Search

Colorectal cancer (CRC) accounts for ~9% of all cancers in the Veteran population, a fact which has focused a great deal of the attention of the VA's research and development efforts. A field-based meeting of CRC experts was convened to discuss both challenges and opportunities in precision medicine for CRC. This group, designated as the VA Colorectal Cancer Cell-genomics Consortium (VA4C), discussed advances in CRC biology, biomarkers, and imaging for early detection and prevention. There was also a discussion of precision treatment involving fluorescence-guided surgery, targeted chemotherapies and immunotherapies, and personalized cancer treatment approaches. The overarching goal was to identify modalities that might ultimately lead to personalized cancer diagnosis and treatment. This review summarizes the findings of this VA field-based meeting, in which much of the current knowledge on CRC prescreening and treatment was discussed. It was concluded that there is a need and an opportunity to identify new targets for both the prevention of CRC and the development of effective therapies for advanced disease. Also, developing methods integrating genomic testing with tumoroid-based clinical drug response might lead to more accurate diagnosis and prognostication and more effective personalized treatment of CRC.

Intronic variants of the MYH9 gene that encodes the nonmuscle myosin heavy chain IIA are associated with diabetic nephropathy in European Americans and with sickle cell disease-associated nephropathy. However, the causal functional variants of MYH9 have remained elusive. Rare missense mutations in MYH9 cause macrothrombocytopenia and are occasionally associated with development of nephropathy. The E1841K mutation is among the common MYH9 missense mutations and has been associated with nephropathy in some carriers. To determine the contribution of the E1841K mutation in kidney disease, we studied the effects of the E1841K mutation in mice subjected to high salt or angiotensin II (Ang II) as models of hypertension and in mice subjected to renal mass reduction as a model of CKD. Despite similar levels of BP among wild-type (MYH9+/+ ) mice and mice heterozygous (MYH9+/E1841K ) and homozygous (MYH9E1841K/E1841K ) for the mutation in each model, MYH9E1841K/E1841K mice exhibited mildly increased albuminuria in response to high salt; severe albuminuria, nephrinuria, FSGS, and podocyte foot effacement in Ang II-induced hypertension; and early mortality in the renal mass reduction model. Treatment with candesartan during Ang II-induced hypertension attenuated kidney disease development in MYH9E1841K/E1841K mice. In vitro, isolated primary podocytes from MYH9E1841K/E1841K mice exhibited increased lamellipodia formation and reorganization of F-actin stress fibers. Wound healing assays revealed that MYH9+/+ podocytes had the lowest migration rate, followed by MYH9+/E1841K then MYH9E1841K/E1841K podocytes. In conclusion, the MYH9 E1841K variant alters podocyte cytoskeletal structure and renders podocytes more susceptible to injury after a damaging stimulus.

Background Bevacizumab is associated with an increased risk of arterial thromboembolism (ATE), however, its effect on venous thromboembolism (VTE) remains controversial. Scant data exist on factors that increase ATE/VTE risk in prostate cancer patients. We investigated the association of bevacizumab treatment and clinical factors with ATE/VTE risk in patients treated on CALGB 90401.

Object Chordoma cells can generate solid-like tumors in xenograft models that express some molecular characteristics of the parent tumor, including positivity for brachyury and cytokeratins. However, there is a dearth of molecular markers that relate to chordoma tumor growth, as well as the cell lines needed to advance treatment. The objective in this study was to isolate a novel primary chordoma cell source and analyze the characteristics of tumor growth in a mouse xenograft model for comparison with the established U-CH1 and U-CH2b cell lines. Methods Primary cells from a sacral chordoma, called “DVC-4,” were cultured alongside U-CH1 and U-CH2b cells for more than 20 passages and characterized for expression of CD24 and brachyury. While brachyury is believed essential for driving tumor formation, CD24 is associated with healthy nucleus pulposus cells. Each cell type was subcutaneously implanted in NOD/SCID/IL2Rγnull mice. The percentage of solid tumors formed, time to maximum tumor size, and immunostaining scores for CD24 and brachyury (intensity scores of 0–3, heterogeneity scores of 0–1) were reported and evaluated to test differences across groups. Results The DVC-4 cells retained chordoma-like morphology in culture and exhibited CD24 and brachyury expression profiles in vitro that were similar to those for U-CH1 and U-CH2b. Both U-CH1 and DVC-4 cells grew tumors at rates that were faster than those for U-CH2b cells. Gross tumor developed at nearly every site (95%) injected with U-CH1 and at most sites (75%) injected with DVC-4. In contrast, U-CH2b cells produced grossly visible tumors in less than 50% of injected sites. Brachyury staining was similar among tumors derived from all 3 cell types and was intensely positive (scores of 2–3) in a majority of tissue sections. In contrast, differences in the pattern and intensity of staining for CD24 were noted among the 3 types of cell-derived tumors (p < 0.05, chi-square test), with evidence of intense and uniform staining in a majority of U-CH1 tumor sections (score of 3) and more than half of the DVC-4 tumor sections (scores of 2–3). In contrast, a majority of sections from U-CH2b cells stained modestly for CD24 (scores of 1–2) with a predominantly heterogeneous staining pattern. Conclusions This is the first report on xenografts generated from U-CH2b cells in which a low tumorigenicity was discovered despite evidence of chordoma-like characteristics in vitro. For tumors derived from a primary chordoma cell and U-CH1 cell line, similarly intense staining for CD24 was observed, which may correspond to their similar potential to grow tumors. In contrast, U-CH2b tumors stained less intensely for CD24. These results emphasize that many markers, including CD24, may be useful in distinguishing among chordoma cell types and their tumorigenicity in vivo.

Chordoma is a rare bone cancer that is believed to originate from notochordal remnants. We previously identified germline T duplication as a major susceptibility mechanism in several chordoma families. Recently, a common genetic variant in T (rs2305089) was significantly associated with the risk of sporadic chordoma. We sequenced all T exons in 24 familial cases and 54 unaffected family members from eight chordoma families (three with T duplications), 103 sporadic cases, and 160 unrelated controls. We also measured T copy number variation in all sporadic cases. We confirmed the association between the previously reported variant rs2305089 and risk of familial [odds ratio (OR) = 2.6, 95 % confidence interval (CI) = 0.93, 7.25, P = 0.067] and sporadic chordoma (OR = 2.85, 95 % CI = 1.89, 4.29, P < 0.0001). We also identified a second common variant, rs1056048, that was strongly associated with chordoma in families (OR = 4.14, 95 % CI = 1.43, 11.92, P = 0.0086). Among sporadic cases, another common variant (rs3816300) was significantly associated with risk when jointly analyzed with rs2305089. The association with rs3816300 was significantly stronger in cases with early age onset. In addition, we identified three rare variants that were only observed among sporadic chordoma cases, all of which have potential functional relevance based on in silico predictions. Finally, we did not observe T duplication in any sporadic chordoma case. Our findings further highlight the importance of the T gene in the pathogenesis of both familial and sporadic chordoma and suggest a complex susceptibility related to T.

