The Association between Polluted Neighborhoods and TP53-Mutated Non-Small Cell Lung Cancer.

BACKGROUND: Poor patients often reside in neighborhoods of lower socioeconomic status (SES) with high levels of airborne pollutants. They also have higher mortality from non-small cell lung cancer (NSCLC) than those living in wealthier communities. We investigated whether living in polluted neighborhoods is associated with somatic mutations linked with lower survival rates, i.e., TP53 mutations. METHODS: In a retrospective cohort of 478 patients with NSCLC treated at a comprehensive cancer center between 2015 and 2018, we used logistic regression to assess associations between individual demographic and clinical characteristics, including somatic TP53 mutation status and environmental risk factors of annual average particulate matter (PM2.5) levels, and neighborhood SES. RESULTS: 277 patients (58%) had somatic TP53 mutations. Of those, 45% lived in neighborhoods with "moderate" Environmental Protection Agency-defined PM2.5 exposure, compared with 39% of patients without TP53 mutations. We found significant associations between living in neighborhoods with "moderate" versus "good" PM2.5 concentrations and minority population percentage [OR, 1.06; 95% confidence interval (CI), 1.04-1.08]. There was a significant association between presence of TP53 mutations and PM2.5 exposure (moderate versus good: OR, 1.66; 95% CI, 1.02-2.72) after adjusting for patient characteristics, other environmental factors, and neighborhood-level SES. CONCLUSIONS: When controlling for individual- and neighborhood-level confounders, we find that the odds of having a TP53-mutated NSCLC are increased in areas with higher PM2.5 exposure. IMPACT: The link between pollution and aggressive biology may contribute to the increased burden of adverse NSCLC outcomes in individuals living in lower SES neighborhoods.

Readmission and complications after robotic surgery: experience of 10,000 operations at a comprehensive cancer center.

Evaluation of safety is of paramount importance with adoption of novel surgical technology. Although robotic surgery has become widely used in oncologic surgery, analysis of safety is lacking in comparison to traditional techniques. Standardized assessment of robotic surgical outcomes and adverse events following oncologic surgery is necessary for quality improvement with innovative technology. Between 2003 and 2016, 10,013 unique robotic operations were performed in 9,858 patients. Our prospectively maintained database was retrospectively reviewed for hospital readmissions and Clavien-Dindo grade ≥ 2 complications within 30 days. Multivariable logistic regression was used to identify predictors of surgical complications and hospital readmissions. Cases were stratified by discipline: genitourinary (n = 8240), gynecologic (n = 857), thoracic (n = 457), gastrointestinal (n = 322), hepatobiliary (n = 60), ear/nose/throat (n = 44) and general (n = 33). Intraoperative complications occurred in 42 surgeries (0.4%). Postoperative complications occurred in 946 patients [9.4%, highest grade 2 (n = 574), 3 (n = 288), 4 (n = 72), 5 (n = 10)]. Most frequent complications were ileus (154, 16.3%), anemia (91, 9.6%), cardiac arrhythmia (62, 6.6%), deep vein thrombosis/pulmonary embolus (47, 5.0%), wound infection (45, 4.8%) and urinary leak (43, 4.5%). 405 patients (4.0%) required readmission. Most common causes for hospital readmission were ileus (44, 10.9%), urinary leak (23, 5.7%), urinary tract infection (23, 5.7%), intra-abdominal abscess/fluid collection (23, 5.7%), and small bowel obstruction (19, 4.7%). On multivariable analysis, longer operative time and older age predicted complications and readmissions (p ≤ 0.02). Robotic-assisted surgery appears a safe for oncologic surgery with acceptable hospital readmission and complication rates. Older age and longer operative time were associated with complications and readmission.

Improving family caregiver and patient outcomes in lung cancer surgery: Study protocol for a randomized trial of the multimedia self-management (MSM) intervention.

