Publications by authors named "Jane L Meza"

81 Publications

Duration on ART, Alcohol Use and HIV Stage May Predict Risky Sexual Behavior in a Resource-Limited Environment: A Cross-Sectional Study.

Curr HIV Res 2021 Jul 25. Epub 2021 Jul 25.

Department of Epidemiology, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska, United States.

Background: The intention of antiretroviral therapy (ART) and regular clinic visits is to engender safe sex attitudes among HIV-infected individuals. However, this may not be the case due to the perceived therapeutic benefits of ART and may result in exposure to drug-resistant HIV strains.

Objective: We aimed to determine the prevalence and predict the factors associated with risky sexual behaviors among ART users in a resource-limited environment.

Methods: Two hundred and ninety-one sexually active ART users aged 18-50 years and seeking care at the HIV clinic in Dodoma, Tanzania, participated in this study. The outcome variables modeled in a logistic regression were condom use, multiple sex partners, casual sex partners, and payment for sex. The predictors included in the models were the patients' socio-demographic characteristics. In addition, a new variable, sexual risk scores, was generated by culminating all the outcome variables. Finally, multiple Poisson regression with the socio-demographic variables of the participants was used to model the sexual risk scores.

Results: Patients reported inconsistent/no condom use (44%), payment for sex (4%), casual sex encounters (13%), multiple sex partners (21%), and STD symptoms (15%). While having a casual sexual partner was significantly associated with age group in a Pearson Chi-square (p=0.0147), participants ≤35 years old were less likely to have single-sex partners than older participants (AOR: 0.188, 95 C.I: 0.042-0.849). Meanwhile, the likelihood of condom use was higher among participants with no HIV-infected family members (AOR= 2.409, 95% C.I:1.236,4.697) and among participants who have single-sex partners (AOR= 2.721, 95% C.I.: 1.115,6.640); these participants were less likely to report STD symptoms (AOR=0.265, 95% C.I.: 0.081-0.865). Adjusted analysis showed that estimated mean sexual risk scores significantly increased (mean, λ=1.61, 95% C.I:1.0817-2.4063) for recent ART recipients (within 1-3 years vs. ≥eight years). However, sexual risk scores of participants with HIV stage 3 were 38.8% lower than participants at stage 4 (95% C.I.: 0.3910-0.9558), and non-alcohol drinkers had an adjusted mean sexual risk score 29% lower than participants who were alcohol drinkers (95% C.I.: 0.5102-0.9879).

Conclusion: Researchers should prioritize patients at HIV CTC for education concerning safe sexual practices for those characterized by alcohol consumption, younger age (less than 35 years old), HIV stage 4, or commencement of ART within three years.
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http://dx.doi.org/10.2174/1570162X19666210726102027DOI Listing
July 2021

The impact of stereotactic body radiation therapy on the overall survival of patients diagnosed with early-stage non-small cell lung cancer.

Radiother Oncol 2021 02 24;155:254-260. Epub 2020 Oct 24.

Department of Radiation Oncology, University of Nebraska Medical Center, United States. Electronic address:

Background And Purpose: Stereotactic Body Radiotherapy (SBRT) has emerged as a standard treatment for inoperable early-stage non-small cell lung cancer (NSCLC) with remarkable local control. However, it is not clear if this local control translates to overall survival (OS). The objective of this study is to investigate the impact of SBRT on the OS of early-stage NSCLC patients and examine if the extent of this impact changes with the era of diagnosis, T stage, age, and comorbidity status.

Materials And Methods: Using the National Cancer Database, we compared the OS of cT1-3 cN0 cM0 NSCLC patients with SBRT or observation. Multivariable analyses were adjusted for age, race, sex, income, education, place of living, hospital type, insurance status, comorbidity score, histology types, and diagnosis year.

Results: Among 50,819 patients, 27,027 (53.18%) received SBRT and 23,792 (46.82%) were observed. Multivariable Cox Proportional-Hazards analysis demonstrated SBRT was associated with an improved OS compared to observation (HR:0.56, p < 0.001). Subset multivariable Cox Proportional-Hazards analyses stratified by T stage, year of diagnosis, age, or Charlson Score revealed that HRs of SBRT vs. observation decrease from cT1 to cT3 (0.73-0.68), from 2004 to 2015 (0.65-0.51), from <50 to ≥80 years old (1.04-0.58) and from a Charlson Score 0 to 2 (0.69-0.58).

