Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery.

To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRß chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A∗02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.

Integrating genomic features for non-invasive early lung cancer detection.

Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

Complications of Outpatient Chest Tube Management for Prolonged Air Leaks After Pulmonary Surgery.

PURPOSE: Air leaks are common after pulmonary surgery. Prolonged air leaks (PALs) may persist through discharge and often are managed with one-way valve devices (OWD). We sought to determine the course and complications of patients discharged with OWDs, risk factors for complications, and to evaluate the utility of clamp trials before chest tube (CT) removal. METHODS: Single-institution, retrospective review of patients discharged with a OWD after pulmonary surgery between 2008 and 2022. Charts were examined for the presence of complications and CT duration. Differences in CT duration were compared by using the Wilcoxon rank-sum test. RESULT: Sixty-four of 1917 (3.3%) pulmonary surgeries resulted in OWD use. Twelve of 64 (19%) patients discharged with a OWD suffered a complication. Nine of 64 (14%) had a CT-related readmission, and seven of 64 (11%) required PAL intervention. Patients sustaining a complication demonstrated longer CT durations before complication compared with duration in patients without complications, with median days of 13 [IQR 6-21] vs. 7 [IQR 6-12], p = 0.04). Five (7.8%) OWD patients developed an empyema; only one (20%) occurred before a CT duration of 14 days. Sixteen of 64 (25%) patients underwent a clamp trial before CT removal. One of ten (10%) failed even with no air leak present, whereas one of six (17%) failed with a present/questionable air leak. CONCLUSIONS: One-way valve device use has a substantial complication rate, and chest tube duration is a risk factor. In-hospital interventions might benefit patients with larger leaks that likely require prolonged OWD use. Because clamp trials occasionally fail, we contend that a clamp trial is the safest course before CT removal.

genRCT: a statistical analysis framework for generalizing RCT findings to real-world population.

When evaluating the real-world treatment effect, the analysis based on randomized clinical trials (RCTs) often introduces generalizability bias due to the difference in risk factors between the trial participants and the real-world patient population. This problem of lack of generalizability associated with the RCT-only analysis can be addressed by leveraging observational studies with large sample sizes that are representative of the real-world population. A set of novel statistical methods, termed "genRCT", for improving the generalizability of the trial has been developed using calibration weighting, which enforces the covariates balance between the RCT and observational study. This paper aims to review statistical methods for generalizing the RCT findings by harnessing information from large observational studies that represent real-world patients. Specifically, we discuss the choices of data sources and variables to meet key theoretical assumptions and principles. We introduce and compare estimation methods for continuous, binary, and survival endpoints. We showcase the use of the R package genRCT through a case study that estimates the average treatment effect of adjuvant chemotherapy for the stage 1B non-small cell lung patients represented by a large cancer registry.

Remdesivir Reduced Mortality in Immunocompromised Patients Hospitalized for COVID-19 Across Variant Waves: Findings From Routine Clinical Practice.

BACKGROUND: Immunocompromised patients are at high risk of severe coronavirus disease 2019 (COVID-19) and death, yet treatment strategies for immunocompromised patients hospitalized for COVID-19 reflect variations in clinical practice. In this comparative effectiveness study, we investigated the effect of remdesivir treatment on inpatient mortality among immunocompromised patients hospitalized for COVID-19 across all variants of concern (VOC) periods. METHODS: Data for immunocompromised patients hospitalized for COVID-19 between December 2020 and April 2022 were extracted from the US PINC AITM Healthcare Database. Patients who received remdesivir within 2 days of hospitalization were matched 1:1 using propensity score matching to patients who did not receive remdesivir. Additional matching criteria included admission month, age group, and hospital. Cox proportional hazards models were used to examine the effect of remdesivir on risk of 14- and 28-day mortality during VOC periods. RESULTS: A total of 19 184 remdesivir patients were matched to 11 213 non-remdesivir patients. Overall, 11.1% and 17.7% of remdesivir patients died within 14 and 28 days, respectively, compared with 15.4% and 22.4% of non-remdesivir patients. Remdesivir was associated with a reduction in mortality at 14 (hazard ratio [HR], 0.70; 95% confidence interval, .62-.78) and 28 days (HR, 0.75; 95% CI, .68-.83). The survival benefit remained significant during the pre-Delta, Delta, and Omicron periods. CONCLUSIONS: Prompt initiation of remdesivir in immunocompromised patients hospitalized for COVID-19 is associated with significant survival benefit across all variant waves. These findings provide much-needed evidence relating to the effectiveness of a foundational treatment for hospitalized COVID-19 patients among a high-risk population.