Design of polymer anti-reflective (AR) optical coatings for plastic substrates is challenging because polymers exhibit a relatively narrow range of refractive indices. Here, we report synthesis of a four-layer AR stack using hybrid polymer:nanoparticle materials deposited by resonant infrared matrix-assisted pulsed laser evaporation. An Er:YAG laser ablated frozen solutions of a high-index composite containing TiO2 nanoparticles and poly(methyl-methacrylate) (PMMA), alternating with a layer of PMMA. The optimized AR coatings, with thicknesses calculated using commercial software, yielded a coating for polycarbonate with transmission over 97 %, scattering

Background:While platinum-based doublet chemotherapy is standard of care for patients presenting with metastatic non–small-cell lung cancer, the optimal platinum agent (cisplatin versus carboplatin) is unclear. We therefore compared survival and toxicity among persons receiving these agents at Department of Veterans Affairs hospitals.Methods:We used the Veterans Affairs Central Cancer Registry to identify veterans presented between 2001 and 2008 with metastatic non–small-cell lung cancer, then selected those receiving initial platinum doublet chemotherapy. We compared survival between those receiving cisplatin and carboplatin using multivariable Cox proportional hazards models and propensity score analyses to adjust for imbalances in demographics and clinical characteristics.Results:We identified 4352 eligible persons; 4061 (93%) received carboplatin. Patients treated with cisplatin were younger (median age 61 versus 63, p < 0.01) and had less comorbidities (summary comorbidity score > 2, 7.7% versus 12.8%, p = 0.01) and higher eGFR (87 versus 84 mL/min/1.73 m2). Median survival was similar for persons receiving cisplatin and carboplatin (8.1 versus 7.5 months, p = 0.54). In an adjusted survival analyses, the use of cisplatin was not associated with a better survival (hazard ratio 0.98, 95% confidence interval 0.84–1.14, p = 0.79). We performed subgroup analysis defined by histology and second agent, the hazard ratio for mortality ranged spanned 1 and none of these approached statistical significance (all p values > 0.20). Cisplatin-treated patients were more likely to have more hospitalization (1.7 versus 1.3, p < 0.01) and outpatient visits (11 versus 9.6, p < 0.01). Cisplatin-treated patient had more subsequent encounters for infection (41.6% versus 34.3%, p < 0.01) and acute kidney injury/dehydration (29.2% versus 15.5%, p < 0.01)Conclusions:Patients receiving cisplatin and carboplatin-based doublets did not have significantly different survival, but cisplatin use was associated with an increase morbidity and healthcare use.

BACKGROUND Despite clinical trials demonstrating improved survival with adjuvant chemotherapy (AC) for patients with American Joint Committee on Cancer stages I to III non-small cell lung cancer (NSCLC), it is unclear whether this survival benefit extends to broader populations. The current study evaluated patterns of AC use and examined the impact of AC on survival. METHODS A retrospective analysis was conducted of patients in the Veterans Affairs Central Cancer Registry diagnosed with stages IB to IIIA NSCLC between 2001 and 2008. Descriptive statistics were used to examine patterns of AC use over an 8-year time period. Cox proportional hazards regression analyses were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CIs) to compare mortality risk among patients treated with and without AC. RESULTS Among 14,306 patients with stages IB to IIIA NSCLC, 4929 underwent surgery and 22% of these received AC. The percentages of patients diagnosed in 2001 through 2003, 2004 through 2005, and 2006 through 2008 receiving AC were 7.0%, 29.8%, and 29.5%, respectively. There was no survival benefit with AC noted for patients diagnosed between 2001 and 2003, but AC was associated with improved survival for the period between 2004 and 2005 (HR, 0.78; 95% CI, 0.67-0.91) and 2006 through 2008 (HR, 0.79; 95% CI, 0.69-0.91). Of those patients receiving AC, 89% received platinum-doublet chemotherapy. Carboplatin remained the most common agent, although cisplatin use reached 43% in the period between 2006 and 2008. The HR for cisplatin relative to carboplatin was 0.96 (95% CI, 0.80-1.15). CONCLUSIONS There was a significant increase in the use of AC between 2001 and 2008 and AC was associated with an improvement in overall survival. Cancer 2014;120:1939–1947. © 2014 American Cancer Society.

The Src pathway in activated in about one-third of non-small cell lung cancer (NSCLC) tumors. Dasatinib has Src-inhibitor activity. We examined the activity of dasatinib in 37 patients with advanced, previously treated NSCLC. Among the 29 patients who underwent pre-treatment biopsy for RNA biomarker analysis, 25 were treated with dasatinib 70 mg twice daily. There were no responses. Five patients discontinued treatment due to toxicity. Three patients had minor biopsy-related pneumothoraces. Given the lack of responses, no biomarkers were analyzed. Dasatinib 70 mg twice daily does not have activity nor is it well tolerated in unselected patients with advanced stage, previously treated NSCLC.

The potential of Nb3Sn for superconducting radio frequency cavities is widely recognized, and renewed R&D efforts continue to bring new insights about the material's structure and properties. We have systematically coated niobium samples with Nb3Sn for different durations. Several samples were coated over (“overcoat”) multiple times to elucidate the growth kinetics of Nb3Sn during the tin vapor-diffusion process. Analysis of coated samples is consistent with the model in which tin diffuses via grain boundaries to the Nb3Sn-Nb interface, where the growth of Nb3Sn into the niobium bulk takes place. Similar scaling laws are found for Nb3Sn grain growth and layer thickness. Nonparabolic layer growth is consistent with significant grain growth, which reduces the number of Sn transport channels. An examination of patchy regions in Nb3Sn coating, revealing large single-crystalline grains, points to impeded Nb3Sn layer growth due to low grain boundary density, resulting in a significantly thinner coating in those areas.

Over the last two decades, advances in Electron Backscatter Diffraction (EBSD) have moved the technique from a research tool to an essential characterization technique in many fields of material research. EBSD is the best suited technique for determining structure as a function of depth. This characterization is critically important but has been previously absent from Nb3Sn efforts. While EBSD is the technique of choice, obtaining quality data can be difficult. Sample preparation in particular is nontrivial. Here, we summarize the general principles of EBSD, discuss specific sample preparation techniques for Nb3Sn coated SRF cavity materials, and give examples of how EBSD is being used to understand fundamental growth mechanisms for Nb3Sn coatings.Over the last two decades, advances in Electron Backscatter Diffraction (EBSD) have moved the technique from a research tool to an essential characterization technique in many fields of material research. EBSD is the best suited technique for determining structure as a function of depth. This characterization is critically important but has been previously absent from Nb3Sn efforts. While EBSD is the technique of choice, obtaining quality data can be difficult. Sample preparation in particular is nontrivial. Here, we summarize the general principles of EBSD, discuss specific sample preparation techniques for Nb3Sn coated SRF cavity materials, and give examples of how EBSD is being used to understand fundamental growth mechanisms for Nb3Sn coatings.

e23120 Background: Cancer patients experience symptoms which may precede diagnosis, occur during therapy, and persist into survivorship. Symptom assessments and patient reported outcomes have been shown to improve quality of life and extend survival in cancer patients. The Veterans Administration Symptom Assessment Scale (VSAS) is a clinical tool to document cancer-related symptoms. Here, we report VSAS adoption in five Veterans Health Administration (VHA) hematology-oncology sites during a five-year period. Methods: Data was collected from the Corporate Data Warehouse (CDW): VSAS data, date of birth, gender, race, ethnicity, vital status, year of cancer diagnosis, ICD-O-3, VHA facility, and clinic stop codes. Descriptive analyses of patient demographics, disease characteristics, and VSAS utilization was performed. VSAS is comprised of 13 symptoms, rated on a 0 to 10 scale. A VSAS visit was defined as the date the VSAS was administered to a patient. Results: From January 2013 through June 2018, there were 41,917 instances of VSAS administered to 9,409 unique patients at five VHA facilities: 8,512 (90.5%) were male; 5,241 (56%) were non-Hispanic White, 3,743 (40%) were Black, and 297 (3%) were other racial categories or not available. The median age at the first VSAS visit was 67 years. In patients whose oncologic diagnosis was recorded by a cancer registrar (4,536), the most common diagnoses were prostate cancer, lung cancer (all histologies), colon cancer, and multiple myeloma. The number of VSAS administrations increased annually, from 866 in 2013 to 12,775 in 2017, which may be attributed to increased adoption of VSAS across and within VHA facilities. Individual patients completed the VSAS 1-57 times (median 2). At the five VHA facilities utilizing VSAS in 2017, VSAS was administered at 56% of hematology-oncology clinic visits. Conclusions: VSAS is a tool to measure and document patient symptom burden, and has been successfully adopted in the last five years at select VHA facilities. Expanded use of VSAS throughout the VHA is an important step in improving the quality of life and extending survival of veterans with cancer and blood disorders.

