p53 and RAS are multifunctional proteins that are critical to cell cycle regulation, apoptosis, cell survival, gene transcription, response to stress, and DNA repair. We have evaluated the prognostic ...and predictive value of p53 gene/protein aberrations using tumor samples from JBR.10, a North American phase III intergroup trial that randomly assigned 482 patients with completely resected stage IB and II non-small-cell lung cancer (NSCLC) to receive four cycles of adjuvant cisplatin plus vinorelbine or observation alone.
p53 protein expression was evaluated by immunohistochemistry. Mutations in exons 5 to 9 of the p53 gene were determined by denaturing high-performance liquid chromatography and confirmed by sequencing. RAS mutations were identified by allelic specific oligonucleotide hybridization.
Of 253 patients, 132 (52%) were positive for p53 protein overexpression. Untreated p53-positive patients had significantly shorter overall survival than did patients with p53-negative tumors (hazard ratio HR = 1.89; 95% CI, 1.07 to 3.34; P = .03). However, these p53-positive patients also had a significantly greater survival benefit from adjuvant chemotherapy (HR = 0.54; P = .02) compared with patients with p53-negative tumors (HR = 1.40; P = .26; interaction P = .02). Mutations of p53 and RAS genes were found in 124 (31%) of 397 and 117 (26%) of 450 patients, respectively. Mutations in these genes were neither prognostic for survival nor predictive of a differential benefit from adjuvant chemotherapy.
p53 protein overexpression is a significant prognostic marker of shortened survival, and also a significant predictive marker for a differentially greater benefit from adjuvant chemotherapy in completely resected NSCLC patients.
Several microarray studies have reported gene expression signatures that classify non-small-cell lung carcinoma (NSCLC) patients into different prognostic groups. However, the prognostic gene lists ...reported to date overlap poorly across studies, and few have been validated independently using more quantitative assay methods.
The expression of 158 putative prognostic genes identified in previous microarray studies was analyzed by reverse transcription quantitative polymerase chain reaction in the tumors of 147 NSCLC patients. Concordance indices and risk scores were used to identify a stage-independent set of genes that could classify patients with significantly different prognoses.
We have identified a three-gene classifier (STX1A, HIF1A, and CCR7) for overall survival (hazard ratio = 3.8; 95% CI, 1.7 to 8.2; P < .001). The classifier was also able to stratify stage I and II patients and further improved the predictive ability of clinical factors such as histology and tumor stage. The predictive value of this three-gene classifier was validated in two large independent microarray data sets from Harvard and Duke Universities.
We have identified a new three-gene classifier that is independent of and improves on stage to stratify early-stage NSCLC patients with significantly different prognoses. This classifier may be tested further for its potential value to improve the selection of resected NSCLC patients in adjuvant therapy.
Complete resection of early-stage non-small cell lung cancer (NSCLC) is potentially curative, yet approximately 50% of patients are at risk for developing metastatic recurrence. Met, the receptor for ...hepatocyte growth factor (HGF) is a receptor tyrosine kinase with demonstrated roles in regulating cellular proliferation, motility, morphogenesis, and apoptosis. Met receptor and its ligand, HGF, are commonly overexpressed in NSCLC, and their overexpression has been associated with poor prognosis, which could potentially involve a paracrine and/or autocrine activation loop. However, there is as yet no direct evidence that HGF-Met signaling directly promotes metastasis in NSCLC cells. Using retroviral transduction, we overexpressed the human c-met and hgf complementary DNA, alone or in combination in the NCI-H460 human large cell carcinoma cell line. The HGF/Met co-overexpressing (H460-HGF/Met) cells demonstrated enhanced tumorigenicity in xenograft SCID mice. When these cells are implanted orthotopically into the lungs of nude rats, only the H460-HGF/Met cells showed higher spontaneous metastases to distant organs including bone, brain, and kidney. These results provide evidence that autocrine overactivation of the Met- HGF loop enhances systemic metastases in NSCLC. Targeted interference of this loop may potentially be an effective adjuvant therapy to improve survival of early-stage NSCLC patients.
Skp2 plays a critical role in cell cycle progression, especially at the G(1)-S transition, putatively through its control of several cell cycle regulator proteins. The Skp2 gene is located on a ...region of chromosome 5p that is commonly overrepresented in lung cancer. The present study aimed to evaluate Skp2 abnormalities and their prognostic value in non-small cell lung cancer (NSCLC).
In total 16 NSCLC cell lines and 163 primary tumors were included in studies to measure Skp2 relative gene copy number, mRNA abundance, and protein level. The tumors were also evaluated for p27 protein expression level and ras mutation. These values were correlated with the clinical and pathological features of the patients.