Treatment and Outcomes of Proximal Esophageal Squamous Cell Carcinoma.

INTRODUCTION: This study evaluated the treatment of proximal (cervical or upper thoracic) esophageal squamous cell carcinoma (SCC), for which chemoradiation is the recommended therapy. METHODS: Treatment and outcomes of patients with cT1-3N0-1M0 proximal esophageal SCC in the National Cancer Database between 2004 and 2016 was evaluated using logistic regression, Kaplan-Meier analysis, and propensity-score matching. RESULTS: Therapy of 2159 patients was chemoradiation (n = 1500, 69.5%), no treatment (n = 205, 9.5%), surgery (n = 203, 9.4%), radiation alone (n = 190, 8.8%), and chemotherapy alone (n = 61, 2.8%). Factors associated with definitive therapy with either chemoradiation or surgery were younger age, non-Black race, being insured, cervical tumor location, clinical T2 and T3 stage, clinical nodal involvement, and treatment at a research/academic program. Five-year survival was significantly better in patients treated with definitive therapy than patients not treated definitively (34.0% vs. 13.3%, p < 0.001). In multivariable survival analysis, receiving definitive therapy (hazard ratio [HR] 0.39, p = 0.017) was associated with improved survival, while increasing age, male sex, clinical T3 stage, positive clinical nodal involvement, and increasing Charlson Comorbidity Index were associated with worse survival. Esophagectomy was not associated with improved survival in multivariable analysis of the definitive therapy cohort (HR 0.84, p = 0.08) or propensity matched analysis. However, the pathologic complete response was only 33.3% (40/120) for patients who did have an esophagectomy after chemoradiation. CONCLUSIONS: This national analysis supports definitive chemoradiation for not only cervical but also proximal thoracic esophageal SCC. Routine surgery does not appear to be necessary but may have a role in patients with residual disease after chemoradiation.

Impact of Delaying Surgery After Chemoradiation on Outcomes for Locally Advanced Esophageal Squamous Cell Carcinoma.

BACKGROUND: Performing selective esophagectomy for locally advanced squamous cell carcinoma may spare patients morbidity, but delayed surgery may infer higher risks. This study evaluated the impact of length of time between chemoradiation and esophagectomy on perioperative outcomes and long-term survival. METHODS: The impact of surgical timing, stratified by surgery performed < 180 and ≥ 180 days from starting radiation, on perioperative outcomes and survival in patients treated with chemoradiation and esophagectomy for cT1N + M0 and cT2-4, any N, M0 squamous cell carcinoma of the mid-distal esophagus in the National Cancer Database (2006-2016) was evaluated with logistic regression, Kaplan-Meier curves, Cox proportional-hazards methods, and propensity-matched analysis. RESULTS: Median time between starting radiation and esophagectomy in 1641 patients was 93 (IQR 81-114) days. Most patients (96.8%, n = 1589) had surgery within 180 days of starting radiation, while 52 patients (3.2%) had delayed surgery. Black race and clinical T stage were associated with delayed surgery. Rates of pathologic upstaging, downstaging, complete response, and positive margins were not significantly different between the groups. Patients with delayed surgery had increased major morbidity as measured by a composite of length of hospital stay, readmission, and 30-day mortality [42.3% (22/52) vs 22.3% (355/1589), p = 0.001]. However, delayed surgery was not associated with a significant difference in survival in both univariate [5-year survival 32.8% (95% CI 21.1-50.7) vs 47.3% (44.7-50.1), p = 0.19] and multivariable analysis [hazard ratio (HR) 1.23 (0.85-1.78), p = 0.26]. CONCLUSIONS: Delaying surgery longer than 180 days after starting chemoradiation for esophageal squamous cell carcinoma is associated with worse perioperative outcomes but not long-term survival.

