The value of high-risk clinicopathologic features for chemotherapy in stage I non-small cell lung cancer: a propensity score-matched study.

Background: Surgical resection is the main treatment for early-stage non-small cell lung cancer (NSCLC), but recurrence remains a concern. Adjuvant chemotherapy has been shown to have survival benefits for resected stage II and III NSCLC, but debate continues regarding its use in stage I NSCLC. High-risk features, such as tumor size and stage, are considered in deciding whether to administer adjuvant chemotherapy. Methods: The data of 666,689 patients diagnosed with lung cancer from 2004 to 2016 were collected from the Surveillance, Epidemiology, and End Results database. Ultimately, 26,160 patients diagnosed with stage I NSCLC were included in the study based on a screening procedure. Results: After matching, 4,285 patients were identified, of whom 1,440 (33.6%) received chemotherapy. High-risk clinicopathologic features, including a high histologic grade, visceral pleural invasion (VPI), the examination of an insufficient number of lymph nodes (LNs), and limited resection, were independent risk factors for a poor prognosis. Chemotherapy significantly improved lung cancer-specific survival (LCSS) and overall survival (OS) in stage I patients with VPI [LCSS: hazard ratio (HR): 0.839, 95% confidence interval (CI): 0.706-0.998, P=0.047; OS: HR: 0.711, 95% CI: 0.612-0.826, P<0.001], regardless of whether or not the patient had fewer than 11 LNs (LCSS: HR: 0.809, 95% CI: 0.664-0.986, P=0.04; OS: HR: 0.677, 95% CI: 0.570-0.803, P<0.001). Chemotherapy was only observed to improve OS for stage IB patients with a high histologic grade when combined with either or both of the following high-risk factors: the presence of VPI and fewer than 11 LNs examined. Conclusions: The presence of VPI was the dominant predictor and the examination of an insufficient number of LNs was the secondary indicator, and a high histologic grade was a potential indicator of the need to administer chemotherapy in the treatment of stage I NSCLC.

Change in quality of life of stage IA non-small cell lung cancer after surgery or radiation therapy.

Background: Few studies have examined the differential impact of stereotactic body radiotherapy (SBRT) and surgery for early-stage non-small cell lung cancer (NSCLC) on quality of life (QoL) during the first post-treatment year. Methods: A prospective cohort of stage IA NSCLC patients undergoing surgery or SBRT at Mount Sinai Health System had QoL measured before treatment, and 2, 6, and 12 months post-treatment using: 12-item Short Form Health Survey version 2 (SF-12v2) [physical component summary (PCS) and mental component summary (MCS)], Functional Assessment of Cancer Therapy-Lung Cancer Subscale (FACT-LCS), and the Patient Health Questionnaire-4 (PHQ-4) measuring depression and anxiety. Locally weighted scatterplot smoothing (LOWESS) was fitted to identify the best interval knot for the change in the QoL trends post-treatment, adjusted piecewise linear mixed effects model was developed to estimate differences in baseline, 2- and 12-month scores, and rates of change. Results: In total, 503 (88.6%) patients received surgery and 65 (11.4%) SBRT. LOWESS plots suggested QoL changed at 2 months post-surgery. Worsening in PCS was observed for both surgery and SBRT within 2 months after treatment but was only significant for surgical patients (-2.11, P<0.001). Two months later, improvements were observed for surgical but not SBRT patients (0.63 vs. -0.30, P<0.001). Surgical patients had significantly better PCS (P<0.001) and FACT-LCS (P<0.001) scores 1-year post-treatment compared to baseline, but not SBRT patients. Both surgical and SBRT patients reported significantly less anxiety 1-year post-treatment compared to baseline (P<0.001 and P=0.03). Decrease in depression from baseline to 1-year post-treatment was only significant for surgical patients (P<0.001). Conclusions: Post-treatment, surgical patients exhibited improvements in physical health and reductions in lung cancer symptoms following initial deterioration within the first two months; in contrast, SBRT patients showed persistent decline in these areas throughout the year. Nonetheless, improved mental health was noted across both patient categories post-treatment. Targeted interventions and continuous monitoring are recommended during the initial 2 months post-surgery and throughout the year post-SBRT to alleviate physical and mental distress in patients.

