Jae Y. Kim

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

BACKGROUNDnTriptolide 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.nnnMETHODSnWe 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.nnnRESULTSnTriptolide 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).nnnCONCLUSIONSnTriptolide 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.

Perceptions and Utilization of Lung Cancer Screening Among Primary Care Physicians

Introduction Lung cancer screening (LCS) with low‐dose computed tomography (LDCT) is effective at reducing lung cancer mortality in high‐risk current and former smokers. Despite the fact that screening is recommended by the U.S. Preventative Services Task Force (USPSTF), few eligible patients are screened. We set out to study the barriers to LCS by surveying primary care physicians (PCPs). Methods We surveyed a randomly selected sample of 1384 eligible PCPs between January and October 2015, using the American Medical Association Physician Masterfile, though surveys sent by mail, fax, and e‐mail. The survey included questions regarding knowledge of LCS guidelines, utilization of LCS over the prior 12 months, and perceptions of barriers to LCS. Training background, years in practice, practice type, and demographics were also collected. Results The survey response rate was 18%. Responders and nonresponders did not differ by practice or demographic characteristics. Of the respondents, 47% indicated that LCS was recommended by the USPSTF, 52% had referred at least one patient for LDCT, and 12% had referred at least one patient to a LCS program over the prior 12 months. Perceived barriers to LCS included uncertainty regarding ther benefit of LCS, concern regarding insurance coverage, and the harm of LCS. Conclusions Although LCS is recommended by the USPSTF, LDCT is utilized in a minority of eligible patients, as reported by surveyed PCPs. Approximately half of PCPs are familiar with USPSTF recommendations for LCS and a number of physician barriers to adherence to guidelines exist. Additional study of physician‐ and system‐based interventions to improve adherence to LCS recommendations is needed.

Palliative care and spiritual well‐being in lung cancer patients and family caregivers

Spiritual well‐being is an important dimension of quality of life (QOL) and is a core component of quality oncology and palliative care. In this analysis, we aimed to describe spiritual well‐being outcomes in a National Cancer Institute (NCI)‐supported Program Project that tested the effectiveness of an interdisciplinary palliative care intervention in lung cancer patients and their family caregivers (FCGs).

Variations in the vascular endothelial growth factor pathway predict pulmonary complications.

BACKGROUNDnClinical factors predicting pulmonary complications after lung resection have been well described, whereas the role of genetics is unknown. The vascular endothelial growth factor (VEGF) signaling pathway has been linked to acute lung injury. We hypothesized that genetic variations in this pathway may be associated with postoperative pulmonary complications after lung resection.nnnMETHODSnOne hundred ninety-six single nucleotide polymorphisms (SNPs) in 17 genes in the VEGF pathway were genotyped in a discovery set of 264 patients and a replication set of 264 patients who underwent lobectomy for lung cancer. Multivariable analysis adjusting for baseline clinical factors was used to identify SNPs associated with pulmonary complications. Cumulative and classification and regression tree (CART) analyses were used to further stratify risk groups.nnnRESULTSnThe overall number of pulmonary complications was 164/528 (31%). The effects of 6 SNPs were consistent in the discovery and replication sets (pooled p value<0.05). The rs9319425 SNP in the VEGF receptor gene FLT1 resulted in a 1.50-fold increased risk (1.15-1.96; p=0.003). A cumulative effect for the number of risk genotypes and complications was also evident (p<0.01). Patients carrying 5 risk genotypes had a 5.76-fold increase in risk (2.73-12.16; p=4.44×10(-6)). Regression tree analysis identified potential gene-gene interactions between FLT1:rs9319425 and RAF1:rs713178. The addition of the 6 SNPs to the clinical model increased the area under the receiver operating characteristic curve by 6.8%.nnnCONCLUSIONSnGenetic variations in the VEGF pathway are associated with risk of pulmonary complications after lobectomy. This may offer insight into the underlying biological mechanisms of pulmonary complications.

Long-Term Effect of an Interdisciplinary Supportive Care Intervention for Lung Cancer Survivors After Surgical Procedures

