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Purpose To investigate whether eosinophils and other white blood cell subtypes could be used as response and prognostic markers to anti-Programmed cell Death-1 or anti-PD-Ligand-1 treatments in non-small cell lung cancer patients. Methods We retrospectively analyzed data from the NSCLC patients consecutively treated at our hospital with a PD-1/PD-L1 inhibitor in monotherapy for advanced disease. A total of 191 patients were evaluated at three time-points to investigate any relation between tumor response and WBC counts. Results Baseline WBC and subtypes did not differ according to the type of response seen under treatment. A higher relative eosinophil count (REC) correlated with more objective responses (p = 0.019 at t1 and p = 0.014 at t2; OR for progression = 0.54 and 0.53, respectively) independently of the smoking status, PD-L1 status, and immune-related toxicity (IRT). Higher REC was also associated with a longer duration of treatment (p = 0.0096). Baseline absolute neutrophil count was prognostic (p = 0.049). At t1 relative lymphocytes, absolute and relative neutrophils, and neutrophil-to-lymphocyte ratio were prognostic (p = 0.044, p = 0.014, p = 0.0033, and p = 0.029, respectively). Conclusion Our results show that in NSCLC patients anti-PD-1/PD-L1 therapy induces an early increase only in blood eosinophils, more prominent in responding patients and independent of the smoking status, PD-L1 status, and IRT. Eosinophils are also associated with a longer duration of treatment. Furthermore, our data support a prognostic role of neutrophils, lymphocytes, and their ratio for NSCLC patients with advanced disease treated with PD(L)-1 blockade., Author(s): A. Sibille [sup.1], M. Henket [sup.2], J. L. Corhay [sup.1], R. Alfieri [sup.3], R. Louis [sup.1], B. Duysinx [sup.1] Author Affiliations: (1) grid.411374.4, 0000 0000 8607 6858, Department of [...]

Background: Data on the long-term symptom burden in patients surviving oesophageal cancer surgery are scarce. The aim of this study was to identify the most prevalent symptoms and their interactions with health-related quality of life. Methods: This was a cross-sectional cohort study of patients who underwent oesophageal cancer surgery in 20 European centres between 2010 and 2016. Patients had to be disease-free for at least 1 year. They were asked to complete a 28-symptom questionnaire at a single time point, at least 1 year after surgery. Principal component analysis was used to assess for clustering and association of symptoms. Risk factors associated with the development of severe symptoms were identified by multivariable logistic regression models. Results: Of 1081 invited patients, 876 (81.0 per cent) responded. Symptoms in the preceding 6 months associated with previous surgery were experienced by 586 patients (66.9 per cent). The most common severe symptoms included reduced energy or activity tolerance (30.7 per cent), feeling of early fullness after eating (30.0 per cent), tiredness (28.7 per cent), and heartburn/acid or bile regurgitation (19.6 per cent). Clustering analysis showed that symptoms clustered into six domains: lethargy, musculoskeletal pain, dumping, lower gastrointestinal symptoms, regurgitation/reflux, and swallowing/conduit problems; the latter two were the most closely associated. Surgical approach, neoadjuvant therapy, patient age, and sex were factors associated with severe symptoms. Conclusion: A long-term symptom burden is common after oesophageal cancer surgery. [ABSTRACT FROM AUTHOR]

The purpose of this case-control study was to evaluate the impact of hybrid minimally invasive esophagectomy for cancer on surgical stress response and nutritional status. All 34 consecutive patients undergoing hybrid minimally invasive esophagectomy for cancer at our surgical unit between 2008 and 2013 were retrospectively compared with 34 patients undergoing esophagectomy with open gastric tubulization (open), matched for neoadjuvant therapy, pathological stage, gender and age. Demographic data, tumor features and postoperative course (including quality of life and systemic inflammatory and nutritional status) were compared. Postoperative course was similar in terms of complication rate. Length of stay in intensive care unit was shorter in patients undergoing hybrid minimally invasive esophagectomy ( P = 0.002). In the first postoperative day, patients undergoing hybrid minimally invasive esophagectomy had lower C-reactive protein levels ( P = 0.001) and white cell blood count ( P = 0.05), and higher albumin serum level ( P = 0.001). In this group, albumin remained higher also at third ( P = 0.06) and seventh ( P = 0.008) postoperative day, and C-reactive protein resulted lower at third post day ( P = 0.04). Hybrid minimally invasive esophagectomy significantly improved the systemic inflammatory and catabolic response to surgical trauma, contributing to a shorter length of stay in intensive care unit. [ABSTRACT FROM AUTHOR]

