Single cell view of tumor microenvironment gradients in pleural mesothelioma.

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing to de novo identify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Throughout cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A-HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases.

Sleep, Nutrition, and Health Maintenance in Cardiothoracic Surgery.

Cardiothoracic surgeons work in high-intensity environments starting in surgical training and throughout their careers. They deal with critical patients. Their routine procedures are delicate, require extensive attention to detail, and can have detrimental effects on patients' lives. Cardiothoracic surgeons are required to perform at their best capacity incessantly. To do this, they must safeguard their mental and physical well-being. Preserving health through sleep, nutrition, exercise, and routine medical checkups ensures a cardiothoracic surgeon's well-being. Great personal effort and discipline is required to maintain health in a busy schedule. We offer our best recommendations from expert peers in the field.

The International Association for the Study of Lung Cancer Pleural Mesothelioma Staging Project: Proposal for Revision of the TNM Stage Groupings in the Forthcoming (Ninth) Edition of the TNM Classification for Pleural Mesothelioma.

INTRODUCTION: The eighth edition of the TNM classification of pleural mesothelioma (PM) saw substantial changes in T and N components and stage groupings. The International Association for the Study of Lung Cancer collected data into a multinational database to further refine this classification. This ninth edition proposal incorporates changes proposed in the clinical (c)T component but not the pathologic T component, to include size criteria, and further refines TNM stage groupings for PM. METHODS: Data were submitted through electronic data capture or batch transfer from institutional databases. Survival was measured from diagnosis date. Candidate stage groups were developed using a recursive partitioning and amalgamation algorithm applied to all cM0 cases for clinical stage and subsequently for pathologic stage. Cox models were developed to estimate survival for each stage group. RESULTS: Of 3598 submitted cases, 2192 were analyzable for overall clinical stage and 445 for overall pathologic stage. Recursive partitioning and amalgamation generated survival tree on overall survival outcomes restricted to cM0, with newly proposed (ninth edition) cT and cN component-derived optimal stage groupings of stage I (T1N0), II (T1N1; T2N0), IIIA (T1N2; T2N1/2; any T3), IIIB (any T4), and IV (any M1). Although cT and pathologic T descriptors are different in the ninth edition, aligning pathologic stage groupings with clinical stage produced better discrimination than did retaining eighth edition pathologic stage groupings. CONCLUSIONS: To our knowledge, this revision of the clinical TNM classification for PM is the first to incorporate the measurement-based proposed changes in cT category. The pathologic TNM aligns with clinical TNM.

The International Association for the Study of Lung Cancer Mesothelioma Staging Project: Proposals for the "N" Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Pleural Mesothelioma.

INTRODUCTION: The International Association for the Study of Lung Cancer developed an international database to inform potential revisions in the ninth edition of the TNM classification of diffuse pleural mesothelioma (PM). This study analyzed the clinical and pathologic N categories to determine whether revisions were indicated relative to the eighth edition staging system. METHODS: Of 7338 PM cases diagnosed from 2013 to 2022 and 3598 met all inclusion criteria for planned analyses. Data on 2836 patients without metastases were included in this study. Overall survival (OS) was measured from date of diagnosis. Patients were included regardless of whether they received neoadjuvant treatment. For the pathologic N analysis, patients who underwent resection (extrapleural pneumonectomy or pleurectomy/decortication) were included. N subgroups were analyzed and OS assessed by the Kaplan-Meier method. RESULTS: The existing eighth edition N categories were performed adequately in the ninth edition data set. A median OS advantage was noted for clinical and pathologic N0 versus N1 patients: 23.2 versus 18.5 and 33.8 versus 25.0 months, respectively. Patients with resected pN0 had a 3-year OS of 48%. No difference in OS was noted for single- versus multiple-station nodal metastases. The number of nodal stations sampled at the time of resection was not associated with a difference in OS. CONCLUSIONS: Data regarding clinical and pathologic N categories corroborate those used in the eighth edition. No changes in the N categories are recommended in the ninth edition of PM staging system.

American Radium Society Appropriate Use Criteria for Unresectable Locally Advanced Non-Small Cell Lung Cancer.

