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Previous laboratory and pilot clinical trial data suggest that vitamin and/or mineral supplementation may prevent tumor growth in small cell lung cancer. However, rates of supplementation and their major purported clinical effects have never before been studied in patients with small cell lung cancer. This study was undertaken to explore associations between vitamin/mineral supplementation and survival and quality of life within a cohort of small cell lung cancer patients. This study focused on a small cell lung cancer patient cohort from a tertiary care medical center. Small cell lung cancer patients who responded to a follow-up questionnaire on vitamin/mineral use were included. Associations between vitamin/mineral use and both survival and quality of life (Lung Cancer Symptom Scale) were assessed. A total of 178 patients or their proxies responded to one or more vitamin/mineral questionnaires. One hundred seven (60%) were vitamin/mineral users of either multivitamins or other more specific vitamin/mineral supplements, and the rest were nonusers. Two different survival analyses were performed. In the first, median survival was 1.8 vs. 1.3 yr for vitamin/mineral users and nonusers, respectively. The relative risk of death was 0.63 (95% confidence interval [CI]: 0.43, 0.92; P = 0.02) in favor of vitamin/mineral use. After adjustment for multiple prognostic factors, including tumor stage, the relative risk for death was 0.65 (95% CI: 0.43, 1.00; P = 0.05). The second analysis was based on an alternative definition of vitamin/mineral use and showed only a trend to suggest an association between vitamin/mineral use and improved survival (P = 0.09). There were no significant improvements in quality of life in any of the analyses. Vitamin/mineral supplementation is common within this cohort of small cell lung cancer patients. These data suggest an association between vitamin/mineral supplementation and improved survival and point to a need for future studies on vitamin and mineral supplementation in small cell lung cancer patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To analyze the outcome of surgical resection for patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: We identified all patients who underwent thoracotomy for SCLC at our institution from January 1985 to July 2002. All patients were staged using the American Joint Committee on Cancer TNM system. RESULTS: The median age of the 77 patients (44 men and 33 women) was 65 years (range, 35-85 years). Operations performed included thoracotomy with biopsy of hilar mass in 10 patients, wedge excision in 30 (6 with talc pleurodesis), segmentectomy in 4, lobectomy in 28, bilobectomy in 3, and pneumonectomy in 2. Mediastinal lymphadenectomy was performed in 50 patients and lymph node sampling in 19. Postoperative therapy Included chemotherapy alone in 20 patients, radiation therapy in 3, and combined chemotherapy and radiation therapy in 40. Median tumor diameter was 4 cm (range, 1.0-10.0 cm). Postsurgical tumor stage was IA in 7 patients, IB in 11, IIA in 8, IIB in 7, IIIA in 30, IIIB in 10, and IV in 4. A total of 19 patients (25%) had complications: atrial arrhythmia in 7 patients, pneumonia in 6, prolonged air leak in 3, and myocardial infarction, postoperative bleeding, and cerebrovascular accident in 1 each. Operative mortality was 3% (2/77). Follow-up ranged from 4 days to 170 months (median, 19 months). At last follow-up, 20 patients were alive. The estimated overall 5-year survival was 27% when excluding the 10 patients who underwent a biopsy without additional surgery. Five-year survival for stage I and II combined (n=33) was 38% compared with only 16% for stage III and IV combined (n=34) (P=.02). Overall median survival was 24 months; median survival for patients who underwent curative surgery was 25 months compared with 16 months for those who had a palliative procedure (P=.34). CONCLUSION: Pulmonary resection in patients with stage I or stage II SCLC is safe with low mortality and morbidity. Curative resection is associated with long-term survival in early stage SCLC in some patients and should be considered in selected patients. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To characterize the etiology of chylothorax in patients encountered at a single tertiary referral center and to compare the findings with those from previous studies. PATIENTS AND METHODS: The medical records of all patients with chylothorax seen at the Mayo Clinic in Rochester, Minn, over a 21-year period, from January 1, 1980, to December 31, 2000, were retrospectively reviewed to ascertain the underlying cause of their condition. RESULTS: We identified 203 patients with chylothorax; 92 were females (male-female ratio, 1.21). The median age was 54.5 years (range, 21 weeks' gestation to 93 years). Dyspnea, the most common presenting symptom, occurred in 98 (56.6%) of 173 patients in whom initial symptoms were recorded, whereas 64 (37.0%) had no respiratory symptoms. Median duration of symptoms before diagnosis was 7.5 weeks (range, 1 day to 4.5 years). Causes of chylothorax included surgery or trauma in 101 patients (49.8%), various medical conditions in 89 (43.8%), and unknown in 13 (6.4%). Among surgical procedures, esophagectomy (29 patients) and surgery for congenital heart disease (28 patients) were the most common causes of chylothorax. Among medical conditions, lymphoma (23 patients), lymphatic disorders (19 patients), and chylous ascites (16 patients) were the most common causes. CONCLUSIONS: Chylothorax has numerous causes. In contrast to previous studies, surgery or trauma was the most common cause of chylothorax at our institution, accounting for nearly 50% of cases. Lymphoma and other malignancies caused chylothorax in only 16.7% of cases. These numbers are possibly related to the high volume of cardiothoracic surgical procedures performed at our tertiary referral center. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic persists despite the availability of vaccines, and it is, therefore, crucial to develop new therapeutic and preventive approaches. In this study, we investigated the potential role of oral microbiome in SARS-CoV-2 infection. Using an in vitro SARS-CoV-2 pseudovirus infection assay, we found a potent inhibitory effect exerted by Porphyromonas gingivalis on SARS-CoV-2 infection mediated by known P. gingivalis compounds such as phosphoglycerol dihydroceramide (PGDHC) and gingipains as well as by unknown bacterial factors. We found that the gingipain-mediated inhibition of infection is likely due to cytotoxicity, whereas PGDHC inhibited virus infection by an unknown mechanism. Unidentified factors present in P. gingivalis supernatant inhibited SARS-CoV-2 likely via the fusion step of the virus life cycle. We addressed the role of other oral bacteria and found certain periodontal pathogens capable of inhibiting SARS-CoV-2 pseudovirus infection by inducing cytotoxicity on target cells. In the human oral cavity, we observed that the modulatory activity of oral microbial communities varied among individuals, in that some saliva-based cultures were capable of inhibiting while others were enhancing infection. These findings contribute to our understanding of the complex relationship between the oral microbiome and viral infections, offering potential avenues for innovative therapeutic strategies in combating COVID-19., Importance: The oral microbiome is important in health and disease, and in this study, we addressed the potential role of the oral microbiome in COVID-19 infection. Our in vitro studies suggest that certain bacteria of the oral microbiome such as P. gingivalis produce compounds that could potentially inhibit SARS-CoV-2 infection. These findings elucidating the interactions between the oral microbiome and SARS-CoV-2 infection will be important in our understanding of COVID-19 pathogenesis and the development of innovative therapeutic and preventive strategies against COVID-19 infection., Competing Interests: The authors declare no conflict of interest.

Background: This study unveils the intricate functional association between cyclic di-3',5'-adenylic acid (c-di-AMP) signaling, cellular bioenergetics, and the regulation of lipopolysaccharide (LPS) profile in Porphyromonas gingivalis , a Gram-negative obligate anaerobe considered as a keystone pathogen involved in the pathogenesis of chronic periodontitis. Previous research has identified variations in P. gingivalis LPS profile as a major virulence factor, yet the underlying mechanism of its modulation has remained elusive., Methods: We employed a comprehensive methodological approach, combining two mutants exhibiting varying levels of c-di-AMP compared to the wild type, alongside an optimized analytical methodology that combines conventional mass spectrometry techniques with a novel approach known as FLAT n ., Results: We demonstrate that c-di-AMP acts as a metabolic nexus, connecting bioenergetic status to nuanced shifts in fatty acid and glycosyl profiles within P. gingivalis LPS. Notably, the predicted regulator gene cdaR , serving as a potent regulator of c-di-AMP synthesis, was found essential for producing N-acetylgalactosamine and an unidentified glycolipid class associated with the LPS profile., Conclusion: The multifaceted roles of c-di-AMP in bacterial physiology are underscored, emphasizing its significance in orchestrating adaptive responses to stimuli. Furthermore, our findings illuminate the significance of LPS variations and c-di-AMP signaling in determining the biological activities and immunostimulatory potential of P. gingivalis LPS, promoting a pathoadaptive strategy. The study expands the understanding of c-di-AMP pathways in Gram-negative species, laying a foundation for future investigations into the mechanisms governing variations in LPS structure at the molecular level and their implications for host-pathogen interactions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ghods, Muszyński, Yang, Seelan, Mohammadi, Hilson, Keiser, Nichols, Azadi, Ernst and Moradali.)