Our study aimed to identify the best prognostic score for fitness for surgery and postoperative morbidity in elderly patients. A prospectively collected database of a consecutive series of patients with esophageal cancer evaluated for possible esophagectomy at our unit was analyzed. Fitness for surgery and postoperative morbidity were used as measures of outcome. The performances of the Physiological and Operative Severity Score for the en Umeration of Mortality and morbidity ( POSSUM) score, the Charlson Comorbidity Index, the age-related Charlson Comorbidity Index ( ACCI), the American Society of Anesthesiologists scale and the prognostic nutritional index ( PNI) were evaluated in elderly patients. Discrimination was measured with receiver operating characteristics curve analysis; calibration was assessed by the Hosmer- Lemeshow goodness-of-fit test. Age did not result a significant predictor for postoperative complications. In elderly patients, ACCI predicted the judgment of the multidisciplinary team about fitness for surgery with the best discrimination ( C-index = 0.94). PNI had the best discrimination for postoperative complications ( C-index = 0.71) in the elderly group. ACCI best predicted the fitness for surgery in elderly patients. In elderly patients, the most discriminative prognostic score for postoperative complication was PNI, which could be used at admission for surgery to correctly inform patients about their risk and, possibly, to take extra precaution in case of high risk. [ABSTRACT FROM AUTHOR]

Background The aim of our study was to investigate the impact of esophagectomy for cancer on patients' occupational status. Methods All 109 consecutive patients presenting with esophageal cancer to the Surgical Oncology Unit of the Veneto Institute of Oncology Padua (Italy) between November 1, 2009 and March 15, 2012, were included in the study. Information on occupational status at diagnosis and at 1 year after esophagectomy was retrieved. Health-related quality of life was evaluated at discharge after surgery using selected aspects of the EORTC QLQ-C30 questionnaire. Non parametric statistics were used. Results Sixty-one patients (49.6%) were active workers at diagnosis and 50 of them (82.0%) underwent esophagectomy. Eighteen active workers (18/50, 36.0%) quit their job within one year from esophagectomy. They received jejunostomy more often than patients still working after surgery (50.0% vs. 18.8%, respectively; p = 0.03) and reported lower social functioning at discharge (mean ± SD 63.6 ± 16.4 vs. 80.2 ± 25.6 in others, p = 0.02). Multivariable analysis identified jejunostomy as independent predictor of job-quitting at 1 year after esophagectomy (p = 0.03; OR 4.75, 95% C.I. 1.11–20.39) but not social functioning at discharge (p = 0.21). Conclusions Patients should be informed that they may experience social and work disability due to cancer treatment and adequate interventions of return-to-work support should be provided. Adequate welfare strategy should be implemented for esophageal cancer survivors, enhancing their role competences and contributing to precision care medicine. [ABSTRACT FROM AUTHOR]

Background Several prognostic scores were designed in order to estimate the risk of postoperative adverse events. None of them includes a component directly associated to the nutritional status. The aims of the study were the evaluation of performance of risk-adjusted models for early outcomes after oesophagectomy and to develop a score for severe complication prediction with special consideration regarding nutritional status. Methods A comparison of POSSUM and Charlson score and their derivates, ASA, Lagarde score and nutritional index (PNI) was performed on 167 patients undergoing oesophagectomy for cancer. A logistic regression model was also estimated to obtain a new prognostic score for severe morbidity prediction. Results Overall morbidity was 35.3% (59 cases), severe complications (grade III–V of Clavien–Dindo classification) occurred in 20 cases. Discrimination was poor for all the scores. Multivariable analysis identified pulse, connective tissue disease, PNI and potassium as independent predictors of severe morbidity. This model showed good discrimination and calibration. Internal validation using standard bootstrapping techniques confirmed the good performance. Conclusions Nutrition could be an independent risk factor for major complications and a nutritional status coefficient could be included in current prognostic scores to improve risk estimation of major postoperative complications after oesophagectomy for cancer. [ABSTRACT FROM AUTHOR]

