Cyclin E is frequently encoded by CCNE1 gene amplification in various malignancies. We reviewed the medical records of patients with solid tumors displaying CCNE1 amplification to determine the ...effect of this amplification for future therapeutic development. We reviewed the medical records of patients with advanced solid tumors harboring CCNE1 amplification who were seen at the phase I clinic between September 1, 2012, and December 31, 2019. Among 79 patients with solid tumors harboring CCNE1 amplification, 56 (71%) received phase 1 clinical trial therapy, 39 (49%) had 3 or more concurrent genomic aberrances, and 52 (66%) had a concurrent TP53 mutation. The median overall survival (OS) after patients' initial phase I visit was 8.9 months and after their initial metastasis diagnosis was 41.4 months. We identified four factors associated with poor risk: age < 45 years, body mass index ≥ 25 kg/m
, presence of the TP53 mutation, and elevated LDH > upper limit of normal. In patients treated with gene aberration-related therapy, anti-angiogenic therapy led to significantly longer OS after their initial phase I trial therapy than those who did not: 26 months versus 7.4 months, respectively (P = 0.04). This study provided preliminary evidence that CCNE1 amplification was associated with frequent TP53 mutation and aggressive clinical outcomes. Survival benefit was observed in patients who received antiangiogenic therapy and gene aberration-related treatment, supporting the future development of a personalized approach to combine gene aberration-related therapy with antiangiogenesis for the treatment of advanced malignancies harboring CCNE1 amplification.
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Dissolution of amorphous solid dispersions (ASDs) is a complicated process, which may involve phase separation from the supersaturated state and formation of a colloidal phase. ...However, relevance of the phase separation behavior to oral absorption from ASDs is still not well understood. We investigated phase separation of a supersaturated fenofibrate (FEN) solution in the presence of polymers, in vitro dissolution of FEN ASDs, and their in vivo absorption. The supersaturation behavior was assessed based on turbidity measurement in an artificial supersaturation system, where FEN ethanol solutions were added to aqueous polymer solutions. The phase separation concentration of FEN was ca. 1 μg/mL regardless of the presence/absence of the polymer, which was approximately 10-fold the equilibrium solubility. In the presence of 0.1% Tween 80 in the media, the phase separation concentration depended on the polymer species, presumably due to differences in their inhibitory effect of crystallization. The degrees of supersaturation achieved by the ASDs were similar to those found in the artificial system, suggesting that the artificial system works for comprehending the effect of polymer species on supersaturation ability for designing ASDs. A robust in vitro-in vivo correlation was achieved using the paddle and the flow-through cell methods by employing non-sink and pH-shift conditions. However, the phase separation concentration may rather be a good and simple indicator to estimate the absorption-enhancing ability of the polymeric excipients for ASDs, if the absorption is limited by solubility.
Higher body mass index (BMI) is a well-established risk factor for type 2 diabetes, and rates of obesity and type 2 diabetes are substantially higher among Mexican-Americans relative to non-Hispanic ...European Americans. Mexican-Americans are genetically diverse, with a highly variable distribution of Native American, European, and African ancestries. Here, we evaluate the role of Native American ancestry on BMI and diabetes risk in a well-defined Mexican-American population. Participants were randomly selected among individuals residing in the Houston area who are enrolled in the Mexican-American Cohort study. Using a custom Illumina GoldenGate Panel, we genotyped DNA from 4,662 cohort participants for 87 Ancestry-Informative Markers. On average, the participants were of 50.2% Native American ancestry, 42.7% European ancestry and 7.1% African ancestry. Using multivariate linear regression, we found BMI and Native American ancestry were inversely correlated; individuals with <20% Native American ancestry were 2.5 times more likely to be severely obese compared to those with >80% Native American ancestry. Furthermore, we demonstrated an interaction between BMI and Native American ancestry in diabetes risk among women; Native American ancestry was a strong risk factor for diabetes only among overweight and obese women (OR = 1.190 for each 10% increase in Native American ancestry). This study offers new insight into the complex relationship between obesity, genetic ancestry, and their respective effects on diabetes risk. Findings from this study may improve the diabetes risk prediction among Mexican-American individuals thereby facilitating targeted prevention strategies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
A novel drug delivery platform, mesoporous phospholipid particle (MPP), is introduced. Its physicochemical properties and ability as a carrier for enhancing oral absorption of poorly soluble ...drugs are discussed.
Methods
MPP was prepared through freeze-drying a cyclohexane/t-butyl alcohol solution of phosphatidylcholine. Its basic properties were revealed using scanning electron microscopy, x-ray diffraction, thermal analysis, hygroscopicity measurement, and so on. Fenofibrate was loaded to MPP as a poorly soluble model drug, and effect of MPP on the oral absorption behavior was observed.