Porphyromonas gingivalis produces five classes of serine/glycine lipids that are recovered in lipid extracts from periodontitis-afflicted teeth and diseased gingival tissues, particularly at sites of periodontitis. Because these lipids are recovered in diseased gingival tissues, the purpose of the present study was to evaluate the capacity of cultured human gingival fibroblasts (HGF), keratinocytes, and macrophages to hydrolyze these lipids. We hypothesize that one or more of these cell types will hydrolyze the serine/glycine lipids. The primary aim was to treat these cell types for increasing time in culture with individual highly enriched serine/glycine lipid preparations. At specified times, cells and culture media samples were harvested and extracted for hydrolysis products. The serine/glycine lipids and hydrolysis products were quantified using liquid chromatography-mass spectrometry (LC-MS) and free fatty acids were quantified using gas chromatograph-mass spectrometer. LC-MS analysis used two different mass spectrometric methods. This study revealed that treatment of HGF or macrophage (THP1) cells with lipid (L) 654 resulted in breakdown to L342 and subsequent release into culture medium. However, L654 was converted only to L567 in gingival keratinocytes. By contrast, L1256 was converted to L654 by fibroblasts and macrophages but no further hydrolysis or release into medium was observed. Gingival keratinocytes showed no hydrolysis of L1256 to smaller lipid products but because L1256 was not recovered in these cells, it is not clear what hydrolysis products are produced from L1256. Although primary cultures of gingival fibroblasts and macrophages are capable of hydrolyzing specific serine/glycine lipids, prior analysis of lipid extracts from diseased gingival tissues revealed significantly elevated levels of L1256 in diseased tissues. These results suggest that the hydrolysis of bacterial lipids in gingival tissues may reduce the levels of specific lipids, but the hydrolysis of L1256 is not sufficiently rapid to prevent significant accumulation at periodontal disease sites., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Prolonged survival of patients with metastatic disease has furthered interest in metastasis-directed therapy (MDT)., Research Question: There is a paucity of data comparing lung MDT modalities. Do outcomes among sublobar resection (SLR), stereotactic body radiation therapy (SBRT), and percutaneous ablation (PA) for lung metastases vary in terms of local control and survival?, Study Design and Methods: Medical records of patients undergoing lung MDT at a single cancer center between January 2015 and December 2020 were reviewed. Overall survival, local progression, and toxicity outcomes were collected. Patient and lesion characteristics were used to generate multivariable models with propensity weighted analysis., Results: Lung MDT courses (644 total: 243 SLR, 274 SBRT, 127 PA) delivered to 511 patients were included with a median follow-up of 22 months. There were 47 local progression events in 45 patients, and 159 patients died. Two-year overall survival and local progression were 80.3% and 63.3%, 83.8% and 9.6%, and 4.1% and 11.7% for SLR, SBRT, and PA, respectively. Lesion size per 1 cm was associated with worse overall survival (hazard ratio, 1.24; P = .003) and LP (hazard ratio, 1.50; P < .001). There was no difference in overall survival by modality. Relative to SLR, there was no difference in risk of local progression with PA; however, SBRT was associated with a decreased risk (hazard ratio, 0.26; P = .023). Rates of severe toxicity were low (2.1%-2.6%) and not different among groups., Interpretation: This study performs a propensity weighted analysis of SLR, SBRT, and PA and shows no impact of lung MDT modality on overall survival. Given excellent local control across MDT options, a multidisciplinary approach is beneficial for patient triage and longitudinal management., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: A significant proportion of patients with clinical stage IA non-small cell lung cancer (NSCLC) experience will recurrence and decreased survival after surgery. This study examined the impact of preoperative primary tumor positron emission tomography (PET) scan maximum standardized uptake value (SUVmax) on oncologic outcomes after surgery., Methods: This was a retrospective review of 251 patients who underwent surgical treatment of clinical stage IA NSCLC at an academic medical center (2005-2014). Patients were classified according to PET SUVmax level (low vs high) for analysis of upstaging, tumor recurrence, and overall survival., Results: Median SUVmax values were higher in squamous cell carcinoma than in adenocarcinoma (median 3.3 vs 7.2; P < .0001). There were 109 (43.4%) patients in the SUVmax low group and 142 (56.6%) in the SUVmax high group. Patients with SUVmax high had larger tumors. SUVmax high was associated with higher rates of nodal upstaging (16.2% vs 4.6% in SUVmax low; P = .004), particularly in N1 nodes. SUVmax high was independently associated with nodal upstaging (adjusted odds ratio, 3.95; 95% CI, 1.36-11.46; P = .011). SUVmax high was associated with time to recurrence (hazard ratio, 1.62; 95% CI, 1.03-2.54; P = .036), but this association was lost on multivariable analysis (hazard ratio, 1.52; 95% CI, 0.91-2.54; P = .106). SUVmax was not associated with overall survival., Conclusions: Preoperative PET SUVmax level is strongly associated with nodal upstaging, particularly in N1 nodes, in patients with clinical stage IA NSCLC who undergo resection. PET SUVmax should be regarded as a risk factor when considering candidacy for sublobar resections and in future trials involving patients with stage I NSCLC., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Esophagectomy for esophageal cancer is a procedure with high morbidity and mortality. This study developed a Multidisciplinary Esophagectomy Enhanced Recovery Initiative (MERIT) pathway and analyzed implementation outcomes in a single institution., Methods: The MERIT pathway was developed as a practice optimization and quality improvement initiative. Patients were studied from November 1, 2021 to June 20, 2022 and were compared with historical control subjects. The Wilcoxon rank sum test and the Fisher exact test were used for statistical analysis., Results: The study compared 238 historical patients (January 17, 2017 to December 30, 2020) with 58 consecutive MERIT patients. There were no significant differences between patient characteristics in the 2 groups. In the MERIT group, 49 (85%) of the patients were male, and their mean age was 65 years (range, 59-71 years). Most cases were performed for esophageal cancer after neoadjuvant therapy. Length of stay improved by 27% from 11 to 8 days (P = .27). There was a 12% (P = .05) atrial arrhythmia rate reduction, as well as a 9% (P = .01) decrease in postoperative ileus. Overall complications were reduced from 54% to 35% (-19%; P = .01)., Conclusions: This study successfully developed and implemented an enhanced recovery after surgery pathway for esophagectomy. In the first year, study investigators were able to reduce overall complications, specifically atrial arrhythmias, and postoperative ileus., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Long-term survival in esophagectomy patients with esophageal cancer is low due to tumor-related characteristics, with few reports of modifiable variables influencing outcome. We identified determinants of overall survival, time to recurrence, and disease-free survival in this patient cohort., Methods: Adult patients who underwent esophagectomy for primary esophageal cancer from January 5, 2000, through December 30, 2010, at our institution were identified. Univariate Cox models and multivariable logistic regression analyses were used to identify associations between modifiable and unmodifiable patient and clinical variables and outcome of survival for the total cohort and a subgroup with locally advanced disease., Results: We identified 870 patients with esophageal cancer who underwent esophagectomy. The median follow-up time was 15 years, and the 15-year overall survival rate was 25.2%, survival free of recurrence was 57.96%, and disease-free survival was 24.21%. Decreased overall survival was associated with the following unmodifiable variables: older age, male sex, active smoking status, history of coronary artery disease, advanced clinical stage, and tumor location. Decreased overall survival was associated with the following modifiable variables: use of neoadjuvant therapy, advanced pathologic stage, resection margin positivity, surgical reintervention, and blood transfusion requirement. The overall survival probability 6 years after esophagectomy was 0.920 (95% CI, 0.895-0.947), and time-to-recurrence probability was 0.988 (95% CI, 0.976-1.000), with a total of 17 recurrences and 201 deaths., Conclusions: Once patients survive 5 years, recurrence is rare. Long-term survival can be achieved in high-volume centers adhering to National Comprehensive Cancer Network guidelines using multidisciplinary care teams that is double what has been previously reported in the literature from national databases., (Published by Elsevier Inc.)