Prospective Cohort Study to Compare Long-Term Lung Cancer-Specific and All-Cause Survival of Clinical Early Stage (T1a-b; ≤20 mm) NSCLC Treated by Stereotactic Body Radiation Therapy and Surgery.

INTRODUCTION: We aimed to compare outcomes of patients with first primary clinical T1a-bN0M0 NSCLC treated with surgery or stereotactic body radiation therapy (SBRT). METHODS: We identified patients with first primary clinical T1a-bN0M0 NSCLCs on last pretreatment computed tomography treated by surgery or SBRT in the following two prospective cohorts: International Early Lung Cancer Action Program (I-ELCAP) and Initiative for Early Lung Cancer Research on Treatment (IELCART). Lung cancer-specific survival and all-cause survival after diagnosis were compared using Kaplan-Meier analysis. Propensity score matching was used to balance baseline demographics and comorbidities and analyzed using Cox proportional hazards regression. RESULTS: Of 1115 patients with NSCLC, 1003 had surgery and 112 had SBRT; 525 in I-ELCAP in 1992 to 2021 and 590 in IELCART in 2016 to 2021. Median follow-up was 57.6 months. Ten-year lung cancer-specific survival was not significantly different: 90% (95% confidence interval: 87%-92%) for surgery versus 88% (95% confidence interval: 77%-99%) for SBRT, p = 0.55. Cox regression revealed no significant difference in lung cancer-specific survival for the combined cohorts (p = 0.48) or separately for I-ELCAP (p = 1.00) and IELCART (p = 1.00). Although 10-year all-cause survival was significantly different (75% versus 45%, p < 0.0001), after propensity score matching, all-cause survival using Cox regression was no longer different for the combined cohorts (p = 0.74) or separately for I-ELCAP (p = 1.00) and IELCART (p = 0.62). CONCLUSIONS: This first prospectively collected cohort analysis of long-term survival of small, early NSCLCs revealed that lung cancer-specific survival was high for both treatments and not significantly different (p = 0.48) and that all-cause survival after propensity matching was not significantly different (p = 0.74). This supports SBRT as an alternative treatment option for small, early NSCLCs which is especially important with their increasing frequency owing to low-dose computed tomography screening. Furthermore, treatment decisions are influenced by many different factors and should be personalized on the basis of the unique circumstances of each patient.

A 20-year Follow-up of the International Early Lung Cancer Action Program (I-ELCAP).

Background The low-dose CT (≤3 mGy) screening report of 1000 Early Lung Cancer Action Program (ELCAP) participants in 1999 led to the International ELCAP (I-ELCAP) collaboration, which enrolled 31 567 participants in annual low-dose CT screening between 1992 and 2005. In 2006, I-ELCAP investigators reported the 10-year lung cancer-specific survival of 80% for 484 participants diagnosed with a first primary lung cancer through annual screening, with a high frequency of clinical stage I lung cancer (85%). Purpose To update the cure rate by determining the 20-year lung cancer-specific survival of participants diagnosed with first primary lung cancer through annual low-dose CT screening in the expanded I-ELCAP cohort. Materials and Methods For participants enrolled in the HIPAA-compliant prospective I-ELCAP cohort between 1992 and 2022 and observed until December 30, 2022, Kaplan-Meier survival analysis was used to determine the 10- and 20-year lung cancer-specific survival of participants diagnosed with first primary lung cancer through annual low-dose CT screening. Eligible participants were aged at least 40 years and had current or former cigarette use or had never smoked but had been exposed to secondhand tobacco smoke. Results Among 89 404 I-ELCAP participants, 1257 (1.4%) were diagnosed with a first primary lung cancer (684 male, 573 female; median age, 66 years; IQR, 61-72), with a median smoking history of 43.0 pack-years (IQR, 29.0-60.0). Median follow-up duration was 105 months (IQR, 41-182). The frequency of clinical stage I at pretreatment CT was 81% (1017 of 1257). The 10-year lung cancer-specific survival of 1257 participants was 81% (95% CI: 79, 84) and the 20-year lung cancer-specific survival was 81% (95% CI: 78, 83), and it was 95% (95% CI: 91, 98) for 181 participants with pathologic T1aN0M0 lung cancer. Conclusion The 10-year lung cancer-specific survival of 80% reported in 2006 for I-ELCAP participants enrolled in annual low-dose CT screening and diagnosed with a first primary lung cancer has persisted, as shown by the updated 20-year lung cancer-specific survival for the expanded I-ELCAP cohort. © RSNA, 2023 See also the editorials by Grenier and by Sequist and Olazagasti in this issue.

