Drip and Ship versus Mothership Model in the Middle Cerebral Artery Stroke: A Propensity-Matched Real-World Analysis Through National Inpatient Sample Data.

BACKGROUND: The superiority of mechanical thrombectomy and intravenous thrombolysis versus intravenous thrombolysis alone for acute ischemic stroke caused by large vessel occlusions has been established. This treatment can be organized into 2 models: drip and ship (DS) versus mothership (MS). We analyzed the National Inpatient Sample (NIS) data to compare the outcomes between these models in real-world settings. METHODS: NIS data were queried for 2017-2018 and propensity matching was used to match the differences. Outcomes for each group (disability at discharge and procedural complications) were compared. RESULTS: A total of 1226 patients were included in analysis (DS, n = 540; MS, n = 686) and groups were matched with respect to age, gender, and comorbidities. A total of 930 patients were included in the final analysis after propensity matching (DS, n = 465, MS, n = 465). The mean age in the DS group was 68.9 years (standard deviation [SD], 14.7) and 69.4 years (SD, 14) in the MS group (P = 0.752). The mean National Institutes of Health Stroke Scale score was 16.75 (SD, 6.07) in the DS group and 16.54 (SD, 5.99) in the MS group (P = 0.478). At discharge, minimal disability was noted in 22.4% in the DS group versus 26.2% in the MS group (P = 0.293). In-hospital mortality was lower in the MS group (8.8% vs. 7.1%; P = 0.32). The intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH) rates were higher in the DS group (ICH, 24.3% vs. 18.7%; IVH, 2.4% vs. 0.9%) (ICH, P = 0.038; IVH, P = 0.068). CONCLUSIONS: Analyzing the efficacy and safety profile of DS versus MS models with the NIS database showed a trend toward better discharge outcomes and lower mortality for the MS group, although it did not reach statistical significance.

Direct thrombectomy versus bridging thrombolysis with mechanical thrombectomy in middle cerebral artery stroke: a real-world analysis through National Inpatient Sample data.

OBJECTIVE: A paradigm shift in the management of acute ischemic stroke (AIS) due to large-vessel occlusion (LVO) occurred after 2015 when 7 randomized controlled trials demonstrated better outcomes using second-generation thrombectomy devices combined with best medical management than did stand-alone intravenous thrombolysis (IVT) with tissue plasminogen activator (tPA). All recently published landmark trials were designed to study the outcome of mechanical thrombectomy (MT); therefore, the majority of the patients enrolled in these trials received intravenous tPA. Currently, initiating IVT before MT is a matter of debate. Recent trials (DIRECT-MT, DEVT) exploring this clinical question showed noninferiority of MT alone compared with the combined treatment. With this uncertainty, the authors aimed to explore real-world data through the latest National Inpatient Sample (NIS) to compare the safety and outcomes of MT alone with bridging IVT and MT in AIS due to LVO in the middle cerebral artery (MCA). METHODS: NIS data from 2017 to 2018 were analyzed to compare the outcomes and safety profiles of patients who underwent MT+IVT with those who underwent MT alone. RESULTS: A total of 2895 patients were included in the final analysis (MT, n = 1669; MT+IVT, n = 1226). The mean National Institutes of Health Stroke Scale score was 16.2 (SD 6.1) in the MT group and 16.6 (SD 5.97) in the MT+IVT group (p = 0.04). With respect to comorbidities, the two groups did not differ in rates of hypertension (p = 0.730), atrial fibrillation/flutter (p = 0.828), and smoking status (p = 0.914). The rate of diabetes mellitus was significantly higher in the MT group (28%) than in the MT+IVT group (22.1%) (p < 0.001). The frequency of intracerebral hemorrhage (ICH) in the MT group was 17.7% (n = 296) and 21.5% (n = 263) in the MT+IVT group (p = 0.012). Intraventricular hemorrhage (p = 0.875), subarachnoid hemorrhage (p = 0.99), and vasospasm (p = 0.976) did not differ significantly between the groups. The primary outcome considered was disability status between the groups; 23.8% of patients in the MT+IVT group had minimal disability versus 18.2% in the MT group (p = 0.001). The risk of progressing to severe disability from minimal disability decreased with the addition of IVT to MT (OR 0.762, 95% CI 0.637-0.912). The adjusted odds ratio for ICH in the MT+IVT group was 1.28 (95% CI 1.043-1.571, p = 0.018) and 2.676 (95% CI 1.259-5.686, p = 0.01) for access-site hemorrhages. CONCLUSIONS: In the analysis of the NIS database, the MT+IVT group had significantly higher rates of minimal disability at the time of hospital discharge versus the MT-alone group, despite a higher rate of ICH. The question of whether to treat patients with MT+IVT rather than MT alone is currently being addressed in ongoing prospective clinical trials (SWIFT-DIRECT [NCT03494920], MR CLEAN-NO IV [ISRCTN80619088], and DIRECT-SAFE [NCT03494920]). The results of these studies will contribute to greater understanding and progressive improvement in outcomes for AIS patients.