The aim of this study was to elucidate the chemistry of cellular degeneration in human neuroblastoma cells upon exposure to outer-membrane vesicles (OMVs) produced by Porphyromonas gingivalis ( Pg ) oral bacteria by monitoring their metabolomic evolution using in situ Raman spectroscopy. Pg -OMVs are a key factor in Alzheimer's disease (AD) pathogenesis, as they act as efficient vectors for the delivery of toxins promoting neuronal damage. However, the chemical mechanisms underlying the direct impact of Pg -OMVs on cell metabolites at the molecular scale still remain conspicuously unclear. A widely used in vitro model employing neuroblastoma SH-SY5Y cells (a sub-line of the SK-N-SH cell line) was spectroscopically analyzed in situ before and 6 h after Pg -OMV contamination. Concurrently, Raman characterizations were also performed on isolated Pg -OMVs, which included phosphorylated dihydroceramide (PDHC) lipids and lipopolysaccharide (LPS), the latter in turn being contaminated with a highly pathogenic class of cysteine proteases, a key factor in neuronal cell degradation. Raman characterizations located lipopolysaccharide fingerprints in the vesicle structure and unveiled so far unproved aspects of the chemistry behind protein degradation induced by Pg -OMV contamination of SH-SY5Y cells. The observed alterations of cells' Raman profiles were then discussed in view of key factors including the formation of amyloid β (Aβ) plaques and hyperphosphorylated Tau neurofibrillary tangles, and the formation of cholesterol agglomerates that exacerbate AD pathologies., Competing Interests: The authors declare no conflict of interest.

2Duf, named after the presence of a transmembrane (TM) Duf421 domain and a small Duf1657 domain in its sequence, is likely located in the inner membrane (IM) of spores in some Bacillus species carrying a transposon with an operon termed spoVA 2mob . These spores are known for their extreme resistance to wet heat, and 2Duf is believed to be the primary contributor to this trait. In this study, we found that the absence of YetF or YdfS, both Duf421 domain-containing proteins and found only in wild-type (wt) B. subtilis spores with YetF more abundant, leads to decreased resistance to wet heat and agents that can damage spore core components. The IM phospholipid compositions and core water and calcium-dipicolinic acid levels of YetF-deficient spores are similar to those of wt spores, but the deficiency could be restored by ectopic insertion of yetF , and overexpression of YetF increased wt spore resistance to wet heat. In addition, yetF and ydfS spores have decreased germination rates as individuals and populations with germinant receptor-dependent germinants and increased sensitivity to wet heat during germination, potentially due to damage to IM proteins. These data are consistent with a model in which YetF, YdfS and their homologs modify IM structure to reduce IM permeability and stabilize IM proteins against wet heat damage. Multiple yetF homologs are also present in other spore forming Bacilli and Clostridia, and even some asporogenous Firmicutes , but fewer in asporogenous species. The crystal structure of a YetF tetramer lacking the TM helices has been reported and features two distinct globular subdomains in each monomer. Sequence alignment and structure prediction suggest this fold is likely shared by other Duf421-containing proteins, including 2Duf. We have also identified naturally occurring 2duf homologs in some Bacilli and Clostridia species and in wt Bacillus cereus spores, but not in wt B. subtilis . Notably, the genomic organization around the 2duf gene in most of these species is similar to that in spoVA 2mob , suggesting that one of these species was the source of the genes on this operon in the extremely wet heat resistant spore formers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yu, Kanaan, Shames, Wicander, Aryal, Li, Korza, Brul, Kramer, Li, Nichols, Hao and Setlow.)

Aims: This work aimed to characterize spore inner membrane (IM) properties and the mechanism of spore killing by wet heat and H2O2 with spores overexpressing the 2Duf protein, which is naturally encoded from a transposon found only in some Bacillus strains with much higher spore resistance than wild-type spores., Methods and Results: Killing of Bacillus subtilis spores by wet heat or hydrogen peroxide (H2O2) was slower when 2Duf was present, and Ca-dipicolinic acid release was slower than killing. Viabilities on rich plates of wet heat- or H2O2 -treated spores +/- 2Duf were lower when NaCl was added, but higher with glucose. Addition of glucose but not Casamino acids addition increased treated spores' viability on minimal medium plates. Spores with 2Duf required higher heat activation for germination, and their germination was more wet-heat resistant than that of wild-type spores, processes that involve IM proteins. IM permeability and lipid mobility were lower in spores with 2Duf, although IM phospholipid composition was similar in spores +/- 2Duf., Conclusions: These results and previous work suggests that wet heat and H2O2 kill spores by damaging an IM enzyme or enzymes involved in oxidative phosphorylation., (© The Author(s) 2023. Published by Oxford University Press on behalf of Applied Microbiology International.)

Bacterial colonization of open wounds is common, and patients with infected wounds often report significantly elevated pain sensitivity at the wound site. Transient Receptor Potential Vanilloid Type 1 (TRPV1) channels are known to play an important role in pain signaling and may be sensitized under pro-inflammatory conditions. Bacterial membrane components, such as phosphoethanolamine dihydroceramide (PEDHC), phosphoglycerol dihydroceramide (PGDHC), and lipopolysaccharide (LPS), are released in the environment from the Gram-negative bacteria of the Bacteroidetes species colonizing the infected wounds. Here, we used intracellular calcium imaging and patch-clamp electrophysiology approaches to determine whether bacterially derived PEDHC, PGDHC, or LPS can modulate the activity of the TRPV1 channels heterologously expressed in HEK cells. We found that PEDHC and PGDHC can sensitize TRPV1 in a concentration-dependent manner, whereas LPS treatment does not significantly affect TRPV1 activity in HEK cells. We propose that sensitization of TRPV1 channels by Bacteroidetes-derived dihydroceramides may at least in part underlie the increased pain sensitivity associated with wound infections.

Reimbursement for cardiothoracic surgery continues to be threatened with enormous financial cuts ranging from 5% to 10% in recent years. In this policy perspective, we describe the history of reimbursement for cardiothoracic surgery, highlight areas in need of urgent reform, propose possible solutions that Congress and the Executive Branch may enact, and call cardiothoracic surgeons to action on this critical issue. Meaningful engagement of members of The Society of Thoracic Surgeons with their elected representatives is the only way to prevent these cuts., (Copyright © 2022. Published by Elsevier Inc.)

Like other members of the phylum Bacteroidetes , the oral anaerobe Porphyromonas gingivalis synthesizes a variety of sphingolipids, similar to its human host. Studies have shown that synthesis of these lipids (dihydroceramides [DHCs]) is involved in oxidative stress resistance, the survival of P. gingivalis during stationary phase, and immune modulation. Here, we constructed a deletion mutant of P. gingivalis strain W83 with a deletion of the gene encoding DhSphK1, a protein that shows high similarity to a eukaryotic sphingosine kinase, an enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate. Our data show that deletion of the dhSphK1 gene results in a shift in the sphingolipid composition of P. gingivalis cells; specifically, the mutant synthesizes higher levels of phosphoglycerol DHCs (PG-DHCs) than the parent strain W83. Although PG1348 shows high similarity to the eukaryotic sphingosine kinase, we discovered that the PG1348 enzyme is unique, since it preferentially phosphorylates dihydrosphingosine, not sphingosine. Besides changes in lipid composition, the W83 ΔPG1348 mutant displayed a defect in cell division, the biogenesis of outer membrane vesicles (OMVs), and the amount of K antigen capsule. Taken together, we have identified the first bacterial dihydrosphingosine kinase whose activity regulates the lipid profile of P. gingivalis and underlies a regulatory mechanism of immune modulation. IMPORTANCE Sphingoid base phosphates, such as s phingosine- 1 - p hosphate (S1P) and d i h ydro s phingosine- 1 - p hosphate (dhS1P), act as ligands for S1P receptors, and this interaction is known to play a central role in mediating angiogenesis, vascular stability and permeability, and immune cell migration to sites of inflammation. Studies suggest that a shift in ratio to higher levels of dhS1P in relation to S1P alters downstream signaling cascades due to differential binding and activation of the various S1P receptor isoforms. Specifically, higher levels of dhS1P are thought to be anti-inflammatory. Here, we report on the characterization of a novel kinase in Porphyromonas gingivalis that phosphorylates dihydrosphingosine to form dhS1P.