OBJECTIVE: To describe the study protocol of the Multimedia Self-Management (MSM) intervention to prepare patients and family caregivers (FCGs) for lung cancer surgery. DESIGN: The study is a five-year, single site, randomized controlled trial of 160 lung cancer surgery FCG and patient dyads (320 total participants), comparing intervention and attention control arms. SETTING: One National Cancer-Institute (NCI) designated comprehensive cancer center in Southern California. PARTICIPANTS: Patients who are scheduled to undergo lung cancer surgery and their FCGs are enrolled as dyads only. INTERVENTION: Based on the Chronic Care Self-Management Model (CCM), the intervention is a nurse-led, caregiver-based, multimedia care program for lung cancer surgery. Its primary focus is to help FCGs develop self-management skills related to their caregiving role through goal setting, proactive planning, building problem-solving skills, and accessing family support services. The intervention also supports dyads to prepare for surgery and post-operative recovery at home. It includes videos, print, web-based, and post-discharge telephone support. MAIN OUTCOME MEASURES: FCG and patient psychological distress and QOL; FCG burden and preparedness for caregiving; FCG and patient healthcare resource use (in-home nursing care, urgent care/ER visits, readmissions). ANALYSIS: Repeated measures ANCOVA statistical design will be used, removing variances prior to examining mean squares for the group by occasion interactions, and co-varying the baseline scores. In addition, structured equation modeling (SEM) will assess whether mediating and moderating factors are associated with outcomes. ClinicalTrials.gov Identifier: NCT03686007.

Perceptions and Utilization of Lung Cancer Screening Among Smokers Enrolled in a Tobacco Cessation Program.

BACKGROUND: Although lung cancer screening (LCS) with low-dose computed tomography (LDCT) reduces lung cancer mortality in high-risk patients, most of those eligible are not referred for screening. Tobacco cessation counseling may be an opportune time to educate people about LCS, but little is known about the utilization and perceptions of LCS among people undergoing tobacco cessation treatment. MATERIALS AND METHODS: We surveyed 185 current smokers, including 122 smokers between the ages of 55 and 80 years, who were attending a tobacco cessation class in a large integrated health care system regarding lung cancer risk perception and perceived benefits, harms, and barriers to LCS. We analyzed results according to whether participants had already undergone LCS and also whether they had undergone colorectal cancer screening. RESULTS: A minority (18.9%) of participants had undergone LCS, and no participant who had not undergone LCS was familiar with LCS. Perceived lung cancer risk was high, and screening was believed to be beneficial. Common barriers included being a current smoker (56.6%), worrying about test results (52.5%), lack of knowledge about the test (50.8%), absence of symptoms of lung cancer (40.2%), costs of the study (35.2%), and worrying about being blamed for having smoked (33.6%). Perceived risk and barriers to LDCT were similar among people who had or had not previously undergone colorectal cancer screening. CONCLUSIONS: Utilization of LCS was low, and few smokers were aware of LDCT for LCS. A number of patient-related barriers to screening exist among smokers. Tobacco cessation counseling may be an opportune time to provide education regarding LCS with LDCT.

The triptolide derivative MRx102 inhibits Wnt pathway activation and has potent anti-tumor effects in lung cancer.