Importance: The treatment of locally advanced non-small cell lung cancer (LA-NSCLC) has been informed by more than 5 decades of clinical trials and other relevant literature. However, controversies remain regarding the application of various radiation and systemic therapies in commonly encountered clinical scenarios. Objective: To develop case-referenced consensus and evidence-based guidelines to inform clinical practice in unresectable LA-NSCLC. Evidence Review: The American Radium Society (ARS) Appropriate Use Criteria (AUC) Thoracic Committee guideline is an evidence-based consensus document assessing various clinical scenarios associated with LA-NSCLC. A systematic review of the literature with evidence ratings was conducted to inform the appropriateness of treatment recommendations by the ARS AUC Thoracic Committee for the management of unresectable LA-NSCLC. Findings: Treatment appropriateness of a variety of LA-NSCLC scenarios was assessed by a consensus-based modified Delphi approach using a range of 3 points to 9 points to denote consensus agreement. Committee recommendations were vetted by the ARS AUC Executive Committee and a 2-week public comment period before official approval and adoption. Standard of care management of good prognosis LA-NSCLC consists of combined concurrent radical (60-70 Gy) platinum-based chemoradiation followed by consolidation durvalumab immunotherapy (for patients without progression). Planning and delivery of locally advanced lung cancer radiotherapy usually should be performed using intensity-modulated radiotherapy techniques. A variety of palliative and radical fractionation schedules are available to treat patients with poor performance and/or pulmonary status. The salvage therapy for a local recurrence after successful primary management is complex and likely requires both multidisciplinary input and shared decision-making with the patient. Conclusions and Relevance: Evidence-based guidance on the management of various unresectable LA-NSCLC scenarios is provided by the ARS AUC to optimize multidisciplinary patient care for this challenging patient population.

The International Association for the Study of Lung Cancer Mesothelioma Staging Project: Proposals for Revisions of the "T" Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Pleural Mesothelioma.

INTRODUCTION: The primary tumor (T) component in the eighth edition of pleural mesothelioma (PM) staging system is based on pleural involvement and extent of invasion. Quantitative assessment of pleural tumor has been found to be prognostic. We explored quantitative and qualitative metrics to develop recommendations for T descriptors in the upcoming ninth edition of the PM staging system. METHODS: The International Association for the Study of Lung Cancer prospectively collected data on patients with PM. Sum of maximum pleural thickness (Psum) was recorded. Optimal combinations of Psum and eighth edition cT descriptors were assessed using recursive binary splitting algorithm, with bootstrap resampling to correct for the adaptive nature of the splitting algorithm, and validated in the eighth edition data. Overall survival (OS) was calculated by the Kaplan-Meier method and differences in OS assessed by the log-rank test. RESULTS: Of 7338 patients submitted, 3598 were eligible for cT analysis and 1790 had Psum measurements. Recursive partitioning identified optimal cutpoints of Psum at 12 and 30 mm, which, in combination with extent of invasion, yielded four prognostic groups for OS. Fmax greater than 5 mm indicated poor prognosis. cT4 category (based on invasion) revealed similar performance to eighth edition. Three eighth edition descriptors were eliminated based on low predictive accuracy. Eighth edition pT descriptors remained valid in ninth edition analyses. CONCLUSION: Given reproducible prognostication by Psum, size criteria will be incorporated into cT1 to T3 categories in the ninth edition. Current cT4 category and all pT descriptors will be maintained, with reclassification of fissural invasion as pT2.

Effectiveness of Community Education for Breast Cancer Screening.

OBJECTIVE: Screening based on individual risk factors results in detection of earlier, more curable breast cancer. There is expectation that improved public education about the importance of personalized screening will result in earlier diagnoses and reduced breast cancer mortality. The purpose of this study is to evaluate the effectiveness of community education on patient perceptions about risk-based screening. METHODS: This study is Health Insurance Portability and Accountability Act-compliant and institutional review board exempt. A standardized curriculum was used by radiologists and experts to conduct nine 1-hour patient education sessions between October 2018 and January 2019 about breast cancer risk factors and screening options. Patient participants completed voluntary, anonymous pre-event and post event surveys to determine if the presented educational program led to attitude changes. Survey results were summarized using statistical analysis including mean, median, range, and percentage of participants responding and comparison of pre- and post event fear and anxiety. RESULTS: Of 336 education session participants, 59.5% (200/336) completed the pre-event and 44.3% (149/336) completed the post event surveys, Respondents reported decreased anxiety and fear regarding breast cancer screening following educational sessions, with 36.1% (64/178) reporting anxiety pre-event compared to 23.3% (31/133) post event, although the difference was not statistically significant (P = .96). Additionally, 64.7% (55/85) of participants stated they were more likely to schedule breast cancer screening based on individual risk factors, and 98.0% (145/148) of participants reported increased knowledge on post event surveys. CONCLUSION: This study demonstrates the importance and effectiveness of community-based educational programs in increasing knowledge of risk-based screening and potentially reducing anxiety related to screening.