193 Background: Progress in understanding molecular changes in advanced prostate cancer has led to promising precision oncology opportunities; to date, most have been concentrated at tertiary research centers and urban centers and unequally available to patients. The VHA is the largest integrated healthcare system in the U.S. and provides medical care to >6 million veterans (~40% living in rural areas). The VHA has implemented a system-wide National Precision Oncology Program (NPOP) to offer tumor NGS testing to veterans with cancer. Methods: VHA patients with advanced stage cancers were offered targeted NGS gene panels (Personalis ACE Extended Cancer Panel; PGDx CancerSELECT/PlasmaSELECT) as part of clinical care. Annotated sequence data is collected by NPOP. We report preliminary findings of the participating veterans with prostate cancer. Results: 372 veterans from 81 sites underwent NGS sequencing of their prostate tumors (n=311) or cfDNA (n=61). Tumors from 165 (44%) were found to have mutations (allelic ratio ≥5%) in 47 genes. Of 372, 62 harbored mutations in TP53 (17%), 9 in NOTCH1 (2%), 16 in PTEN (4%), 16 in AR (4%), 13 in ATM (4%), 11 in BRCA2 (3%), 2 in MSH2 (0.5%), 1 in NBN (0.3%), and 1 in PALB2 (0.3%). 7 men (1.8%) had adequate tumor, but no identifiable somatic mutations. NPOP findings were compared to the existing databases SU2C/PCF (of metastatic biopsies in metastatic castration resistant disease) and TCGA (of primary tumors in localized disease), see table. Findings will be updated at presentation. Conclusions: The VA NPOP has been successfully implemented, and prostate tumors from veterans were found to carry potentially actionable mutations, including BRCA2 and ATM, for which there are precision treatment trials. The program will be expanded and will facilitate more diverse and equitable distribution of access to precision oncology diagnostics and therapeutic opportunities, in alignment with the Cancer Moonshot Initiative. (e.g. VA-ABCD clinicaltrials.gov; NCT02985021). [Table: see text]

In their introduction to Modern Fiction Studies’ 2006 special issue on graphic narratives, Hillary Chute and Marianne DeKoven direct attention to the unique powers of the genre’s layered language of text and image, calling these narratives works that are ‘in their very structure and grammar, cross-discursive’ (768). In graphic narrative, they state, the rhetorical capacities of word and image, often perceived as binary, enter into dialogue. Alison Bechdel uses this cross-discursiveness in a candid, effective and affective representation of the formative experiences captured in Fun Home. To date, however, what has been left out of the conversation on Bechdel’s work is how the affective nature of her complex relationship with her father – the anger, guilt and shame Bechdel confronts, which both create and inhibit her self-realization – so well mirrors the historical context in which this relationship occurs. I submit that by framing the narrative of her father’s and her own discovery of sexual identity as b...

Barrier materials on thin-film organic optoelectronic devices inhibit the uptake of water, oxygen, or environmental contaminants, and fabricating them is a major challenge. By definition, these barrier layers must be insoluble, so the usual routes to polymer- or organic-film deposition by spin coating are not problematic. In this paper, we report comparative studies of pulsed laser deposition of cyclic olefin copolymer (COC), an excellent moisture barrier and a model system for a larger class of protective materials that are potentially useful in organic electronic devices, such as organic light-emitting diodes (OLEDs). Thin films of COC were deposited by resonant and nonresonant infrared pulsed laser ablation of solid COC targets, using a free-electron laser tuned to the 3.43 μm C–H stretch of the COC, and a high-intensity nanosecond Q-switched laser operated at 1064 nm. The ablation craters and deposited films were characterized by scanning-electron microscopy, Fourier-transform infrared spectrometry, atomic-force microscopy, high-resolution optical microscopy, and surface profilometry. Thermal-diffusion calculations were performed to determine the temperature rise induced in the film at the C–H resonant wavelength. The results show that resonant infrared pulsed laser deposition (RIR-PLD) is an effective, low-temperature thin-film deposition technique that leads to evaporation and deposition of intact molecules in homogeneous, smooth films. Nonresonant PLD, on the other hand, leads to photothermal damage, degradation of the COC polymers, and to the deposition only of particulates.

A growing set of quality measures is being implemented to evaluate all components of cancer care, from diagnosis through the end of life. We investigated the Quality Oncology Practice Initiative (QOPI) quality measures portfolio. Additionally, we explored the effect of quality measure type on conformance.We performed QOPI data collections twice per year from fall 2007 through fall 2010 and spring 2012, using chart review of the Durham Veterans Administration outpatient oncology clinic. We categorized QOPI measures as nontreatment-related supportive care (NTSC), treatment-related supportive care (TSC), diagnostic, or therapeutic. Descriptive statistics and χ(2) were used to compare longitudinal conformance.The majority of QOPI measures in spring 2012 assess processes of chemotherapy treatment (therapeutic, 54.3%; TSC, 8.7%) or diagnostic modalities (19.6%). Measures targeting NTSC are few (17.4%) but increased from three measures in fall 2007 to eight measures in spring 2012. During those 5 years, average conformance to NTSC, TSC, diagnostic, and therapeutic measures was 71.4%, 86.1%, 89.3%, and 75.4%, respectively (P.001). Within the NTSC measures, emotional well-being and constipation assessment were least documented (41.0% and 46.3%, respectively). In spring 2012, NTSC measure conformance (75.8%) remained significantly lower than diagnostic measure conformance (91.5%; P.001).Most QOPI quality measures assess diagnosis or treatment processes of care and not supportive care. Aggregate conformance to the NTSC measures was lower than that of other categories. The differential conformance demonstrates the necessity of standardized documentation methods and quality improvement efforts that remain commensurate with the increasing portfolio of supportive care measures.

Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry. To rapidly and efficiently identify small molecules that inhibit chordoma cell growth, we screened the NCGC Pharmaceutical Collection (NPC) containing approximately 2800 clinically approved and investigational drugs at 15 different concentrations in chordoma cell lines, U-CH1 and U-CH2. We identified a group of drugs including bortezomib, 17-AAG, digitoxin, staurosporine, digoxin, rubitecan, and trimetrexate that inhibited chordoma cell growth, with potencies from 10 to 370 nM in U-CH1 cells, but less potently in U-CH2 cells. Most of these drugs also induced caspase 3/7 activity with a similar rank order as the cytotoxic effect on U-CH1 cells. Cantharidin, digoxin, digitoxin, staurosporine, and bortezomib showed similar inhibitory effect on cell lines and 3 primary chordoma cell cultures. The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures. Our results provide information useful for repurposing currently approved drugs for chordoma and potential approach of combination therapy.