Characterization of Epidural Analgesia Interruption and Associated Outcomes After Esophagectomy.

INTRODUCTION: Interruption of thoracic epidural analgesia may impact the postoperative course following esophagectomy. This study investigates the incidence and causes of epidural interruption in esophagectomy patients along with associated postoperative outcomes. METHODS: This single-institution retrospective analysis examined patients undergoing esophagectomy who received a thoracic epidural catheter from 2016 to 2020. Patients were stratified according to whether epidural catheter infusion was interrupted or not postoperatively. Outcomes were compared between the two groups, and predictors of epidural interruption and postoperative complications were estimated using multivariable logistic regression. RESULTS: Of the 168 patients who received a thoracic epidural before esophagectomy, 60 (35.7%) required epidural interruption and 108 (64.3%) did not. Interruption commonly occurred on postoperative day 1 and was due to hypotension 80% of the time. Heart failure (10.0% versus 0.9%, P = 0.009), atrial fibrillation (20.0% versus 3.7%, P = 0.002), preoperative opioid use (30.0% versus 16.7%, P = 0.043), and higher American Society of Anesthesiology classification (88.4% versus 70.4%, P = 0.008) were more prevalent in the epidural interruption cohort. The female gender was associated with epidural interruption on multivariable logistic regression (adjusted odds ratio [AOR] 2.45, P = 0.039). Patients in the epidural interruption cohort had a higher incidence of delirium (30.5% versus 13.9%, P = 0.010), sepsis (13.6% versus 3.7%, P = 0.028), and severe anastomotic leak (18.3% versus 7.4%, P = 0.032). On adjusted analysis, heart disease (AOR 4.26, P = 0.027), BMI <18.5 (AOR 9.83, P = 0.031), and epidural interruption due to hypotension (AOR 3.51, P = 0.037) were associated with severe anastomotic leak. CONCLUSIONS: Early epidural interruption secondary to hypotension in esophagectomy patients may be a harbinger of postoperative complications such as sepsis and severe anastomotic leak. Patients requiring epidural interruption due to hypotension should have a low threshold for additional workup and early intervention.

Effectiveness of 2-Dose BNT162b2 (Pfizer BioNTech) mRNA Vaccine in Preventing SARS-CoV-2 Infection Among Children Aged 5-11 Years and Adolescents Aged 12-15 Years - PROTECT Cohort, July 2021-February 2022.

The BNT162b2 (Pfizer-BioNTech) mRNA COVID-19 vaccine was recommended by CDC's Advisory Committee on Immunization Practices for persons aged 12-15 years (referred to as adolescents in this report) on May 12, 2021, and for children aged 5-11 years on November 2, 2021 (1-4). Real-world data on vaccine effectiveness (VE) in these age groups are needed, especially because when the B.1.1.529 (Omicron) variant became predominant in the United States in December 2021, early investigations of VE demonstrated a decline in protection against symptomatic infection for adolescents aged 12-15 years and adults* (5). The PROTECT† prospective cohort of 1,364 children and adolescents aged 5-15 years was tested weekly for SARS-CoV-2, irrespective of symptoms, and upon COVID-19-associated illness during July 25, 2021-February 12, 2022. Among unvaccinated participants (i.e., those who had received no COVID-19 vaccine doses) with any laboratory-confirmed SARS-CoV-2 infection, those with B.1.617.2 (Delta) variant infections were more likely to report COVID-19 symptoms (66%) than were those with Omicron infections (49%). Among fully vaccinated children aged 5-11 years, VE against any symptomatic and asymptomatic Omicron infection 14-82 days (the longest interval after dose 2 in this age group) after receipt of dose 2 of the Pfizer-BioNTech vaccine was 31% (95% CI = 9%-48%), adjusted for sociodemographic characteristics, health information, frequency of social contact, mask use, location, and local virus circulation. Among adolescents aged 12-15 years, adjusted VE 14-149 days after dose 2 was 87% (95% CI = 49%-97%) against symptomatic and asymptomatic Delta infection and 59% (95% CI = 22%-79%) against Omicron infection. Fully vaccinated participants with Omicron infection spent an average of one half day less sick in bed than did unvaccinated participants with Omicron infection. All eligible children and adolescents should remain up to date with recommended COVID-19 vaccinations.