Cancer Radiation Therapy May Be Associated With Atrial Fibrillation.

Background: The association of atrial fibrillation (AF) with cancer and cancer types is inconclusive. Similarly, data regarding the association of AF with different cancer therapies are controversial. Objectives: To study the association of AF with cancer subtypes and cancer therapies. Methods: We studied all patients aged 18-89 years who presented to the Feist Weiller Cancer Center, with or without a diagnosis of cancer, between January 2011 and February 2016. Electronic health records were systematically queried for baseline demographics and ICD-9 and ICD-10 codes for specific co-morbidities. Patients with a diagnosis of AF were tabulated based on cross-validation with the ECG database and/or by recorded history. We assessed the prevalence and risk of AF based on cancer diagnosis, specific cancer type, and cancer therapy. Results: A total of 14,600 patients were analyzed. Compared to non-cancer patients (n = 6,801), cancer patients (n = 7,799) had a significantly higher prevalence of AF (4.3 vs. 3.1%; p < 0.001). However, following correction for covariates in a multivariable logistic regression model, malignancy was not found to be an independent risk factor for AF (p = 0.32). While patients with solid tumors had a numerically higher prevalence of AF than those with hematological malignancies (4.3 vs. 4.1%), tumor type was not independently associated with AF (p = 0.13). AF prevalence was higher in patients receiving chemotherapy (4.1%), radiation therapy (5.1%), or both (6.9%) when compared to patients not receiving any therapy (3.6%, p = 0.01). On multivariable logistic regression, radiation therapy remained an independent risk factor for AF for the entire study population (p = 0.03) as well as for the cancer population (p < 0.01). Conclusions: Radiation therapy for cancer is an independent risk factor for AF. The known association between cancer and AF may be mediated, at least in part, by the effects of radiation therapy.

Cervical Human Papillomavirus Testing With Two Home Self-Collection Methods Compared With a Standard Clinically Collected Sampling Method.

BACKGROUND: The purpose of this study was to compare the outcomes of 2 self-collection methods to detect cervical human papillomavirus (HPV) DNA with outcomes from a standard clinical method. The standard method samples were collected by a clinician at a routine pelvic examination. Self-samples were taken at home and mailed to the clinical laboratory. METHODS: The 2 self-collection methods were a tampon-based method and a swab-based method using a commercial device, an Eve Medical HerSwab. All HPV samples were processed by a clinical laboratory using the Food and Drugs Administration approved Roche Cobase HPV method, which specifically identifies HPV 16, HPV 18, and a set of 12 other high-risk subtypes. Patients were recruited from 2 cancer screening clinics 2015 to 2017. All patients signed an informed consent. Screening outcomes, such as prevalence, percent agreement with standard, sensitivity, and specificity, were calculated for each self-collection method. Measures of similarity between self and standard collection outcomes, Cohen's κ, percent concordance, McNemar equivalence, and others were tested statistically. RESULTS: One hundred seventy-four patients were randomized. The prevalence of 1 or more positive HPV high-risk subtypes from the standard clinical specimens was 13.5%. All clinical specimens were sufficient for valid HPV detection. For the tampon method, 15 (27%) of the specimens were insufficient quality. Only 1 (2%) swab specimen was insufficient. Only the swab self-collection method was found to be statistically noninferior to the clinical method. The tampon method had an unacceptably high rate of insufficient quality specimens and also failed the equivalency tests. CONCLUSIONS: The swab home collection samples were equivalent to the clinical samples, but the tampon method had an unacceptably high rate of specimens insufficient for HPV detection.