Oral and gut Bacteroidetes produce unique classes of serine-glycine lipodipeptides and glycine aminolipids that signal through host Toll-like receptor 2. These glycine lipids have also been detected in human arteries, but their effects on atherosclerosis are unknown. Here, we sought to investigate the bioactivity of bacterial glycine lipids in mouse models of atherosclerosis. Lipid 654 (L654), a serine-glycine lipodipeptide species, was first tested in a high-fat diet (HFD)-fed Ldlr -/- model of atherosclerosis. Intraperitoneal administration of L654 over 7 weeks to HFD-fed Ldlr -/- mice resulted in hypocholesterolemic effects and significantly attenuated the progression of atherosclerosis. We found that L654 also reduced liver inflammatory and extracellular matrix gene expression, which may be related to inhibition of macrophage activation as demonstrated in vivo by lower major histocompatibility complex class II gene expression and confirmed in cell experiments. In addition, L654 and other bacterial glycine lipids in feces, liver, and serum were markedly reduced alongside changes in Bacteroidetes relative abundance in HFD-fed mice. Finally, we tested the bioactivities of L654 and related lipid 567 in chow-fed Apoe -/- mice, which displayed much higher fecal glycine lipids relative to HFD-fed Ldlr -/- mice. Administration of L654 or lipid 567 for 7 weeks to these mice reduced the liver injury marker alanine aminotransferase, but other effects seen in Ldlr -/- were not observed. Therefore, we conclude that conditions in which gut microbiome-derived glycine lipids are lost, such as HFD, may exacerbate the development of atherosclerosis and liver injury, whereas correction of such depletion may protect from these disorders., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Toll-like receptor 2 (TLR2) activation has been implicated in the pathogenesis of periodontal disease but the identity of the TLR2 agonists has been an evolving story. The serine/glycine lipids produced by Porphyromonas gingivalis are reported to engage human TLR2 and will promote the production of potent pro-inflammatory cytokines. This investigation compared the recovery of serine/glycine lipids in periodontal organisms, teeth, subgingival calculus, subgingival plaque, and gingival tissues, either from healthy sites or periodontally diseased sites. Lipids were extracted using the phospholipid extraction procedure of Bligh and Dyer and were analyzed using liquid chromatography/mass spectrometry for all serine/glycine lipid classes identified to date in P. gingivalis . Two serine/glycine lipid classes, Lipid 567 and Lipid 1256, were the dominant serine/glycine lipids recovered from oral Bacteroidetes bacteria and from subgingival calculus samples or diseased teeth. Lipid 1256 was the most abundant serine/glycine lipid class in lipid extracts from P. gingivalis, Tannerella forsythia , and Prevotella intermedia whereas Lipid 567 was the most abundant serine/glycine lipid class recovered in Capnocytophaga species and Porphyromonas endodontalis . Serine/glycine lipids were not detected in lipid extracts from Treponema denticola, Aggregatibacter actinomycetemcomitans , or Fusobacterium nucleatum . Lipid 1256 was detected more frequently and at a significantly higher mean level in periodontitis tissue samples compared with healthy/gingivitis tissue samples. By contrast, Lipid 567 levels were essentially identical. This report shows that members of the Bacteroidetes phylum common to periodontal disease sites produce Lipid 567 and Lipid 1256, and these lipids are prevalent in lipid extracts from subgingival calculus and from periodontally diseased teeth and diseased gingival tissues., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nichols, Bhuse, Clark, Provatas, Carrington, Wang, Zhu, Davey and Dewhirst.)

Background: A prolonged air leak (PAL) is the most frequent complication after pulmonary resection. This study aimed to assess the safety and efficacy of autologous blood patch pleurodesis (ABPP) to treat PAL., Methods: A prospectively maintained database identified patients with a PAL after pulmonary resection for lung cancer between 2015-2019. In this observational cohort study, clinical data were collected to retrospectively compare patients undergoing ABPP to no ABPP in a propensity-matched analysis. Kaplan Meier estimates and Cox models accounting for inverse probability weighting (IPTW) were used to assess the association of ABPP with each outcome., Results: Of the 740 patients undergoing lung resection, 110 (15%) were identified as having a PAL at postoperative day (POD) 5. There was no difference between baseline characteristics among those undergoing ABPP (n=34) versus no ABPP (n=76). Propensity-weighted analysis did not reveal a significant association of ABPP treatment with in-hospital complication (P=0.18), hospital length of stay (LOS) (P=0.13), or post-discharge complication (P=0.13). However, ABPP treatment was associated with a lower risk of hospital readmission [P=0.02, hazard ratio (HR) 0.16] and reoperation for air leak or empyema (P=0.05, HR 0.11). Although not statistically significant, the mean chest tube (CT) removal of 11 days for the ABPP group was less than the no ABPP group (16 days) (P=0.14, HR 1.5-2). Those treated with ABPP were less likely to be discharged with a CT (ABPP 7/34, 21% vs. no ABPP 40/76, 53%). There was no statistical difference in empyema development between groups (ABPP 0/34, 0% vs. no ABPP 4/76, 5%, P=0.39, HR 0.24)., Conclusions: ABPP administration is safe compared to traditional PAL management. In a retrospective propensity-matched analysis, postoperative patients treated with ABPP required less readmission and reoperation for PAL. Larger powered randomized trials may demonstrate the magnitude of benefit from treatment with ABPP., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-20-1761). The authors have no conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Dr O.T. "Jim" Clagett was a pioneer in surgery of the great vessels and thorax. The procedure that bears his name for treatment of postpneumonectomy empyema was only one of his many innovations in aortic, lung, and esophageal surgery. He performed over 35,000 operations and trained over 115 residents during his tenure at Mayo Clinic. His distinguished career highlights include: helping develop the field of cardiothoracic surgery during its infancy, starting the Thoracic Surgery Residency Program at Mayo Clinic, serving in numerous institutional and national leadership roles, and countless awards., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Porphyromonas gingivalis is a Gram-negative anaerobic periodontal microorganism strongly associated with tissue-destructive processes in human periodontitis. Following oral infection with P. gingivalis, the periodontal bone loss in mice is reported to require the engagement of Toll-like receptor 2 (TLR2). Serine-glycine lipodipeptide or glycine aminolipid classes of P. gingivalis engage human and mouse TLR2, but a novel lipid class reported here is considerably more potent in engaging TLR2 and the heterodimer receptor TLR2/TLR6. The novel lipid class, termed Lipid 1256, consists of a diacylated phosphoglycerol moiety linked to a serine-glycine lipodipeptide previously termed Lipid 654. Lipid 1256 is approximately 50-fold more potent in engaging TLR2 than the previously reported serine-glycine lipid classes. Lipid 1256 also stimulates cytokine secretory responses from peripheral blood monocytes and is recovered in selected oral and intestinal Bacteroidetes organisms. Therefore, these findings suggest that Lipid 1256 may be a microbial TLR2 ligand relevant to chronic periodontitis in humans., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2020 Nichols et al.)