Purpose. When a patient is diagnosed with lung cancer, members of his/her social network may be more likely to engage in smoking cessation efforts. Proactive telephone counseling combined with a tailored self-directed intervention may be more effective at promoting smoking cessation than a tailored self-directed intervention alone. Design. Randomized controlled trial. Setting. Four clinical sites. Subjects. Current smokers who are family members and close friends of patients with lung cancer. Intervention. Six counselor-initiated counseling calls using motivational interviewing techniques and focusing on teaching adaptive coping skills based on the transactional model of stress and coping along with tailored self-directed materials (including nicotine patches, if not contraindicated) (n = 245) vs. tailored self-directed materials (including nicotine patches, if not contraindicated) (n = 251). Measures. Participants were surveyed at baseline and at 2 weeks, 6 months, and 12 months postintervention. The outcome was 7-day point prevalent abstinence. Analysis. The objective of this study was to test for arm differences in smoking cessation rates at 2 weeks and 6 months postintervention (primary) and at 12 months postintervention (secondary). Results. We found no overall effect of the proactive intervention on cessation rates. Among younger participants (age 50), there were no group differences. Conclusion. Proactive telephone counseling focusing on adaptive coping skills was difficult to implement among smokers in lung cancer patients' social network. Although this study did not demonstrate any added benefit to cessation rates, this null finding may be a result of an intervention that was weaker than intended, owing to difficulties in completing the counseling phone calls. We discuss lessons learned and areas for future research in this special population.

Introduction: We sought to determine the efficacy of using both irinotecan- and etoposide-containing regimens sequentially for patients with untreated limited-stage small-cell lung cancer. Methods: Patients with untreated, measurable, limited-stage small-cell lung cancer with performance status 0 to 2, and adequate organ function were eligible. Treatment consisted of induction with cisplatin 30 mg/m 2 and irinotecan 65 mg/m 2 intravenously on day 1 and 8, every 21 days for two cycles. Beginning day 43, daily chest irradiation to 70 Gy was administered concurrently with carboplatin area under curve 5 on day 1, and etoposide 100 mg/m 2 on days 1 to 3, every 21 days for three cycles. The primary objective was to differentiate between 45% and 60% 2-year survival. Results: Two induction cycles were delivered to 72 of 75 eligible patients (96%) and all planned treatment was delivered to 59 patients (79%). Cisplatin and irinotecan induction chemotherapy resulted in complete responses in 7% and partial responses in 64% (response rate 71%, 95% confidence interval [CI], 59%–81%). The best response to all therapy included 88% complete or partial responses (95% CI, 78%–94%). With median follow-up of 57 months, the median progression-free survival and overall survival are 12.6 (95% CI, 9.4–14.7) and 18.1 months (15.8–22.9), respectively. The 1- and 2-year survival was 69% and 31%, respectively. Frequent (>20%) grade 3 and 4 toxicities were neutropenia in 84%, hemoglobin in 36%, platelets in 51%, esophagitis in 22%, and dehydration in 24%. There were no fatal toxicities. Conclusions: This treatment regimen of irinotecan–cisplatin induction chemotherapy followed by 70 Gy concurrent radiation and etoposide–carboplatin had tolerable toxicity but did not meet the preplanned 2-year survival target for further development.

Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy. Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy. Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10−8, adjusted P = 5.88 × 10−7). siRNA knockdown of VAC14 in stem cell–derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001). Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR.

Extensive stage small cell lung cancer (SCLC) is an aggressive disease that leaves less than 10% of patients alive at 2 years (1).

Guideline-concordant cancer care is a priority within the Department of Veterans Affairs (VA). In 2009, the VA expanded its capacity to treat breast cancer patients within VA medical centers (VAMCs). We sought to determine whether male and female Veterans diagnosed with breast cancer received BRCA testing as recommended by the National Comprehensive Cancer Network (NCCN) guidelines on Genetic/Familial High-Risk Assessment in Breast and Ovarian Cancer (v. 1.2010-1.2012). Using the 2011-2012 VA Central Cancer Registry and BRCA test orders from Myriad Genetics, we conducted a retrospective study. The outcome variable was a recommendation for genetic counseling or BRCA testing, determined by chart review. Independent variables expected to predict testing included region, site of care, and patient characteristics. We performed descriptive analysis of all patients and conducted multivariable logistic regression on patients who sought care at VAMCs that offered BRCA testing. Of the 462 Veterans who met NCCN testing criteria, 126 (27 %) received guideline-concordant care, either a referral for counseling or actual testing. No BRCA testing was recommended in 49 (50 %) VAMCs that provide cancer treatment. Surprisingly, patients with second primary breast cancer were less likely to be referred/tested (OR 0.39; CI 0.17, 0.89; p = 0.025). For patients under age 51, a yearly increase in age decreased likelihood of referral or testing (OR 0.85; CI 0.76, 0.94; p

To mitigate the potential harms of screening, professional societies recommend that lung cancer screening be conducted in multidisciplinary programs with the capacity to provide comprehensive care, from screening through pulmonary nodule evaluation to treatment of screen-detected cancers. The degree to which this standard can be met at the national level is unknown.To assess the readiness of clinical facilities in a national healthcare system for implementation of comprehensive lung cancer screening programs, as compared with the ideal described in policy recommendations.This was a cross-sectional, self-administered survey of staff pulmonologists in pulmonary outpatient clinics in Veterans Health Administration facilities.The facility-level response rate was 84.1% (106 of 126 facilities with pulmonary clinics); 88.7% of facilities showed favorable provider perceptions of the evidence for lung cancer screening, and 73.6% of facilities had a favorable provider-perceived local context for screening implementation. All elements of the policy-recommended infrastructure for comprehensive screening programs were present in 36 of 106 facilities (34.0%); the most common deficiencies were the lack of on-site positron emission tomography scanners or radiation oncology services. Overall, 26.5% of Veterans Health Administration facilities were ideally prepared for lung cancer screening implementation (44.1% if the policy recommendations for on-site positron emission tomography scanners and radiation oncology services were waived).Many facilities may be less than ideally positioned for the implementation of comprehensive lung cancer screening programs. To ensure safe, effective screening, hospitals may need to invest resources or coordinate care with facilities that can offer comprehensive care for screening through downstream evaluation and treatment of screen-detected cancers.

Rationale: To mitigate the potential harms of screening, professional societies recommend that lung cancer screening be conducted in multidisciplinary programs with the capacity to provide comprehensive care, from screening through pulmonary nodule evaluation to treatment of screen-detected cancers. The degree to which this standard can be met at the national level is unknown.Objectives: To assess the readiness of clinical facilities in a national healthcare system for implementation of comprehensive lung cancer screening programs, as compared with the ideal described in policy recommendations.Methods: This was a cross-sectional, self-administered survey of staff pulmonologists in pulmonary outpatient clinics in Veterans Health Administration facilities.Measurements and Main Results: The facility-level response rate was 84.1% (106 of 126 facilities with pulmonary clinics); 88.7% of facilities showed favorable provider perceptions of the evidence for lung cancer screening, and 73.6% of facilities had a fav...

