Epidemiologic and preclinical data support the oral-cancer prevention potential of green tea extract (GTE). We randomly assigned patients with high-risk oral premalignant lesions (OPLs) to receive GTE at 500 mg/m2, 750 mg/m2, or 1000 mg/m2 or placebo TID for 12 weeks, evaluating biomarkers in baseline and 12-week biopsies. The OPL clinical response rate was higher in all GTE arms (n=28; 50%) versus placebo (n=11; 18.2%; p=0.09) but did not reach statistical significance. However, the 2 higher-dose GTE arms (58.8% [750, 1000 mg/m2], 36.4% [500 mg/m2], and 18.2%, [placebo], p=0.03) had higher responses, suggesting a dose-response effect. GTE treatment also improved histology (21.4% versus 9.1%, p=0.65), though not statistically significant. GTE was well-tolerated although higher doses increased insomnia/nervousness but produced no grade-4 toxicity. Higher mean baseline stromal VEGF correlated with a clinical (p=0.04) but not histologic response. Baseline scores of other biomarkers (epithelial VEGF, p53, Ki-67, cyclin D1, and p16 promoter methylation) were not associated with a response or survival. Baseline p16 promoter methylation (n=5) was associated with a shorter cancer-free survival. Stromal VEGF and cyclin D1 expression were downregulated in clinically responsive GTE patients and upregulated in non-responsive patients at 12 weeks (versus at baseline). An extended (median 27.5 months) follow-up showed a median time to oral cancer of 46.4 months. GTE may suppress OPLs, in part through reducing angiogenic stimulus (stromal VEGF). Higher doses of GTE may improve short-term (12 week) OPL outcome. The present results support longer-term clinical testing of GTE for oral cancer prevention.

IMPORTANCEThe use of benzodiazepines to control agitation in delirium in the last days of life is controversial.OBJECTIVE To compare the effect of lorazepam vs placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium in the setting of advanced cancer. DESIGN, SETTING, AND PARTICIPANTS Single-center, double-blind, parallel-group, randomized clinical trial conducted at an acute palliative care unit at MD Anderson Cancer Center, Texas, enrolling 93 patients with advanced cancer and agitated delirium despite scheduled haloperidol from February 11, 2014, to June 30, 2016, with data collection completed in October 2016.INTERVENTIONS Lorazepam (3 mg) intravenously (n = 47) or placebo (n = 43) in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode. MAIN OUTCOMES AND MEASURES The primary outcome was change in Richmond Agitation-Sedation Scale (RASS) score (range, −5 [unarousable] to 4 [very agitated or combative]) from baseline to 8 hours after treatment administration. Secondary end points were rescue neuroleptic use, delirium recall, comfort (perceived by caregivers and nurses), communication capacity, delirium severity, adverse effects, discharge outcomes, and overall survival.RESULTS Among 90 randomized patients (mean age, 62 years; women, 42 [47%]), 58 (64%) received the study medication and 52 (90%) completed the trial. Lorazepam + haloperidol resulted in a significantly greater reduction of RASS score at 8 hours (−4.1 points) than placebo + haloperidol (−2.3 points) (mean difference, −1.9 points [95% CI, −2.8 to −0.9]; P < .001). The lorazepam + haloperidol group required less median rescue neuroleptics (2.0 mg) than the placebo + haloperidol group (4.0 mg) (median difference, −1.0 mg [95% CI, −2.0 to 0]; P = .009) and was perceived to be more comfortable by both blinded caregivers and nurses (caregivers: 84% for the lorazepam + haloperidol group vs 37% for the placebo + haloperidol group; mean difference, 47% [95% CI, 14% to 73%], P = .007; nurses: 77% for the lorazepam + haloperidol group vs 30% for the placebo + haloperidol group; mean difference, 47% [95% CI, 17% to 71%], P = .005). No significant between-group differences were found in delirium-related distress and survival. The most common adverse effect was hypokinesia (3 patients in the lorazepam + haloperidol group [19%] and 4 patients in the placebo + haloperidol group [27%]). CONCLUSIONS AND RELEVANCEIn this preliminary trial of hospitalized patients with agitated delirium in the setting of advanced cancer, the addition of lorazepam to haloperidol compared with haloperidol alone resulted in a significantly greater reduction in agitation at 8 hours. Further research is needed to assess generalizability and adverse effects.