The International Association for the Study of Lung Cancer Pleural Mesothelioma Staging Project: Expanded Database to Inform Revisions in the Ninth Edition of the TNM Classification of Pleural Mesothelioma.

The International Association for the Study of Lung Cancer collaborated with the International Mesothelioma Interest Group to propose the first TNM stage classification system for diffuse pleural mesothelioma in 1995, accepted by the Union for International Cancer Control and the American Joint Committee on Cancer for the sixth and seventh edition stage classification manuals. The International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee Mesothelioma Domain developed and analyzed an international registry of patients with pleural mesothelioma and updated TNM descriptors for the eighth edition of the stage classification system. To inform revisions for the forthcoming ninth edition of the TNM stage classification system, data submission was solicited for patients diagnosed between 2013 and 2022 with expanded data elements on the basis of the first project's exploratory analyses, including pleural thickness measurements, updated surgical nomenclature, and molecular markers. The resulting database consisted of a total of 3598 analyzable cases from Europe, Australia, Asia, North America, and South America, with a median age of 71 years (range: 18-99 y), 2775 (77.1%) of whom were men. With only 1310 patients (36.4%) undergoing curative-intent operations, this iteration of the database includes far more patients treated nonsurgically compared with prior. Four separate manuscripts on T, N, M, and stage groupings submitted to this journal will summarize analyses of these data and will serve collectively as the primary source of the proposed changes to the upcoming ninth edition of the pleural mesothelioma stage classification system.

Genomic profiling of tissue and blood predicts survival outcomes in patients with resected pleural mesothelioma.

PURPOSE: Pleural mesothelioma (PM) is an aggressive tumor still considered incurable, in part due to the lack of predictive biomarkers. Little is known about the clinical implications of molecular alterations in resectable PM tissues and blood. Here, we characterized genetic alterations to identify prognostic and predictive biomarkers in patients with resected PM. EXPERIMENTAL DESIGN: Targeted next-generation sequencing was performed in retrospective pleural tumor tissue and paired plasma samples from stage IB-IIIB resected PM. Association between prognosis and presence of specific mutations was validated in silico. RESULTS: Thirty PM tissues and paired blood samples from 12 patients were analyzed. High tissue tumor mutational burden (TMB) (>10 mutations/Mb), tissue median minor allele frequency (MAF) (>9 mutations/Mb), and blood TMB (>6 mutations/Mb), tissue KMT2C, PBRM1, PKHD1,EPHB1 and blood LIFR mutations correlated with longer disease-free survival and/or overall survival. High concordance (>80%) between tissue and blood was found for some mutations. CONCLUSIONS: Tissue TMB and MAF, blood TMB, and specific mutations correlated with outcomes in patients with resected PM and should be further studied to validate their role as prognostic biomarkers and potentially predictive factors for combinations with immune-checkpoint inhibitors. This suggest that molecular profiling could identify longer survivors in patients with resected PM.

Postoperative CT surveillance in the evaluation of local recurrence after sub-lobar resection of neoplastic lesions of the lung.

