RET-MAP: An International Multicenter Study on Clinicobiologic Features and Treatment Response in Patients With Lung Cancer Harboring a RET Fusion.

INTRODUCTION: Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. METHODS: This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. RESULTS: For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1-4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%-55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7-72.1] versus 16.3 mo [12.7-28.8], p < 0.0001). CONCLUSIONS: Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients.

Thymoma and thymic carcinoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Thymic tumors are epithelial tumors arising from the anterior mediastinum and constitute 0.2-1.5% of all adult malignancies but are exceptional in pediatric population. Thymic epithelial tumors (TETs) encompass a variety of histologic subtypes associated with different clinical outcomes. Due to its rarity in children, TETs' management requires a multidisciplinary approach. However, prognosis remains still poor, especially among patients with thymic carcinoma. This study presents the internationally recognized recommendations for the diagnosis and treatment of thymic tumors in children and adolescents, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) group within the EU-funded project Paediatric Rare Tumours Network - European Registry (PARTNER).

Thenar oxygen saturation (StO2) alterations during a spontaneous breathing trial predict extubation failure.

BACKGROUND: Weaning from mechanical ventilation (MV) is a cardiovascular stress test. Monitoring the regional oxygenation status has shown promising results in predicting the tolerance to spontaneously breathe in the process of weaning from MV. Our aim was to determine whether changes in skeletal muscle oxygen saturation (StO2) measured by near-infrared spectroscopy (NIRS) on the thenar eminence during a vascular occlusion test (VOT) can be used to predict extubation failure from mechanical ventilation. METHODS: We prospectively studied 206 adult patients with acute respiratory failure receiving MV for at least 48 h from a 30-bed mixed ICU, who were deemed ready to wean by their physicians. Patients underwent a 30-min spontaneous breathing trial (SBT), and were extubated according to the local protocol. Continuous StO2 was measured non-invasively on the thenar eminence. A VOT was performed prior to and at 30 min of the SBT (SBT30). The rate of StO2 deoxygenation (DeO2), StO2 reoxygenation (ReO2) rate and StO2 hyperemic response to ischemia (HAUC) were calculated. RESULTS: Thirty-six of the 206 patients (17%) failed their SBT. The remainder 170 patients (83%) were extubated. Twenty-three of these patients (13.5%) needed reinstitution of MV within 24 h. Reintubated patients displayed a lower HAUC at baseline, and higher relative changes in their StO2 deoxygenation rate between baseline and SBT30 (DeO2 Ratio). A logistic regression-derived StO2 score, combining baseline StO2, HAUC and DeO2 ratio, showed an AUC of 0.84 (95% CI 0.74-0.91) for prediction of extubation failure. CONCLUSIONS: Extubation failure was associated to baseline and dynamic StO2 alterations during the SBT. Monitoring StO2-derived parameters might be useful in predicting extubation outcome.

Impact of hemoperfusion with polymyxin B added to hemofiltration in patients with endotoxic shock: a case-control study.

BACKGROUND: Septic shock is a leading cause of death in critical patients. In patients with gram-negative septic shock, hemoperfusion with polymyxin B aims to remove endotoxins from plasma. We analyzed the clinical and biological response to hemoperfusion in patients with septic shock and acute kidney injury. METHODS: This prospective case-control study in the medical-surgical intensive care unit of a university hospital included consecutive adults patients with septic shock and suspected gram-negative bacteria infection with elevated plasma endotoxin activity (EAA > 0.6 EU/ml) and acute kidney injury requiring continuous renal replacement therapy (CRRT). At onset of septic shock, half underwent CRRT plus hemoperfusion with polymyxin B for two hours a day during two consecutive days (hemoperfusion group) and half received only CRRT (control group). We measured clinical, physiological, and biological parameters (EAA, C-reactive protein, procalcitonin, and cytokines) daily during the first 5 days. RESULTS: We included 18 patients (male, 33%; mean age, 67.5; mean SOFA score, 11.3). Abdominal infections predominated (50% had peritonitis). At the beginning of CRRT, RIFLE classification was "failure" for 72% and "injury" for 28%. Baseline characteristics did not differ between groups. Patients in the hemoperfusion group required longer mechanical ventilation (12.4 vs. 9.4 days, p = 0.03) and CRRT (8.5 vs. 6 days, p = 0.01) than in the control group. Noradrenaline doses, lactate, procalcitonin, and C-reactive protein decreased in both groups. At day 5, EAA was significantly lower in the hemoperfusion group (0.58 EU/ml vs. 0.73 EU/ml in controls, p = 0.03). There were no significant differences between groups in other biomarkers or ICU mortality (33.3% in the treatment group vs. 44.4% in the control group, p = 0.5). No adverse effects of hemoperfusion were observed. CONCLUSIONS: Hemoperfusion with polymyxin B added to CRRT resulted in faster decrease in endotoxin levels, but we observed no improvements in clinical, physiological, or biological parameters.

Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.

Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry.

Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.

Operational evaluation of the earlobe arterialized blood collector in critically ill patients.

BACKGROUND: The new Earlobe Arterialized Blood Collector (EABC®) is a minimally invasive prototype system able to perform capillary blood collection from the earlobe (EL) with minimal training and risk. This system could improve medical emergency management in extreme environments. Consequently, a prospective validation study was designed to evaluate operational performance of the EABC® in a cohort of critically ill patients. METHODS: Arterialized capillary blood was sampled from the EL of 55 invasively ventilated patients using the EABC® following a validated procedure. Operational characteristics such as the number of cuts and cartridges required, sampling failure/success ratio, bleeding complications, storage requirements and other auxiliary aspects were recorded. Result turnaround laboratory times (TAT) were compared with published references. RESULTS: Blood collection was as easily performed on one earlobe as the other. Twenty-six minutes (mean 25.8; SD = 3.8) were required to obtain results, 15 min for patient preparation (mean 15.3; SD = 2.6) + 11 min for sampling and analysis (mean 11.4; SD = 2.1), which is similar to published hospital reference laboratory TAT. The average number of cartridges required was 1.3 (1-3; mode = 1) with the mean number of cut attempts being 1.2 (1-4; mode = 1). Problems/difficulties occurred in 59% of cases but were mainly attributed to patient's demographic characteristics, with only 10% attributable to the collector (superficial cut, blood leak, collector misalignment and obstructed vision). Haemostasis was quickly achieved with minimum complications. Storage of the complete sampling kit required a 300 × 300 × 300 mm box. Two 9-V batteries were used during the 2-year study period. CONCLUSIONS: The new EABC® system concept is safe, fast and easy to use. Observed problems/difficulties are easily amendable with certain design modifications. Definitive versions of the prototype have the potential for significant benefits for isolated and extreme environments in medicine.

Earlobe arterialized capillary blood gas analysis in the intensive care unit: a pilot study.

BACKGROUND: Earlobe arterialized capillary blood gas analysis can be used to estimate arterial gas content and may be suitable for diagnosis and management of critically ill patients. However, its utility and applicability in the ICU setting remains unexplored. METHODS: A prospective observational validation study was designed to evaluate this technique in a cohort of mechanically ventilated adult critically ill patients admitted to a polyvalent ICU. Precision and agreement between capillary gas measures and arterial references was examined. Acute Respiratory Distress Syndrome (ARDS) diagnosis capabilities with the proposed technique were also evaluated. Finally, factors associated with sampling failure were explored. RESULTS: Fifty-five patients were included into this study. Precision of capillary samples was high (Coefficient of Variation PO2 = 9.8%, PCO2 = 7.7%, pH = 0.3%). PO2 measures showed insufficient agreement levels (Concordance Correlation Coefficient = 0.45; bias = 12 mmHg; percentage of error = 19.3%), whereas better agreement was observed for PCO2 and pH (Concordance Correlation Coefficient = 0.94 and 0.93 respectively; depreciable bias; percentage of error 11.4% and 0.5% respectively). The sensitivity and specificity for diagnosing ARDS were 100% and 92.3% using capillary gasometric measures. Sampling was unsuccessful in 43.6% of cases due to insufficient blood flow. Age > 65 years was independently associated with failure (odds ratio = 1.6), however hemodynamic failure and norepinephrine treatment were also influencing factors. CONCLUSIONS: Earlobe capillary blood gas analysis is precise and can be useful for detecting extreme gasometrical values. Diagnosis of ARDS can be done accurately using capillary measurements. Although this technique may be insufficient for precise management of patients in the ICU, it has the potential for important benefits in the acute phase of various critical conditions and in other critical care arenas, such as in emergency medicine, advanced medical transport and pre-hospital critical care.