Results
MPP is spherical in shape with a diameter typically in the range of 10–15 μm and a wide surface area that exceeds 10 m
2
/g. It has a bilayer structure that may accommodate hydrophobic drugs in the acyl chain region. When fenofibrate was loaded in MPP as a model drug, it existed partially in a crystalline state and improvement in the dissolution behavior was achieved in the presence of a surfactant, because of the formation of mixed micelles composed of phospholipids and surfactants in the dissolution media. MPP greatly improved the oral absorption of fenofibrate compared to that of the crystalline drug and its efficacy was almost equivalent to that of an amorphous drug dispersion.
Conclusion
MPP is a promising option for improving the oral absorption of poorly soluble drugs based on the novel mechanism of dissolution improvement.
Purpose: Several lines of evidence suggest that diet and weight gain may be important environmental factors implicated in prostate
carcinogenesis, especially in tumor progression. The purpose of this ...study was to evaluate obesity at different ages in a
well-characterized cohort of prostate cancer patients treated with prostatectomy and to develop a prognostic model that incorporates
body mass index (BMI) as a measure of obesity.
Experimental Design: We carried out a prospective study of 526 patients registered at the M.D. Anderson Cancer Center from 1992 to 2001. Kaplan-Meier
and Cox proportional hazard analyses were done.
Results: During an average follow-up of 54 months, 97 (18%) post-prostatectomy patients experienced biochemical failure. Patients
who were obese (BMI ≥ 30 kg/m 2 ) at diagnosis had a higher rate of biochemical failure than nonobese men ( P = 0.07). Those obese at 40 years had an even greater rate of biochemical failure ( P = 0.001). Higher BMI at diagnosis hazard ratio (HR), 1.07; P = 0.01 and Gleason score = 7(4 + 3) and ≥8 (HR, 3.9; P = 0.03 and HR, 10.0; P ≤ 0.001, respectively) remained significant independent predictors of biochemical failure in multivariate analysis. Men who
gained weight at the greatest rate (>1.5 kg/y) between 25 years and diagnosis progressed significantly sooner (mean time,
17 months) than those who exhibited a slower weight gain (mean time, 39 months; P trend = 0.005). The inclusion of obesity to the clinical nomogram improved performance.
Conclusions: Our findings validate the importance for a role of obesity in prostate cancer progression and suggest a link to the biological
basis of prostate cancer progression that can be therapeutically exploited.
To date, little is known about the risk factors for the development of chronic myeloid leukemia (CML). Obesity, measured as
body mass index, has been identified as a possible risk factor for several ...solid tumors as well as some adult hematopoietic
malignancies. This case-control study ( N = 253 cases and 270 controls), conducted at the University of Texas M. D. Anderson Cancer Center, investigated the role of
obesity and adulthood weight gain in CML risk. Cases and controls were similar with respect to smoking, alcohol consumption,
and occupational solvent and ionizing radiation exposure. Cases were significantly more likely to have a history of occupational
exposure to agricultural chemicals (11% cases versus 3% controls, P = 0.001). Cases were more likely to be obese during adulthood compared with controls at age 25 odds ratios (OR) = 4.29;
95% confidence intervals (95% CI), 1.63-11.3, at age 40 (OR = 5.12; 95% CI, 1.92-13.6), and at diagnosis (OR = 3.09; 95%
CI, 1.56-6.13). Obesity at all ages was found to be an independent risk factor, with a significant dose-response effect. Among
participants ≥45 years, cases gained significantly more weight each year between ages 25 and 40 compared with controls (0.78
versus 0.44 kg/y, P < 0.001) with the association strongest among those who gained >1 kg/y between 25 and 40 years of age (OR, 3.63; 95% CI,
1.46-9.04). Our results suggest that obesity and adulthood weight gain play important roles in CML risk. Several plausible
biological mechanisms have been proposed and warrant further investigation. In the future, cancer prevention interventions
aimed at reducing the incidence of CML could be developed. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1501–6)
Purpose: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer. Nuclear expression of p53 protein in breast
cancer correlates with more aggressive tumors. We retrospectively ...analyze the expression of p53 as a prognostic marker to
predict pathological complete response and survival in patients with IBC.
Experimental Design: Fifty-nine patients with IBC were treated from January 1994 to April 2000. Forty-eight patients were included. Diagnostic
core biopsies were taken before treatment was started. Expression of hormone receptors and p53 was determined by immunohistochemistry.
All patients received an anthracycline-based regimen preoperatively; 22 patients (46%) also received paclitaxel. Forty-four
patients (92%) achieved an objective clinical response and underwent mastectomies.