Background: Extraanatomic retrosternal and presternal esophageal reconstruction performed after esophagectomy poses a significant technical challenge to those patients who require cardiac surgery. This study reviewed a single-center experience with cardiac surgical procedures in patients with extraanatomic esophageal conduits, to examine the relative advantages of median sternotomy and thoracotomy approaches., Methods: This case series identified patients who underwent cardiac surgery after extraanatomic esophageal reconstruction between January 1, 1999 and October 1, 2019 at the Mayo Clinic in Rochester, Minnesota. Electronic medical records were reviewed for patient demographics, surgical indications, characteristics, and outcomes. Continuous variables were reported as the mean or as the median and range, as appropriate., Results: Seven individual patients had 8 cardiac surgical procedures after extraanatomic esophageal reconstruction (5 retrosternal, 2 presternal). All were male, with a median age of 65.5 years (range, 51 to 71 years). Preoperative computed tomography was obtained in all but 1 patient. Median sternotomy was performed in 4 patients, left thoracotomy in 2, right thoracotomy in 1, and right anterior thoracotomy in 1. Median bypass time was 91 minutes (interquartile range, 113.5 minutes). The median cross-clamp time was 57.5 minutes (interquartile range, 27.0 minutes). There was 1 delayed injury to a retrosternal conduit after median sternotomy approach. There were no injuries to the blood supply of any conduit. In-hospital mortality was 0%. The median length of stay was 7.5 days (range, 5 to 34 days)., Conclusions: Different cardiac surgical procedures can be performed safely in patients with extraanatomic esophageal reconstructions through median sternotomy or thoracotomy. Preoperative planning with computed tomography with intravenous contrast enhancement of the chest, abdomen, and pelvis is essential for individualization of the surgical approach., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Patient-reported reflux is among the most common symptoms after esophagectomy. This study aimed to determine predictors of patient-reported reflux and to ascertain whether a preserved pylorus would protect patients from symptomatic reflux., Methods: A prospective clinical study recorded patient-reported reflux after esophagectomy from August 2015 to July 2018. Eligible patients were at least 6 months from creation of a traditional posterior mediastinal gastric conduit, had completed at least 1 reflux questionnaire, and had the pylorus treated either temporarily (≥100 IU Botox [onabotulinumtoxinA]) or permanently (pyloromyotomy or pyloroplasty)., Results: Of the 110 patients meeting inclusion criteria, the median age was 65 years, and 88 of the 110 (80%) were male. Botox was used in 15 (14%) patients, pyloromyotomy in 88 (80%), and pyloroplasty in 7 (6%). A thoracic anastomosis was performed in 78 (71%) patients, and a cervical anastomosis was performed in 32 (29%). Esophagectomy was performed for malignant disease in 105 of 110 (95%), and 78 of 110 (71%) patients were treated with perioperative chemoradiation. Multivariable linear regression analysis revealed that patient-reported reflux was significantly worse in patients with shorter gastric conduit lengths (P = .02) and in patients who did not undergo perioperative chemoradiation (P = .01). No significant difference was found between patients treated with pyloric drainage and those treated with Botox., Conclusions: The absence of perioperative chemoradiation therapy and a shorter gastric conduit were predictors of patient-reported reflux after esophagectomy. Although few patients had Botox, preservation of the pylorus did not appear to affect patient-reported reflux. Further objective studies are needed to confirm these findings., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the safety and local recurrence-free survival in patients after cryoablation for treatment of pulmonary metastases., Methods: This multicenter, prospective, single-arm, phase 2 study included 128 patients with 224 lung metastases treated with percutaneous cryoablation, with 12 and 24 months of follow-up. The patients were enrolled on the basis of the outlined key inclusion criteria, which include one to six metastases from extrapulmonary cancers with a maximal diameter of 3.5 cm. Time to progression of the index tumor(s), metastatic disease, and overall survival rates were estimated using the Kaplan-Meier method. Complications were captured for 30 days after the procedure, and changes in performance status and quality of life were also evaluated., Results: Median size of metastases was 1.0 plus or minus 0.6 cm (0.2-4.5) with a median number of tumors of 1.0 plus or minus 1.2 cm (one to six). Local recurrence-free response (local tumor efficacy) of the treated tumor was 172 of 202 (85.1%) at 12 months and 139 of 180 (77.2%) at 24 months after the initial treatment. After a second cryoablation treatment for recurrent tumor, secondary local recurrence-free response (local tumor efficacy) was 184 of 202 (91.1%) at 12 months and 152 of 180 (84.4%) at 24 months. Kaplan-Meier estimates of 12- and 24-month overall survival rates were 97.6% (95% confidence interval: 92.6-99.2) and 86.6% (95% confidence interval: 78.7-91.7), respectively. Rate of pneumothorax that required pleural catheter placement was 26% (44/169). There were eight grade 3 complication events in 169 procedures (4.7%) and one (0.6%) grade 4 event., Conclusion: Percutaneous cryoablation is a safe and effective treatment for pulmonary metastases., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The objective of this initiative was to perform a prospective, multicenter survey of patients after lung resection to assess the amount of opioid medication consumed and the disposition of unused opioids to inform the development of evidence-based prescribing guidelines., Methods: Adults undergoing lung resection with either minimally invasive surgery (MIS; n = 108) or thoracotomy (n = 45) were identified prospectively from 3 academic centers (from March 2017 to January 2018) to complete a 28-question telephone survey 21 to 35 days after discharge. Discharge opioids were converted into morphine milligram equivalents (MME) and were compared across patient and surgical details., Results: Of the 153 patients who completed the survey, 89.5% (137) received opioids at discharge with a median prescription of 320 MME (interquartile range [IQR], 225, 450 MME) after MIS and 450 MME (IQR, 300, 600 MME) after thoracotomy (P = .001). Median opioid consumption varied by surgical approach: 90 MME (IQR, 0, 262.5) after MIS and 300 MME (IQR, 50, 382.5 MME) after thoracotomy (P < .001). The majority of patients (73.7%; 101) had residual opioid medication at the time of the survey, and patients after MIS had a relative increase in amount of remaining opioid medication: 58.3% vs 33.3% (P = .05) of the original prescription. Only 5.9% of patients with opioids remaining had properly disposed of them., Conclusions: Although patients undergoing MIS lung resection used significantly less opioid medication over a shorter duration of time than did patients after thoracotomy, they had relatively more excess opioid prescription. Evidence-based, procedure-specific guidelines with tailored pain regimens should be developed and implemented to reduce the amount of postoperative opioid medication remaining in the community., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The optimal treatment sequence for localized malignant pleural mesothelioma (MPM) is controversial. We aimed to assess outcomes and toxicities of treating localized MPM with neoadjuvant radiation therapy (RT) followed by extrapleural pneumonectomy (EPP). Methods: Patients were enrolled on an institutional protocol of surgery for mesothelioma after radiation therapy (SMART) between June 2016 and May 2017. Eligible patients were adults with MPM localized to the ipsilateral pleura. Patients underwent staging with PET/CT, pleuroscopy, bronchoscopy/EBUS, mediastinoscopy, and laparoscopy. Five fractions of RT were delivered using intensity modulated radiation therapy (IMRT), with 30 Gy delivered to gross disease and 25 Gy to the entire pleura. EPP was performed 4-10 days following completion of RT. Results: Five patients were treated on protocol. Median age was 62 years (range 36-66). Histology was epithelioid on initial biopsy in all patients, but one was found to have biphasic histology after surgery. Three patients had surgeon-assessed gross total resection, and two had gross residual disease. While all patients were clinically node negative by pretreatment staging, three had positive nodal disease at surgery. Patients were hospitalized for a median 24 days (range 5-69) following surgery. Two patients developed empyema, one of whom developed respiratory failure and subsequently renal failure requiring dialysis, while the other required multiple surgical debridements. Two patients developed atrial fibrillation with rapid ventricular response after surgery, one of whom developed acute respiratory distress requiring intubation and tracheostomy. At last follow-up, one patient died at 1.4 years after local and distant progression, two were alive with local and distant progression, and the remaining two were alive without evidence of disease at 0.1 and 2.7 years. Median time to progression was 9 months. Three patients received salvage chemotherapy. Conclusions: SMART provided promising oncologic outcomes at the cost of significant treatment related morbidity. Due to the significant treatment associated morbidity and favorable treatment alternatives, we have not broadly adopted SMART at our institution., (Copyright © 2020 Breen, Garces, Olivier, Park, Merrell, Nichols, Peikert, Molina, Mansfield, Roden, Blackmon and Wigle.)

The serine-glycine dipeptide lipid classes, including lipid 430 and lipid 654, are produced by the periodontal pathogen Porphyromonas gingivalis and can be detected in lipid extracts of diseased periodontal tissues and teeth of humans. Both serine-glycine lipid classes were previously shown to engage human and mouse Toll-like receptor 2 (TLR2) and to inhibit mouse osteoblast differentiation and function through engagement of TLR2. It is not clear if other lipids related to serine-glycine lipids are also produced by P. gingivalis The goal of this investigation was to determine whether P. gingivalis produces additional lipid classes similar to the serine-glycine lipids that possess biological properties. P. gingivalis (ATCC 33277) was grown in broth culture, and lipids were extracted and fractionated by high-performance liquid chromatography (HPLC). Lipids were separated using semipreparative HPLC, and specific lipid classes were identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography-multiple reaction monitoring (LC-MRM) mass spectrometric approaches. Two glycine lipid classes were identified, termed lipid 567 and lipid 342, and these lipid classes are structurally related to the serine-glycine dipeptide lipids. Both glycine lipid classes were shown to promote TLR2-dependent tumor necrosis factor alpha (TNF-α) release from bone marrow macrophages, and both were shown to activate human embryonic kidney (HEK) cells through TLR2 and TLR6 but not TLR1. These results demonstrate that P. gingivalis synthesizes glycine lipids and that these lipids engage TLR2 similarly to the previously reported serine-glycine dipeptide lipids., (Copyright © 2020 American Society for Microbiology.)

