Adaptor proteins and ubiquinators in TGF-beta signaling.

The emergence of research analyzing the TGF-beta signaling pathway and its role in stem cell plasticity and differentiation has been a source of new insights into multiple cancers. TGF-beta signaling mediator Smads are tightly dependent on modulation by adaptor proteins, such as ELF, SARA, filamin, and crkl as well as ubiquitinators, such as PRAJA and SMURFs. Despite widespread inactivation of the TGF-beta pathway in gastrointestinal tumors, only a fraction of sporadic tumors exhibit inactivating mutations in early tumor formation, which suggests a role for the modulation of TGF-beta signals by stem/progenitor cell proteins, such as ELF and PRAJA. Delineating these key interactions of the TGF-beta signaling pathway could yield powerful new therapeutics aimed at treating hitherto difficult to treat cancers.

Lung cancer stem cells.

Lung cancer remains a major cause of cancer-related lethality because of high incidence and recurrence in spite of significant advances in staging and therapies. Recent data indicates that stem cells situated throughout the airways may initiate cancer formation. These putative stem cells maintain protumorigenic characteristics including high proliferative capacity, multipotent differentiation, drug resistance and long lifespan relative to other cells. Stem cell signaling and differentiation pathways are maintained within distinct cancer types, and destabilization of this machinery may participate in maintenance of cancer stem cells. Characterization of lung cancer stem cells is an area of active research and is critical for developing novel therapies. This review summarizes the current knowledge on stem cell signaling pathways and cell markers used to identify the lung cancer stem cells.

Complications of thoracic computed tomography-guided fiducial placement for the purpose of stereotactic body radiation therapy.

PURPOSE: This study examined the complication rates associated with percutaneous fiducial placement for the purpose of stereotactic body radiation therapy of primary and metastatic lung neoplasms. PATIENTS AND METHODS: This is a retrospective review of computed tomography (CT) scans and follow-up chest radiographs of 48 consecutive patients who underwent CT-guided percutaneous fiducial placement. The effect of age, sex, number of fiducials placed, and performance of a concomitant biopsy on the complication rates were assessed. RESULTS: Of 48 patients with a total of 221 fiducials placed, 16 (33%) had a procedure-related pneumothorax. There was no significant difference in pneumothorax rate based on age (P = 0.16), sex (P > 0.99), and number of fiducials placed (P = 0.21). Overall, 6 of 48 patients (12.5%) required a thoracostomy tube. Performance of a concomitant core needle biopsy at the time of fiducial placement was associated with pneumothorax rates of 64% compared with 26% without biopsies (P = 0.03). Postprocedural CT demonstrated hemorrhage in 9 patients (19%). Two patients had hemoptysis; one required admission. Patients' age, sex, number of fiducials placed, and performance of concomitant biopsy had no statistically significant implications on parenchymal hemorrhage incidence. CONCLUSION: Approximately one third of the patients develop a pneumothorax during CT-guided fiducial placement. Most are asymptomatic and do not require a thoracostomy. A concurrent biopsy at the time of fiducial placement is associated with an increased risk of pneumothorax. Hemorrhage occurs but is usually clinically insignificant.

Inactivation of ELF/TGF-beta signaling in human gastrointestinal cancer.

TGF-beta/Smads regulate a wide variety of biological responses through transcriptional regulation of target genes. ELF, a beta-spectrin, plays a key role in the transmission of TGF-beta-mediated transcriptional response through Smads. ELF was originally identified as a key protein involved in endodermal stem/progenitor cells committed to foregut lineage. Also, as a major dynamic adaptor and scaffolding protein, ELF is important for the generation of functionally distinct membranes, protein sorting and the development of polarized differentiated epithelial cells. Disruption of elf results in the loss of Smad3/Smad4 activation and, therefore, a disruption of the TGF-beta pathway. These observations led us to pursue the function of ELF in gastrointestinal (GI) epithelial cell-cell adhesion and tumor suppression. Here, we show a significant loss of ELF and reduced Smad4 expression in human gastric cancer tissue samples. Also, of the six human gastric cancer cell lines examined, three show deficient ELF expression. Furthermore, we demonstrate the rescue of E-cadherin-dependent homophilic cell-cell adhesion by ectopic expression of full-length elf. Our results suggest that ELF has an essential role in tumor suppression in GI cancers.

The Society of Thoracic Surgeons Lung Cancer Resection Risk Model: Higher Quality Data and Superior Outcomes.

BACKGROUND: The Society of Thoracic Surgeons (STS) creates risk-adjustment models for common cardiothoracic operations for quality improvement purposes. Our aim was to update the lung cancer resection risk model utilizing the STS General Thoracic Surgery Database (GTSD) with a larger and more contemporary cohort. METHODS: We queried the STS GTSD for all surgical resections of lung cancers from January 1, 2012, through December 31, 2014. Logistic regression was used to create three risk models for adverse events: operative mortality, major morbidity, and composite mortality and major morbidity. RESULTS: In all, 27,844 lung cancer resections were performed at 231 centers; 62% (n = 17,153) were performed by thoracoscopy. The mortality rate was 1.4% (n = 401), major morbidity rate was 9.1% (n = 2,545), and the composite rate was 9.5% (n = 2,654). Predictors of mortality included age, being male, forced expiratory volume in 1 second, body mass index, cerebrovascular disease, steroids, coronary artery disease, peripheral vascular disease, renal dysfunction, Zubrod score, American Society of Anesthesiologists rating, thoracotomy approach, induction therapy, reoperation, tumor stage, and greater extent of resection (all p < 0.05). For major morbidity and the composite measure, cigarette smoking becomes a risk factor whereas stage, renal dysfunction, congestive heart failure, and cerebrovascular disease lose significance. CONCLUSIONS: Operative mortality and complication rates are low for lung cancer resection among surgeons participating in the GTSD. Risk factors from the prior lung cancer resection model are refined, and new risk factors such as prior thoracic surgery are identified. The GTSD risk models continue to evolve as more centers report and data are audited for quality assurance.