Perioperative Outcomes After Combined Esophagectomy and Lung Resection.

INTRODUCTION: The impact of concomitant lung resection during esophagectomy on short-term outcomes is not well characterized. This study tests the hypothesis that lung resection at the time of esophagectomy is not associated with increased perioperative morbidity or mortality. METHODS: Perioperative outcomes for esophageal cancer patients who underwent esophagectomy alone (EA) were compared to patients who had concurrent esophagectomy and lung resection (EL) using the NSQIP database between 2006-2017. Predictors of morbidity and mortality, including combined surgery, were evaluated using multivariable logistic regression. RESULTS: Among the 6,225 study patients, 6,068 (97.5%) underwent EA and 157 (2.5%) underwent EL. There were no differences in baseline characteristics between the two groups. Operating time for EL was longer than EA (median 416 versus 371 minutes, P < 0.01). Median length of stay was 10 d for both groups. Perioperative mortality was not significantly different between EL and EA patients (5.1% versus 2.8%, P = 0.08). EL patients had higher rates of postoperative pneumonia (22.3% versus 16.2%, P = 0.04) and sepsis (11.5% versus 7.1%, P = 0.03), however major complication rates overall were similar (40.8% versus 35.3%, P = 0.16). Combining lung resection with esophagectomy was not independently associated with increased postoperative morbidity (AOR 1.21 [95% CI 0.87-1.69]) or mortality (AOR 1.63 [95% CI 0.74-3.58]). CONCLUSIONS: Concurrent lung resection during esophagectomy is not associated with increased mortality or overall morbidity, but is associated with higher rates of pneumonia beyond esophagectomy alone. Surgeons considering combined lung resection with esophagectomy should carefully evaluate the patient's risk for pulmonary complications and pursue interventions preoperatively to optimize respiratory function.

Cancer diagnoses and survival rise as 65-year-olds become Medicare-eligible.

BACKGROUND: A Medicare effect has been described to account for increased health care utilization occurring at the age of 65 years. The existence of such an effect in cancer care, where it would be most likely to reduce mortality, has been unclear. METHODS: Patients aged 61 to 69 years who were diagnosed with lung, breast, colon, or prostate cancer from 2004 to 2016 were identified with the Surveillance, Epidemiology, and End Results database and were dichotomized on the basis of eligibility for Medicare (61-64 vs 65-69 years). With age-over-age (AoA) percent change calculations, trends in cancer diagnoses and staging were characterized. After matching, uninsured patients who were 61 to 64 years old (pre-Medicare group) were compared with insured patients who were 65 to 69 years old (post-Medicare group) with respect to cancer-specific mortality. RESULTS: In all, 134,991 patients were identified with lung cancer, 175,558 were identified with breast cancer, 62,721 were identified with colon cancer, and 238,823 were identified with prostate cancer. The AoA growth in the number of cancer diagnoses was highest at the age of 65 years in comparison with all other ages within the decade for all 4 cancers (P < .01, P < .001, P < .01, and P < .001, respectively). In a comparison of diagnoses at the age of 65 years with those in the 61- to 64-year-old cohort, the greatest difference for all 4 cancers was seen in stage I. In matched analyses, the 5-year cancer-specific mortality was worse for lung (86.3% vs 78.5%; P < .001), breast (32.7% vs 11.0%; P < .001), colon (57.1% vs 35.6%; P < .001), and prostate cancer (16.9% vs 4.8%; P < .001) in the uninsured pre-Medicare group than the insured post-Medicare group. CONCLUSIONS: The age threshold of 65 years for Medicare eligibility is associated with more cancer diagnoses (particularly stage I), and this results in lower long-term cancer-specific mortality for all cancers studied. LAY SUMMARY: Contributing to the current debate regarding Medicare for all, this study shows that the expansion of Medicare would improve cancer outcomes for the near elderly.