Thenar oxygen saturation during weaning from mechanical ventilation: an observational study.

Our aim was to determine whether thenar tissue oxygen saturation (S(tO2)), measured by noninvasive near-infrared spectroscopy, and its changes derived from an ischaemic challenge are associated with weaning outcome. Our study comprised a prospective observational study in a 26-bed medical-surgical intensive care unit. Patients receiving mechanical ventilation for >48 h, and considered ready to wean by their physicians underwent a 30-min weaning trial. S(tO2) was measured continuously on the thenar eminence. A transient vascular occlusion test was performed prior to and at the end of the 30-min weaning trial, in order to obtain S(tO2) deoxygenation and reoxygenation rates, and estimated local oxygen consumption. 37 patients were studied. Patients were classified as weaning success (n=24) or weaning failure (n=13). No significant demographic, respiratory or haemodynamic differences were observed between the groups at inclusion. Patients who failed the overall weaning process showed a significant increase in deoxygenation and in local oxygen consumption from baseline to 30 min of weaning trial, whereas no significant changes were observed in the weaning success group. Failure to wean from mechanical ventilation was associated with higher relative increases in deoxygenation after 30 min of spontaneous ventilation.

Near-infrared spectroscopy StO2 monitoring to assess the therapeutic effect of drotrecogin alfa (activated) on microcirculation in patients with severe sepsis or septic shock.

BACKGROUND: Sepsis is a leading cause of death despite appropriate management. There is increasing evidence that microcirculatory alterations might persist independently from macrohemodynamic improvement and are related to clinical evolution. Future efforts need to be directed towards microperfusion monitoring and treatment. This study explored the utility of thenar muscle oxygen saturation (StO2) and its changes during a transient vascular occlusion test (VOT) to measure the microcirculatory response to drotrecogin alfa (activated) (DrotAA) in septic patients. METHODS: A prospective, observational study was performed in three general intensive care units at three university hospitals. We studied 58 patients with recent onset of severe sepsis or septic shock and at least two organ dysfunctions. Thirty-two patients were treated with DrotAA and 26 were not treated because of formal contraindication. StO2 was monitored using near-infrared spectroscopy (NIRS), and VOT was performed to obtain deoxygenation (DeOx) and reoxygenation (ReOx) slopes. Measurements were obtained before DrotAA was started and were repeated daily for a 96-hour period. RESULTS: Patients' characteristics, outcome, severity, and baseline values of StO2, DeOx, and ReOx did not differ between groups. Treated patients significantly improved DeOx and ReOx values over time, whereas control patients did not. In treated patients, ReOx improvements were correlated to norepinephrine dose reductions. Early clinical response (SOFA improvement after 48 hours of treatment) was not associated to changes in VOT-derived slopes. In the treated group, the relative improvement of DeOx within 48 hours was able to predict mortality (AUC 0.91, p < 0.01). CONCLUSIONS: In patients with severe sepsis or septic shock, DrotAA infusion was associated with improvement in regional tissue oxygenation. The degree of DeOx amelioration after 2 days in treated patients predicted mortality with high sensitivity and specificity. Thus, StO2 derived variables might be useful to evaluate the microcirculatory response to treatment of septic shock.

Thenar oxygen saturation and invasive oxygen delivery measurements in critically ill patients in early septic shock.

This prospective study was aimed to test the hypothesis that tissue hemoglobin oxygen saturation (StO2) measured noninvasively using near-infrared spectroscopy is a reliable indicator of global oxygen delivery (DO2) measured invasively using a pulmonary artery catheter (PAC) in patients with septic shock. The study setting was a 26-bed medical-surgical intensive care unit at a university hospital. Subjects were adult patients in septic shock who required PAC hemodynamic monitoring for resuscitation. Interventions included transient ischemic challenge on the forearm. After blood pressure normalization, hemodynamic and oximetric PAC variables and, simultaneously, steady-state StO2 and its changes from ischemic challenge (deoxygenation and reoxygenation rates) were measured. Fifteen patients were studied. All the patients had a mean arterial pressure above 65 mmHg. The DO2 index (iDO2) range in the studied population was 215 to 674 mL O2/min per m. The mean mixed venous oxygen saturation value was 61% ± 10%, mean cardiac index was 3.4 ± 0.9 L/min per m, and blood lactate level was 4.6 ± 2.7 mmol/L. Steady-state StO2 significantly correlated with iDO2, arterial and venous O2 content, and O2 extraction ratio. A StO2 cutoff value of 75% predicted iDO2 below 450, with a sensitivity of 0.9 and a specificity of 0.9. In patients in septic shock and normalized MAP, low StO2 reflects extremely low iDO2. Steady-state StO2 does not correlate with moderately low iDO2, indicating poor sensitivity of StO2 to rule out hypoperfusion.