Unequal racial distribution of immunotherapy for late-stage non-small cell lung cancer.

Immunotherapy has increased survival for non-small cell lung cancer (NSCLC), especially for those diagnosed with late-stage disease. However, it is not known if its use is equally distributed across races. We assessed immunotherapy use in 21 098 pathologically confirmed stage IV NSCLC patients according to race in the Surveillance Epidemiology, and End Results-Medicare linked dataset. Multivariable models were conducted to evaluate the independent association of receipt of immunotherapy with race and overall survival according to race. Black patients had statistically significantly lower odds of receiving immunotherapy (adjusted odds ratio = 0.60, 95% confidence interval = 0.44 to 0.80); receipt of immunotherapy was lower in Asian and Hispanic patients but not statistically significant. When immunotherapy was received, survival was similar across races. Immunotherapy for NSCLC is not used equally among races, underscoring the racial disparities that exist in access to the newest cancer treatment. Efforts should be directed toward expanding access to novel, efficacious treatments for advanced stage lung cancer.

Purse-indigitation mechanical anastomosis vs. traditional mechanical anastomosis undergoing McKeown esophagectomy: a retrospective comparative cohort study.

Background: Postoperative anastomosis-related complication rates remain high in patients undergoing McKeown esophagectomy with cervical anastomosis, and the optimal anastomotic technique remains under debate. We describe a new method of anastomosis, referred to as purse-indigitation mechanical anastomosis (PIMA) by reinforcing esophagogastric anastomosis, which can be performed after minimally invasive surgery. This study was designed to compare its feasibility, efficacy, and safety with those of traditional mechanical anastomosis (TMA). Methods: Between September 2020 and January 2022, 264 patients undergoing McKeown esophagectomy at a single center were included. Demographic data, including patient age, sex, diagnosis, neoadjuvant chemotherapy/radiation therapy in cases of malignancy, comorbidities, and operation time, anastomotic time, estimated blood loss, post­operative complications were collected. Their medical records were retrospectively reviewed, analyzed and compared between the PIMA and TMA cohorts. Results: The baseline comparability of the PIMA and TMA before the comparisons is no statistical difference. Univariable analysis revealed significantly decreased anastomotic leak rate with PIMA compared to TMA (4.10% vs. 11.59%, P=0.04). No significant difference was demonstrated in total operation time, estimated blood loss, postoperative hospital stay, or pulmonary complications between PIMA and TMA (243.94±21.98 vs. 238.70±28.45 min; 201.10±67.83 vs. 197.39±65.13 mL; 8.83±2.77 vs. 9.35±3.78 days; 8.21% vs. 11.59%; all P>0.05). The incidence of postoperative pulmonary complications (3.44% vs. 50%) was significantly associated with an increased rate of anastomotic leak [odds ratio (OR): 15.50; 95% confidence interval (CI): 4.81-43.71; P<0.01]. Conclusions: PIMA is feasible, safe to perform, and demonstrated a leak rate less than half that of TMA in this study. PIMA may represent a superior alternative to standard esophagogastric cervical anastomosis techniques. Larger sample size and long-term survival are required to fully evaluate PIMA.

Spatial Positioning and Matrix Programs of Cancer-Associated Fibroblasts Promote T-cell Exclusion in Human Lung Tumors.

