significantly higher levels of both IL-8 (p=0.04) and IL-1beta (p=0.03) compared to adenocarcinoma patients who were NF-kappaB negative.
The proinflammatory cytokines IL-8 and IL-1beta are elevated in esophagitis and Barrett's epithelium, and markedly elevated in adenocarcinoma. NF-kappaB activation is infrequent in esophagitis, but is increased in Barrett's epithelium and adenocarcinoma. The association of NF-kappaB activation with cytokine upregulation was only evident in patients with adenocarcinoma. These patterns may play an important role in Barrett's inflammation and tumourigenesis, and inhibition of the NF-kappaB/proinflammatory cytokine pathway may be an important target for future chemoprevention strategies.
Summary
The aim of this prospective cohort study is to analyze the impact of supplemental home enteral nutrition (HEN) post-esophageal cancer surgery on nutritional parameters, quality of life (QL), ...and patient satisfaction. A systematic review reported that over 60% of patients lose >10% of both body weight and BMI by 6 months after esophagectomy. Enteral feeding (EF) is increasingly a modern standard postoperatively; however, the impact of extended HEN postdischarge has not been systematically studied. One hundred forty-nine consecutive patients mean age 62 ± 9, 80% male,76% adenocarcinoma, 66% on multimodal protocols, and 69% with BMI ≥ 25 kg/m2 were studied. Jejunal EF commenced day 1 postoperatively, and supplemental overnight HEN (764 kcal; 32g protein) continued on discharge for a planned further 4 weeks. Weight, BMI, and body composition analysis (bioimpedance analysis) were measured at baseline, preoperatively and at 1, 3, and 6 months, along with the EORTC QLQ-C30/OES18 QL measures. A patient satisfaction questionnaire addressed eight key items in relation to HEN (max score 100/item). Median (range) total duration of EF was 49 days (28–96). Overall compliance was 96%. At 6 months, compared with preoperatively, 58 (39%) patients lost >10% weight, with median (IQR) loss of 6.8 (4–9) kg, and 62 (41%) patients lost >10% BMI. Lean body mass and body fat were significantly (p < 0.001) decreased. Mean global QL decreased (p < 0.01) from 82 to 72. A high mean satisfaction score (>70 ± 11/100) was reported, >80 for practical training, activities of daily living, pain, anxiety, recovery and impact on caregivers, with lower scores for appetite (33 ± 24) and sleep (63 ± 30). Supplemental HEN for a minimum of one month postdischarge is associated with high compliance and patient satisfaction. Weight and BMI loss may still be substantial, however this may be less than published literature, in addition the impact on HR-QL may be attenuated. HEN has both subjective and objective rationale and merits further validation toward optimizing nutritional recovery and overall wellbeing.
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