Curcumin gum formulation for prevention of oral cavity head and neck squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: Head and neck squamous cell carcinoma represents the sixth most common cancer. As a result of field cancerization, second primaries and recurrences are high. Hence, research has focused on chemoprevention. Curcumin, a polyphenol compound with anticarcinogenic properties, is one such promising nutraceutical. As poor bioavailability limits curcumin's use, a novel gum formulation was tested allowing for direct mucosal absorption into the bloodstream. This preliminary study validates curcumin gum efficacy by assessing release and transmucosal absorption, along with measuring its effects on serum cytokine levels. STUDY DESIGN: Clinical trial. METHODS: Protocols consisting of initial chew (chewing gum for 30 minutes) and revised chew (alternating chewing and parking gum against buccal mucosa for 30 minutes) were tested in healthy volunteers. High-performance liquid chromatography measured remnant curcumin in chewed gum, serum, and saliva. Serum levels were assayed for 15 proinflammatory cytokines via multiplex analysis. RESULTS: Revised chew samples demonstrated significantly higher curcumin release and absorption (P = .0078). Curcumin serum levels were significantly higher at 4 hours in samples > 2.0 g of curcumin release (P = .01). As saliva levels decreased, a concurrent increase in serum levels was observed, with no significance in the inverse relationship (P = .1423). When evaluating differences between gender, race, and age, the Asian population showed significantly lower curcumin release and serum levels (P = .009). CXCL1 (GRO-α) and TNF-α were significantly decreased in serum after chewing the gum (P = .036, P < .001, respectively). CONCLUSIONS: Enhanced mucosal contact appears critical in improving curcumin release and absorption. CXCL1 and TNF-α both represent potential biomarkers for the future study of curcumin chemoprevention. LEVEL OF EVIDENCE: 2b Laryngoscope, 129:1597-1603, 2019.

Tyler asbestos workers: A mortality update in a cohort exposed to amosite.

The Tyler asbestos plant produced pipe insulation from 1954 to 1972 and exclusively used amosite asbestos. There were 1130 former workers of this plant during the period of operation. A death certificate mortality analysis was published regarding this plant in 1998 for the period through 1993. This study represents an update of the mortality analysis with additional certificates collected for deaths occurring through 2011.Searches of the National Death Index database were conducted in 2004 and again in 2013. At the time of the latter search, only deaths occurring through 2011 were available. In total, 265 distinct additional death certificates were secured and added to 304 available from the original study. After the new certificates were coded (ICD-9), data were analyzed using the Centers for Disease Control and Prevention Life Table Analysis System (LTAS) and standard mortality ratios (SMR) generated with 95% confidence limits (CL). LTAS constructs cause-specific mortality rates by age, gender, race, and person-time at risk, and compares observed rates with a referent population in order to derive SMR. A significant excess number of deaths due to nonmalignant respiratory disease (asbestosis) and from select malignant neoplasms were identified. There were in total 23 mesothelioma deaths (4% of deaths), with 16 pleural and 7 peritoneal. The SMR for malignant neoplasms of the trachea, bronchus, and lung was 244 (with 95% CL 196, 300), suggesting that exposed workers from this cohort were nearly 2.5-fold (244 %) more likely to die from this cause as the general referent population. The analysis also showed that exposures of short duration (<6 mo) produced significantly elevated SMR for all respiratory cancers, lung cancer, and pleural mesothelioma. There was a significant difference in median duration of exposure for mesothelioma types, confirming association of peritoneal mesothelioma with longer duration of exposure. Deaths due to intestinal cancer (predominantly colon; not including rectum) were also found in excess. The mortality experience of the Tyler cohort continues to be followed with great interest, given the exclusivity of exposure to amosite. Data confirm the inherent pathogenicity of this fiber type for nonmalignant disease as well as select cancers, particularly relevant given the importance of this amphibole's use in the United States.