BACKGROUND. Nuclear factor‐κB (NF‐κB), a key transcription factor thought to play a major role in carcinogenesis, regulates many important signaling pathways involved in tumor promotion. Although NF‐κB can be activated in lung cancer cell lines by tobacco exposure, there have been no studies of the expression of NF‐κB in lung cancer pathogenesis. METHODS. The immunohistochemical expression of NF‐κB p65 was investigated in 394 lung cancers (370 nonsmall cell lung carcinomas [NSCLC]; and 24 small cell lung carcinomas [SCLC]) and 269 lung normal epithelium and preneoplastic lesions, including hyperplasias, squamous metaplasias, dysplasias, and atypical adenomatous hyperplasias. RESULTS. High levels of nuclear immunohistochemical expression of NF‐κB p65 were detected in the lung cancers, with significantly higher levels in SCLCs compared with NSCLCs (P<.0001). In adenocarcinomas the NF‐κB p65 expression level was significantly higher in advanced TNM stages (III‐IV) than in earlier stages (I‐II) (P<.0001), and when NF‐κB p65 is dichotomized using 50% as the cutoff point (high vs low), a higher NF‐κB p65 expression level was detected in tumors having either K‐RAS (P = .02) or EGFR (P = .009) mutations compared with wildtype tumors. A relatively high level of nuclear NF‐κB p65 expression was detected in normal and mildly abnormal epithelium, and a progression with increasing histology severity was detected in preneoplastic lesions. CONCLUSIONS. NF‐κB p65 nuclear expression is an early and frequent phenomenon in the pathogenesis of lung cancer. The findings indicate that NF‐κB activation plays an important role in lung cancer pathogenesis and is a suitable target for the development of new lung cancer therapies and chemoprevention strategies. Cancer 2006. © 2006 American Cancer Society.

CXCR2 in non-small cell lung cancer (NSCLC) has been studied mainly in stromal cells and is known to increase tumor inflammation and angiogenesis. Here, we examined the prognostic importance of CXCR2 in NSCLC and the role of CXCR2 and its ligands in lung cancer cells. The effect of CXCR2 expression on tumor cells was studied using stable knockdown clones derived from a murine KRAS/p53-mutant lung adenocarcinoma cell line with high metastatic potential and an orthotopic syngeneic mouse model and in vitro using a CXCR2 small molecule antagonist (SB225002). CXCR2 protein expression was analyzed in tumor cells from 262 NSCLC. Gene expression profiles for CXCR2 and its ligands (CXCR2 axis) were analyzed in 52 human NSCLC cell lines and 442 human lung adenocarcinomas. Methylation of CXCR2 axis promoters was determined in 70 human NSCLC cell lines. Invasion and metastasis were decreased in CXCR2 knockdown clones in vitro and in vivo. SB225002 decreased invasion in vitro. In lung adenocarcinomas, CXCR2 expression in tumor cells was associated with smoking and poor prognosis. CXCR2 axis gene expression profiles in human NSCLC cell lines and lung adenocarcinomas defined a cluster driven by CXCL5 and associated with smoking, poor prognosis and RAS pathway activation. Expression of CXCL5 was regulated by promoter methylation. The CXCR2 axis may be an important target in smoking-related lung adenocarcinoma.

Background. Delirium is a common neuropsychiatric condition seen in patients with severe illness, such as advanced cancer. Few published studies are available of the frequency, course, and outcomes of standardized management of delirium in advanced cancer patients admitted to acute palliative care unit (APCU). In this study, we examined the frequency, characteristics, and outcomes of delirium in patients with advanced cancer admitted to an APCU. Methods. Medical records of 609 consecutive patients admitted to the APCU from January 2011 through December 2011 were reviewed. Data on patients’ demographics; Memorial Delirium Assessment Scale (MDAS) score; palliative care specialist (PCS) diagnosis of delirium; delirium etiology, subtype, and reversibility; late development of delirium; and discharge outcome were collected. Delirium was diagnosed with MDAS score ≥7 and by a PCS using Diagnostic and Statistical Manual, 4th edition, Text Revision criteria. All patients admitted to the APCU received standardized assessments and management of delirium per best practice guidelines in delirium management. Results. Of 556 patients in the APCU, 323 (58%) had a diagnosis of delirium. Of these, 229 (71%) had a delirium diagnosis on admission and 94 (29%) developed delirium after admission to the APCU. Delirium reversed in 85 of 323 episodes (26%). Half of patients with delirium (n = 162) died. Patients with the diagnosis of delirium had a lower median overall survival than those without delirium. Patients who developed delirium after admission to the APCU had poorer survival (p ≤ .0001) and a lower rate of delirium reversal (p = .03) compared with those admitted with delirium. Conclusion. More than half of the patients admitted to the APCU had delirium. Reversibility occurred in almost one‐third of cases. Diagnosis of delirium was associated with poorer survival. Implications for Practice: Delirium is the most common neuropsychiatric condition in patients with severe medical illness and those at the end of life. It can be a source of distress for patients, their families, and the medical team. When missed, or if symptoms are misinterpreted, delirium may also lead to unnecessary interventions. This underlines the importance of diagnosis and detection of delirium in populations that are at increased risk. This study has important implications in practice, as it can assist clinicians in making decisions regarding other medical interventions, advance care planning, and communicating with families relating to end‐of‐life issues.