Conclusion: SBRT was associated with improved OS compared to no treatment in early-stage NSCLC. The magnitude of the impact of SBRT on OS increases in patients with advanced age, higher T stages, higher comorbidity scores and more recent treatment eras.
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http://dx.doi.org/10.1016/j.radonc.2020.10.028DOI Listing
February 2021

Quantifying the under-estimation of cervical Cancer in remote regions of Tanzania.

BMC Cancer 2020 Sep 30;20(1):939. Epub 2020 Sep 30.

City University of New York Medical School, 160 Convent Avenue, New York, NY, 10031, USA.

Background: Cervical cancer is the most common cancer among women in Sub-Saharan countries, including Tanzania. While early detection and diagnosis are available in some parts of this large country, radiotherapy has been only available at the Ocean Road Cancer Institute (ORCI), in the capital city of Dar es Salaam and is just starting in a few regions.

Methods: The objective of this study was to compare the observed incidence of cervical cancer for the two remote regions of Mwanza in western Tanzania and Mbeya in southern Tanzania, based on their patients treated at the ORCI from 2011 to 2014.

Results: The number patients referred and treated at ORCI were (120 from Mwanza, and 171 from Mbeya, representing 24.6 and 32.8% of the patients histopathologically confirmed in the two sites, respectively. The results showed significant underestimation of cervical cancer in the two regions. The vast majority of patients who were histopathologically-confirmed in their local regions (73.92% from Mwanza and 65.1% from Mbeya), but did not receive the needed radiotherapy treatment at the ORCI. The estimated incidence for the two regions based on the number of patients treated at the ORCI were underestimated by 53.9% for Mwanza and 68.9% for Mbeya.

Conclusions: Local establishment of radiotherapy treatment facilities in remote regions in Tanzania and similar other low-income countries is essential for providing effective treatment and improving survival of diagnosed cervical cancer patients. Linkage between the records of local remote hospitals and the main cancer treatment center in the capital city can also help support the emerging the population-based cancer registry at ORCI.
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http://dx.doi.org/10.1186/s12885-020-07439-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526175PMC
September 2020

The Association of the Sequence of Immunotherapy With the Survival of Unresectable Pancreatic Adenocarcinoma Patients: A Retrospective Analysis of the National Cancer Database.

Front Oncol 2020 2;10:1518. Epub 2020 Sep 2.

Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, United States.

Immunotherapy has shown great success in various malignancies. However, its efficacy in pancreatic ductal adenocarcinoma (PDAC) remains a challenge, and the lack of understanding about the appropriate timing of immunotherapy with other standard-of-care cancer treatments may be one of the causes. The objective of the current study is to investigate the impact of the timing of immunotherapy with chemotherapy and radiation therapy (RT) on the overall survival (OS) of PDAC patients who did not receive surgical resection of the pancreatic tumor. Patients with pancreatic adenocarcinoma who did not receive surgical resection of the pancreatic tumor were identified from the National Cancer Database (NCDB). Cox proportional hazard models were employed to compare the OS between patients who received immunotherapy with chemotherapy or RT with a different sequence of treatment. The multivariable analysis was adjusted for age of diagnosis, race, sex, place of living, income, education, treatment facility type, insurance status, and year of diagnosis. In total, 705 patients received chemotherapy and immunotherapy, while 226 received radiation therapy and immunotherapy. In the multivariable analysis, there was no significant difference in the OS of patients who started immunotherapy 31-90 days before the start of chemotherapy with a hazard ratio (HR) of [HR:1.057 (CI: 0.716-1.56; < 0.781)] and patients who started immunotherapy 91-180 days before the start of chemotherapy [HR: 0.900 (CI: 0.584-1.388; < 0.635)] compared to patients who started chemotherapy and immunotherapy within 30 days of each other. There was also no significant difference in the OS of patients who started RT> 30 days before the start of immunotherapy [HR: 0.636 (CI: 0.346-1.171; < 0.146)] and patients who started immunotherapy > 30 days before the start of RT [HR: 0.660 (CI: 0.328-1.329; < 0.246)] compared to patients who started RT and immunotherapy within 30 days of each other. The sequence of immunotherapy with chemotherapy or RT was not associated with improved OS. Future studies with a larger subgroup sample size investigating the impact of the timing of immunotherapy with chemotherapy and RT on the OS of PDAC patients who do not receive surgical resection of the pancreatic tumor are needed.
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http://dx.doi.org/10.3389/fonc.2020.01518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492650PMC
September 2020

Association of Immunotherapy With Survival Among Patients With Brain Metastases Whose Cancer Was Managed With Definitive Surgery of the Primary Tumor.