Objective: Approximately 40,000 incident cancer cases are reported in the Veterans Affairs Central Cancer Registry (VACCR) annually (approximately 3% of U.S. cancer cases). Our objective was to provide the first comprehensive description of cancer incidence as reported in VACCR. Methods: Data were obtained from VACCR for incident cancers diagnosed in VA. Analyses focused on 2007 data. Cancer incidence among VA patients was compared to the general U.S. cancer population. Results: In 2007, 97.5% of VA cancers were diagnosed among men. Approximately 78.5% of newly diagnosed patients were White, 19.0% Black, and 2.5% were another race. Median age at diagnosis was 66 years. The geographic distribution of cancer patients in VA aligns that of VA users. The most commonly diagnosed cancers were similar between VA and the U.S. male cancer population. The five most frequently diagnosed cancers among VA cancer patients were: prostate (31.8%), lung/bronchus (18.8%), colon/rectum (8.6%), urinary bladder (3.6%),...

Protection of the heart from ischemia-reperfusion injury can be achieved by ischemic preconditioning and ischemic postconditioning. Previous studies revealed that a complex of pannexin-1 with the P2X7 receptor forms a channel during ischemic preconditioning and ischemic postconditioning that results in the release of endogenous cardioprotectants. ATP binds to P2X7 receptors, inducing the formation of a channel in association with pannexin-1. We hypothesized that this channel would provide a pathway for the release of these same cardioprotectants. Preconditioning-isolated perfused rat hearts with 0.4 μM ATP preceding 40 min of ischemia minimized infarct size upon subsequent reperfusion (5% of risk area) and resulted in >80% recovery of left ventricular developed pressure. Postconditioning with ATP after ischemia during reperfusion was also protective (6% infarct and 72% recovery of left ventricular developed pressure). Antagonists of both pannexin-1 (carbenoxolone and mefloquine) and P2X7 receptors (brilliant blue G and A438079) blocked ATP pre- and postconditioning, indicating that ATP protection was elicited via the opening of a pannexin-1/P2X7 channel. An antagonist of binding of the endogenous cardioprotectant sphingosine 1-phosphate to its G protein-coupled receptor diminished protection by ATP, which is also consistent with an ATP-dependent release of cardioprotectants. Suramin, an antagonist of binding of ATP (and ADP) to P2Y receptors, was without effect on ATP protection. Benzoyl benzoyl-ATP, a more specific P2X7 agonist, was also a potent pre- and postconditioning agent and sensitive to blockade by pannexin-1/P2X7 channel antagonists. The data point out for the first time the potential of P2X7 agonists as cardioprotectants.

This report describes the characteristics associated with successful enrollment of smokers in the social networks (i.e., family and close friends) of patients with lung cancer into a smoking cessation intervention.Lung cancer patients from four clinical sites were asked to complete a survey enumerating their family members and close friends who smoke, and provide permission to contact these potential participants. Family members and close friends identified as smokers were interviewed and offered participation in a smoking cessation intervention. Repeated measures logistic regression model examined characteristics associated with enrollment.A total of 1062 eligible lung cancer patients were identified and 516 patients consented and completed the survey. These patients identified 1325 potentially eligible family and close friends. Of these, 496 consented and enrolled in the smoking cessation program. Network enrollment was highest among patients who were white and had late-stage disease. Social network members enrolled were most likely to be female, a birth family, immediate family, or close friend, and live in close geographic proximity to the patient.Proactive recruitment of smokers in the social networks of lung cancer patients is challenging. In this study, the majority of family members and friends declined to participate. Enlisting immediate female family members and friends, who live close to the patient as agents to proactively recruit other network members into smoking cessation trials could be used to extend reach of cessation interventions to patients' social networks. Moreover, further consideration should be given to the appropriate timing of approaching network smokers to consider cessation.

Attainment of the greatest possible interior surface smoothness is critical to meeting the performance demands placed upon niobium superconducting radiofrequency (SRF) accelerator cavities by next generation projects. Electropolishing with HF–H2SO4 electrolytes yields cavities that meet SRF performance goals, but a less-hazardous, more environmentally-friendly process is desirable. Reported studies of EP on chemically-similar tantalum describe the use of sulfuric acid–methanol electrolytes as an HF-free alternative. Reported here are the results of experiments on niobium samples with this electrolyte. Voltammetry experiments indicate a current plateau whose voltage range expands with increasing acid concentration and decreasing temperature. Impedance spectroscopy indicates that a compact salt film is responsible for the current plateau. Equivalent findings in electropolishing chemically-similar tantalum with this electrolyte were interpreted due to as mass transfer limitation by diffusion of Ta ions away from the anode surface. We infer that a similar mechanism is at work here. Conditions were found that yield leveling and brightening comparable to that obtained with HF–H2SO4 mixtures.

As superconducting niobium radio-frequency (SRF) cavities approach fundamental material limits, there is increased interest in understanding the details of topographical influences on realized performance limitations. Micro- and nano-roughness are implicated in both direct geometrical field enhancements as well as complications of the composition of the 50 nm surface layer in which the super-currents typically flow. Interior surface chemical treatments such as buffered chemical polishing (BCP) and electropolishing (EP) used to remove mechanical damage leave surface topography, including pits and protrusions of varying sharpness. These may promote RF magnetic field entry, locally quenching superconductivity, so as to degrade cavity performance. A more incisive analysis of surface topography than the widely used average roughness is needed. In this study, a power spectral density (PSD) approach based on Fourier analysis of surface topography data acquired by both stylus profilometry and atomic force microscopy (AFM) is introduced to distinguish the scale-dependent smoothing effects, resulting in a novel qualitative and quantitative description of Nb surface topography. The topographical evolution of the Nb surface as a function of different steps of well-controlled EP is discussed. This study will greatly help to identify optimum EP parameter sets for controlled and reproducible surface levelling of Nb for cavity production.

Despite efforts for patient stabilization before radiologic procedures, cardiopulmonary arrests still occur. The purpose of our study was to define the incidence, patient characteristics, and outcomes of patients having cardiopulmonary arrest in a radiology department. We retrospectively reviewed patients sustaining cardiopulmonary arrest in the radiology department from 2002 to 2007. Patient characteristics and outcomes were documented. Descriptive statistics were calculated. Over the 6 years of the study, 1,480,578 radiographic procedures were performed, and 27 patients sustained a cardiopulmonary arrest in the radiology department for an incidence rate of 0.002 per cent. The average patient age was 66 years (range, 35 to 88 years); 12 were male (44%). Radiological procedures were diagnostic in 15 cases and therapeutic in 12 cases. The most common locations for arrest were in the CT area (9 patients) and the vascular procedures area (8 patients). The most common preprocedural patient locations were the hospital wards (11 patients [41%]), the emergency department/trauma bay (5 patients [19%]), the intensive care unit (4 patients [15%]), and an outpatient setting (four patients [15%]). Nineteen patients (70%) survived the initial code, 14 patients (52%) survived 24 hours, and 9 patients (33%) survived until discharge. Survival to discharge was significantly impacted by body mass index ( P = 0.005) and type of radiologic procedure ( P = 0.04) but not by the preprocedure patient location. Cardiopulmonary arrest occurring in the radiology department is a rare but potentially lethal occurrence. Patients undergoing vascular access procedures may be an at-risk group. Further study is needed to evaluate potential risk factors for cardiopulmonary arrest occurring in the radiology department.