Objective: To collect patient-reported outcomes after esophagectomy to establish a set of preliminary normative standards to aid in symptom-score interpretation., Patients and Methods: Patients undergoing esophagectomy often have little understanding about postoperative symptom management. The Mayo Clinic esophageal CONDUIT tool is a validated questionnaire comprising 5 multi-item symptom-assessment domains and 2 health-assessment domains. A prospective nonrandomized cohort study was conducted on adult patients who have had esophagectomies using the CONDUIT tool from August 17, 2015, to July 30, 2018 (NCT02530983). The Statistical Analysis System v9.4 (SAS Institute Inc., Cary, NC) was used to calculate and analyze the scores., Results: Over the study period, 569 patients were assessed for eligibility, and 241 patients consented and were offered the tool. Of these, 188 patients (median age: 65 years; range: 24 to 87 years; 80% male patients) had calculable scores. Of the 188 patients, 50 (26.6%) patients were identified as potential beneficiaries for educational intervention to improve symptoms (received moderate scores for a domain), and 131 (69.7%) patients were identified as needing further testing or provider intervention (received poor scores for a domain) based on the tool., Conclusion: The CONDUIT tool scores, when compared with standardized scales with established preliminary normative scores, could be used to identify and triage patients who need targeted education, further testing, or provider interventions. These score ranges will serve as the first set of normative standards to aid in the interpretation of conduit performance among providers and patients., (© 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

Purpose: To evaluate the incidence of major hemorrhage after image-guided percutaneous chest tube placement in patients with an abnormal international normalized ratio (INR) measured before the procedure., Materials and Methods: Between January 2013 and September 2017, 49 image-guided percutaneous chest tubes were placed in 45 adult patients who had an elevated INR of greater than 1.6. Data collected included routine serum pre-procedure coagulation studies, indication for chest tube placement, insertion technique, size of chest tube, and presence of complications after drain placement. Major bleeding complications were defined using the Society of Interventional Radiology classification system., Results: Mean patient age was 62 years (range, 22-94 years), with median American Society of Anesthesiologists score of 4. Mean INR was 2.1 (range, 1.7-3), with 21 (43%) procedures with an INR between 1.7 and 1.9, 20 (41%) procedures with an INR between 2.0 and 2.4, and 8 (16%) procedures with an INR between 2.5 and 3.0. Computed tomography guidance was used for 27 (55%) procedures; ultrasound guidance was used for 22 (45%) procedures. Median size of chest tube was 10 Fr (range, 8-14 Fr) used in 27 (55%) procedures. No major bleeding complications were observed. There was a small, significant decrease in mean hemoglobin after the procedure (mean = 0.9g/dL; P < .0001), which correlated to increasing chest tube size (P = .0269)., Conclusions: No major bleeding complications were observed after image-guided percutaneous chest tube placement in patients with an elevated INR. Major bleeding complications in these patients may be safer than initially considered, and this study encourages the conduct of larger trials for further evaluation., (Copyright © 2019 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by both inflammatory demyelination and impaired remyelination. Studies indicate that Toll-like receptor 2 (TLR2) signaling contributes to both the inflammatory component and the defective remyelination in MS. While most MS therapeutics target adaptive immunity, we recently reported that reducing TLR2 signaling in innate immune cells by inducing TLR2 tolerance attenuates adoptively transferred experimental autoimmune encephalomyelitis. Given that previous reports suggest TLR2 signaling also inhibits myelin repair, the objective of this study was to assess how reducing TLR2 signaling through TLR2 tolerance induction affects CNS myelin repair., Methods: Chow containing 0.2% cuprizone was fed to male and female wild-type (WT) C57BL/6 mice or TLR2-deficient (TLR2 -/- ) mice for 5 weeks to induce demyelination. During a 2-week remyelination period following discontinuation of cuprizone, WT mice received either low dose TLR2 ligands to induce systemic TLR2 tolerance or vehicle control (VC). Remyelination was evaluated via electron microscopy and immunohistochemical analysis of microglia and oligodendrocytes in the corpus callosum. Statistical tests included 2-way ANOVA and Mann-Whitney U analyses., Results: Inducing TLR2 tolerance in WT mice during remyelination significantly enhanced myelin recovery, restoring unmyelinated axon frequency and myelin thickness to baseline levels compared to VC-treated mice. Mechanistically, enhanced remyelination in TLR2 tolerized mice was associated with a shift in corpus callosum microglia from a pro-inflammatory iNOS + phenotype to a non-inflammatory/pro-repair Arg1 + phenotype. This result was confirmed in vitro by inducing TLR2 tolerance in WT microglia cultures. TLR2 -/- mice, without TLR2 tolerance induction, also significantly enhanced myelin recovery compared to WT mice, adding confirmation that reduced TLR2 signaling is associated with enhanced remyelination., Discussion: Our results suggest that reducing TLR2 signaling in vivo by inducing TLR2 tolerance significantly enhances myelin repair. Furthermore, the enhanced remyelination resulting from TLR2 tolerance induction is associated with a shift in corpus callosum microglia from a pro-inflammatory iNOS + phenotype to a non-inflammatory/pro-repair Arg1 + phenotype. While deletion of TLR2 would be an impractical approach in vivo, reducing innate immune signaling through TLR2 tolerance induction may represent a novel, two-pronged approach for treating both inflammatory and myelin repair components of MS.