JAMA Netw Open 2020 09 1;3(9):e2015444. Epub 2020 Sep 1.

Department of Radiation Oncology, University of Nebraska Medical Center, Omaha.

Importance: Immunotherapy has shown significant control of intracranial metastases in patients with melanoma. However, the association of immunotherapy combined with other cancer treatments and overall survival (OS) of patients with brain metastases, regardless of primary tumor site, is unknown.

Objective: To explore the association of immunotherapy with OS in patients with cancer and brain metastases who received definitive surgery of the primary site.

Design, Setting, And Participants: This comparative effectiveness study included 3112 adult patients in the National Cancer Database from 2010 to 2016 with non-small cell lung cancer, breast cancer, melanoma, colorectal cancer, or kidney cancer and brain metastases at the time of diagnosis and who received definitive surgery of the primary site. Data analysis was conducted from March to April 2020.

Exposures: Treatment groups were stratified as follows: (1) any treatment with or without immunotherapy, (2) chemotherapy with or without immunotherapy, (3) radiotherapy (RT) with or without immunotherapy, and (4) chemoradiation with or without immunotherapy.

Main Outcomes And Measures: The association of immunotherapy with OS was assessed with Cox proportional hazards regression, adjusted for age at diagnosis, race, sex, place of living, income, education, treatment facility type, primary tumor type, and year of diagnosis.

Results: Of 3112 patients, 1436 (46.14%) were men, 2714 (87.72%) were White individuals, 257 (8.31%) were Black individuals, and 123 (3.98%) belonged to other racial and ethnic groups. The median (range) age at diagnosis was 61 (19-90) years. Overall, 183 (5.88%) received immunotherapy, 318 (10.22%) received chemotherapy alone, 788 (25.32%) received RT alone, and 1393 (44.76%) received chemoradiation alone; 22 (6.47%) received chemotherapy plus immunotherapy, 72 (8.37%) received RT plus immunotherapy, and 76 (5.17%) received chemoradiation plus immunotherapy. In the multivariable analysis, patients who received immunotherapy had significantly improved OS compared with no immunotherapy (hazard ratio, 0.62; 95% CI, 0.51-0.76; P < .001). Treatment with RT plus immunotherapy was associated with significantly improved OS compared with RT alone (hazard ratio, 0.59; 95% CI, 0.42-0.84; P = .003). Chemotherapy plus immunotherapy or chemoradiation plus immunotherapy were not associated with improved OS in the multivariable analysis.

Conclusions And Relevance: In this study, the addition of immunotherapy to RT was associated with improved OS compared with radiotherapy alone in patients with brain metastases who received definitive surgery of the primary tumor site.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.15444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489857PMC
September 2020

Cervical Cancer Screening among Women Receiving Antiretroviral Therapy in a Resource-Limited Environment.

Asian Pac J Cancer Prev 2020 Jul 1;21(7):2035-2045. Epub 2020 Jul 1.

Tanzania Commission for AIDS, Tanzania.

Background: Cervical cancer is among the most prevalent cancer among women worldwide and women living with HIV are at increased risk, especially in a resource-limited environment.

Objective: This study aimed to determine levels of awareness, knowledge, uptake, and willingness to screen for cervical cancer among women receiving care in an HIV clinic at Dodoma Regional Referral Hospital (DRRH), Tanzania.

Methods: Data were collected for a period of three weeks from July 21 to August 11, 2017 using a mobile phone data collection App. A total of 421 Women aged 18-50 years old were included in the study.

Results: Majority of the women interviewed (n=306, 73%) were aware of cervical cancer. Among those who were aware, 84% (n=257) did not recall ever being screened for cervical cancer, and majority had a poor knowledge of cervical cancer. Educational level completed (p=0.01), income per month (p=0.02), age group (p<0.0001), and area of residence (p<0.0001) were all significantly associated to awareness of cervical cancer. Most of the women who have never screened (n=231, 91%) expressed willingness to be screened. Prior uptake of cervical cancer screening was associated with number of live births (p=0.001) and area of residence (p=0.04). And Willingness to screen was significantly associated with age groups (p=0.03) and the number of live births (p=0.03). Moreover, we found that younger age and urban residence was positively associated with awareness and uptake of cervical cancer screening. Willingness was found to decrease as age increased.