The Shreveport Myeloma Experience: Survival, Risk Factors and Other Malignancies in the Age of Stem Cell Transplantation.

BACKGROUND: The overall prognosis of multiple myeloma has improved significantly over the last 15 years. We wondered whether the overall improvement would also be seen in unselected patients in an academic center in Northwest Louisiana with a high proportion of minority patients, and if second malignant neoplasms are relevant for our patients. MATERIALS AND METHODS: Between 1998 and 2009, 215 patients were treated for multiple myeloma at our center and had complete follow-up until May 2013. RESULTS: The mean survival of patients with multiple myeloma increased from 3.25 to 5.34 years, which is comparable to patients treated at larger centers. No prognostic difference was observed in the subgroups of myeloma patients. Among 215 patients followed for the development of secondary cancers, 16 already had a preexisting or concomitant malignancy (7.4%) and 10 developed secondary cancers. Our data indicate a significant background of histologically unrelated cancers and a cumulative incidence of new cancers of about 20% after 10 years of follow-up. Based on SEER data, preexisting or secondary cancers were not statistically increased in our population. CONCLUSIONS: The use of autologous transplantation and the introduction of new agents resulted in a significant improvement in the prognosis of multiple myeloma. Other cancers are not statistically increased before or after multiple myeloma is diagnosed and are not prognostically relevant.

Effects of payer status on breast cancer survival: a retrospective study.

BACKGROUND: Breast cancer outcomes are influenced by multiple factors including access to care, and payer status is a recognized barrier to treatment access. To further define the influence of payer status on outcome, the National Cancer Data Base data from 1998-2006 was analyzed. METHOD: Data was analyzed from 976,178 female patients diagnosed with breast cancer registered in the National Cancer Data Base. Overall survival was the primary outcome variable while payer status was the primary predictor variable. Secondary predictor variables included stage, age, race, Charlson Comorbidity index, income, education, distance travelled, cancer program, diagnosing/treating facility, and treatment delay. Multivariate Cox regression was used to investigate the effect of payer status on overall survival while adjusting for secondary predictive factors. RESULTS: Uninsured (28.68%) and Medicaid (28.0%) patients had a higher percentage of patients presenting with stage III and stage IV cancer at diagnosis. In multivariate analysis, after adjusting for secondary predictor variables, payer status was a statistically significant predictor of survival. Patients with private, unknown, or Medicare status showed a decreased risk of dying compared to uninsured, with a decrease of 36%, 22%, and 15% respectively. However, Medicaid patients had an increased risk of 11% compared to uninsured. The direct adjusted median overall survival was 14.92, 14.76, 14.56, 13.64, and 12.84 years for payer status of private, unknown, Medicare, uninsured, and Medicaid respectively. CONCLUSION: We observed that patients with no insurance or Medicaid were most likely to be diagnosed at stage III and IV. Payer status showed a statistically significant relationship with overall survival. This remained true after adjusting for other predictive factors. Patients with no insurance or Medicaid had higher mortality.

Randomized, Placebo-Controlled Trial of Green Tea Catechins for Prostate Cancer Prevention.