Time series evaluation of an intervention to increase statin tablet splitting by general practitioners.

BACKGROUND: Tablet splitting, in which a higher-dose tablet is split to get 2 doses, reduces patients' drug costs. Statins can be split safely. General practitioners (GPs) may not direct their patients to split statins because of safety concerns or unawareness of costs. Medical chart inserts provide cost-effective education to physicians. OBJECTIVE: The aim of this study was to assess whether providing GPs with statin-splitting chart inserts would increase splitting rates, and to identify predictors of splitting. METHODS: In 2005 and 2006, we faxed a statin chart insert to British Columbia GPs with a request for a telephone interview. Consenting GPs were mailed 3 statin chart inserts and interviewed by phone (the intervention). In an interrupted time series, we compared monthly rates of statin-splitting prescriptions among intervention and nonintervention GPs before, during, and after the intervention. In multivariate logistic regressions accounting for patient clustering, predictors of splitting included physician and patient demographics and the specific statin prescribed. RESULTS: Of 5051 GPs reached, 282 (6%) agreed to the intervention. Before the intervention, GPs' splitting rate was 2.6%; after intervention, GPs' splitting rate was 7.5%. The rate for the nonintervention GPs was 4.4%. Intervention GPs were 1.68 (95% CI, 1.12-2.53) times more likely to prescribe splitting after the intervention than were nonintervention GPs. Other predictors were a patient's female sex (odds ratio [OR] = 1.26; 95% CI, 1.18-1.34), lower patient income (OR = 1.33; 95% CI, 1.18-1.34), and a lack of drug insurance (OR = 1.89; 95% CI, 1.69-2.04). CONCLUSIONS: An inexpensive intervention was effective in producing a sustained increase in GPs' splitting rate during 22 months of observed follow-up. Expanding statin-splitting education to all GPs might reduce prescription costs for many patients and payors.

Does knowledge of medication prices predict physicians' support for cost effective prescribing policies.

BACKGROUND: British Columbia implemented a generic substitution (GS) and Reference Drug Program (RDP) to contain drug expenditures without negatively affecting health outcomes. Years after implementation, these policies remain controversial among physicians. OBJECTIVE: To assess British Columbia general practitioners' (GPs) opinions of RDP and GS stratified by knowledge of drug costs. METHODS: In telephone interviews, GPs ranked the economic and clinical appropriateness of drug policy options on a 5-point Likert scale. Responses to economic questions were stratified and compared according to the accuracy (+ $10 of the actual cost) of GPs' cost estimates for a 30-day supply of atorvastatin and omeprazole. RESULTS: The majority of 210 interviewed GPs rated the economic appropriateness of GS and RDP positively (79% and 65%) but fewer rated them clinically appropriate (60% and 43%). Ratings for GS were more favorable than RDP, economically (mean=4.3 vs. 3.8, p=0.0005) and clinically (mean=3.7 vs. 3.1, p=0.006). GP's assessment of the therapeutic equivalence among ACE inhibitors and among CCBs correlated with their ratings of the respective RDPs (I=0.3, p=0.03, and I=0.4, p=0.02). GPs underestimated the price for omeprazole by C$28 (33%) and atorvastatin by C$28 (34%). GPs with accurate cost estimates were equally as likely to favorably rank the economic appropriateness of RDP as those with inaccurate estimates (mean = 3.7 vs. 4.0, p=0.0847). GS was assessed similarly (mean = 4.2 vs. 4.5, p=0.0712). CONCLUSIONS: In British Columbia, the majority of GPs hold favorable opinions of GS and RDP; but, simply educating physicians about drug prices will not make them more supportive of cost-containment policies.

TGF-beta signaling pathway inactivation and cell cycle deregulation in the development of gastric cancer: role of the beta-spectrin, ELF.

We have shown that loss of ELF, a stem cell adaptor protein, disrupts TGF-beta signaling through Smad3 and Smad4 localization. Notably elf(+/-)/smad4(+/-) mice develop gastric cancer presenting this as an important model for analyzing molecular event in gastric carcinogenesis. To gain further insight into the functional role of ELF in gastric cancer suppression, we carried out a detailed characterization of cell cycle events leading to gastric tumorigenesis. elf(-/-) cells and elf(+/-)/smad4(+/-) mice demonstrate a marked alteration of cell cycle regulators, such as Cdk4, K-Ras, and p21. Levels of Cdk4 increased compared to normal controls, suggesting loss of ELF results in functional abnormalities in cell cycle regulation. We further demonstrate that the elf(-/-) MEFs show a disruption of G1/S cell cycle transition and a significant reduction in senescence. Thus, in response to ELF deficiency, the abnormalities of G1/S checkpoint and senescence contribute their increment of susceptibility to malignant transformation.