Conclusion: The study found that despite older women's higher risk of cervical cancer, those who indicated willingness to screen were younger. Additional education, health promotion, and integration of cervical cancer screening services is needed to improve cervical cancer awareness and screening uptake at the HIV clinic.
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http://dx.doi.org/10.31557/APJCP.2020.21.7.2035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573407PMC
July 2020

Symptom Clusters and Quality of Life over 1 Year in Breast Cancer Patients Receiving Adjuvant Chemotherapy.

Asia Pac J Oncol Nurs 2020 Apr-Jun;7(2):134-140. Epub 2020 Mar 30.

College of Public Health, University of Nebraska Medical Center, Omaha, NE, USA.

Objective: Evidence is scant regarding symptom clusters and quality of life (QOL) over 1 year in women who receive adjuvant breast cancer chemotherapy (CTX). Our purpose was to identify the prevalence and severity of individual symptoms, symptom clusters, and QOL in women receiving adjuvant breast cancer CTX from baseline over 1 year.

Methods: Symptoms were identified in a sample ( = 219) at three times: baseline (prior to the first adjuvant CTX treatment), 1 month after the last CTX (approximately 6 months after baseline), and 1 year after baseline. The Hospital Anxiety and Depression Scale and Symptom Experience Scale measured symptoms. The Medical Outcomes Study, Short-Form Survey, measured QOL. Exploratory factor analysis identified symptom clusters at each time and core symptoms in clusters over time.

Results: The prevalence and severity of 10 symptoms decreased over time ( < 0.05). Fatigue, sleep disturbance, and pain were most prevalent; all were of mild severity. Two symptom clusters were identified at baseline and one met internal consistency reliability criteria at the later times. Core symptoms were identified. Both the physical and mental component scores of QOL improved over time ( < 0.01), but physical was below the general population norms 1 year after baseline.

Conclusions: The symptom experience was dynamic, and symptom clusters changed over 1 year. Despite mild severity, core symptoms and clusters persisted over 1 year, and physical health was below the general population norms. Breast cancer survivors with persistent single and co-occurring symptoms need to be taught to manage the patterns of symptoms over time because they may not resolve by 1 year.
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http://dx.doi.org/10.4103/apjon.apjon_57_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233556PMC
March 2020

Trans Collaborations Clinical Check-In (TC): Initial Validation of a Clinical Measure for Transgender and Gender Diverse Adults Receiving Psychological Services.

Behav Ther 2019 11 11;50(6):1136-1149. Epub 2019 Apr 11.

University of Nebraska-Lincoln.

One key aspect of evidence-based psychological services is monitoring progress to inform treatment decision making, often using a brief self-report measure. However, no such measure exists to support measurement-based care, given the distinct needs of transgender and gender diverse people (TGD), a group facing large documented health disparities and marginalization in health care. The purpose of the present study was to develop and provide initial psychometric validation of a short, behavioral health progress monitoring self-report measure, the Trans Collaborations Clinical Check-in (TC). TGD communities, providers identified as TGD-affirmative, and relevant academic experts contributed to item and scale development. The final 18-item version was administered to 215 TGD adults (75 transfeminine, 76 transmasculine, 46 nonbinary, 18 unknown; mean age of 30 with a range of 19 to 73), who were recruited for an online study, with other questionnaires assessing negative affect, well-being, gender dysphoria, gender minority stressors, and resilience. Higher scores on the TC (indicating better adjustment and comfort with gender) were generally associated with lower depression, anxiety, minority stress, and gender dysphoria and greater life satisfaction, body congruence, and positive aspects of being TGD such as pride in identity and community belongingness. These results support the validity of the TC as a brief measure to be used as a clinical tool for TGD people receiving mental health services. Additional research is needed on the reliability and validity of the TC across multiple time points to determine utility as a progress monitoring measure. The TC should also be further validated with more culturally diverse samples.
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http://dx.doi.org/10.1016/j.beth.2019.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405917PMC
November 2019

Phase I/II Trial of Neoadjuvant Oregovomab-based Chemoimmunotherapy Followed by Stereotactic Body Radiotherapy and Nelfinavir For Locally Advanced Pancreatic Adenocarcinoma.

Am J Clin Oncol 2019 10;42(10):755-760

Internal Medicine, Division of Hematology Oncology, University of Nebraska Medical Center.