Preclinical, epidemiologic, and prior clinical trial data suggest that green tea catechins (GTC) may reduce prostate cancer risk. We conducted a placebo-controlled, randomized clinical trial of Polyphenon E (PolyE), a proprietary mixture of GTCs, containing 400 mg (-)-epigallocatechin-3-gallate (EGCG) per day, in 97 men with high-grade prostatic intraepithelial neoplasia (HGPIN) and/or atypical small acinar proliferation (ASAP). The primary study endpoint was a comparison of the cumulative one-year prostate cancer rates on the two study arms. No differences in the number of prostate cancer cases were observed: 5 of 49 (PolyE) versus 9 of 48 (placebo), P = 0.25. A secondary endpoint comparing the cumulative rate of prostate cancer plus ASAP among men with HGPIN without ASAP at baseline, revealed a decrease in this composite endpoint: 3 of 26 (PolyE) versus 10 of 25 (placebo), P < 0.024. This finding was driven by a decrease in ASAP diagnoses on the Poly E (0/26) compared with the placebo arm (5/25). A decrease in serum prostate-specific antigen (PSA) was observed on the PolyE arm [-0.87 ng/mL; 95% confidence intervals (CI), -1.66 to -0.09]. Adverse events related to the study agent did not significantly differ between the two study groups. Daily intake of a standardized, decaffeinated catechin mixture containing 400 mg EGCG per day for 1 year accumulated in plasma and was well tolerated but did not reduce the likelihood of prostate cancer in men with baseline HGPIN or ASAP.

Improved wound healing of postischemic cutaneous flaps with the use of bone marrow-derived stem cells.

OBJECTIVES/HYPOTHESIS: To determine if the intravascular delivery of mesenchymal stem cells improves wound healing and blood perfusion to postischemic cutaneous flap tissues. STUDY DESIGN: Randomized controlled study. METHODS: A murine model of a cutaneous flap was created based on the inferior epigastric vessels. Mice (n = 14) underwent 3.5 hours of ischemia followed by reperfusion. Bone marrow stromal cells (BMSCs) 1 × 10(6) were injected intravenously. Wound healing was then assessed measuring percent flap necrosis, flap perfusion, and tensile strength of the flap after a period of 14 days. Localization of BMSCs was determined with radiolabeled and fluorescent labeled BMSCs. RESULTS: Postischemic cutaneous flap tissues treated with BMSCs demonstrated significantly less necrosis than control flaps (P <0.01). Beginning on postoperative day 5, BMSC-treated flaps demonstrated greater blood perfusion than untreated flaps (P <0.01). Tensile strength of BMSC-treated cutaneous flaps was significantly higher (P <0.01), with a mean strength of 283.4 ± 28.4 N/m than control flaps with a mean of 122.4 ± 23.5 N/m. Radiolabeled BMSCs localized to postischemic flaps compared to untreated tissues (P = 0.001). Fluorescent microscopy revealed incorporation of BMSCs into endothelial and epithelial tissues of postischemic flaps. CONCLUSIONS: This study demonstrates that the intravascular delivery of BMSCs increases wound healing and promotes flap survival following ischemia-reperfusion injury of cutaneous tissue flaps.

Commercial insurance triples chances of breast cancer survival in a public hospital.

Breast cancer survival is affected both by endogenous factors and exogenous factors such as socioeconomic status. This study explored the relationship between insurance status and overall survival of 987 female breast cancer patients in a population served by a public hospital. All patients were offered the same level of care regardless of ability to pay. Of the 987 breast cancer patients investigated, 54.6% were African-American. 54.1% of patients were insured (commercial insurance or Medicare), 27.1% with Medicaid, and 18.8% who were uninsured. Overall median survival was 15.5 years and was not statistically significant between Caucasian and African-American women. Median survival times were 15.8, 11.3, and 8.2 years for insured, Medicaid, and uninsured groups, respectively. Uninsured patients had worse overall survival rates compared with insured patients (p < 0.05). Adjusting for other factors (e.g., stage, age, race, body mass index, and income), insurance was a significant factor affecting survival with hazard ratios of 2.24 and 3.22 for Medicaid and uninsured patients, respectively, compared with insured patients. Even in a public hospital, after adjusting for potential risk factors, insurance status still proved to be an important factor in the survival of breast cancer patients. Further research is necessary to identify causal factors related to the survival disparities associated with insurance status.

The effect of a clinical medical librarian on in-patient care outcomes.