Objective: The purpose of this retrospective cohort study was to evaluate resource consumption of clinically significant esophageal anastomotic leaks., Methods: Between September 1, 2008, to December 31, 2014, a prospectively maintained database was queried to identify patients with grade III to IV anastomotic leaks after esophagectomy for esophageal cancer. Inflation-adjusted standardized costs were applied to billed services related to leak diagnosis and treatment, from time of leak detection to resumption of oral diet. A matched analysis was used to compare average expenditures in patients without vs. those with an anastomotic leak., Results: Of 448 patients undergoing esophagectomy after neoadjuvant treatment, 399 patients met inclusion criteria. Twenty-four grade III to IV anastomotic leaks were identified (6% leak rate). Five transhiatal esophagectomies accounted for 20.8% of cases, whereas 9 Ivor Lewis and 10 McKeown esophagectomies accounted for 37.5% and 41.7%, respectively. The median time required to treat an anastomotic leak was 73 days (range 14-701). The additional median standardized cost per leak was $68,296 (mean $119,822). Matched analysis demonstrated that mean treatment costs were 2.6 times greater for patients with an anastomotic leak. This was primarily attributed to prolonged hospitalization, with post-leak detection length of stay ranging from 7 to 73 days. The largest contributors to cost for all patients were intensive care stay (30%), hospital room (17%), pharmacy (16%), and surgical intervention (13%)., Conclusions: Grade III to IV esophageal anastomotic leaks more than double the cost of an esophagectomy and have a significant cost burden. Focus should be placed on preventative measures to avoid leaks at the time of the index operation., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Morgagni hernias are rare congenital diaphragmatic hernias that often do not become clinically significant until adulthood. The purpose of this study was to characterize the preoperative findings and describe surgical outcomes of Morgagni hernia repair based on operative approach., Methods: Charts of patients who underwent repair of a Morgagni hernia were retrospectively reviewed from 1987 to 2015. Medical records were reviewed for demographics, symptoms, comorbidities, surgical approach, hospital course, complications, and preoperative imaging., Results: Forty-three cases were identified, 23 male and 20 female. Median age was 50.4 years, and median body mass index was 33.1 kg/m 2 . Most common presenting symptoms were respiratory (35.7%) and gastrointestinal (28.6%). Although 83.3% of cases were newly diagnosed, none required emergent repair. Preoperative imaging demonstrated an average hernia size of 8.2 cm. Surgical approaches included laparotomy (62.8%), laparoscopic (23.3%), and thoracotomy (14%). Primary hernia repair was most common (72%). Comparing laparotomy, thoracotomy, and laparoscopic approaches, mesh repair was more common with laparoscopy (p = 0.005), operative time was shortest with laparotomy (p = 0.029), and hospital length of stay was shortest with laparoscopy (p = 0.024). The most common complication was incisional/port site hernia, with no statistical significance between surgical approaches. There was one Morgagni hernia recurrence., Conclusions: Morgagni hernias often present with respiratory and gastrointestinal symptoms and require repair. All cases in our series were repaired electively. Regardless of approach recurrence rate was low (2.3%) and complication rate was similar between laparoscopic, laparotomy, and thoracotomy. Given the shorter length of stay with similar recurrence rates, a laparoscopic approach is a viable option for repair of Morgagni hernia., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms. Most follow a benign course, but a subset will recur or metastasize. Various risk stratification schemes have been proposed for SFTs, but none has been universally endorsed and few have focused on pleuropulmonary SFTs., Methods: Histologic sections from surgically resected pleuropulmonary SFTs were examined, with confirmatory immunohistochemistry. Patients were risk-stratified by using four prediction models as proposed by de Perrot, Demicco (original and modified), and Tapias. Kaplan-Meier analysis was used to estimate overall survival (OS) and progression-free survival (PFS)., Results: The 147 study patients included 78 females (53.1%) with a median age of 61.5 years (range 25-87). The median follow-up was 5.5 years (range 0-33). Recurrence or metastasis occurred in 15 patients (10.2%), with five deaths from disease. Significant predictors of worse OS included male sex, age at least 55 years, tumor size at least 10 cm, nonpedunculated growth, severe atypia, necrosis, and mitotic count of at least four per 10 high-power fields. Predictors of recurrence included tumor size of at least 10 cm, severe atypia, necrosis, at least four mitoses per 10 high-power fields, and Ki67 labeling index of at least 2%. All systems predicted PFS, but only the Demicco and Tapias systems significantly predicted OS. The modified Demicco system provided the best discrimination for PFS (C-statistic = 0.80 compared with 0.78)., Conclusion: The risk scoring systems proposed by Tapias et al. and Demicco et al. were both predictive of OS and PFS. The Demicco system has the advantages of simplicity and applicability to SFTs from other sites, as well as provision of the best discrimination for PFS, and thus may be the best system to apply in general practice., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Laparoscopic Nissen fundoplication is the most commonly performed operation for the repair of large hiatal hernias. We compared outcomes between the Belsey Mark IV fundoplication and the laparoscopic Nissen fundoplication., Methods: A retrospective review was performed over a 10-year period on patients who had repair of large paraesophageal hernia. Patients who received the Belsey Mark IV (n = 118) were matched 1 to 1, by year of surgery, gender, and age, with patients who received laparoscopic Nissen fundoplication. We compared these 2 groups, examining recurrence, need for reoperation, perioperative outcomes, and symptomatic follow-up as defined by the Gastroesophageal Reflux Disease-Health Related Quality of Life questionnaire., Results: Recurrence rates were similar between patients who had a Belsey Mark IV and laparoscopic Nissen fundoplication (8.4% vs 16.1%, P = .11). However, the esophageal leak rate was higher in patients who received a laparoscopic Nissen fundoplication compared with the Belsey Mark IV (6.8% vs 0%, respectively, P = .006), and patients who received a laparoscopic Nissen fundoplication had higher rates of reoperation (9.3% vs 2.5%, respectively, P = .05). Gastroesophageal Reflux Disease-Health Related Quality of Life symptom scores were similar between groups with symptoms in laparoscopic Nissen fundoplication and Belsey Mark IV, being excellent (74.4% vs 81.4%), good (9.3% vs 7.0%), fair (9.3% vs 0), and poor (7.0% vs 11.6%), respectively (P = .52)., Conclusions: Laparoscopic Nissen fundoplication for large paraesophageal hernias was associated with an increased incidence of leak and reoperation when compared with Belsey fundoplication. Belsey Mark IV fundoplication should be considered when deciding on what operation to perform in patients with large paraesophageal hernias., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

The keystone periodontal pathogen Porphyromonas gingivalis produces phosphorylated dihydroceramide lipids (sphingolipids) such as phosphoethanolamine dihydroceramide (PE DHC) and phosphoglycerol dihydroceramide (PG DHC) lipids. Phosphorylated DHCs (PDHCs) from P. gingivalis can affect a number of mammalian cellular functions, such as potentiation of prostaglandin secretion from gingival fibroblasts, promotion of RANKL-induced osteoclastogenesis, promotion of apoptosis, and enhancement of autoimmunity. In P. gingivalis , these lipids affect anchoring of surface polysaccharides, resistance to oxidative stress, and presentation of surface polysaccharides (anionic polysaccharides and K-antigen capsule). In addition to phosphorylated dihydroceramide lipids, serine dipeptide lipids of P. gingivalis are implicated in alveolar bone loss in chronic periodontitis through interference with osteoblast differentiation and function and promotion of osteoclast activity. As a prerequisite for designation as bacterial virulence factors, bacterial sphingolipids and serine dipeptide lipids are recovered in gingival/periodontal tissues, tooth calculus, human blood, vascular tissues, and brain. In addition to P. gingivalis , other bacteria of the genera Bacteroides , Parabacteroides , Porphyromonas , Tannerella , and Prevotella produce sphingolipids and serine dipeptide lipids. The contribution of PDHCs and serine dipeptide lipids to the pathogenesis of periodontal and extraoral diseases may be an underappreciated area in microbe-host interaction and should be more intensively investigated., (Copyright © 2018 American Society for Microbiology.)

Background: Persistent air leak can complicate pulmonary resection, and one management option is dismissal with a chest tube in place. This study evaluated the rate of empyema and readmission after dismissal with a chest tube., Methods: A retrospective review of our prospective database from January 2004 to December 2013 identified 236 patients who were discharged from our institution with an indwelling chest tube and attached one-way valve for air leak. Empyema was defined by leukocytosis or fever and undrained effusion on chest roentgenogram or computed tomography. Readmission was defined as readmission for any reason. Logistic regression analyses were performed to identify risk factors for empyema or readmission., Results: Median age was 67 years (range, 18 to 91 years). Median chest tube duration was 18 days (range, 6 to 90 days). Empyema occurred in 40 patients (16.9%), and 62 patients (26.3%) were readmitted. Treatment required included antibiotics alone in 45% (18 of 40), further drainage in 30% (12 of 40), fibrinolytic therapy in 12.5% (5 of 40), and operative decortication in 12.5% (5 of 40). Predictors of empyema included male sex, coronary artery disease, and peripheral vascular disease. A secondary analysis grouping patients into an earlier era (2004 to 2008) vs a later era (2009 to 2013) revealed that the use of thoracoscopy increased from 34% to 48% of lung resections and dismissal with a chest tube increased from 3.4% to 4.5% (p = 0.03)., Conclusions: Dismissal with an indwelling chest tube is not without consequence, having significant risk for further complications and potential need for additional interventions., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Goal: The purpose of this study was to characterize outcomes of esophagorespiratory fistulas (ERF) by etiology and initial treatment strategy., Background: ERF is a morbid condition for which optimal treatment strategies and outcomes are still in evolution., Study: Medical records and images were reviewed for all patients diagnosed with ERF at Mayo Clinic in Rochester, MN, between September 1, 2001 and January 1, 2012. Fistulas were classified as malignant or benign. Treatment strategies were classified as surgical or nonsurgical (typically esophageal stent placement). Technical and clinical success, survival, and survival free of second intervention were assessed., Results: A total of 123 patients with acquired ERF were identified, of whom 65 (53%) were malignant and 58 (47%) benign. Initial treatment strategy was nonsurgical in 88 (72%) patients and surgical in 35 (28%); lower Charlson comorbidity scores were associated with increased likelihood of surgery. Technical and clinical success was seen in a majority of patients treated both surgically and nonsurgically. Patients with malignant ERF treated surgically survived longer than patients undergoing nonsurgical treatment (hazard ratio=5.6, P=0.005). In contrast, those with benign ERF had similar overall survival regardless of whether they received initial surgical or nonsurgical treatment; reintervention was more common in those who underwent nonsurgical treatment (hazard ratio=2.3, P=0.03)., Conclusions: We conclude that survival in malignant ERF is better with surgical intervention in selected patients. Surgical and nonsurgical techniques achieve similar survival in benign ERF, but reintervention is more common in those treated endoscopically.