A National Analysis of Short-term Outcomes and Long-term Survival Following Thoracoscopic Versus Open Lobectomy for Clinical Stage II Non-Small-Cell Lung Cancer.

OBJECTIVE: To compare outcomes after open versus thoracoscopic (VATS) lobectomy for clinical stage II (cN1) non-small-cell lung cancer (NSCLC). BACKGROUND: There have been no published studies evaluating the impact of a VATS approach to lobectomy for N1 NSCLC on short-term outcomes and survival. METHODS: Outcomes of patients with clinical T1-2, N1, M0 NSCLC who underwent lobectomy without induction therapy in the National Cancer Data Base (2010-2012) were evaluated using multivariable Cox proportional hazards modeling and propensity score-matched analysis. RESULTS: Median follow-up of 1559 lobectomies (1204 open and 355 VATS) was 43.2 months. The VATS approach was associated with a shorter median hospitalization (5 vs 6 d, P < 0.001) than the open approach. There were no significant differences between the VATS and open approach with regard to nodal upstaging (12.0% vs 10.5%, P = 0.41), 30-day mortality (2.3% vs 3.1%, P = 0.31), and overall survival (5-yr survival: 48.6% vs 48.7%, P = 0.76; multivariable-adjusted HR for VATS approach: 1.08, 95% CI: 0.90-1.30, P = 0.39). A propensity score-matched analysis of 334 open and 334 VATS patients who were well matched by 14 common prognostic covariates, including tumor size, and comorbidities, continued to show no significant differences in nodal upstaging, 30-day mortality, and 5-year survival between the VATS and open groups. CONCLUSION: In this national analysis, VATS lobectomy was used in the minority of N1 NSCLC cases but was associated with shorter hospitalization and similar nodal upstaging rates, 30-day mortality, and long-term survival when compared to open lobectomy. These findings suggest thoracoscopic techniques are feasible for the treatment of stage II (cN1) NSCLC.

Strong for Surgery: Association Between Bundled Risk Factors and Outcomes After Major Elective Surgery in the VA Population.

BACKGROUND: Strong for Surgery (S4S) is a public health campaign focused on optimizing patient health prior to surgery by identifying evidence-based modifiable risk factors. The potential impact of S4S bundled risk factors on outcomes after major surgery has not been previously studied. This study tested the hypothesis that a higher number of S4S risk factors is associated with an escalating risk of complications and mortality after major elective surgery in the VA population. METHODS: The Veterans Affairs Surgical Quality Improvement Program (VASQIP) database was queried for patients who underwent major non-emergent general, thoracic, vascular, urologic, and orthopedic surgeries between the years 2008 and 2015. Patients with complete data pertaining to S4S risk factors, specifically preoperative smoking status, HbA1c level, and serum albumin level, were stratified by number of positive risk factors, and perioperative outcomes were compared. RESULTS: A total of 31,285 patients comprised the study group, with 16,630 (53.2%) patients having no S4S risk factors (S4S0), 12,323 (39.4%) having one (S4S1), 2,186 (7.0%) having two (S4S2), and 146 (0.5%) having three (S4S3). In the S4S1 group, 60.3% were actively smoking, 35.2% had HbA1c > 7, and 4.4% had serum albumin < 3. In the S4S2 group, 87.8% were smokers, 84.8% had HbA1c > 7, and 27.4% had albumin < 3. Major complications, reoperations, length of stay, and 30-day mortality increased progressively from S4S0 to S4S3 groups. S4S3 had the greatest adjusted mortality risk (adjusted odds radio [AOR] 2.56, p = 0.04) followed by S4S2 (AOR 1.58, p = 0.02) and S4S1 (AOR 1.34, p = 0.02). CONCLUSION: In the VA population, patients who had all three S4S risk factors, namely active smoking, suboptimal nutritional status, and poor glycemic control, had the greatest risk of postoperative mortality compared to patients with fewer S4S risk factors.