OBJECTIVE: The research sought to determine the effect of a clinical medical librarian (CML) on outcomes of in-patients on the internal medicine service. METHODS: A prospective study was performed with two internal medicine in-patient teams. Team 1 included a CML who accompanied the team on daily rounds. The CML answered questions posed at the point of care immediately or in emails post-rounds. Patients on Team 2, which did not include a CML, as well as patients who did not require consultation by the CML on Team 1, served as the control population. Numerous clinical and library metrics were gathered on each question. RESULTS: Patients on Team 1 who required an answer to a clinical question were more ill and had a longer length of stay, higher costs, and higher readmission rates compared to those in the control group. Using a matched pair analysis, we showed no difference in clinical outcomes between the intervention group and the control group. CONCLUSIONS: This study is the largest attempt to prospectively measure changes in patient outcomes when physicians were accompanied by a CML on rounds. This approach may serve as a model for further studies to define when and how CMLs are most effective.

Assessing the FACTTS: an evidence-based medicine and critical appraisal course for medical students.

The Fourth-year Academic Clinical Training and Teaching Selective (FACTTS) is a course taught by medical and library faculty on the practice of evidence-based medicine and critical appraisal of the medical literature. This study assesses the impact of the course on students' understanding of the subject matter by examining three years of pre- and post-test data and addresses whether the number of sessions in the course affects the knowledge gained by the students. The data show an improvement in the students' understanding of course material, but no benefit was found in having two versus three sessions.

Curcumin inhibits UV radiation-induced skin cancer in SKH-1 mice.

OBJECTIVE: As skin cancer incidence increases, research has focused on novel chemopreventive agents that inhibit tumor formation. In prior experimentation, curcumin, a naturally occurring food substance and anticarcinogenic agent, inhibited cutaneous squamous cell carcinoma xenograft growth. We hypothesize curcumin will inhibit UVB radiation-induced skin cancer growth in mice, approximating a human chemopreventive model. STUDY DESIGN: Randomized experimental animal and laboratory study. SETTING: Louisiana State University Health Sciences Center-Shreveport, Louisiana. SUBJECTS AND METHODS: SKH-1 mice were pretreated with oral or topical curcumin or oral or topical control (n = 11/group) for 14 days. Mice received UVB radiation 3 times weekly for 24 weeks or were not radiated. Number of tumors formed and time to tumor onset for each mouse were recorded through tumor harvest after week 24. Tumor multiplicity and time to tumor onset were compared. RESULTS: Time to tumor onset was significantly shorter in control mice compared to mice receiving either oral (P = .025) or topical (P = .015) curcumin. A significant difference in the average number of tumors formed per mouse was seen, as fewer tumors were formed in the oral curcumin (P = .01) and topical curcumin (P = .01) groups, compared with respective controls. No significant difference in average number of tumors per mouse was seen between oral and topical curcumin (P = .56), suggesting that both routes were equally effective. CONCLUSION: Curcumin appears to inhibit skin cancer formation and prolong time to tumor onset when administered by either an oral or topical route. These data suggest that curcumin may have chemopreventive potential against skin cancer, necessitating future experimentation with human subjects.

Critical appraisal process: step-by-step.

We present information describing how to search to identify those reports that provide insight into the answer to the query. We have presented a reasonable approach to searching, with our end-point being the identification of published articles which appear to answer our queries. The decision as to whether these articles are applicable to the patient under discussion is determined by our clinical knowledge and the specifics of the patient's medical concerns. This process is recognized as critical analysis. Our structure for optimal searching includes use of the PICO model, formulating a focused clinical question, and defining key search terms. Using these principles, we have addressed an example important controversy in the practice of clinical medicine; in other words, the effectiveness of screening for prostate cancer and whether it alters the natural history of this illness.

Challenges and potential solutions to meeting accrual goals in a Phase II chemoprevention trial for prostate cancer.