3 Background: It is imperative to provide quality end of life (EOL) care for cancer patients. This entails minimizing aggressive measures at the EOL. Although rates of hospice utilization within the Veteran’s Health Administration have improved, chemotherapy administration and intensive care unit (ICU) admission at the EOL, indicators of aggressive care, are not clearly declining over recent years. Methods: We identified 32,665 veterans diagnosed with stage IV lung, colorectal, or pancreatic cancer who died between 2009-2016 using VA cancer registry and Corporate Data Warehouse data through a novel EOL Dashboard Tool, which has been validated at multiple VA sites. This EOL tool reports three indicators; incidence of chemotherapy use in the last 14 days of life, ICU admission in the last 30 days of life and hospice admission or consult. Change over time, 2009-2016, was assessed using a repeated measures one-way ANOVA with post hoc test for linear trend of time for individual cancers and two-way ANOVA for all cancers combined. Results: Chemotherapy use in the last 14 days of life declined from 6.8% in 2009 to 4.4% in 2016 (p < 0.05). ICU admission in the last 30 days did not change significantly, from 13.3% in 2009 to 14.7% in 2016. The exception was stage IV lung cancer patients in whom ICU admissions increased from 12.9% to 16.2% (p = 0.01). Patients utilizing hospice services increased from 32.4% to 52.6% (p < 0.01). When combined for all years in an unadjusted analysis by VA regional network (VISN), chemotherapy use ranged geographically from 4.2% to 8.1% and for ICU admission from 8.4% to 18.0%. Conclusions: While chemotherapy administration at the EOL is declining for veterans with stage IV cancer, ICU admissions are unchanged and becoming more common in stage IV lung cancer despite increasing hospice utilization. Compared to prior Medicare reports, veterans have similar rates of EOL chemotherapy use and fewer EOL ICU admissions, adding to a growing body of literature showing that despite veterans having poorer health and utilizing more medical resources, the VA performs at or above non-veteran health care institutions on end of life cancer care. There is notable geographic variation in aggressive EOL care.

Historically, many advances in superconducting radio frequency (SRF) cavities destined for use in advanced particle accelerators have come empirically, through the iterative procedure of modifying processing and then performance testing. However, material structure is directly responsible for performance. Understanding the link between processing, structure, and performance will streamline and accelerate the research process. In order to connect processing, structure, and performance, accurate and robust materials characterization methods are needed. Here, one such method, secondary ion mass spectrometry (SIMS), is discussed with focus on the analysis of SRF materials. In addition, several examples are presented, showing how SIMS is being used to further understanding of material-based SRF technologies.Historically, many advances in superconducting radio frequency (SRF) cavities destined for use in advanced particle accelerators have come empirically, through the iterative procedure of modifying processing and then performance testing. However, material structure is directly responsible for performance. Understanding the link between processing, structure, and performance will streamline and accelerate the research process. In order to connect processing, structure, and performance, accurate and robust materials characterization methods are needed. Here, one such method, secondary ion mass spectrometry (SIMS), is discussed with focus on the analysis of SRF materials. In addition, several examples are presented, showing how SIMS is being used to further understanding of material-based SRF technologies.

Purpose The Veterans Affairs (VA) healthcare system treats approximately 3% of patients with cancer in the United States each year. We measured the quality of nonmetastatic colorectal cancer (CRC) care in VA as indicated by concordance with National Comprehensive Cancer Network practice guidelines (six indicators) and timeliness of care (three indicators). Patients and Methods A retrospective medical record abstraction was done for 2,492 patients with incident stages I to III CRC diagnosed between October 1, 2003, and March 31, 2006, who underwent definitive CRC surgery. Patients were treated at one or more of 128 VA medical centers. The proportion of patients receiving guideline-concordant care and time intervals between care processes were calculated. Results More than 80% of patients had preoperative carcinoembryonic antigen determination (ie, stages II to III disease) and documented clear surgical margins (ie, stages II to III disease). Between 72% and 80% of patients had appropriate referral to a medical oncologist (ie, stages II to III disease), preoperative computed tomography scan of the abdomen and pelvis (ie, stages II to III disease), and adjuvant fluorouracil-based chemotherapy (ie, stage III disease). Less than half of patients with stages I to III CRC (43.5%) had a follow-up colonoscopy 7 to 18 months after surgery. The mean number of days between major treatment events included the following: 26.6 days (standard deviation [SD], 38.2; median, 20 days) between diagnosis and initiation of treatment (in stages II to III disease); 64.9 days (SD, 54.9; median, 50 days) between definitive surgery and start of adjuvant chemotherapy (in stages II to III disease); and 444.1 days (SD, 182.1; median, 393 days) between definitive surgery and follow-up colonoscopies (in stages I to III disease). Conclusion Although there is opportunity for improvement in the area of cancer surveillance, the VA performs well in meeting established guidelines for diagnosis and treatment of CRC.

e20571Background: Accurate staging for small cell lung cancer (SCLC) is critical to selecting appropriate therapy. The impact of positron emission tomography (PET) and stage migration are well-desc...

e24274Background: Immune checkpoint inhibitors (CPIs) induce prolonged tumor responses in a minority of patients with solid tumors including those with MSI-high, melanoma and NSCLC. Established pre...

4 Background: The growing number of colorectal cancer (CRC) survivors often have multiple chronic conditions. Comparing CRC survivors and matched non-cancer controls, our objectives were to determine the odds of CRC survivors being diagnosed with CVD-related chronic conditions and their likelihood of control during the year after CRC diagnosis. Methods: We retrospectively identified patients diagnosed with non-metastatic CRC in the Veterans Affairs (VA) healthcare system from fiscal years 2009-2012 and matched each with up to 3 non-cancer control patients. We used logistic regression to assess differences in the likelihood of being diagnosed with CVD-related chronic conditions and control between CRC survivors and non-cancer controls. Results: We identified 9,758 CRC patients and matched them to 29,066 non-cancer controls. At baseline, 69.4% of CRC survivors and their matched controls were diagnosed with hypertension, 52.4% with hyperlipidemia, and 36.7% with diabetes. Compared to matched non-cancer controls, CRC survivors had 57% higher odds of being diagnosed with hypertension (OR = 1.57, 95% CI = 1.49-1.64) and 12% higher odds of poor blood pressure control (OR = 1.12, 95% CI 1.06-1.18) in the subsequent year. Compared to matched non-cancer control patients, CRC survivors had half the odds of being diagnosed with hyperlipidemia (OR = 0.50, 95% CI = 0.48-0.52) and higher odds of LDL control (OR 1.14, 95% CI 1.06-1.23). There were no significant differences between groups for diabetes diagnoses or control. Conclusions: Compared to non-cancer controls, CRC survivors have: 1) greater likelihood of being diagnosed with hypertension and worse blood pressure control in the year following diagnosis; 2) lower likelihood of being diagnosed with hyperlipidemia or LDL control; and 3) comparable diabetes diagnoses and control. There may be a need for hypertension control interventions targeting cancer survivors.