Trace Amines and Their Receptors.

Trace amines are endogenous compounds classically regarded as comprising ß-phenylethyalmine, p-tyramine, tryptamine, p-octopamine, and some of their metabolites. They are also abundant in common foodstuffs and can be produced and degraded by the constitutive microbiota. The ability to use trace amines has arisen at least twice during evolution, with distinct receptor families present in invertebrates and vertebrates. The term "trace amine" was coined to reflect the low tissue levels in mammals; however, invertebrates have relatively high levels where they function like mammalian adrenergic systems, involved in "fight-or-flight" responses. Vertebrates express a family of receptors termed trace amine-associated receptors (TAARs). Humans possess six functional isoforms (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9), whereas some fish species express over 100. With the exception of TAAR1, TAARs are expressed in olfactory epithelium neurons, where they detect diverse ethological signals including predators, spoiled food, migratory cues, and pheromones. Outside the olfactory system, TAAR1 is the most thoroughly studied and has both central and peripheral roles. In the brain, TAAR1 acts as a rheostat of dopaminergic, glutamatergic, and serotonergic neurotransmission and has been identified as a novel therapeutic target for schizophrenia, depression, and addiction. In the periphery, TAAR1 regulates nutrient-induced hormone secretion, suggesting its potential as a novel therapeutic target for diabetes and obesity. TAAR1 may also regulate immune responses by regulating leukocyte differentiation and activation. This article provides a comprehensive review of the current state of knowledge of the evolution, physiologic functions, pharmacology, molecular mechanisms, and therapeutic potential of trace amines and their receptors in vertebrates and invertebrates.

TAAR1 Expression in Human Macrophages and Brain Tissue: A Potential Novel Facet of MS Neuroinflammation.

TAAR1 is a neuroregulator with emerging evidence suggesting a role in immunomodulation. Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Here, we investigate TAAR1 expression in human primary monocytes, peripherally-derived macrophages, and MS brain tissue. RT-qPCR was used to assess TAAR1 levels in MS monocytes. Using a previously validated anti-human TAAR1 antibody and fluorescence microscopy, TAAR1 protein was visualized in lipopolysaccharide-stimulated or basal human macrophages, as well as macrophage/microglia populations surrounding, bordering, and within a mixed active/inactive MS lesion. In vivo, TAAR1 mRNA expression was significantly lower in MS monocytes compared to age- and sex-matched healthy controls. In vitro, TAAR1 protein showed a predominant nuclear localization in quiescent/control macrophages with a shift to a diffuse intracellular distribution following lipopolysaccharide-induced activation. In brain tissue, TAAR1 protein was predominantly expressed in macrophages/microglia within the border region of mixed active/inactive MS lesions. Considering that TAAR1-mediated anti-inflammatory effects have been previously reported, decreased mRNA in MS patients suggests possible pathophysiologic relevance. A shift in TAAR1 localization following pro-inflammatory activation suggests its function is altered in pro-inflammatory states, while TAAR1-expressing macrophages/microglia bordering an MS lesion supports TAAR1 as a novel pharmacological target in cells directly implicated in MS neuroinflammation.