OBJECTIVE: The goal of this report is to describe the on going strategies, successes, challenges and solutions for recruitment in this multi-center, phase II chemoprevention trial targeting men at high risk for prostate cancer. METHODS: We developed and implemented a multi-center clinical trial in institutions with supportive infrastructure, lead by a recruitment team of experienced and committed physicians and clinical trial staff, implementing multi-media and community outreach strategies to meet recruitment goals. Screening logs were reviewed to identify trends as well as patient, protocol and infrastructure -related barriers impacting accrual and revisions to protocol implemented. RESULTS: Between January 2008 and February 2011 a total of 3547 individuals were prescreened with 94% (n=3092) determined to be ineligible based on diagnosis of cancer or benign biopsy results. Of these, 216 were considered eligible for further screening with 52% (n=113) declining to participate due to patient related factors and 14% (n=29) eliminated due to protocol-related criteria for exclusion. Ninety-four (94) subjects consented to participate with 34% of these subjects (n=74) meeting all eligibility criteria to be randomized to receive study agent or placebo. Across all sites, 99% of the recruitment of subjects in this clinical trial is via physician recruitment and referral with less than 1% responding to other recruitment strategies. CONCLUSION: A contemporary approach to subject recruitment and frequent evaluation is needed to assure responsiveness to emerging challenges to accrual and the evolving scientific literature. A focus on investing on improving systems for physician recruitment may be key to meeting recruitment target in chemoprevention trials.

Prostate Cancer Chemoprevention Targeting Men with High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and Atypical Small Acinar Proliferation (ASAP): Model for Trial Design and Outcome Measures.

In spite of the large number of nutrient-derived agents demonstrating promise as potential chemopreventive agents, most have failed to prove effectiveness in clinical trials. Critical requirements for moving nutrient-derived agents to recommendation for clinical use include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as are used to evaluate other pharmacological agents. Preliminary data on a mechanistic rationale for chemoprevention activity as observed from epidemiological, in vitro and preclinical studies, phase I data of safety in suitable cohorts, duration of intervention based on time to progression of preneoplastic disease to cancer and the use of a valid panel of biomarkers representing the hypothesized carcinogenesis pathway for measuring efficacy must inform the design of phase II clinical trials. The goal of this paper is to provide a model for evaluating a well characterized agent- Polyphenon E- in a phase II clinical trial of prostate cancer chemoprevention.

Aggressive mammary carcinoma progression in Nrf2 knockout mice treated with 7,12-dimethylbenz[a]anthracene.

BACKGROUND: Activation of nuclear factor erythroid 2-related factor (Nrf2), which belongs to the basic leucine zipper transcription factor family, is a strategy for cancer chemopreventive phytochemicals. It is an important regulator of genes induced by oxidative stress, such as glutathione S-transferases, heme oxygenase-1 and peroxiredoxin 1, by activating the antioxidant response element (ARE). We hypothesized that (1) the citrus coumarin auraptene may suppress premalignant mammary lesions via activation of Nrf2/ARE, and (2) that Nrf2 knockout (KO) mice would be more susceptible to mammary carcinogenesis. METHODS: Premalignant lesions and mammary carcinomas were induced by medroxyprogesterone acetate and 7,12-dimethylbenz[a]anthracene treatment. The 10-week pre-malignant study was performed in which 8 groups of 10 each female wild-type (WT) and KO mice were fed either control diet or diets containing auraptene (500 ppm). A carcinogenesis study was also conducted in KO vs. WT mice (n = 30-34). Comparisons between groups were evaluated using ANOVA and Kaplan-Meier Survival statistics, and the Mann-Whitney U-test. RESULTS: All mice treated with carcinogen exhibited premalignant lesions but there were no differences by genotype or diet. In the KO mice, there was a dramatic increase in mammary carcinoma growth rate, size, and weight. Although there was no difference in overall survival, the KO mice had significantly lower mammary tumor-free survival. Also, in the KO mammary carcinomas, the active forms of NF-κB and ß-catenin were increased ~2-fold whereas no differences in oxidized proteins were observed. Many other tumors were observed, including lymphomas. Interestingly, the incidences of lung adenomas in the KO mice were significantly higher than in the WT mice. CONCLUSIONS: We report, for the first time, that there was no apparent difference in the formation of premalignant lesions, but rather, the KO mice exhibited rapid, aggressive mammary carcinoma progression.