Objective: Cancer antigen (CA)-125 influences progression, metastasis, and outcomes in pancreatic cancer. This phase I/II trial (NCT01959672) evaluated the safety, efficacy, and immunologic correlates of chemoimmunotherapy (CIT) with oregovomab (anti-CA-125), followed by stereotactic body radiotherapy (SBRT) with the radiosensitizer nelfinavir.

Materials And Methods: Following imaging, pathologic confirmation, and staging laparoscopy, subjects received three 3-week cycles of CIT (gemcitabine/leucovorin/fluorouracil/oregovomab). Thereafter, nelfinavir was delivered (1250 mg bid) for 5 weeks, with SBRT (40 Gy/5 fractions) occurring during the third week of nelfinavir. Following another cycle of CIT, pancreaticoduodenectomy was performed if resectable. Three more cycles of CIT were then delivered (total 7 cycles). In subjects with high (≥10 U/mL) CA-125, oregovomab (2 mg) was administered for 7 total doses (3 pre-SBRT, 1 between SBRT and resection, and 3 postoperatively). The enzyme-linked immunospot assay evaluated the development of CA-125-specific CD8 T-lymphocytes.

Results: The trial was prematurely closed because gemcitabine/leucovorin/fluorouracil was replaced by FOLFIRINOX and gemcitabine/nab-paclitaxel as the standard of care. Median follow-up was 13 months. Of 11 enrolled patients, 10 had high CA-125; 1 patient suffered an unexpected cardiac-related death, so 9 subjects received oregovomab. Ten received SBRT and 4 underwent resection. Overall, 6/11 patients experienced any grade ≥3 event. The median survival and time to progression were 13 and 8.6 months, respectively. Five patients had samples available for immunospot testing, of whom 2 (40%) developed CA-125-specific CD8 T-lymphocytes.

Conclusion: A combined pancreatic cancer multimodality approach using CIT and radiosensitized radiotherapy is feasible and safe; delivery of immunotherapy can lead to T-cell immunity. Re-evaluation with modern systemic paradigms is recommended.
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http://dx.doi.org/10.1097/COC.0000000000000599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768754PMC
October 2019

Phase I trial of concurrent stereotactic body radiotherapy and nelfinavir for locally advanced borderline or unresectable pancreatic adenocarcinoma.

Radiother Oncol 2019 03 20;132:55-62. Epub 2018 Dec 20.

Department of Internal Medicine, Division of Hematology Oncology, University of Nebraska Medical Center, Omaha, USA.

Introduction: The HIV protease inhibitor nelfinavir (NFV) displays notable radiosensitizing effects. There have been no studies evaluating combined stereotactic body radiotherapy (SBRT) and NFV for borderline/unresectable pancreatic cancer. The primary objective of this phase I trial (NCT01068327) was to determine the maximum tolerated SBRT/NFV dose, and secondarily evaluate outcomes.

Methods: Following initial imaging, pathologic confirmation, and staging laparoscopy, subjects initially received three 3-week cycles of gemcitabine/leucovorin/fluorouracil; patients without radiologic progression received 5-fraction SBRT/NFV. Dose escalation was as follows: (1) 25 Gy/625 mg BID ×3wks; (2) 25 Gy/1250 mg BID ×3wks; (3) 30 Gy/1250 mg BID ×3wks; (4) 35 Gy/1250 mg BID ×3wks; (5) 35 Gy/1250 mg BID ×5wks; and (6) 40 Gy/1250 mg BID ×5wks. Pancreaticoduodenectomy was performed thereafter if resectable; if not, gemcitabine/leucovorin/fluorouracil was administered.

Results: Forty-six patients enrolled (10/2008-5/2013); 39 received protocol-directed therapy. Sixteen (41%) experienced any grade ≥2 event during and 1 month after SBRT. Four grade 3 and both grade 4 events occurred in a single patient at the initial dose level. 40 Gy/1250 mg BID ×5wks was the maximum tolerated dose. Five patients had late gastrointestinal bleeding (n = 2 superior mesenteric artery pseudo-aneurysm, n = 1 disease progression, n = 1 lower GI tract, n = 1 unknown location). The median overall survival was 14.4 months. Six (15%) patients recurred locally; median local failure-free survival was not reached. The median distant failure-free survival was 11 months, and median all failure-free survival was 10 months.

Conclusions: Concurrent SBRT (40 Gy)/NFV (1250 mg BID) for locally advanced pancreatic cancer is feasible and safe, although careful attention to treatment planning parameters is recommended to reduce the incidence of late gastrointestinal bleeding.
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http://dx.doi.org/10.1016/j.radonc.2018.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400311PMC
March 2019

Changes in Uterine Cancer Incidence Rates in Egypt.