Low reticulocyte hemoglobin content is associated with a higher blood transfusion rate in critically ill patients: a cohort study.

BACKGROUND: Intensive care unit (ICU) patients often need blood transfusion, but no reliable predictors of transfusion requirements are available at ICU admission. The authors hypothesized that ICU patients with functional iron deficiency may be at higher risk for developing anemia, requiring blood transfusion. Their objective was to determine whether low reticulocyte hemoglobin content (CHr) was associated with transfusion requirements in ICU patients. METHODS: This is a prospective cohort study in a general ICU. The authors studied 62 patients, after excluding those transfused on or before ICU admission. The authors recorded age, diagnosis, severity score, presence of sepsis, ICU complications, ICU treatments, and transfusion-free interval. Threshold for low CHr was 29 pg. The authors also recorded ICU and hospital outcome. The statistical analysis included Cox proportional hazard function for transfusion. RESULTS: Twenty-three patients (37%) presented with low CHr on ICU admission and tended to be sicker and more likely to have sepsis than those with normal CHr. They were also more prone to complications, particularly acute renal failure (39 vs. 13% P = 0.02) and ICU-acquired infection (30 vs. 10% P = 0.04). The overall transfusion rate was 22.6%, being higher in low-CHr patients than in normal-CHr patients (39.1 vs. 12.8%, P = 0.02). After adjusting for severity of illness, age, trauma, and hemoglobin level, low CHr remained significantly associated with transfusion, with a hazard ratio of 3.6 (95% CI, 1.2-10.7; P = 0.02). Median ICU stay was also longer in patients with low CHr (8 vs. 5 days, P = 0.01). Differences in mortality did not reach statistical significance. CONCLUSION: Low CHr is common at ICU admission and is associated with higher transfusion requirements.

Thenar oxygen saturation measured by near infrared spectroscopy as a noninvasive predictor of low central venous oxygen saturation in septic patients.

OBJECTIVE: To validate thenar oxygen saturation (StO(2)) measured by near-infrared spectroscopy (NIRS) as a noninvasive estimation of central venous saturation (ScvO(2)) in septic patients. DESIGN: Prospective observational study. SETTING: A 26-bed medical-surgical intensive care unit at a university-affiliated hospital. PATIENTS: Patients consecutively admitted to the ICU in the early phase of severe sepsis and septic shock, after normalization of blood pressure with fluids and/or vasoactive drugs. MEASUREMENTS: We recorded demographic data, severity score, hemodynamic data, and blood lactate, as well as ScvO(2), and StO(2) measured simultaneously on inclusion. Patients were divided into two groups according to ScvO(2) values: group A, with ScvO(2) < 70%, and group B, with ScvO(2) > or = 70%. RESULTS: Forty patients were studied. StO(2) was significantly lower in group A than in group B (74.7 +/- 13.0 vs. 83.3 +/- 6.2, P 0.018). No differences in age, severity score, hemodynamics, vasoactive drugs, or lactate were found between groups. Simultaneously measured ScvO(2) and StO(2) showed a significant Pearson correlation (r = 0.39, P 0.017). For a StO(2) value of 75%, sensitivity was 0.44, specificity 0.93, positive predictive value 0.92, and negative predictive value 0.52 for detecting ScvO(2) values lower than 70%. CONCLUSIONS: StO(2) correlates with ScvO(2) in normotensive patients with severe sepsis or septic shock. We propose a StO(2) cut-off value of 75% as a specific, rapid, noninvasive first step for detecting patients with low ScvO(2) values. Further studies are necessary to analyze the role of noninvasive StO(2) measurement in future resuscitation algorithms.

Medicinas complementarias en oncología / Complementary medicines in oncology

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