In Jurkat cells, the decreased cell growth rate associated with a long-lasting deactivation of the mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (S6K)-signaling pathway generates a cell population of progressively reduced cellular mass and size. When promoted by rapamycin as prototype inhibitor, the mTOR deactivation-dependent cell size reduction was associated with slowed, but not suppressed, proliferation. Small-size cells were significantly protected from apoptosis induced by Fas/Apo-1 death-receptor activation (as shown by reduced procaspase cleavage and decreased catalytic activity of relevant caspases) or by stress signals-dependent mitochondrial perturbation (as shown by reduced cleavage of caspase-2, lower dissipation of mitochondrial membrane potential and decreased release of cytochorome c and apoptosis-inducing factor from mitochondria). Protection faded when reactivation of the mTOR/S6K pathway promoted the cell recovery to normal size. These results suggest that cells induced to reduce their mass by the mTOR deactivation-dependent inhibition of cell growth become more resilient to lethal assaults by curbing the cell's suicidal response.Cell Death and Differentiation (2005) 12, 1344–1357. doi:10.1038/sj.cdd.4401660; published online 20 May 2005 [ABSTRACT FROM AUTHOR]

Objective: To evaluate prognostic differences between minimally invasive esophagectomy (MIE) and open esophagectomy (OE) in patients with surgery after a prolonged interval (>12 wk) following chemoradiotherapy (CRT)., Background: Previously, we established that a prolonged interval after CRT before esophagectomy was associated with poorer long-term survival., Methods: This was an international multicenter cohort study involving 17 tertiary centers, including patients who received CRT followed by surgery between 2010 and 2020. Patients undergoing MIE were defined as thoracoscopic and laparoscopic approaches., Results: A total of 428 patients (145 MIE and 283 OE) had surgery between 12 weeks and 2 years after CRT. Significant differences were observed in American Society of Anesthesiologists grade, radiation dose, clinical T stage, and histologic subtype. There were no significant differences between the groups in age, sex, body mass index, pathologic T or N stage, resection margin status, tumor location, surgical technique, or 90-day mortality. Survival analysis showed MIE was associated with improved survival in univariate ( P =0.014), multivariate analysis after adjustment for smoking, T and N stage, and histology (HR=1.69; 95% CI: 1.14-2.5) and propensity-matched analysis ( P =0.02). Further subgroup analyses by radiation dose and interval after CRT showed survival advantage for MIE in 40 to 50 Gy dose groups (HR=1.9; 95% CI: 1.2-3.0) and in patients having surgery within 6 months of CRT (HR=1.6; 95% CI: 1.1-2.2)., Conclusions: MIE was associated with improved overall survival compared with OE in patients with a prolonged interval from CRT to surgery. The mechanism for this observed improvement in survival remains unknown, with potential hypotheses including a reduction in complications and improved functional recovery after MIE., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Radical esophagectomy, including thoracic duct resection (TDR), has been proposed to improve regional lymphadenectomy and possibly reduce the risk of locoregional recurrence. However, because of its impact on immunoregulation, some authors have expressed concerns about its possible detrimental effect on long-term survival. The purpose of this review was to assess the influence of TDR on long-term survival., Patients and Methods: PubMed, MEDLINE, Scopus, and Web of Science databases were searched through 15 March 2024. Overall survival (OS), cancer specific survival (CSS), and disease-free survival (DFS) were primary outcomes. Restricted mean survival time difference (RMSTD), risk ratio (RR), standardized mean difference (SMD), and 95% confidence intervals (CI) were used as pooled effect size measures. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology was employed to evaluate the certainty of evidence., Results: The analysis included six studies with 5756 patients undergoing transthoracic esophagectomy. TDR was reported in 49.1%. Patients' ages ranged from 27 to 79 years and 86% were males. At 4-year follow-up, the multivariate meta-analysis showed similar results for the comparison noTDR versus TDR in term of OS [- 0.8 months, 95% confidence interval (CI) - 3.1, 1.3], CSS (0.1 months, 95% CI - 0.9, 1.2), and DFS (1.5 months, 95% CI - 2.6, 5.5). TDR was associated with a significantly higher number of harvested mediastinal lymph nodes (SMD 0.57, 95% CI 0.01-1.13) and higher risk of postoperative chylothorax (RR = 1.32; 95% CI 1.04-2.23). Anastomotic leak and pulmonary complications were comparable., Conclusions: TDR seems not to improve long-term OS, CSS, and DFS regardless of tumor stage. Routine TDR should not be routinely recommended during esophagectomy., (© 2024. Society of Surgical Oncology.)