A National Analysis of Long-term Survival Following Thoracoscopic Versus Open Lobectomy for Stage I Non-small-cell Lung Cancer.

OBJECTIVE: The objective of this study was to compare the long-term survival of open versus thoracoscopic (VATS) lobectomy for early stage non-small-cell lung cancer (NSCLC). BACKGROUND: Data from national studies on long-term survival for VATS versus open lobectomy are limited. METHODS: Outcomes of patients who underwent open versus VATS lobectomy for clinical T1-2, N0, M0 NSCLC in the National Cancer Data Base were evaluated using propensity score matching. RESULTS: The median follow-up of 7114 lobectomies (5566 open and 1548 VATS) was 52.0 months. The VATS approach was associated with a better 5-year survival when compared to the open approach (66.0% vs. 62.5%, P = 0.026). Propensity score matching resulted in 1464 open and 1464 VATS patients who were well matched by 14 common prognostic covariates including tumor size and comorbidities. After propensity score matching, the VATS approach was associated with a shorter median length of stay (5 vs. 6 days, P < 0.001). The VATS approach was not significantly different compared with the open approach with regard to nodal upstaging (11.6% vs 12.3%, P = 0.53), 30-day mortality (1.7% vs 2.3%, P = 0.50) and 5-year survival (66.3% vs 65.8%, P = 0.92). CONCLUSIONS: In this national analysis, VATS lobectomy was used in the minority of patients with stage I NSCLC. VATS lobectomy was associated with shorter length of stay and noninferior long-term survival when compared with open lobectomy. These results support previous findings from smaller single- and multi-institutional studies that suggest that VATS does not compromise oncologic outcomes when used for early-stage lung cancer and suggest the need for broader implementation of VATS techniques.

TAAR1 levels and sub-cellular distribution are cell line but not breast cancer subtype specific.

Trace amine-associated receptors are G protein-coupled receptors of which TAAR1 is the most well-studied. Recently, Vattai et al. (J Cancer Res Clin Oncol 143:1637-1647 https://doi.org/10.1007/s00432-017-2420-8 , 2017) reported that expression of TAAR1 may be a marker of breast cancer (BC) survival, with a positive correlation also suggested between TAAR1 expression and HER2 positivity. Neither a role for TAAR1 in breast tissue, nor in cancer, had previously been suspected. We, therefore, sought to provide independent validation and to further examine these putative relationships. First, a bioinformatic analysis on 58 total samples including normal breast tissue, BC-related cell lines, and tumour samples representing different BC sub-types found no clear correlation between TAAR1 mRNA levels and any BC subtype, including HER2 + . We next confirmed the bioinformatics data correlated to protein expression using a well validated anti-human TAAR1 antibody. TAAR1 mRNA levels correlated with the relative intensity of immunofluorescence staining in six BC cell lines (MCF-7, T47D, MDA-MB-231, SKBR3, MDA-MB-468, BT-474), but not in the MCF-10A immortalized mammary gland line, which had high mRNA but low protein levels. As expected, TAAR1 protein was intracellular in all cell lines. Surprisingly MCF-7, SKBR3, and MDA-MB-468 showed pronounced nuclear localization. The relative protein expression in MCF-7, MDA-MB-231, and MCF-10A lines was further confirmed by semi-quantitative flow cytometry. Finally, we demonstrate that the commercially available anti-TAAR1 antibody has poor selectivity, which likely explains the lack of correlation with the previous study. Therefore, while we clearly demonstrate variable expression and sub-cellular localization of TAAR1 across BC cell lines, we find no evidence for association with BC subtype.

Gill damage and delayed mortality of Northern shrimp (Pandalus borealis) after short time exposure to anti-parasitic veterinary medicine containing hydrogen peroxide.