Ischemic pre- and postconditioning protect ex vivo rat hearts from ischemia/reperfusion injury by promoting the release of cardioprotective agents by an unknown mechanism. Because P2X 7 purinergic receptors are known to combine with pannexin-1 to form channels that allow adenosine triphosphate (ATP) release from cells, we hypothesized that these channels have a role in the release of multiple cardioprotectants during ischemic preconditioning (IPC). Addition of either a pannexin-1 hemichannel blocker (5 μmol/L carbenoxolone [CBX] or 0.4 μmol/L mefloquine [MF]) or a selective antagonist of the rat P2X7 purinergic receptor (2 μmol/L brilliant blue G [BBG]) blocked IPC. These antagonists also blocked ischemic postconditioning. Preconditioning by exogenous addition of either sphingosine-1-phosphate or adenosine was not blocked by either CBX or BBG, indicating that they only affected the release of endogenous mediators, not any subsequent steps. To determine if only ATP release was mediated by pannexin-1/P2X7 channels, we added an extra cycle of IPC to release sufficient quantities of additional cardioprotectants to eliminate the dependence on adenosine derivatives. This did not override the inhibition of IPC by CBX or MF, suggesting that the channel mediates the release of multiple cardioprotectants. Inhibitors of other P2X receptors, P2Y receptors, or connexins did not affect IPC. We conclude that a pannexin-1/P2X7 channel is responsible for the release of cardioprotectants induced by ischemic pre- and postconditioning.

Introduction SRC is an oncogene with an essential role in the invasiveness and metastasis of solid tumors including small cell lung cancer. Dasatinib is a potent inhibitor of SRC as well as other tyrosine kinases. The primary objective of this study was to determine the efficacy of second-line dasatinib in patients with chemosensitive (relapse or progression ≥90 days after completing first-line therapy) small cell lung cancer. Methods Patients with measurable disease; performance status 0 to 1; no more than one prior platinum-based chemotherapy regimen; and adequate hematologic, hepatic, and renal function were eligible. Dasatinib was administered orally at 70 mg twice daily continuously (1 cycle=21 days) until disease progression or unacceptable toxicity. Response was determined after every two cycles. Patients were followed until disease progression or death. The study was prospectively designed to simultaneously discriminate between complete plus partial response rates of 5% versus 20% and progression-free survival (PFS) rates at 6 weeks of 50% versus 70.7% in 53 evaluable patients with at least 92% power. The study was to be terminated early and declared negative if 1 or less objective response and 14 or fewer instances of PFS ≥6 weeks were observed among the initial 27 patients; however, patient accrual continued while the initial 27 patients were evaluated. Results Between April 2007 and December 2008, 45 patients were enrolled, but one patient never received any protocol therapy and one patient was ineligible: male/female, 17/26; white/black/unknown, 40/2/1; median age, 64 years (range, 35–84 years); and performance status 0/1, 12/31. No objective response was recorded among the 43 eligible and treated patients. Among the initial 27 patients, only 13 instances of PFS ≥6 weeks were observed. With a median follow-up time of 7.1 months, median estimated overall survival and PFS times for the 43 eligible and treated patients were 17.0 and 5.9 weeks, respectively. Common reasons for removal of patients from protocol treatment were progressive disease (65%) and adverse events (26%). Toxicity was generally mild to moderate: grade 3 events of >5% frequency included fatigue and pleural and pericardial effusions; and no grade 4 or 5 events were encountered. Conclusions Dasatinib did not reach our specified efficacy criteria in this clinical setting, and the study was terminated.

741 Background: Adjuvant chemotherapy (AC) following chemoradiation (CRT) and total mesorectal excision (TME) for locoregionally advanced rectal cancer (LARC) is a standard of care in the United States despite limited data. The purpose of this study was to examine the role, optimal regimen, and duration of AC in the mandatory, prospectively collected cancer registry of the largest integrated health system in the US. Methods: Using the VA Central Cancer Registry, stage II-III rectal cancer patients diagnosed between 1/2001-4/2011 were included if they received neoadjuvant CRT followed by TME with or without AC. Adequate chemotherapy was defined as at least 4 months of therapy. Kaplan-Meier and Log-Rank tests were used to assess survival. Propensity score (PS) adjustment was performed to compare survival outcomes while adjusting for baseline characteristics, including AJCC stage, age, gender, race, smoking status, and comorbidity. Results: 649 patients were identified; 323 received AC while 326 did not (OBS). Median follow-up was 66 months. Mean age was 63 years. 85.1% were white; 98.8% were male. 49.2% had stage II disease. Median overall survival (OS) for all patients was 92 months; 6-year OS was 56.8%. Median OS was 72 months for the OBS group and not reached (NR) for the AC group (p < 0.001). OS at 6 years was 49.5% for OBS and 64.1% for AC (p < 0.0001). On PS matched analysis, OS was improved favoring AC (p < 0.0001). Median disease-specific survival (DSS) was NR for the whole group and NR for the OBS and AC groups. 6-year DSS was 73.6% for the whole group and 67.9% for OBS vs. 79.2% for AC (p < 0.001). PS matched analysis for DSS favored AC (p = 0.0004). There was no significant difference in OS (p = 0.554) or DSS (p = 0.680) when comparing single versus multi-agent chemotherapy and no significant difference in OS (p = 0.766) or DSS (p = 0.271) when comparing adequate ( > / = 4 months) versus inadequate chemotherapy ( < 4 months). Conclusions: In this VA population of LARC patients treated with neoadjuvant CRT followed by TME, the addition of AC was found to improve both OS and DSS compared to OBS. There was no improvement in OS or DSS with the addition of a multi-agent over single-agent chemotherapy.

The Veterans Affairs (VA) Quality Enhancement Research Initiative (QUERI) seeks to develop partnerships between VA health services researchers and clinical managers, with the goal of designing and evaluating interventions to improve the quality of VA health care.In the present report we describe one such initiative aimed at enhancing the continuum of colorectal cancer (CRC) care, including diagnosis, treatment and surveillance-the Colorectal Cancer Care Collaborative (C4).We describe the process and thinking that led to two parallel quality improvement "collaboratives" that addressed (1) CRC screening and diagnostic follow-up and (2) the guideline concordance and timeliness of CRC treatment. Additionally, we discuss ongoing effort to spread lessons learned during the first stages of the project, which initially occurred at only a subset of VA facilities, throughout the VA health care system. The description of this initiative is organized around key questions that must be answered when developing, sustaining and spreading multi-component quality improvement interventions.We conclude with a discussion of lessons learned that we believe would apply to similar initiatives elsewhere, even if they address different clinical issues in health care settings with different organizational structures.

It was possible to determine the maximum loading of salicylic acid adsorbed onto γ-alumina and kaolinite clay after exposure to salicylic acid dissolved in hexane by examination using diffuse reflectance infrared Fourier transform infrared spectroscopy (DRIFTS). The maximum surface loading of salicylic acid (which resisted washing with fresh hexane) on γ-alumina was four times that observed using water as a solvent (approximately 3.0 compared with 0.7 molecules/nm 2 ). Washing the sample with water removed the organic which was in excess to the maximum level observed for samples prepared with aqueous solution. The spectra of samples prepared with a loading up to the maximum observed with aqueous solution showed no significant differences to those of samples where the organic had been adsorbed from hexane (with the same surface loading). New peaks were observed for loadings greater than 1 molecules/nm 2 , but the salicylic acid was still present as carboxylate (with no clear evidence for the carbonyl group). Salicylic acid adsorbed more readily to the surface of kaolinite from solution in hexane than from aqueous solution (up to maximum average loading of 2 molecules/nm 2 ). Washing the samples with water removed the organic to a loading in the region of 0.2 molecules/nm 2 , independent of the initial loading. Salicylic acid was adsorbed onto kaolinite as the carboxylate. The findings indicate that uptake is mediated by a surface water layer even in the absence of bulk water.