It is currently accepted that cancer-associated fibroblasts (CAF) participate in T-cell exclusion from tumor nests. To unbiasedly test this, we used single-cell RNA sequencing coupled with multiplex imaging on a large cohort of lung tumors. We identified four main CAF populations, two of which are associated with T-cell exclusion: (i) MYH11+αSMA+ CAF, which are present in early-stage tumors and form a single cell layer lining cancer aggregates, and (ii) FAP+αSMA+ CAF, which appear in more advanced tumors and organize in patches within the stroma or in multiple layers around tumor nests. Both populations orchestrate a particular structural tissue organization through dense and aligned fiber deposition compared with T cell-permissive CAF. Yet they produce distinct matrix molecules, including collagen IV (MYH11+αSMA+ CAF) and collagen XI/XII (FAP+αSMA+ CAF). Hereby, we uncovered unique molecular programs of CAF driving T-cell marginalization, whose targeting should increase immunotherapy efficacy in patients bearing T cell-excluded tumors. SIGNIFICANCE: The cellular and molecular programs driving T-cell marginalization in solid tumors remain unclear. Here, we describe two CAF populations associated with T-cell exclusion in human lung tumors. We demonstrate the importance of pairing molecular and spatial analysis of the tumor microenvironment, a prerequisite to developing new strategies targeting T cell-excluding CAF. See related commentary by Sherman, p. 2501. This article is highlighted in the In This Issue feature, p. 2483.

Comparisons of prognosis prediction accuracy between modified and unmodified versions of 8th edition ypTNM.

Background: The prognostic value of the existing 8th edition post-neoadjuvant treatment (ypTNM) appears to be limited, and necessary reassessment and modification should be carried out as needed. This study aimed to compare the prognosis prediction accuracy of modified and unmodified versions of the 8th edition ypTNM. Methods: Esophageal cancer patients who had received neoadjuvant therapy from the Surveillance, Epidemiology, and End Results (SEER) database were included in this observational longitudinal study. The median follow-up time was 26 months. All-cause mortality was the outcome variable. Demographic and clinical variables were collected as covariates. Kaplan-Meier (log-rank test) and Cox proportional hazards models were conducted for developing modified ypTNM staging. The concordance index (C-index) was calculated to analyze the discriminative ability of modified ypTNM staging. Results: Overall, 3,595 patients met inclusion criteria. The 8th edition staging was not able to significantly discriminate between patients with ypT1- and ypT2-, ypT3- and ypT4-, ypN2- and ypN3- disease, respectively. Using the modified staging, we found that patients with ypT0-2 [hazard ratio (HR) =1.232; 95% confidence interval (CI): 1.053-1.441] and ypT3-4 (HR =1.257; 95% CI: 1.136-1.390) with grade III + IV had a significant risk of death compared to those with grade I + II. As was the case for the ypN0 (HR =1.295; 95% CI: 1.073-1.562) group with middle and upper tumor locations compared to those with low tumor location. The modified staging possessed better homogeneity in terms of the chi-square likelihood ratio (143.443 vs. 102.044), Akaike information criterion (AIC) (32,683.716 vs. 32,719.115), and Schwarz's Bayesian criterion (SBC) (32,723.496 vs. 32,741.847), as well as better discriminatory ability (C-index of 0.577 vs. 0.560, P=0.045) compared to the 8th edition staging. Conclusions: Although the modified ypTNM staging system we created by incorporating tumor grade and location to the original T and N displayed certain prognosis prediction accuracy compared with the 8th edition ypTNM staging, a larger sample size and prospective studies are needed to explore.

Medical and Surgical Care of Patients With Mesothelioma and Their Relatives Carrying Germline BAP1 Mutations.

The most common malignancies that develop in carriers of BAP1 germline mutations include diffuse malignant mesothelioma, uveal and cutaneous melanoma, renal cell carcinoma, and less frequently, breast cancer, several types of skin carcinomas, and other tumor types. Mesotheliomas in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. Some BAP1 carriers have asymptomatic mesothelioma that can be followed by close clinical observation without apparent adverse outcomes: they may survive many years without therapy. Others may grow aggressively but very often respond to therapy. Detecting BAP1 germline mutations has, therefore, substantial medical, social, and economic impact. Close monitoring of these patients and their relatives is expected to result in prolonged life expectancy, improved quality of life, and being cost-effective. The co-authors of this paper are those who have published the vast majority of cases of mesothelioma occurring in patients carrying inactivating germline BAP1 mutations and who have studied the families affected by the BAP1 cancer syndrome for many years. This paper reports our experience. It is intended to be a source of information for all physicians who care for patients carrying germline BAP1 mutations. We discuss the clinical presentation, diagnostic and treatment challenges, and our recommendations of how to best care for these patients and their family members, including the potential economic and psychosocial impact.