OBJECTIVE: As indications for sub-lobar resections increase, it will become more important to identify risk factors for postsurgical recurrence. We investigated retrospectively the association between local recurrence after sub-lobar resection of neoplastic lung lesions and pre- and post-operative CT imaging and pathologic features. MATERIALS AND METHODS: We reviewed retrospectively neoplastic lung lesions with postoperative chest CT surveillance of sub-lobar resections in 2006-2016. We defined "suspicious" findings as nodularity ≥3 mm or soft tissue thickening ≥4 mm along the suture line and/or progression and explored their association with local recurrence. Primary lung cancer stage, tumoral invasion of lymphatics, visceral pleura or large vessels, bronchial and vascular margin distance were also assessed. RESULTS: Our study group included 45 cases of sub-lobar resection took for either primary (n = 37) or metastatic (n = 8) lung tumors. Local recurrence was observed in 16 of those patients. New nodularity ≥3 mm or soft tissue thickening ≥4 mm along the suture line on surveillance CT was significantly associated with local recurrence (p = 0.037). Additionally, solid nodule (p = 0.005), age at surgery ≤60 years (p = 0.006), two or more sites of invasion (p < 0.0001) and poor histologic differentiation (p = 0.0001) were also significantly associated with local tumor recurrence. Of 16 patients with surveillance post-surgical PET-CT, 15 had elevated FDG uptake. CONCLUSION: The postoperative changes along the suture line should follow a predictable time course demonstrating a pattern of stability, thinning or resolution on CT surveillance. New or increasing postoperative nodularity ≥3 mm or soft tissue thickening ≥4 mm along the suture line requires close diagnostic work-up. Surgical pathology characteristics added prognostic value on postoperative recurrence surveillance.

Assessment of the well-being of significant others of cardiothoracic surgeons.

OBJECTIVES: We aimed to evaluate how the current working climate of cardiothoracic surgery and burnout experienced by cardiothoracic surgeons influences their spouses and significant others (SOs). METHODS: A 33-question well-being survey was developed by the American Association for Thoracic Surgery Wellness Committee and distributed by e-mail to the SOs of cardiothoracic surgeons and to all surgeon registrants of the 2020 and 2021 American Association for Thoracic Surgery Annual Meetings with a request to share it with their SO. The 5-item Likert-scale survey questions were dichotomized, and associations were determined by χ2 or independent samples t tests, as appropriate. RESULTS: Responses from 238 SOs were analyzed. Sixty-six percent reported that the stress on their cardiothoracic surgeon partner had a moderate to severe influence on their family, and 63% reported that their partner's work demands didn't leave enough time for family. Fifty-one percent reported that their partner rarely had time for intimacy, 27% reported poor work-life balance, and 23% reported that interactions at home were usually or always not good-natured. SOs were most affected when their partner was <5 years out from training, worked in private vs academic practice, and worked longer hours. Having children, particularly younger than age 19 years, and a lack of workplace support resources further diminished well-being. CONCLUSIONS: The current work culture of cardiothoracic surgeons adversely affects their SOs, and the risk for families is concerning. These data present a major area for exploration as we strive to understand and mitigate the factors that lead to burnout among cardiothoracic surgeons.

The International Association for the Study of Lung Cancer Pleural Mesothelioma Staging Project: Updated Modeling of Prognostic Factors in Pleural Mesothelioma.

INTRODUCTION: The International Association for the Study of Lung Cancer developed an international pleural mesothelioma database to improve staging. Data entered from 1995 to 2009 (training data set) were analyzed previously to evaluate supplemental prognostic factors. We evaluated these factors with new clinical data to determine whether the previous models could be improved. METHODS: Patients entered into the database from 2009 to 2019 (validation cohort) were assessed for the association between previous prognosticators and overall survival using Cox proportional hazards regression with bidirectional stepwise selection. Additional variables were analyzed and models were compared using Harrell's C-index. RESULTS: The training data set included 3101 patients and the validation cohort, 1733 patients. For the multivariable pathologic staging model applied to the training cohort, C-index was 0.68 (95% confidence interval [CI]: 0.656-0.705). For the validation data set (n = 497), C-index was 0.650 (95% CI: 0.614-0.685), and pathologic stage, histologic diagnosis, sex, adjuvant therapy, and platelet count were independently associated with survival. Adding anemia to the model increased the C-index to 0.652 (95% CI: 0.618-0.686). A basic presentation model including all parameters before staging yielded a C-index of 0.668 (95% CI: 0.641-0.695). In comparison, the European Organization for Research and Treatment of Cancer model yielded C-indices of 0.550 (95% CI: 0.511-0.589) and 0.577 (95% CI: 0.550-0.604) for pathologic staging and presentation models, respectively. CONCLUSIONS: Although significant predictors differed slightly, the International Association for the Study of Lung Cancer training model performed well in the validation set and better than the model of the European Organization for Research and Treatment of Cancer. International collaboration is critical to improve outcomes in this rare disease.

Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation.

NLRP3 inflammasome activation is a highly regulated process for controlling secretion of the potent inflammatory cytokines IL-1ß and IL-18 that are essential during bacterial infection, sterile inflammation, and disease, including colitis, diabetes, Alzheimer's disease, and atherosclerosis. Diverse stimuli activate the NLRP3 inflammasome, and unifying upstream signals has been challenging to identify. Here, we report that a common upstream step in NLRP3 inflammasome activation is the dissociation of the glycolytic enzyme hexokinase 2 from the voltage-dependent anion channel (VDAC) in the outer membrane of mitochondria. Hexokinase 2 dissociation from VDAC triggers activation of inositol triphosphate receptors, leading to release of calcium from the ER, which is taken up by mitochondria. This influx of calcium into mitochondria leads to oligomerization of VDAC, which is known to form a macromolecule-sized pore in the outer membranes of mitochondria that allows proteins and mitochondrial DNA (mtDNA), often associated with apoptosis and inflammation, respectively, to exit the mitochondria. We observe that VDAC oligomers aggregate with NLRP3 during initial assembly of the multiprotein oligomeric NLRP3 inflammasome complex. We also find that mtDNA is necessary for NLRP3 association with VDAC oligomers. These data, together with other recent work, help to paint a more complete picture of the pathway leading to NLRP3 inflammasome activation.

Peptidoglycan-induced modulation of metabolic and inflammatory responses.

Bacterial cell wall peptidoglycan is composed of innate immune ligands and, due to its important structural role, also regulates access to many other innate immune ligands contained within the bacteria. There is a growing body of literature demonstrating how innate immune recognition impacts the metabolic functions of immune cells and how metabolic changes are not only important to inflammatory responses but are often essential. Peptidoglycan is primarily sensed in the context of the whole bacteria during lysosomal degradation; consequently, the innate immune receptors for peptidoglycan are primarily intracellular cytosolic innate immune sensors. However, during bacterial growth, peptidoglycan fragments are shed and can be found in the bloodstream of humans and mice, not only during infection but also derived from the abundant bacterial component of the gut microbiota. These peptidoglycan fragments influence cells throughout the body and are important for regulating inflammation and whole-body metabolic function. Therefore, it is important to understand how peptidoglycan-induced signals in innate immune cells and cells throughout the body interact to regulate how the body responds to both pathogenic and nonpathogenic bacteria. This mini-review will highlight key research regarding how cellular metabolism shifts in response to peptidoglycan and how systemic peptidoglycan sensing impacts whole-body metabolic function.

American Radium Society Appropriate Use Criteria for Radiation Therapy in the Multidisciplinary Management of Thymic Carcinoma.

Importance: Thymic carcinoma is rare, and its oncologic management is controversial due to a paucity of prospective data. For this reason, multidisciplinary consensus guidelines are crucial to guide oncologic management. Objective: To develop expert multidisciplinary consensus guidelines on the management of common presentations of thymic carcinoma. Evidence Review: Case variants spanning the spectrum of stage I to IV thymic carcinoma were developed by the 15-member multidisciplinary American Radium Society (ARS) Thoracic Appropriate Use Criteria (AUC) expert panel to address management controversies. A comprehensive review of the English-language medical literature from 1980 to 2021 was performed to inform consensus guidelines. Variants and procedures were evaluated by the panel using modified Delphi methodology. Agreement/consensus was defined as less than or equal to 3 rating points from median. Consensus recommendations were then approved by the ARS Executive Committee and subject to public comment per established ARS procedures. Findings: The ARS Thoracic AUC panel identified 89 relevant references and obtained consensus for all procedures evaluated for thymic carcinoma. Minimally invasive thymectomy was rated as usually inappropriate (regardless of stage) due to the infiltrative nature of thymic carcinomas. There was consensus that conventionally fractionated radiation (1.8-2 Gy daily) to a dose of 45 to 60 Gy adjuvantly and 60 to 66 Gy in the definitive setting is appropriate and that elective nodal irradiation is inappropriate. For radiation technique, the panel recommended use of intensity-modulated radiation therapy or proton therapy (rather than 3-dimensional conformal radiotherapy) to reduce radiation exposure to the heart and lungs. Conclusions and Relevance: The ARS Thoracic AUC panel has developed multidisciplinary consensus guidelines for various presentations of thymic carcinoma, perhaps the most well referenced on the topic.