Hydrogen peroxide (H2O2) is used as anti-parasitic veterinary medicine in salmon farms worldwide. In the period from 2009 to 2018 a total of 135 million kg of H2O2 was used in Norway, the world's largest producer of Atlantic salmon. Since the treatment water is discharged to the sea, concerns have been raised about effects of H2O2 on the coastal ecosystem. In the present study, Northern shrimp (Pandalus borealis) have been exposed to short pulses of H2O2 in the PARAMOVE® formulation, followed by a recovery period in clean seawater. The exposure concentrations represented 100, 1000 and 10 000 times dilutions of the prescribed treatment concentration for salmon; 15 mg/L, 1.5 mg/L and 0.15 mg/L H2O2. Significantly increased mortality was observed after 2 h exposure to 15 mg/L H2O2 (50%) and after 2 h exposure to 1.5 mg/L H2O2 on 3 consecutive days (33%), but no mortality was observed after 2 h exposure to 0.15 mg/L. The mortality occurred 2-4 days after the first pulse of exposure. The patterns of acute effects (immobility and death) could be captured with a toxicokinetic-toxicodynamic model (GUTS), which allows extrapolations to LC50s for constant exposure, or thresholds for effects given untested exposure profiles. Effects of H2O2 were also detected in shrimp that survived until the end of the recovery period. The feeding rate was 66% lower than in the control after 12 days of recovery for the three-pulse 1.5 mg/L exposure. Furthermore, dose dependent tissue damage was detected in the gills and evidence of lipid peroxidation in the hepatopancreas in shrimp exposed for 1 h to 1.5 mg/L and 15 mg/L and kept in recovery for 8 days. Fluorescence intensity in the hepatopancreas of treated shrimp increased 47% and 157% at 1.5 mg/L and 15 mg/L, respectively, compared to the control. Local hydrodynamic conditions will determine how fast the concentration of H2O2 will be diluted and how far it will be transported horizontally and vertically. Results from dispersion modelling (literature data) together with the current experiments indicate that treatment water with toxic concentrations of H2O2 (1.5 mg/L) could reach P. borealis living more than 1 km from a treated salmon farm.

Long-term Survival After Surgery Compared With Concurrent Chemoradiation for Node-negative Small Cell Lung Cancer.

OBJECTIVE: To determine whether surgery with adjuvant chemotherapy offers a survival advantage over concurrent chemoradiation for patients with cT1-2N0M0 small cell lung cancer (SCLC). BACKGROUND: Although surgery with adjuvant chemotherapy is the recommended treatment for patients with cT1-2N0M0 SCLC per international guidelines, there have been no prospective or retrospective studies evaluating the impact of surgery versus optimal medical management for cT1-2N0M0 SCLC. METHODS: Outcomes of patients with cT1-2N0M0 SCLC who underwent surgery with adjuvant chemotherapy or concurrent chemoradiation in the National Cancer Data Base (2003-2011) were evaluated using Cox proportional hazards analyses and propensity-score-matched analyses. RESULTS: During the study period, 681 (30%) patients underwent surgery with adjuvant chemotherapy and 1620 (70%) underwent concurrent chemoradiation. After propensity-score matching, all 14 covariates were well balanced between the surgery (n = 501) and concurrent chemoradiation (n = 501) groups. Surgery was associated with a higher overall survival (OS) than concurrent chemoradiation (5-year OS 47.6% vs 29.8%, P < 0.01). To minimize selection bias due to comorbidities, we limited the propensity-matched analysis to 492 patients with no comorbidities; surgery remained associated with a higher OS than concurrent chemoradiation (5-year OS 49.2% vs 32.5%, P < 0.01). CONCLUSIONS: In a national analysis, surgery with adjuvant chemotherapy was used in the minority of patients for early stage SCLC. Surgery with adjuvant chemotherapy for node-negative SCLC was associated with improved long-term survival when compared to concurrent chemoradiation. These results suggest a significant underuse of surgery among patients with early stage SCLC and support an increased role of surgery in multimodality therapy for cT1-2N0M0 SCLC.