Early-Stage Lung Cancer Patients' Perceptions of Presurgical Discussions.

Background: Patients with early-stage non-small-cell lung cancer (NSCLC) have high survival rates, but patients often say they did not anticipate the effect of the surgery on their postsurgical quality of life (QoL). This study adds to the literature regarding patient and surgeon interactions and highlights the areas where the current approach is not providing good communication. Design: Since its start in 2016, the Initiative for Early Lung Cancer Research on Treatment (IELCART), a prospective cohort study, has enrolled 543 patients who underwent surgery for stage I NSCLC within the Mount Sinai Health System. Presurgical patient and surgeon surveys were available for 314 patients, postsurgical surveys for 420, and both pre- and postsurgical surveys for 285. Results: Of patients with presurgical surveys, 31.2% said that their surgeon recommended multiple types of treatment. Of patients with postsurgical surveys, 85.0% felt very well prepared and 11.4% moderately well prepared for their postsurgical recovery. The median Functional Assessment of Cancer Therapy-Lung Cancer score and social support score of the patients who felt very well prepared was significantly higher than those moderately or not well prepared (24.0 v. 22.0, P < 0.001) and (5.0 [interquartile range: 4.7-5.0] v. 5.0 [IQR: 4.2-5.0], p = 0.015). Conclusions: This study provides insight into the areas where surgeons are communicating well with their patients as well as the areas where patients still feel uninformed. Most surgeons feel that they prepare their patients well or very well for surgical recovery, whereas some patients still feel that their surgeons did not prepare them well for postsurgical recovery. Surgeons may want to spend additional time emphasizing postsurgical recovery and QoL with their patients or provide their patients with additional avenues to get their questions and concerns addressed. Highlights: Pretreatment discussions could help surgeons understand patient priorities and patients understand the anticipated outcomes for their surgeries.There is an association between feeling prepared for surgery and higher quality of life and social support scores after adjustment for confounders.Despite these pretreatment discussions, patients still feel that they are not well prepared about what to expect during their postsurgical recovery.

Effects of Smoking, Obesity, and Pulmonary Function on Home Oxygen Use after Curative Lung Cancer Surgery.

Rationale: Lung cancer surgical morbidity has been decreasing, increasing attention to quality-of-life measures. A chronic sequela of lung cancer surgery is the use of postoperative oxygen at home after discharge. Prospective studies are needed to identify risk predictors for home oxygen (HO2) use after curative lung cancer surgery. Objectives: To prospectively assess risk factors for postoperative oxygen use and postsurgical morbidity in patients undergoing curative lung cancer surgery. We hypothesized that obesity, poor preoperative pulmonary function, and smoking status would contribute to the risk of postoperative oxygen use. Methods: This study included patients undergoing surgery for a first primary non-small cell lung cancer at Mount Sinai from 2016 to 2020. Univariate, multivariable logistic regression analyses and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were assessed. Results: Of the 433 patients with diagnosed pathologic stage I non-small cell lung cancer, 63 (14.5%) were discharged with HO2. By using multivariable analyses, we found that the body mass index (BMI) (OR for a BMI of 25-30 kg/m2, 4.0; 95% CI, 1.6-11.2; OR for a BMI ⩾30 kg/m2, 6.1; 95% CI, 2.4-17.5) and the preoperative diffusing capacity of the lung for carbon monoxide (DlCO) (OR for a DlCO of <40%, 24.9; 95% CI, 3.6-234.1; OR for a DlCO of 40-59%, 3.1; 95% CI, 1.3-7.2) were significant independent risk factors associated with the risk of HO2 use after adjusting for other covariates. Although current smoking significantly increased the risk in the univariate analysis, it was no longer significant in the multivariable model. Conclusions: Obesity and the DlCO were significant as risk factors for oxygen use at home after discharge. These findings allow for identification of patients at risk of being discharged with HO2 after lung resection surgery.