BACKGROUNDnSurgical procedures provide the best chance for cure and long-term survival in non-small cell cancer (NSCLC). Persistent symptoms after surgical procedures are common, and they can negatively affect health-related quality of life (HRQOL). The purpose of this study was to examine the long-term effect of an interdisciplinary supportive care intervention to improve HRQOL, psychological distress, and symptoms in lung cancer survivors who were treated surgically.nnnMETHODSnPatients undergoing curative intent resection for NSCLC were enrolled in a prospective sequential design whereby the control group was accrued first, followed by the intervention group. Patients in the intervention group were assessed and presented by nurses at weekly interdisciplinary care meetings before surgical procedures, and received four educational sessions (physical, psychological, social, and spiritual well-being) after surgical procedures. Appropriate symptom management, social work, rehabilitation, and spiritual support interventions were coordinated by the study nurse. In both groups, HRQOL, psychological distress, and symptom severity were assessed at baseline and at 6, 12, 24, 36, and 52 weeks with the use of surveys that included the validated Functional Assessment of Cancer Therapy-Lung (FACT-L), Lung Cancer Subscale (LCS), and Distress Thermometer. Mean survey scores were analyzed with factorial analysis of covariance at 12 months.nnnRESULTSnA total of 71 survivors (controlxa0= 33; interventionxa0= 38) were accrued. No difference was found in age, baseline performance status, or stage of disease between groups. Patients in the intervention group had significantly less distress (mean, 1.0 versus 4.0; range, 0 to 10; p < 0.001) and more favorable mean FACT-L scores (126.1 versus 98.7; range, 0 to 140; p < 0.001) and LCS scores (29.4 versus 23.6; range, 0 to 32; p < 0.001) at 12 months. The mean scores of all categories of questions in FACT-L (physical, social/family, emotional, and functional well-being) were considerably more favorable in the intervention group at 12 months.nnnCONCLUSIONSnAn interdisciplinary supportive care intervention improves psychological distress and HRQOL at 12 months after lung cancer surgical procedures. This study has important implications in improving HRQOL of lung cancer survivors after surgical procedures. Further study is warranted on incorporating the interdisciplinary personalized interventions used in this study into clinical practice for lung cancer survivors.

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

BackgroundThe 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.MethodsMice 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.ResultsHere 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.ConclusionsThese 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.

Survival following lung resection in immunocompromised patients with pulmonary invasive fungal infection.

OBJECTIVESnPulmonary invasive fungal infections (IFIs) are associated with high mortality in patients being treated for haematological malignancy. There is limited understanding of the role for surgical lung resection and outcomes in this patient population.nnnMETHODSnThis is a retrospective cohort of 50 immunocompromised patients who underwent lung resection for IFI. Patient charts were reviewed for details on primary malignancy and treatment course, presentation and work-up of IFI, reasons for surgery, type of resection and outcomes including postoperative complications, mortality, disease relapse and survival. Analysis was also performed on two subgroups based on year of surgery from 1990-2000 and 2001-2014.nnnRESULTSnThe median age was 39 years (range: 5-64 years). Forty-seven patients (94%) had haematological malignancies and 38 (76%) underwent haematopoietic stem cell transplantation (HSCT). Surgical indications included haemoptysis, antifungal therapy failure and need for eradication before HSCT. The most common pathogen was Aspergillus in 34 patients (74%). Wedge resections were performed in 32 patients (64%), lobectomy in 9 (18%), segmentectomy in 2 (4%) and some combination of the 3 in 7 (14%) for locally extensive, multifocal disease. There were 9 (18%) minor and 14 (28%) major postoperative complications. Postoperative mortality at 30 days was 12% (n = 6). Acute respiratory distress syndrome was the most common cause of postoperative death. Overall 5-year survival was 19%. Patients who had surgery in the early period had a median survival of 24 months compared with 5 months for those who had surgery before 2001 (P = 0.046). At the time of death, 15 patients (30%) had probable or proven recurrent IFI. Causes of death were predominantly related to refractory malignancy, fungal lung disease or complications of graft versus host disease (GVHD). Patients who had positive preoperative bronchoscopy cultures had a trend towards worse survival compared with those with negative cultures (hazard ratio: 1.80, P = 0.087).nnnCONCLUSIONSnSurgical resection of IFI in immunocompromised patients is associated with high perioperative mortality. Long-term survival is limited by recurrent malignancy, persistent fungal infection and GVHD but has improved in recent years. Selection for surgical resection is difficult in this patient population, but should be carefully considered in those who are symptomatic, or have failed antifungal treatment.

The Effect of Primary Care Physician Knowledge of Lung Cancer Screening Guidelines on Perceptions and Utilization of Low-Dose Computed Tomography