BackgroundIn Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival and demonstrated no significant benefit from the addition of induction chemotherapy. The primary objective of this analysis was to dichotomize patients into prognostic groups using factors predictive of survival and to investigate whether induction chemotherapy was beneficial in either prognostic group.Patients and MethodsA Cox proportional hazard model was used to assess the impact on survival of the following factors: (≥70 versus

Purpose The prognostic significance of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) expression remains unestablished, although EGFR and COX-2 are frequently overexpressed in non-small cell lung cancer (NSCLC). Considering the importance of EGFR activation after ligand binding, however, the expression of phosphorylated EGFR (p-EGFR) may have more significance in predicting tumor aggressiveness in NSCLC than either EGFR or COX-2 expression. Patients and methods We studied the relationships between p-EGFR, EGFR, and COX-2 overexpression and examined their association with prognosis in localized NSCLC. The expression of p-EGFR, EGFR, and COX-2 was studied by immunohistochemistry in 77 surgically-resected stage I/II NSCLC cases. EGFR mutational status was determined by sequencing exons 18–21. Correlation of expression with clinical outcome and other biomarkers, including Ki-67 and microvessel density (MVD), was also examined. Results Out of the 77 patients, EGFR overexpression was observed in 37 (48.1%), p-EGFR expression was found in 22 (28.6%), and COX-2 overexpression was seen in 45 (58.4%). Expression of p-EGFR was associated with COX-2 overexpression (P = 0.047), but not EGFR overexpression or high Ki-67 (P = 0.087 and P = 0.092, respectively). COX-2 overexpression was significantly associated with high Ki-67 (P = 0.011). Expression of p-EGFR correlated with lower disease-free survival (P = 0.045), but not overall survival. Neither EGFR nor COX-2 overexpression was associated with prognosis. Conclusion p-EGFR appears to be a better indicator for lower disease-free survival than EGFR overexpression itself in localized NSCLC. Pathways other than EGFR activation may influence COX-2 overexpression.

Aging hearts are known to have diminished capacity to be protected against reoxygenation ischemia/reperfusion (IR) injury provided by various cardioprotective regimens. In search of a more successful regimen, we have studied the response of aged hearts to preconditioning (PC) and postconditioning (POST) elicited by sphingosine or sphingosine 1-phosphate treatment.An ex vivo rat heart model was used to study the ability of PC and POST to protect old hearts (27 month) against I/R injury generated by 40 minutes (min) of index ischemia followed by 40 min of reperfusion. The response to ischemic PC was reduced in 27 month old hearts relative to 3–6 month (young) hearts as noted by a poor recovery of left ventricular developed pressure (LVDP) upon reperfusion (45% vs. 74% in young hearts) and a large infarct size after 40 min of reperfusion (37% versus 8% in young hearts). PC with sphingosine 1-phosphate (S1P) was also poor in old hearts yielding only 49% recovery of LVDP and a 27% infarct size. In contrast, PC with sphingosine was unaffected by aging; the 78% recovery of LVDP and 8% infarct size were not different from young hearts. Ischemic POST was less affected by aging than ischemic PC, but the old hearts still experienced infarct sizes of 28%. POST of old hearts with S1P was also associated with a substantial infarct size (24%). However, POST of old hearts with sphingosine was superior to the other forms of POST in that it reduced the infarct size to 12%. S1P levels were found to be lower in old hearts which may contribute to the decreased effectiveness of ischemic PC and POST. Further, phospho-Akt levels and distribution were altered in response to cardioprotection in the old hearts. In conclusion, POST was less affected by aging than PC; and sphingosine is a uniquely effective agent for both PC and POST of aging hearts.

This article reports on a line of research exploring mobile phone use in the recovery efforts of Alcoholics Anonymous (AA) members. A preliminary investigation indicated that many individuals in AA have come to rely on the mobile phone for both instrumental and expressive recovery-related interactions. This article reports on follow-up initiatives to assess whether and how these forms of use are linked to its perceived value and explores more deeply how the technology is used in these ways. Using both quantitative and qualitative approaches, the study found that expressive use of the mobile phone made a particularly meaningful contribution to the perceived value of the technology as a tool for recovery. In addition, it uncovered ways that AA members are using mobile communication for social support and to stay connected with others in the program. The discussion offers implications of the findings and directions for future research.

Both sphingosine and sphingosine 1-phosphate (S1P) were able to protect the ex vivo rat heart from ischemia reperfusion injury when added to the perfusion medium at the time of reperfusion after a 40 min ischemia (postconditioning). Inhibitor studies revealed distinct mechanisms of protection, with S1P employing a G-protein coupled receptor pathway and sphingosine a cyclic nucleotide dependent protein kinase pathway. However, both restored ischemia-induced depletion of phospho-AKT. Extending the ischemia to 75 min reduced protection by both S1P and sphingosine, but protection could be enhanced by employing them in combination. Extending the time of ischemia further to 90 min almost eliminated cardioprotection by S1P or sphingosine; and their combination gave only modest protection. However, when S1P plus sphingosine was combined with a novel ramped ischemic postconditioning regimen, left ventricle developed pressure recovered by 66% and there was only a 6% infarct size. The data indicate that detrimental changes are accumulating during protracted ischemia but for up to 90 min this damage is not irreversible and hearts can still recover with proper treatment.

The adsorption of simple organic molecules to mineral surfaces was investigated by Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS) and by solution chemical analysis. Salicylic acid, myristic acid or octacosane were deposited from water or hexane onto gamma-alumina and kaolinite, and examined without evacuation or blending with KBr. The DRIFTS results replicated those from ATR-IR, where available, supporting the validity of DRIFTS as a versatile and convenient alternative to ATR. Results were obtained for coverage as low as 0.02 molecules/nm(2). Monolayer coverage on gamma-alumina was determined from spectra as 0.7 molecules/nm(2) for salicylic acid, confirmed by solution analysis, and 2 molecules/nm(2) for myristic acid. Spectral features of salicylic acid deposited on gamma-alumina from hexane were not distinguishable from those deposited from water. In almost all cases, spectral features associated with the carboxyl moiety were substantially altered, indicating a significant role in the adsorption mechanism. Adsorption of salicylic acid from hexane onto kaolinite was also as carboxylate, but myristic acid showed both carboxylate and carbonyl. The results from using hexane as solvent compared to water suggest that surface-adsorbed hydroxyl and molecular water, present on mineral oxides under ambient conditions, may be a key determinant of the adsorbate architecture.

Background Lung cancer is the most common cause of cancer death in the United States. Cigarette smoking is the main risk factor. Former smokers are at a substantially increased risk for lung cancer compared with lifetime never-smokers. Chemoprevention is the use of specific agents to reverse, suppress, or prevent the process of carcinogenesis. This article reviews the major agents that have been studied for chemoprevention. Methods Articles of primary, secondary, and tertiary prevention trials were reviewed and summarized to obtain recommendations. Results None of the phase III trials with the agents beta carotene, retinol, 13-cis-retinoic acid, α-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results. For facilitating the evaluation of promising agents and for lessening the need for a large sample size, extensive time commitment, and expense, focus is now turning toward the assessment of surrogate end point biomarkers for lung carcinogenesis. With the understanding of important cellular signaling pathways, various inhibitors that may prevent or reverse lung carcinogenesis are being developed. Conclusions By integrating biological knowledge, more trials can be performed in a reasonable time frame. The future of lung cancer chemoprevention should entail the evaluation of single agents or combinations that target various pathways while working toward identification and validation of intermediate end points.