BACKGROUND: The natural compound triptolide has been shown to decrease cell proliferation and induce apoptosis and cellular senescence. We previously demonstrated that triptolide decreases tumor formation and metastasis of human non-small cell lung cancer cells (NSCLC). Due to the toxicity of triptolide, derivatives of the natural compound have been developed that show more favorable toxicity profiles and pharmacokinetics in animal models. The purpose of this study was to evaluate MRx102 as a novel therapeutic for lung cancer. METHODS: Mice injected subcutaneously with H460 lung cancer cells were treated with MRx102 or carboplatin to determine the effect of MRx102 on tumor formation in comparison to standard treatment. Patient-derived xenografts (PDX) with different WIF1 expression levels were treated with MRx102 or cisplatin. We tested the effects of MRx102 treatment on migration and invasion of lung cancer cells using Transwell filters coated with fibronectin and Matrigel, respectively. Tail vein injections using H460 and A549 cells were performed. RESULTS: Here we report that the triptolide derivative MRx102 significantly decreases NSCLC proliferation and stimulates apoptosis. Further, MRx102 potently inhibits NSCLC haptotactic migration and invasion through Matrigel. In vivo, NSCLC tumor formation and metastasis were greatly decreased by MRx102 treatment. The decrease in tumor formation by MRx102 in the patient-derived xenograft model was WIF1-dependent, demonstrating that MRx102 is a potent inhibitor of the Wnt pathway in low WIF1 expressing NSCLC patient tumors. CONCLUSIONS: These results indicate that MRx102 has potent antitumor effects both in vitro and in vivo, and is a potential novel therapy for the treatment of NSCLC.

Triptolide Inhibits Lung Cancer Cell Migration, Invasion, and Metastasis.

BACKGROUND: Triptolide is an extract from Tripterygium wilfordii used in traditional Chinese medicine to treat autoimmune disorders. Triptolide has anticancer effects in vitro and is reported to impair cancer cell migration. We studied whether triptolide inhibits lung cancer cell migration and metastasis. METHODS: We determined the microRNA expression profile of triptolide-treated cells. We tested the effects of triptolide treatment on migration and invasion of lung cancer cells by using Transwell filters coated with fibronectin and Matrigel, respectively. Western blot analyses were used to compare expression of proteins involved in cell migration before and after 10 nmol/L triptolide treatment. Tail vein injections with H358 cells were performed. The mice were treated with 1 mg/kg triptolide or vehicle by intraperitoneal injection three times per week. Lung and liver metastases were compared at 9 weeks. Means of groups were compared by using a t test. RESULTS: Triptolide altered the expression of microRNAs involved in cellular movement and significantly decreased migration and invasion of lung cancer cells from approximately 18 to 3 cells per field (p < 0.001). Triptolide decreases focal adhesion kinase expression, which leads to impairment of downstream signaling. Finally, triptolide-treated mice injected with lung cancer cells significantly decreased metastatic colony formation in the lungs (p < 0.01). CONCLUSIONS: Triptolide decreases lung cancer cell migration and invasion in vitro and inhibits metastatic tumor formation in mice. Triptolide suppresses focal adhesion kinase, which causes deregulation of the migration machinery. These results suggest that triptolide inhibits lung cancer metastasis and should be investigated as a new lung cancer therapy.

Interdisciplinary Palliative Care for Patients With Lung Cancer.

CONTEXT: Palliative care, including symptom management and attention to quality of life (QOL) concerns, should be addressed throughout the trajectory of a serious illness such as lung cancer. OBJECTIVES: This study tested the effectiveness of an interdisciplinary palliative care intervention for patients with Stage I-IV non-small cell lung cancer (NSCLC). METHODS: Patients undergoing treatments for NSCLC were enrolled in a prospective, quasi-experimental study whereby the usual care group was accrued first followed by the intervention group. Patients in the intervention group were presented at interdisciplinary care meetings, and appropriate supportive care referrals were made. They also received four educational sessions. In both groups, QOL, symptoms, and psychological distress were assessed at baseline and 12 weeks using surveys which included the Functional Assessment of Cancer Therapy-Lung and the Lung Cancer Subscale, the 12-item Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being, and the Distress Thermometer. RESULTS: A total of 491 patients were included in the primary analysis. Patients who received the intervention had significantly better scores for QOL (109.1 vs. 101.4; P < 0.001), symptoms (25.8 vs. 23.9; P < 0.001) spiritual well-being (38.1 vs. 36.2; P = 0.001), and lower psychological distress (2.2 vs. 3.3; P < 0.001) at 12 weeks, after controlling for baseline scores, compared to patients in the usual care group. Patients in the intervention group also had significantly higher numbers of completed advance care directives (44% vs. 9%; P < 0.001), and overall supportive care referrals (61% vs. 28%; P < 0.001). The benefits were seen primarily in the earlier stage patients vs. those with Stage IV disease. CONCLUSION: Interdisciplinary palliative care in the ambulatory care setting resulted in significant improvements in QOL, symptoms, and distress for NSCLC patients.