Biomarkers for checkpoint inhibitor therapy in mucinous epithelial ovarian cancer.

OBJECTIVE: The prognosis of patients with advanced stage mucinous epithelial ovarian cancer remains poor due to a modest response to platinum-based chemotherapy and the absence of therapeutic alternatives. As targeted approaches may help to overcome these limitations, the present study evaluates biomarkers indicative of potential immune-checkpoint inhibitor therapy response. METHODS: All patients who underwent primary cytoreductive surgery from January 2001 to December 2020 and for whom formalin-fixed paraffin-embedded tissue samples were available were included (n=35; 12 International Federation of Gynecology and Obstetrics (FIGO) stage ≥IIb). To define sub-groups potentially suitable for checkpoint inhibition, expression of programmed death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (CD3+, CD8+, CD20+, CD45+, CD68+, FoxP3+), and AT-rich interactive domain-containing protein 1A (ARID1A) immunostaining were evaluated in whole tissue sections and compared with clinicopathologic parameters and next-generation sequencing results, where available (n=11). Survival analyses were performed to assess whether identified sub-groups were associated with specific clinical outcomes. RESULTS: In total, 34.3% (n=12/35) of tumors were PD-L1 positive. PD-L1 expression was associated with infiltrative histotype (p=0.027) and correlated with higher CD8+ (r=0.577, p<0.001) and CD45+ (r=0.424, p=0.011), but reduced ARID1A expression (r=-4.39, p=0.008). CD8+ expression was associated with longer progression-free survival (hazard ratio (HR) 0.85 (95% CI 0.72 to 0.99), p=0.047) and disease-specific survival (HR 0.85 (95% CI 0.73 to 1.00), p=0.044) in the sub-group with FIGO stage ≥IIb. Three (8.6%) samples demonstrated high PD-L1 expression at a combined positive score of >10, which was associated with increased CD8+ expression (p=0.010) and loss of ARID1A expression (p=0.034). Next-generation sequencing, which was available for all samples with a combined positive score of >10, showed KRAS mutations, BRCA wild-type status, and mismatch repair proficiency in all cases, but did not reveal genetic alterations potentially associated with a pro-immunogenic tumor environment. CONCLUSIONS: A sub-group of mucinous ovarian cancers appear to demonstrate a pro-immunogenic tumor environment with high PD-L1 expression, decreased ARID1A expression, and characteristic tumor-infiltrating lymphocyte infiltration patterns. Further clinical validation of anti-PD-L1/PD-1 targeting in selected mucinous ovarian cancers appears promising.

Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn's disease and leads to impaired CFB cleavage and phagocytosis.

OBJECTIVE: Perianal Crohn's disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in Complement Factor B (CFB). DESIGN: Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from CFB risk, or protective CD or healthy subjects was assessed by flow cytometry. RESULTS: Perianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in CFB, in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum. CONCLUSION: pCD-associated rs4151651 in CFB is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.

Malignant pleural mesothelioma characteristics and outcomes: A SEER-Medicare analysis.

BACKGROUND: Pleural mesothelioma is rare cancer linked to asbestos exposure. Previous research has indicated that female individuals have better survival than male individuals, but this has never been examined in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. MATERIALS AND METHODS: Malignant pleural mesothelioma cases diagnosed from 1992 to 2015 were queried from the linked SEER-Medicare database. Multivariable logistic regression was used to assess the clinical and demographic factors associated with sex. A multivariable Cox proportional hazards model and propensity matching methods were used to assess sex differences in overall survival (OS) while accounting for potential confounders. RESULTS: Among 4201 patients included in the analysis, 3340 (79.5%) were males and 861 (20.5%) females. Females were significantly older, with more epithelial histology than males were, and had significantly better OS, adjusted for confounders (adjusted hazard ratio, 0.83, 95% confidence interval: 0.76-0.90). Other variables independently associated with improved survival included younger age at diagnosis, having a spouse/domestic partner, epithelial histology, lower comorbidity score, and receipt of surgery or chemotherapy. CONCLUSIONS: The study describes sex differences in mesothelioma occurrence, treatment, and survival and is the first to examine SEER-Medicare. It provides directions for future research into potential therapeutic targets.