Skp2 relative gene copy number aberrations were found in 88 and 65% of NSCLC cell lines and primary tumors, respectively. Overrepresentation was especially common among squamous cell carcinoma (74%). Both gene copy overrepresentation (13%) and loss (35%) were found in adenocarcinoma. Skp2 relative gene copy number was significantly correlated with mRNA and protein levels, but none of these were correlated with p27 protein levels. Neither high Skp2 protein expression nor ras mutation was prognostically significant. In NSCLCs with ras mutation, however, high Skp2 protein expression was a significant independent poor prognostic marker.
There appears to be a synergistic interaction between high Skp2 protein expression and ras mutation with negative impact on the survival of NSCLC patients.
Abstract Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric tumor of the pons affecting over 300 children in the U.S. each year. Chimeric antigen receptor (CAR) T cells are a targeted ...immunotherapy with remarkable clinical success against hematological malignancies and now are being investigated against central nervous system (CNS) tumors. B7-H3 is a surface antigen specifically expressed on nearly all DIPG but not on normal brain providing an attractive therapeutic window. Therefore, Seattle Children’s opened BrainChild-03 (NCT04185038), a first-in-human phase 1 trial of repeatedly dosed intracranial B7-H3 CAR T cells for children with DIPG. We found the highest planned dose (10x107 cells) to be tolerable and observed preliminary signals of efficacy. ONC206 is a small molecule ClpP-agonist and DRD2-antagonist derivative of ONC201 that is currently being evaluated on PNOC-023 (NCT04732065). Here, we set out to evaluate the combinatorial potential of these modalities. ONC206 effectively reduced DIPG tumor cell viability (IC50 = ~300 nM compared to ONC201 ~1400 nM) against four treatment-naïve patient-deriving DIPG models representing a range of molecular subtypes. Using multiple orthogonal systems, apoptosis of DIPG cells was confirmed. We found that ONC206 drives tumor cell mitochondrial dysfunction and upregulation of DR5, a cell-death receptor involved in the TRAIL pathway, whereas levels of B7-H3, DRD2, and ClpP remain constant. We previously published the efficacy of B7-H3 CAR T cells against DIPG, but here - using low effector:tumor (E:T) ratios (e.g. 0.5:1) of activated B7-H3 CAR T cells and low-dose ONC206 (e.g. 200 nM) - we found a significant in vitro combinatorial benefit against DIPG (p<0.01). Supportive biologic studies suggest this could be an additive benefit and in vivo studies are currently ongoing. Based on the clinical translation of B7-H3 CAR T cells and ONC206, we aim to further validate this combinatorial benefit to help future patients.
Glypican-3 is a membrane-bound proteoglycan whose expression has been linked to malignancies through the existence of both mutations and aberrant protein expression. Reports on glypican-3 expression ...in lung cancer were limited, with some evidence for loss of expression, which suggested a tumor-suppressor role. We sought to evaluate glypican-3 expression in lung cancer at the protein and mRNA levels and correlate it with clinical, histological and genomic characteristics such as RAS mutation status. We used immunohistochemistry on tissue microarray to study glypican-3 expression in 97 patients, evaluated glypican-3 mRNA levels by quantitative polymerase chain reaction in 143 patients and identified RAS mutations by allele-specific oligonucleotide hybridization. We correlated the results with clinical and histological data. Glypican-3 immunostaining was negative in all normal lung tissues, but positive in 23% of lung carcinoma samples. High protein and mRNA expression was associated with squamous histology (positive stain in 55% of squamous cell carcinoma vs 8% of adenocarcinoma, P<0.0001 for both immunostaining and mRNA). RAS mutations were highly associated with adenocarcinoma and low glypican-3 mRNA expression (P<0.0001 for both). Among smokers, glypican-3 mRNA expression was reduced in adenocarcinoma patients (P=0.013), and was elevated in those with squamous cell carcinoma (P=0.03, interaction P=0.0009). These opposing associations also correlated with the smoking burden. Patients with tumors staining positively for glypican-3 smoked significantly more than patients with tumors staining negatively (P=0.013). No association was found between glypican-3 expression and patient outcome. In conclusion, glypican-3 was overexpressed in cancerous compared with normal lung tissue. Adenocarcinoma and squamous cell carcinoma had differential expression of glypican-3, with predilection to squamous cell carcinoma patients who smoked. Glypican-3 expression in squamous cell carcinoma as an oncofetal protein renders it a potential candidate marker for early detection of lung squamous cell carcinoma.