Teasing out the best molecular marker in the AKT/mTOR pathway in head and neck squamous cell cancer patients.

OBJECTIVES/HYPOTHESIS: No reliable molecular biomarker is currently available for clinical application in the management of head and neck cancer patients. The AKT/mTOR pathway is activated in 90% to 100% of head and neck squamous cell cancer (HNSCC) and could be promising biomarkers closely linked to cancer incidence. STUDY DESIGN: Retrospective study of HNSCC and non-cancer patients. METHODS: Oral mucosa from noncancer patients were compared to HNSCC tumors and junctional zone mucosa. The candidate biomarkers mTOR, AKT, 4EBP1, and S6 kinase, signaling components upstream and downstream of mTOR that appear dysregulated in HNSCC, were evaluated using immunohistochemistry (IHC) and Western blot analysis. RESULTS: Expression of phosphorylated AKT and phosphorylated mTOR were significantly higher in cancer patient tumors compared to noncancer oral mucosa samples (P = .004 and P = .026, respectively) by Western blot analysis. Expression of p-mTOR and p-4EBP1 were higher in patient junctional zones compared to tumors (p = 0.017 and p = 0.022, respectively) and no difference in p-AKT or p-S6 expression in HNSCC patients' junctional zone compared to tumors. IHC-demonstrated p-mTOR expression was 81.9% sensitive and 100% specific in differentiating cancer from noncancer mucosa, whereas p-4EBP1 expression by IHC was only 50.0% sensitive and 95.5% specific in differentiating normal mucosa from HNSCC (P < .01). CONCLUSIONS: Phosphorylated mTOR appears to be a reliable biomarker by both Western blot analysis (P = .026) and IHC in human head and neck cancer (P < .001). Moreover, phosphorylated AKT, which is immediately upstream of mTOR, is a potential biomarker that should be further studied. Clinical trials with mTOR inhibitors are being evaluated for HNSCC, and selecting patients that are likely to respond to these inhibitors requires identifying and validating predictive biomarkers of response.

Stromal expression of actin is a marker of aggressiveness in basal cell carcinoma.

Basal cell carcinoma is a very common malignant skin tumor that rarely metastasizes but is often locally aggressive. In a number of studies conducted by different investigators, Bcl2, beta-catenin, cyclin D1, hMSH2, and alpha-smooth muscle actin have been reported to have potential for predicting basal cell carcinoma aggressiveness. However, these reports were inconclusive and sometimes contradictory. We therefore studied the expression and topographic locations (tumor versus stroma) of all these gene products in a group of clinically proven aggressive basal cell carcinomas (n = 30) and randomly selected control cases of nonaggressive basal cell carcinomas (n = 33). The results were subjected to statistical analysis with Mann-Whitney test and logistic regression. The accuracy of the resulting significant discriminating criteria was further tested using the omnibus tests of model coefficients. With multivariate analysis, differential expression of Bcl-2, beta-catenin, and cyclin D1 was not significantly different between aggressive and nonaggressive tumors. hMSH2 expression was up-regulated in the aggressive tumors (P = .005). Alpha-smooth muscle actin was expressed by tumor cells in both study groups, but stromal expression of alpha-smooth muscle actin was restricted to the aggressive tumors and highly predictive of aggressive behavior (P < .001; accuracy, 87%). Logistic regression combining the expression of alpha-smooth muscle actin and hMSH2 yielded a predictive model with 97% accuracy (P < .001). These data show conclusively that aggressive basal cell carcinomas express alpha-smooth muscle actin in the stroma, whereas nonaggressive basal cell carcinomas express alpha-smooth muscle actin in the tumor cells, and that stromal expression of alpha-smooth muscle actin is an accurate, reliable, and easy to use marker of aggressiveness in basal cell carcinomas and can be used in clinical practice for surgical therapeutic decisions.