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Distinct Stromal and Immune Features Collectively Contribute to Long-Term Survival in Pancreatic Cancer.
No full textThe aggressive biology and treatment refractory nature of pancreatic ductal adenocarcinoma (PDAC) significantly limits long-term survival. Examining the tumor microenvironment (TME) of long-term survivors (LTS) of PDAC offers the potential of unveiling novel biological insights and therapeutic targets. We performed an integrated approach involving immunophenotyping, stromal scoring and histomorphological profiling of a cohort of 112 PDAC-cases, including 25 long-term survivors (LTSs, OS ≥ 60 months). Mutational frequencies were assessed using targeted next generation sequencing. Finally, we validated our findings using an external cohort of microarray data from PDAC patients. LTS cases exhibit a largely quiescent population of cancer-associated fibroblasts (CAFs). Immune profiling revealed key differences between LTS and NON-LTS cases in the intratumoral and stromal compartments. In both compartments, LTS cases exhibit a T cell inflamed profile with higher density of CD3 T cells, CD4 T cells, iNOS leukocytes and strikingly diminished numbers of CD68 total macrophages, CD163 (M2) macrophages and FOXP3 Tregs. A large proportion of LTS cases exhibited tertiary lymphoid tissue (TLT) formation, which has been observed to be a positive prognostic marker in a number of tumor types. Using a Random-Forest variable selection approach, we identified the density of stromal iNOS cells and CD68 cells as strong positive and negative prognostic variables, respectively. In an external cohort, computational cell-type deconvolution revealed a higher abundance of T cells, B lymphocytes and dendritic cells (DCs) in patients with long-term OS compared to short-term survivors. Thus, profiling of long-term survivors in an external cohort, strongly corroborated the T cell-inflamed TME observed in our LTS group. Collectively, our findings highlight the prognostic importance of TME profiles in PDAC, underlining the crucial role of tumor associated macrophages (TAMs) and the potential interdependence between immunosuppressive TAMs and activated CAFs in pancreatic cancer. Additionally, our data has potential for precision medicine and patient stratification. Patients with a T cell inflamed TME might derive benefit from agonistic T cell antibodies (e.g., OX40 or CD137 agonists). Alternately, patients with activated CAFs and high infiltration of immunosuppressive TAMs are highly likely to exhibit therapeutic responses to macrophage targeted drugs (e.g., anti-CSF1R) and anti-CAF agents
Resting cardiac sympathetic firing frequencies suppress terminal norepinephrine transporter uptake.
No full textThe prejunctional norepinephrine transporter (NET) is responsible for the clearance of released norepinephrine (NE) back into the sympathetic nerve terminal. NET regulation must be tightly controlled as variations could have important implications for neurotransmission. Thus far, the effects of sympathetic neuronal activity on NET function have been unclear. Here, we optically monitor single-terminal cardiac NET activity ex vivo in response to a broad range of sympathetic postganglionic action potential (AP) firing frequencies. Isolated murine left atrial appendages were loaded with a fluorescent NET substrate [Neurotransmitter Transporter Uptake Assay (NTUA)] and imaged with confocal microscopy. Sympathetic APs were induced with electrical field stimulation at 0.2-10 Hz (0.1-0.2 ms pulse width). Exogenous NE was applied during the NTUA uptake- and washout phases to investigate substrate competition and displacement, respectively, on transport. Single-terminal NET reuptake rate was rapidly suppressed in a frequency-dependent manner with an inhibitory EF of 0.9 Hz. At 2 Hz, the effect was reversed by the α-adrenoceptor antagonist yohimbine (1 μM) (p < 0.01) with no further effect imposed by the muscarinic receptor antagonist atropine (1 μM). Additionally, high exogenous NE concentrations abolished NET reuptake (1 μM NE; p < 0.0001) and displaced terminal specific NTUA during washout (1-100 μM NE; p < 0.0001). We have also identified α-adrenoceptor-induced suppression of NET reuptake rate during resting stimulation frequencies, which could oppose the effect of autoinhibition-mediated suppression of exocytosis and thus amplify the effects of sympathetic drive on cardiac function
Radical surgery versus organ preservation for early-stage rectal cancer - Authors' reply.
No full textNew dimensions for hospital services and early detection of disease: a Review from the Lancet Commission into liver disease in the UK.