Chyloptysis is a rare clinical presentation. Diagnosis is challenging and requires recognition of milky-sputum or bronchial casts. We describe a case of chyloptysis secondary to thoracic lymphangiectasia that necessitated surgical ligation of the main thoracic duct and accessory branches. The patient had no postoperative complications, and at 6-month follow-up remained symptom-free. A paucity of literature describes the management of chyloptysis. We review diagnosis, treatment considerations and operative principles., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Postoperative chylothorax can be managed by any or all of observation, parenteral nutrition, surgical duct ligation, pleurodesis, or thoracic duct embolization. The objective of this study was to determine the efficacy of standard therapies, such as surgical duct ligation and observation, compared with newer treatment methods (thoracic duct embolization)., Methods: A prospectively maintained database at a single institution was used to identify and review patients with postoperative chylothorax from 2008 to 2015., Results: Postoperative chylothorax occurred in 97 patients, including 54 men (56%). The median age was 61 years (range, 24 to 87 years). Thoracic duct leak followed esophagectomy in 46 patients (47%), pulmonary resection in 30 (31%), mediastinal mass resection in 7 (8%), and after other procedures in 15. Of 28 medically observed patients achieving resolution without intervention, the median peak chest tube output in 24 hours was 725 mL compared with 1,910 mL in the group that required intervention (p = 0.0001). Thoracic duct ligation was successful in 44 of 52 patients that proceeded to the operating room (85%). Of the 40 patients undergoing diagnostic lymphangiography, a leak was identified in 34 (85%), but the cisterna chyli could only be cannulated in 19 (48%) and was subsequently successful in 15 (38%)., Conclusions: Patients with chylous chest tube outputs of 1,100 mL or more in 24 hours postoperatively should be considered for intervention. Intention-to-treat analysis shows surgical duct ligation is more effective than thoracic duct embolization, with the ability to cannulate the cisterna chyli being the limiting factor. Lymphangiography may help determine which patients are better treated with ligation or embolization., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The current national trends, practice patterns, and outcomes after sleeve resection compared with pneumonectomy in the United States are not known. In addition, whether hospital sleeve-to-pneumonectomy (S:P) ratios are a valid marker of hospital quality is unclear. We describe practice patterns and evaluate the utility of the S:P ratio., Methods: We identified all patients (N = 23,964) undergoing sleeve resection (n = 1,713) or pneumonectomy (n = 22,251) in the National Cancer Data Base between 1998 and 2012 at 644 hospitals. We used propensity score matching to compare short-term outcomes and overall survival between pneumonectomy and sleeve resection. We grouped hospitals into S:P ratio quintiles and used multilevel modeling to analyze hospital-level outcomes., Results: There has been a 1% yearly increase in sleeve resection rates, with wide variation in hospital S:P ratios (middle quintile, 1:12; range, 1:38 to 1:3). After propensity score matching, differences in age, clinical T and N stage, and the incidence of main bronchus tumors were negligible among other variables. Sleeve resections were associated with lower 30-day (1.6% vs 5.9%; p < 0.001) and 90-day mortality (4% vs 9.4%; p < 0.001) and improved overall survival. Hospitals with higher S:P ratios were not associated with better risk-adjusted 30-day (7.2% vs 7.4%; p = 0.244) or 90-day mortality (11.9% vs 12.2%; p = 0.308) or same-hospital readmission rates (3.7% vs 4.3%; p = 0.523)., Conclusions: Compared with pneumonectomy, sleeve resections are associated with improved short-term outcomes and improved overall survival. However, hospital S:P ratios were not associated with better risk-adjusted outcomes and thus may not be a valid quality measure., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Dispute arises in the tumor category of non-small cell lung cancer invading the fissure to the adjacent lobe. The purpose of this study is to determine the long-term prognosis of non-small cell lung cancer with such an invasion and to propose an appropriate T category., Methods: In total, 53 cases of non-small cell lung cancer invading the fissure to the adjacent lobe (fissure group) were identified in patients who underwent pulmonary resection from 1997 to 2014. Propensity score matching was applied to balance known confounders for prognosis between each paired group, resulting in 3 matched sets (fissure vs T2a, fissure vs T2b, and fissure vs T3). The overall survival of the fissure group was compared with the survival of patients with T2a, T2b, and T3 diseases, as classified in the eighth edition of TNM classification., Results: The 5-year survivals of the T2a, T2b, T3, and fissure groups were 64.2% (95% confidence interval, 53.2-72.6), 54.6% (95% confidence interval, 44.7-65.8), 35.8% (95% confidence interval, 22.8-44.2), and 38.6% (95% confidence interval, 25.0-52.2), respectively. Specifically, the difference between the fissure group and T2a is statistically significant at P = .01; between the fissure group and T2b at P = .02; and between the fissure group and T3 at P = .93. Multivariate analyses indicate that the fissure group had a similar risk of dying as the T3 disease group (hazard ratio, 1.10; 95% confidence interval, 0.69-1.37) and was at a significantly higher risk compared with the T2a group (hazard ratio, 2.34; 95% confidence interval, 1.50-3.39) and T2b group (hazard ratio, 1.71; 95% confidence interval, 1.19-2.76)., Conclusions: On the basis of our single-institution study, we propose that non-small cell lung cancer invading the fissure to the adjacent lobe should be further investigated and the impact on patients' prognoses validated as a T3 disease., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Multiple reaction monitoring-MS analysis of lipid extracts from human carotid endarterectomy and carotid artery samples from young individuals consistently demonstrated the presence of bacterial serine dipeptide lipid classes, including Lipid 654, an agonist for human and mouse Toll-like receptor (TLR)2, and Lipid 430, the deacylated product of Lipid 654. The relative levels of Lipid 654 and Lipid 430 were also determined in common oral and intestinal bacteria from the phylum Bacteroidetes and human serum and brain samples from healthy adults. The median Lipid 430/Lipid 654 ratio observed in carotid endarterectomy samples was significantly higher than the median ratio in lipid extracts of common oral and intestinal Bacteroidetes bacteria, and serum and brain samples from healthy subjects. More importantly, the median Lipid 430/Lipid 654 ratio was significantly elevated in carotid endarterectomies when compared with control artery samples. Our results indicate that deacylation of Lipid 654 to Lipid 430 likely occurs in diseased artery walls due to phospholipase A2 enzyme activity. These results suggest that commensal Bacteriodetes bacteria of the gut and the oral cavity may contribute to the pathogenesis of TLR2-dependent atherosclerosis through serine dipeptide lipid deposition and metabolism in artery walls., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)

Introduction: Multifocal lung cancer is an increasingly common clinical scenario, but there is lack of high-level evidence for its optimal treatment. Thus, we surveyed members of the interdisciplinary International Association for the Study of Lung Cancer on their therapeutic approaches and analyzed the resultant practice patterns., Methods: We described the clinical scenario of an otherwise healthy 60-year-old man with bilateral pulmonary nodules and asked the 6373 members of the International Association for the Study of Lung Cancer whether they would recommend surgery, and if so, the extent of surgery. We also asked what other measures would be recommended to complete the staging and whether radiation therapy or chemotherapy would be suggested., Results: We received 221 responses (response rate 3.5%) from multiple specialists. Most respondents (140 [63%]) recommended surgery for this scenario. Surgeons were significantly more likely to recommend surgery than were those in other specialties. Of those who recommended surgery, most would obtain a PET/CT scan to rule out distant metastases and a magnetic resonance imaging scan to rule out brain metastases; but in the absence of radiographic lymph node involvement, most would not stage the mediastinum by bronchoscopy or mediastinoscopy before resection. When surgery was not recommended or declined, respondents commonly recommended radiation., Conclusions: This survey suggests that therapeutic recommendations for multifocal lung cancer are influenced to a large extent by physicians' specialty training, probably because of the lack of high-level evidence for its standard treatment. Ongoing systematic and multidisciplinary approaches with robust short-term and long-term patient outcomes may improve the quality of evidence for the optimal management of this clinical entity., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Bacterial serine dipeptide lipids are known to promote inflammatory processes and are detected in human tissues associated with periodontal disease or atherosclerosis. Accurate quantification of bacterial serine lipid, specifically lipid 654 [((S)-15-methyl-3-((13-methyltetradecanoyl)oxy)hexadecanoyl)glycyl-l-serine, (3S)-l-serine] isolated from Porphyromonas gingivalis, in biological samples requires the preparation of a stable isotope internal standard for sample supplementation and subsequent mass spectrometric analysis. This report describes the convergent synthesis of a deuterium-substituted serine dipeptide lipid, which is an isotopically labeled homologue that represents a dominant form of serine dipeptide lipid recovered in bacteria., (Copyright © 2017 John Wiley & Sons, Ltd.)