A narrative review of hyperthermic intrathoracic chemotherapy for advanced lung cancer.

The traditional treatment of stage IV lung cancer is predominantly supportive or palliative. No current standardized guidelines promote the use of hyperthermic intrathoracic chemotherapy (HITHOC) in the treatment of advanced lung cancer with pleural involvement. Several small studies have examined the safety and utilization of HITHOC for this population, though the data is extremely limited. A review of the literature is presented in accordance with the Narrative Review checklist. The MEDLINE electronic database was searched for articles published in English from January 1999 - August 2020 using relevant keywords such as "hyperthermic intrathoracic chemotherapy", "hyperthermic intrapleural chemotherapy" and "HITHOC". This was supplemented by review and hand search of the reference lists. While data suggest a potential though controversial role for HITHOC for certain intrathoracic tumors such as malignant pleural mesothelioma and thymoma, there is insufficient evidence to confidently promote a role for hyperthermic intrathoracic chemotherapy in the treatment of advanced lung cancers. Existing studies are small, nonrandomized, and prone to bias. Hyperthermic intrathoracic chemotherapy is not a standardized treatment for advanced lung cancer, and is characterized by potentially serious side effects with little clinical benefit. Recent developments in targeted therapy and immunotherapy are unlikely to leave room for the development of large randomized controlled trials.

Major modifications to minimize thoracic esophago-gastric leak and eradicate esophageal stricture after Ivor Lewis esophagectomy.

BACKGROUND: The Ivor Lewis esophagectomy (ILE) remains the procedure of choice for localized middle or lower esophageal carcinoma. Nevertheless, anastomotic leak remains a common complication with rates from 3% to 25% and a stricture rate as high as 40%. The frequency of these complications suggests that the procedure itself may have inherent limitations including the use of potentially ischemic tissue for the esophagogastric anastomosis. We introduce a modified technique that reduces operative steps, preserves blood supply, and uses a modified esophagogastric anastomosis. METHODS: All consecutive patients undergoing ILE with the described modified technique were identified. An esophagram was performed on postoperative day six or seven. To ensure that all cases were identified, anastomotic leaks were defined as any radiographic evidence of contrast extravasation. RESULTS: A total of 110 patients underwent the modified esophagectomy with 2 anastomotic leaks (1.82%) and zero strictures. There was 1 late death but no early deaths (<30 or 90 days) or early re-admissions (<30 days). The average number of risk factors was 2.12, and 98 patients (90%) had at least 1 risk factor in their medical history. CONCLUSIONS: The modifications proposed simplify procedural steps, limit unnecessary dissection and introduce a technique that ends the practice of connecting ischemic tissue. We believe this technique contributes to surgical durability and reduces the rate of postoperative leak and eliminates stricture.

Changes in E-Cigarette Perceptions Over Time: A National Youth Tobacco Survey Analysis.

INTRODUCTION: This multiyear, cross-sectional study explores the changes over time in how U.S. middle- and high-school students perceive the harm and addiction risk of E-cigarettes. METHODS: This study analyzed 83,779 participants in the National Youth Tobacco Survey from 2015 to 2019. Associations of survey year with perceived harm and addiction risk of E-cigarettes were assessed using multivariable multinomial logistic regression models, adjusted for sociodemographic characteristics. RESULTS: Smoking decreased over the 5 years (-1.85 percentage points, p=0.07); vaping increased (9.03 percentage points, p<0.01). Perceived harm of both combustible cigarettes and E-cigarettes increased with time. Male, older, and non-White students perceived less harm from smoking or vaping. Perceptions of the addictiveness of E-cigarettes increased over time: 26.31% of students considered E-cigarettes to be more addictive than combustible cigarettes in 2019, compared with 7.26% in 2016. Female and non-White students were more likely to think that E-cigarettes were at least as addictive as combustible cigarettes but also reported less knowledge about them. CONCLUSIONS: The perceptions of both harm and addictiveness of E-cigarettes have increased over time, independent of current use. Perceptions vary on the basis of age, sex, race/ethnicity, and current use. Efforts should be made to further educate adolescents about E-cigarettes and to regulate their sale and advertisement. Efforts to reduce the uptake of combustible cigarettes among adolescents have been successful and should be duplicated for E-cigarettes.