Augmented meaningful use criteria to identify patients eligible for lung cancer screening.

BACKGROUND: Lung cancer screening (LCS) with low-dose-radiation (low-dose computed tomography [LDCT]) saves lives. Despite recent US Preventive Services Task Force (USPTF) draft endorsement of LCS, a minority of eligible patients get screened. Meaningful use is a set of standards for electronic health records (EHR) established by the Centers for Medicare and Medicaid Services and includes reporting of smoking status. We sought to improve rates of LCS among patients treated at our institution by identifying eligible patients using augmented smoking-related meaningful use criteria. METHODS: We launched an LCS program at our institution, a National Comprehensive Cancer Network (NCCN) cancer center, in January 2013. We developed a "tobacco screen," administered by clinic staff to all adult outpatients every 6 months and entered into the EHR. This contained smoking-related meaningful use criteria as well as a pack-year calculation and quit date if applicable. Weekly electronic reports of patients who met eligibility criteria for LCS were generated, and EHR review excluded patients who had had chest computed tomography (CT) within 12 months or who were undergoing cancer treatment. We then contacted eligible patients to review eligibility for LCS and communicated with the primary treating physician regarding the plan for LCS. RESULTS: During the first 3 months of the program, 4 patients were enrolled, 2 by physician referral and 2 by self-referral. We then began to use the tobacco screen reports and identified 418 patients potentially eligible for LCS. Over the next 7 months, we enrolled a total of 110 patients. Fifty-eight (53%) were identified from the tobacco screen, 32 (29%) were self-referred, and 20 (18%) were physician referrals. Three stage I lung cancers were detected and treated. The tobacco screen was easily implemented by clinic staff and took a median time of 2 minutes to enter for current and former smokers. Lack of response to attempts at telephone contact and objection to paying out-of-pocket costs were the most common reasons for failing to screen eligible patients. CONCLUSIONS: Use of augmented meaningful use criteria containing detailed tobacco exposure history is feasible and allows for identification of patients eligible for LCS in a medical center. Barriers to LCS include lack of insurance coverage and lack of systematic referral of patients at high risk.

Quality of life and symptoms following stereotactic body radiotherapy in early-stage lung cancer patients.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has emerged in recent years as a clinically viable treatment option for early-stage non-small-cell lung cancer (NSCLC) patients. Comprehensive assessment of quality of life (QoL) after SBRT is relatively sparse. OBJECTIVE: To describe QoL and symptoms in a small, prospective cohort of early-stage NSCLC patients treated with SBRT. METHODS: 19 NSCLC patients who were medically unfit for surgery or chose not to undergo surgery were included in the study. All of the patients were treated with SBRT between 2009 and 2013 at a single comprehensive cancer center. Patients completed a baseline assessment of functional and cognitive status, symptoms, psychological distress, and overall QoL. Questionnaires were repeated at 6 and 12 weeks after accrual. RESULTS: There were no significant differences in all outcomes across the 3 evaluation time points. Overall QoL scores were moderate, and the lowest score was observed for the functional well-being domain. The most severe symptoms at baseline were pain, lack of energy, cough, nervousness, difficulty sleeping, shortness of breath, and worry. Severity scores for pain, lack of energy, and cough increased, whereas nervousness, difficulty sleeping, and worry decreased at the 12 week evaluation. LIMITATIONS: Small sample size and lack of sufficient diversity in the cohort. CONCLUSIONS: QoL scores remained relatively stable across time. Anxiety improved after SBRT, whereas symptoms such as generalized pain, lack of energy, and cough worsened. The findings suggest that SBRT is overall a well-tolerated treatment with no significant decrement in patient-centered outcomes.