Osimertinib, a tyrosine kinase inhibitor targeting mutant EGFR, has received approval for initial treatment in patients with Non-Small Cell Lung Cancer (NSCLC). While effective in both first- and second-line treatments, patients eventually develop acquired resistance. Metabolic reprogramming represents a strategy through which cancer cells may resist and adapt to the selective pressure exerted by the drug. In the current study, we investigated the metabolic adaptations associated with osimertinib-resistance in NSCLC cells under low glucose culture conditions. We demonstrated that, unlike osimertinib-sensitive cells, osimertinib-resistant cells were able to survive under low glucose conditions by increasing the rate of glucose and glutamine uptake and by shifting towards mitochondrial metabolism. Inhibiting glucose/pyruvate contribution to mitochondrial respiration, glutamine deamination to glutamate, and oxidative phosphorylation decreased the proliferation and survival abilities of osimertinib-resistant cells to glucose starvation. Our findings underscore the remarkable adaptability of osimertinib-resistant NSCLC cells in a low glucose environment and highlight the pivotal role of mitochondrial metabolism in mediating this adaptation. Targeting the metabolic adaptive responses triggered by glucose shortage emerges as a promising strategy, effectively inhibiting cell proliferation and promoting cell death in osimertinib-resistant cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The approval of immune checkpoint inhibitors (ICIs) has revolutionized the management of metastatic renal cell carcinoma (RCC), introducing several ICI-based combinations as the new standard of care for affected patients. Nonetheless, monotherapy with antiangiogenic tyrosine kinase inhibitors (TKIs), such as pazopanib or sunitinib, still represents a first-line treatment option for selected patients belonging to the favorable risk group according to the International mRCC Database Consortium (IMDC) model. After TKI monotherapy, the main second-line option is represented by ICI monotherapy with the anti-Programmed Death Receptor 1(PD-1) nivolumab. To date, the expected clinical outcomes are similar with pazopanib or sunitinib and there is no clear indication for selecting one TKI over the other. Moreover, their impact on subsequent ICI treatment outcomes is not well defined, yet. Based on these premises, we investigated the immunomodulatory activity of these drugs in vitro and in vivo.Both TKIs induced Programmed Cell Death Ligand-1 (PD-L1) expression and soluble PD-L1 release in RCC cells, and hampered T cell activation, reducing cytokine production and the proportion of activated T cells. Nevertheless, in a syngeneic co-culture system with peripheral blood mononuclear cells (PBMCs) and tumor cells, incubation with anti-PD-1 antibody following TKIs treatment significantly restored T cell function, potentiating the cytotoxic effects against tumor cells. Pazopanib and sunitinib followed by anti-PD-1 antibody produced a comparable inhibition of tumor growth in a RCC syngeneic mouse model. Our findings suggest that pazopanib and sunitinib, showing similar immunomodulatory effects, may have a comparable impact on the subsequent effectiveness of PD-1/PD-L1 blockade., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pier Giorgio Petronini received institutional research grant from Novartis Farma S.p.A. Sebastiano Buti received honoraria as a speaker at scientific events and advisory role by Bristol-Myers Squibb (BMS), Merck, Pfizer, MSD, Ipsen, Roche, Eli-Lilly, Pierre-Fabre, AstraZeneca and Novartis; he also received research funding from Novartis and Pfizer. The remaining authors have not conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)