Somatic Epigenetic Silencing of RIPK3 Inactivates Necroptosis and Contributes to Chemoresistance in Malignant Mesothelioma.

PURPOSE: Receptor-interacting protein kinase 3 (RIPK3) phosphorylates effector molecule MLKL to trigger necroptosis. Although RIPK3 loss is seen in several human cancers, its role in malignant mesothelioma is unknown. This study aimed to determine whether RIPK3 functions as a potential tumor suppressor to limit development of malignant mesothelioma. EXPERIMENTAL DESIGN: RIPK3 expression was examined in 66 malignant mesothelioma tumors and cell lines. Promoter methylation and DNMT1 siRNA studies were performed to assess the mode of RIPK3 silencing in RIPK3-deficient malignant mesothelioma cells. Restoration of RIPK3 expression in RIPK3-negative malignant mesothelioma cells, either by treatment with 5-aza-2'-deoxycytidine or lentiviral expression of cDNA, was performed to assess effects on cell viability, necrosis, and chemosensitization. RESULTS: Loss of RIPK3 expression was observed in 42/66 (63%) primary malignant mesotheliomas and malignant mesothelioma cell lines, and RT-PCR analysis demonstrated that downregulation occurs at the transcriptional level, consistent with epigenetic silencing. RIPK3-negative malignant mesothelioma cells treated with 5-aza-2'-deoxycytidine resulted in reexpression of RIPK3 and chemosensitization. Ectopic expression of RIPK3 also resulted in chemosensitization and led to necroptosis, the latter demonstrated by phosphorylation of downstream target MLKL and confirmed by rescue experiments. Mining of RIPK3 expression and survival outcomes among patients with malignant mesothelioma available from The Cancer Genome Atlas repository revealed that promoter methylation of RIPK3 is associated with reduced RIPK3 expression and poor prognosis. CONCLUSIONS: These data suggest that RIPK3 acts as a tumor suppressor in malignant mesothelioma by triggering necroptosis and that epigenetic silencing of RIPK3 by DNA methylation impairs necroptosis and contributes to chemoresistance and poor survival in this incurable disease.

The Association of Cerebral Desaturation During One-Lung Ventilation and Postoperative Recovery: A Prospective Observational Cohort Study.

OBJECTIVES: This study was designed to investigate whether cerebral oxygen desaturations during thoracic surgery are predictive of patients' quality of recovery. As a secondary aim, the authors investigated the relationship among cerebral desaturations and postoperative delirium and hospital length of stay. DESIGN: This study was a prospective observational cohort study. SETTING: A single tertiary-care medical center from September 2012 through March 2014. PATIENTS: Adult patients scheduled for elective pulmonary surgery requiring one-lung ventilation. INTERVENTIONS: All patients were monitored with the ForeSight cerebral oximeter. MEASUREMENTS AND MAIN RESULTS: The primary assessment tool was the Postoperative Quality of Recovery Scale. Delirium was assessed using the Confusion Assessment Method. Of the 117 patients analyzed in the study, 60 of the patients desaturated below a cerebral oximetry level of 65% for a minimum of 3 minutes (51.3%). Patients who desaturated were significantly less likely to have cognitive recovery in the immediate postoperative period (p = 0.012), which did not persist in the postoperative period beyond day 0. Patients who desaturated also were more likely to have delirium (p = 0.048, odds ratio 2.81 [95% CI 1.01-7.79]) and longer length of stay (relative duration 1.35, 95% CI 1.05-1.73; p = 0.020). CONCLUSIONS: Intraoperative cerebral oxygen desaturations, frequent during one-lung ventilation, are associated significantly with worse early cognitive recovery, high risk of postoperative delirium, and prolonged length of stay. Large interventional studies on cerebral oximetry in the thoracic operating room are warranted.