No full textThis Review, in addressing the unacceptably high mortality of patients with liver disease admitted to acute hospitals, reinforces the need for integrated clinical services. The masterplan described is based on regional, geographically sited liver centres, each linked to four to six surrounding district general hospitals-a pattern of care similar to that successfully introduced for stroke services. The plan includes the establishment of a lead and deputy lead clinician in each acute hospital, preferably a hepatologist or gastroenterologist with a special interest in liver disease, who will have prime responsibility for organising the care of admitted patients with liver disease on a 24/7 basis. Essential for the plan is greater access to intensive care units and high-dependency units, in line with the reconfiguration of emergency care due to the COVID-19 pandemic. This Review strongly recommends full implementation of alcohol care teams in hospitals and improved working links with acute medical services. We also endorse recommendations from paediatric liver services to improve overall survival figures by diagnosing biliary atresia earlier based on stool colour charts and better caring for patients with impaired cognitive ability and developmental mental health problems. Pilot studies of earlier diagnosis have shown encouraging progress, with 5-6% of previously undiagnosed cases of severe fibrosis or cirrhosis identified through use of a portable FibroScan in primary care. Similar approaches to the detection of early asymptomatic disease are described in accounts from the devolved nations, and the potential of digital technology in improving the value of clinical consultation and screening programmes in primary care is highlighted. The striking contribution of comorbidities, particularly obesity and diabetes (with excess alcohol consumption known to be a major factor in obesity), to mortality in COVID-19 reinforces the need for fiscal and other long delayed regulatory measures to reduce the prevalence of obesity. These measures include the food sugar levy and the introduction of the minimum unit price policy to reduce alcohol consumption. Improving public health, this Review emphasises, will not only mitigate the severity of further waves of COVID-19, but is crucial to reducing the unacceptable burden from liver disease in the UK
ASO Author Reflections: Postoperative Chemotherapy After Neoadjuvant Therapy and Pancreatectomy for Pancreatic Cancer: Balancing Patient Physiology and Disease Biology.
No full textPulmonary function and COVID-19.
No full textIn people recovering from COVID-19, there is concern regarding potential long-term pulmonary sequelae and associated impairment of functional capacity. Data published thus far indicate that spirometric indices appear to be generally well preserved, but that a defect in diffusing capacity (DLco) is a prevalent abnormality identified on follow-up lung function; present in 20-30% of those with mild to moderate disease and 60% in those with severe disease. Reductions in total lung capacity were commonly reported. Functional capacity is also often impaired, with data now starting to emerge detailing walk test and cardiopulmonary exercise test outcome at follow-up. In this review, we evaluate the published evidence in this area, to summarise the impact of COVID-19 infection on pulmonary function and relate this to the clinico-radiological findings and disease severity
The utility of arterial blood gas parameters and chest radiography in predicting appropriate intubations in burn patients with suspected inhalation injury-A retrospective cohort study.
No full textBACKGROUND
This study evaluates the utility of arterial blood gas (ABG) parameters and chest radiography in predicting intubation need in patients with burn injuries with suspected inhalation injury.
METHODS
Patients with suspected inhalation injury admitted to a single centre, Burn Intensive Care Unit, between April 4th 2016 and July 5th 2019, were included. Admission ABG parameters and chest radiograph opacification were compared with whether the patient received an appropriate intubation: defined as intubation for a duration of over 48 h. Area under the receiver operator characteristic curve was calculated (AUROC).
RESULTS
Eighty-nine patients were included. The majority (84%; n = 75) were intubated, of which 81% (n = 61) received appropriate intubations. pH had an AUROC of 0.88 and a pH of <7.30 had an 80% sensitivity and specificity for detecting appropriate intubation. P/F ratio had an AUROC of 0.81 and a P/F ratio of <40 had a 70% sensitivity and specificity for appropriate intubation. Chest radiograph opacification had poor utility in this regard (AUROC = 0.69). Adding pH and P/F ratio to the ABA criteria improved their sensitivity in detecting appropriate intubations (sensitivity: ABA + pH + P/F = 0.97 vs ABA = 0.86; p = 0.013), without altering their specificity.
CONCLUSIONS
In patients suspected inhalation injury, pH and P/F ratio were good predictors for appropriate intubations. Incorporating the parameters into the ABA criteria improved their clinical utility
Elderly patients have increased perioperative morbidity and mortality from oesophagectomy for oesophageal cancer: A systematic review and meta-analysis.
No full textBACKGROUND
Although oesophagectomy remains technically challenging and associated with high morbidity and mortality, it is now increasingly performed in an ever-ageing population with improvement in perioperative care. However, the risks in the elderly population are poorly quantified. The study aims to review the current evidence to quantify further the postoperative risk of oesophagectomy for cancer in the elderly population compared to younger patients.
METHOD
A systematic literature search of PubMed, EMBASE and the Cochrane Library databases was conducted including studies reporting oesophagectomy for cancer in the elderly population. A meta-analysis was reported in accordance with the recommendations of the Cochrane Library and PRISMA guidelines. Primary outcome was overall complications and secondary outcomes were pulmonary and cardiac complications, anastomotic leaks, overall and disease-free survival.
RESULTS
This review identified 37 studies incorporating 30,836 patients. Increasing age was significantly associated with increased rates of overall complications (OR 1.67, CI: 1.42-1.96), pulmonary complications (OR 1.87, CI: 1.48-2.35), and cardiac complications (OR: 2.22, CI: 1.95-2.53). However, there was no increased risk of anastomotic leak (OR: 0.98, CI: 0.85-1.18). Elderly patients were significantly more likely to have lower rates of 5-year overall survival (OR: 1.36, CI: 1.11-1.66) and 5-year disease-free survival (OR: 1.72, CI: 1.51-1.96).
CONCLUSION
Elderly patients undergoing oesophagectomy for cancer are at increased risk of overall, pulmonary and cardiac complications, irrespective of age subgroups, albeit no difference in anastomotic leaks. Therefore, they represent high-risk patients warranting implementation of preoperative pathways such as prehabilitation to improve cardiopulmonary fitness prior to surgery, although benefit of prehabilitation is yet to be proven. This information will also aid future pre-operative counselling and informed consent