Introduction Lung cancer screening (LCS) with low‐dose computed tomography (LDCT) is recommended by the U.S. Preventive Services Task Force (USPSTF) in high‐risk patients, but a minority of eligible people are screened. It is not clear whether knowledge of USPSTF recommendations among primary care physicians (PCP) affects utilization of LDCT. Methods A randomly selected sample of 1384 PCPs in Los Angeles County was surveyed between January and October 2015, using surveys sent by mail, fax, and e‐mail. The response rate was 18% (n = 250). Training background, years in practice, practice type, and respondent demographics were collected. We analyzed results based on the response to a question on whether the USPSTF recommends the use of LDCT to screen high‐risk individuals for lung cancer. Results A total of 117 (47%) PCPs responded that the USPSTF recommends LDCT for LCS. Of PCPs who were aware of USPSTF recommendations, 97% responded that CT was effective at reducing lung cancer mortality among individuals meeting eligibility criteria, compared with 90% who were unaware of guidelines (P = .02). A larger proportion of PCPs aware of guidelines ordered LDCT (71% vs. 38%, P < .001) and initiated a discussion on screening (86% vs. 62%, P < .001). Both groups of PCPs reported similar perceptions of barriers to screening, such as insurance coverage, risks of LCS, and cost to society. Practice size, training background, and years in practice did not affect knowledge of guidelines. Discussion Awareness of USPSTF recommendations for LDCT is associated with increased utilization of LDCT for screening. Educational interventions for PCPs may improve adherence with LCS recommendations. Micro‐Abstract Lung cancer screening with low‐dose computed tomography (LDCT) is recommended in high‐risk patients, but a minority of eligible people are screened. Here we analyzed the results of a survey of 250 PCPs to determine whether knowledge guidelines were associated with utilization of LDCT, and to understand what physician features were associated with guidelines knowledge. We found that awareness of guidelines was associated with increased LDCT utilization.

Non–Small Cell Lung Cancer as a Second Primary Among Patients With Previous Malignancy: Who Is at Risk?

BACKGROUNDnPatients with previous malignancies could be at increased risk of non-small cell lung cancer (NSCLC). However, the extent of the risk is unknown for many cancer types; thus, it is unclear who might benefit from screening.nnnMATERIALS AND METHODSnThe Surveillance, Epidemiology, and End Results data set from 1992 to 2012 was used to identify patients with previous malignancies who received a diagnosis of NSCLCxa0≥ 6 months after their initial cancer diagnosis. Standardized incidence ratios (SIRs) for NSCLC were calculated as a ratio of the observed to expected cases adjusted by person-years at risk. Cancers with a SIR > 1.0 had a risk of NSCLC greater than expected. The analyses were stratified by sex, radiation therapy use, and histologic type.nnnRESULTSnAmong the cancer survivors, 32,058 developed NSCLC. Smoking-related (lung, head and neck, bladder) and hematologic malignancies, regardless of previous radiation therapy, had the greatest SIR for NSCLC (range, 1.97-4.88). Colorectal and renal cancer survivors also had an increased SIR for NSCLC (1.16 and 1.21, respectively). Women with previous pancreatic cancer treated with radiation, breast cancer with or without radiation therapy, and those with thyroid cancer demonstrated a greater SIR for lung adenocarcinoma. Men with previous irradiated prostate cancer also had an elevated SIR (1.08; 99% confidence interval, 1.01-1.15) for lung adenocarcinoma. Patients with melanoma, prostate or uterine cancer had a lower SIR for NSCLC than expected.nnnCONCLUSIONnSmoking-related malignancies had the greatest risk of NSCLC. Radiation therapy conferred an elevated risk of NSCLC for certain cancers. Melanoma, prostate, and uterine cancer survivors had a low risk of NSCLC. These results could help identify high-risk screening candidates in the growing population of cancer survivors.

Empowering survivors after colorectal and lung cancer treatment: Pilot study of a Self-Management Survivorship Care Planning intervention

PURPOSEnThis study evaluates the feasibility and acceptability of a Self-Management Survivorship Care Planning (SM-SCP) intervention in colorectal and lung cancer survivors.nnnMETHODSnThis is a single-group, pre- and post-mixed methods study of an advance practice nurse-driven survivorship care intervention that integrates a survivorship care plan with self-management skills coaching. Colorectal and lung cancer survivors with stage I-III disease were enrolled at 3-6 months after completing treatments, and the intervention was administered in one in-person or telephone session. Survivor outcome measures included depression, anxiety, self-efficacy, QOL, and satisfaction. Paired t-tests were used for exploratory evaluations of pre-to post-intervention score changes. Content analysis was conducted to analyze the qualitative data to describe survivors experience with the intervention.nnnRESULTSnThirty participants (15 colorectal, 15 lung) enrolled and completed the study (73% retention). It took an average of 40xa0min to complete the TS/CP and 34.2xa0min to deliver the intervention. Exploratory analysis revealed significant differences from baseline to post-intervention in depression, anxiety, self-efficacy, physical functioning, role limitations-physical, pain, general health, health transition, physical health summary, and total QOL. Three qualitative themes emerged: 1) Feeling empowered about having a plan; 2) Struggling with psychosocial concerns; and 3) Suggestions for intervention content and delivery.nnnCONCLUSIONSnThe SM-SCP intervention was feasible and acceptable for colorectal and lung cancer survivors after treatment completion. Survivorship care interventions have potential to fulfill the unmet needs of colorectal and lung cancer survivors. Their effectiveness might be greater by integrating conceptually-based models of care, such as self-management skills building.