ObjectivesThe current systematic review (SR) was undertaken to summarise the published literature reporting the clinical and economic value of automation for chemotherapy preparation management to ...include compounding workflow software and robotic compounding systems.MethodsLiterature searches were conducted in MEDLINE, Embase and the Cochrane Library on 16 November 2017 to identify publications investigating chemotherapy compounding workflow software solutions used in a hospital pharmacy for the preparation of chemotherapy.Results5175 publications were screened by title and abstract and 18 of 72 full publications screened were included. Grey literature searching identified an additional seven publications. The SR identified 25 publications relating to commercial technologies for compounding (Robotic compounding systems: APOTECAchemo (n=12), CytoCare (n=5) and RIVA (n=1); Workflow software: Cato (n=6) and Diana (n=1)). The studies demonstrate that compounding technologies improved accuracy in dose preparations and reduced dose errors compared with manual compounding. Comparable levels of contamination were reported for technologies compared with manual compounding. The compounding technologies were associated with reductions in annual costs compared with manual compounding, but the impact on compounding times was not consistent and was dependent on the type of compounding technology.ConclusionsThe published evidence suggests that the implementation of chemotherapy compounding automation solutions may reduce compounding errors and reduce costs; however, this is highly variable depending on the form of automation. In addition, the available evidence is heterogeneous, sparse and inconsistently reported. A key finding from the current SR is a ‘call to action’ to encourage pharmacists to publish data following implementation of chemotherapy compounding technologies in their hospital, which would allow for evidence-based recommendations on the benefits of chemotherapy compounding technologies.
Patient-centered discharge tools provide an opportunity to engage patients, enhance patient understanding, and improve capacity for self-care and postdischarge outcomes.
To review studies that ...engaged patients in the design or delivery of discharge instruction tools and that tested their effect among hospitalized patients.
We conducted a search of 12 databases and journals from January 1994 through May 2014, and references of retrieved studies.
English-language studies that tested discharge tools meant to engage patients were selected. Studies that measured outcomes after 3 months or without a control group or period were excluded.
Two independent reviewers assessed the full-text papers and extracted data on features of patient engagement.
Thirty articles met inclusion criteria, 28 of which examined educational tools. Of these, 13 articles involved patients in content creation or tool delivery, with only 6 studies involving patients in both. While many of these studies (10 studies) demonstrated an improvement in patient comprehension, few studies found improvement in patient adherence despite their engagement. A few studies demonstrated an improvement in self-efficacy (2 studies) and a reduction in unplanned visits (3 studies).
Improving patient engagement through the use of media, visual aids, or by involving patients when creating or delivering a discharge tool improves comprehension. However, further studies are needed to clarify the effect on patient experience, adherence, and healthcare utilization postdischarge. Better characterization of the level of patient engagement when designing discharge tools is needed given the heterogeneity found in current studies. Journal of Hospital Medicine 2017;12:110-117.
Transitions of care leave patients vulnerable to the unintentional discontinuation of medications with proven efficacy for treating chronic diseases. Older adults residing in nursing homes may be ...especially susceptible to this preventable adverse event. The effect of large-scale policy changes on improving this practice is unknown.The objective of this study was to analyze the effect of a national medication reconciliation accreditation requirement for nursing homes on rates of unintentional medication discontinuation after hospital discharge.It was a population-based retrospective cohort study that used linked administrative records between 2003 and 2012 of all hospitalizations in Ontario, Canada. We identified nursing home residents aged ≥66 years who had continuous use of ≥1 of the 3 selected medications for chronic disease: levothyroxine, HMG-CoA reductase inhibitors (statins), and proton pump inhibitors (PPIs).In 2008 medication reconciliation became a required practice for accreditation of Canadian nursing homes.The main outcome measures included the proportion of patients who restarted the medication of interest after hospital discharge at 7 days. We also performed a time series analysis to examine the impact of the accreditation requirement on rates of unintentional medication discontinuation.The study included 113,088 adults aged ≥66 years who were nursing home residents, had an acute hospitalization, and were discharged alive to the same nursing home. Overall rates of discontinuation at 7-days after hospital discharge were highest in 2003-2004 for all nursing homes: 23.9% for thyroxine, 26.4% for statins, and 23.9% for PPIs. In most of the cases, these overall rates decreased annually and were lowest in 2011-2012: 4.0% for thyroxine, 10.6% for statins, and 8.3% for PPIs. The time series analysis found that nursing home accreditation did not significantly lower medication discontinuation rates for any of the 3 drug groups.From 2003 to 2012, there were marked improvements in rates of unintentional medication discontinuation among hospitalized older adults who were admitted from and discharged to nursing homes. This change was not directly associated with the new medication reconciliation accreditation requirement, but the overall improvements observed may have been reflective of multiple processes and not 1 individual intervention.
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