Results: Median age at diagnosis was 48 years. Thirty patients (63%) had hormone receptor-negative tumors. Twenty-eight patients (58%)
had p53-positive tumors, and 20 patients (42%) had p53-negative tumors. Nine patients (19%) achieved a pathological complete
response. At a median follow-up of 77 months, 28 recurrences (58%) and 26 deaths (54%) had occurred. Patients with p53-positive
tumors were younger ( P = 0.02) and tended to have lower 5-year progression-free survival rates (35% versus 55%; P = 0.3) and overall survival rates (44% versus 54%; P = 0.4).
Conclusions: This retrospective analysis demonstrates that nuclear p53 protein expression may represent an adverse prognostic marker in
IBC and may provide a valuable tool for selecting treatment for this aggressive disease.
TPS4610 Background: Complete response (CR) is still a rare event in patients with advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently ...approved for the first-line treatment of ccRCC based on the CheckMate 9ER phase 3 study demonstrating improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, the CR rate was only 9%. Since the anti-tumor effects of immune checkpoint inhibitors are dependent on the presence of activated tumor-infiltrating T cells, drugs that could synergize with T cells' anti-tumor activity can allow us to improve CR rates. Activation of the cGAS-STING pathway which is induced by radiation-induced DNA damage, is one promising mechanism that has been investigated. Many studies have shown that radiation treatment augments immune checkpoint inhibition. However, it is not always possible to radiate all metastatic lesions. Therefore, targeted peptide receptor radionuclide therapies, have been developed by conjugating radioisotopes to receptor binding analogs targeting specific cancer cell surface proteins, thereby delivering targeted radiation to cancer cells in the body with minimal damage to surrounding healthy cells. 177 Lu girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase 9-expressing cells, which includes >90% of ccRCC. It has been tested in metastatic ccRCC as a single agent and shown to be safe and effective in stabilizing disease in 57% of pts. In this study, we hypothesize that 177 Lu girentuximab-induced DNA damage will potentiate the STING pathway, and this activation will synergize with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells to tumors and achieve higher CR rates. Methods: Up to 100 patients with treatment naive, biopsy-proven ccRCC with adequate organ/marrow function with 1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety, and futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate (primary endpoint) of 18% as better than 9% using a beta(0.09, 0.91) prior. Secondary endpoints are ORR, PFS by RECIST 1.1, and overall survival. 177 Lu-girentuximab 1480 MBq/m 2 (61% of single agent MTD) will be administered every 12 weeks for up to 3 cycles. Starting with the second cycle, nivolumab and cabozantinib will be added at standard dose. To explore the effects of the treatment on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with 18 F-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics and proteomics studies. Clinical trial information: NCT05663710 .
Abstract
Hispanics comprise 17% of the overall US population and 40% of the population in Texas. Approximately 90% of Hispanic Texans are of Mexican descent. This population presents unique ...challenges in access to health care and utilization of preventive screening. Although the internet has been rapidly integrated into education and outreach strategies for cancer prevention, its potential impact in reducing health disparities among Hispanics has not been evaluated. The few surveys conducted to date among Hispanics have focused on only those individuals who use the internet and were primarily done for marketing purposes. This study was conducted to identify differences between individuals who use internet compared to non-users in a large cohort of Mexican Americans residing in inner city neighborhoods (Houston, TX). Given that technology has evolved so quickly over the past decade, we limited our analyses to 1313 individuals enrolled in the past 2 years. In our population, most of the participants (58%, N=756) reported that they do not use the internet.
Using multivariable logistic regression, we constructed the final model in a backwards, stepwise approach to determine factors associated with internet use. Compared to those who reported using the internet, non-users were significantly (P<0.05) more likely to be male, older (mean age 51.4 vs. 41.3 years old), non-English speakers (71.4% vs. 42.0%), and not have private insurance (14% vs. 25%). Notably, 87% of participants that did not use the internet reported that they almost always spoke in Spanish; in contrast, 44% of internet users reported that they almost always spoke in English. Overall, individuals who do not use the internet were more likely to have traits associated with poorer health and higher risk for health disparity.
One of the most important findings from this study is that almost 60% of the Hispanics in this population do not use the internet; additionally, among individuals who use the internet, only 61% reported using any form of social media (Facebook, Google+, Twitter, myspace). These results suggest that the use of social media and internet would not be effective methods to reach this population and have an impact in reducing health disparities in an inner city minority population.
Citation Format: Sara S. Strom, Yuko Yamamura. Planning for the future: Reaching an inner city Mexican American population. abstract. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C09. doi:10.1158/1538-7755.DISP13-C09
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