A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies.

BACKGROUND: The frequent recurrence of early-stage non-small-cell lung cancer (NSCLC) is generally attributable to metastatic disease undetected at complete resection. Management of such patients depends on prognostic staging to identify the individuals most likely to have occult disease. We aimed to develop and validate a practical, reliable assay that improves risk stratification compared with conventional staging. METHODS: A 14-gene expression assay that uses quantitative PCR, runs on formalin-fixed paraffin-embedded tissue samples, and differentiates patients with heterogeneous statistical prognoses was developed in a cohort of 361 patients with non-squamous NSCLC resected at the University of California, San Francisco. The assay was then independently validated by the Kaiser Permanente Division of Research in a masked cohort of 433 patients with stage I non-squamous NSCLC resected at Kaiser Permanente Northern California hospitals, and on a cohort of 1006 patients with stage I-III non-squamous NSCLC resected in several leading Chinese cancer centres that are part of the China Clinical Trials Consortium (CCTC). FINDINGS: Kaplan-Meier analysis of the Kaiser validation cohort showed 5 year overall survival of 71·4% (95% CI 60·5-80·0) in low-risk, 58·3% (48·9-66·6) in intermediate-risk, and 49·2% (42·2-55·8) in high-risk patients (p(trend)=0·0003). Similar analysis of the CCTC cohort indicated 5 year overall survivals of 74·1% (66·0-80·6) in low-risk, 57·4% (48·3-65·5) in intermediate-risk, and 44·6% (40·2-48·9) in high-risk patients (p(trend)<0·0001). Multivariate analysis in both cohorts indicated that no standard clinical risk factors could account for, or provide, the prognostic information derived from tumour gene expression. The assay improved prognostic accuracy beyond National Comprehensive Cancer Network criteria for stage I high-risk tumours (p<0·0001), and differentiated low-risk, intermediate-risk, and high-risk patients within all disease stages. INTERPRETATION: Our practical, quantitative-PCR-based assay reliably identified patients with early-stage non-squamous NSCLC at high risk for mortality after surgical resection. FUNDING: UCSF Thoracic Oncology Laboratory and Pinpoint Genomics.

Intraperitoneal photodynamic therapy causes a capillary-leak syndrome.

BACKGROUND: In patients undergoing intraperitoneal (IP) photodynamic therapy (PDT), the combination of aggressive surgical debulking and light therapy causes an apparent systemic capillary-leak syndrome that necessitates significant intensive care unit (ICU) management after surgery. METHODS: From May 1997 to May 2001, 65 patients underwent surgical debulking and PDT as part of an ongoing phase II trial for disseminated IP cancer. Perioperative data were reviewed retrospectively, and statistical analyses were performed to determine whether any identifiable factors were associated with the need for mechanical ventilation for longer than 1 day and with the occurrence of postoperative complications. RESULTS: Forty-three women and 22 men (mean age, 49 years) were treated. Operative time averaged 9.8 hours, and mean estimated blood loss was 1450 mL. The mean crystalloid requirement for the first 48 hours after surgery was 29.3 L, and 49 patients required blood products. Twenty-four patients were intubated for longer than 24 hours, with a mean of 8.3 days for those intubated longer than 1 day. The median ICU stay was 4 days. Overall, 110 complications developed in 45 (69%) of the 65 patients. Significant complications included 6 patients with acute respiratory distress syndrome, 28 patients with infectious complications, and 4 patients with anastomotic complications. Statistical analyses revealed that surgery-related factors were significantly associated with these complication outcomes. CONCLUSIONS: Patients who undergo surgical debulking and IP PDT develop a significant capillary-leak syndrome after surgery that necessitates massive volume resuscitation, careful ICU monitoring, and, frequently, prolonged ventilatory support.