Obstet Gynecol Int 2018 14;2018:3632067. Epub 2018 Jun 14.

Department of Community Health and Social Medicine, School of Medicine, City University of New York, New York, NY, USA.

Background: Uterine cancer is one of the top-ranking cancers in women with wide international variations in incidence rates. Developed countries have higher incidence rates than the developing countries. Egypt has significantly lower incidence of uterine cancer than other countries in the Middle East. This study aimed at verifying the incidence rate of uterine cancer and characterizing the demographic and clinical profiles of patients residing in the Gharbiah province in the Nile delta region of Egypt.

Methods: Data from 660 uterine cancer patients diagnosed during the period of 1999 to 2010 were abstracted from the Gharbiah Cancer Registry, the only population-based registry in Egypt. The data included age, marital status, number of children, residence, smoking, occupation, date and basis of diagnosis, tumor topography, morphology, stage and grade, and treatment. Crude rate, age-standardized rate (ASR), and age-specific rate were calculated and associated with demographic and clinical characteristics of patients.

Results: The study confirmed the low ASR of uterine cancer in Egypt, (4.1 per 100,000 (95% CI: 3.8-4.4)). The incidence rate increased significantly over the 12-year period. The crude rate (CR) was 1.95, 95% CI (1.64-2.25) in 1999-2002; 2.9, 95% CI (2.5-3.2) in 2003-2006; and 3.5, 95% CI (3.1-3.9) in 2007-2010. The rate ratio was 1.5, 95% CI (1.2-1.8) in 2003-2006 and 1.8, 95% CI (1.5-2.2) in 2007-2010 compared to 1999-2002. The majority of patients (83%) were postmenopausal with the highest age-specific rate in the 60-69-year age group (22.07 per 100,000 (95% CI: 19.3-25.2). The majority of patients were diagnosed at early stages (60% localized and 5% regional), had adenocarcinoma (68%), and resided in urban areas (54%).

Conclusions: The study confirmed the low incidence rate of uterine cancer in the Gharbiah province of Egypt and significant increase in incidence in recent years. Future studies should focus on verifying the possible effect of hysterectomy on lowering the incidence, the factors related to the changes in rates between rural and urban areas, and the possible impact of nutritional and epidemiologic transitions on the increasing rates.
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http://dx.doi.org/10.1155/2018/3632067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022259PMC
June 2018

Loss of the Nuclear Pool of Ubiquitin Ligase CHIP/STUB1 in Breast Cancer Unleashes the MZF1-Cathepsin Pro-oncogenic Program.

Cancer Res 2018 05 6;78(10):2524-2535. Epub 2018 Mar 6.

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska.

CHIP/STUB1 ubiquitin ligase is a negative co-chaperone for HSP90/HSC70, and its expression is reduced or lost in several cancers, including breast cancer. Using an extensive and well-annotated breast cancer tissue collection, we identified the loss of nuclear but not cytoplasmic CHIP to predict more aggressive tumorigenesis and shorter patient survival, with loss of CHIP in two thirds of ErbB2 and triple-negative breast cancers (TNBC) and in one third of ER breast cancers. Reduced CHIP expression was seen in breast cancer patient-derived xenograft tumors and in ErbB2 and TNBC cell lines. Ectopic CHIP expression in ErbB2 lines suppressed oncogenic traits and xenograft tumor growth. An unbiased screen for CHIP-regulated nuclear transcription factors identified many candidates whose DNA-binding activity was up- or downregulated by CHIP. We characterized myeloid zinc finger 1 (MZF1) as a CHIP target, given its recently identified role as a positive regulator of cathepsin B/L (CTSB/L)-mediated tumor cell invasion downstream of ErbB2. We show that CHIP negatively regulates CTSB/L expression in ErbB2 and other breast cancer cell lines. CTSB inhibition abrogates invasion and matrix degradation and halts ErbB2 breast cancer cell line xenograft growth. We conclude that loss of CHIP remodels the cellular transcriptome to unleash critical pro-oncogenic pathways, such as the matrix-degrading enzymes of the cathepsin family, whose components can provide new therapeutic opportunities in breast and other cancers with loss of CHIP expression. These findings reveal a novel targetable pathway of breast oncogenesis unleashed by the loss of tumor suppressor ubiquitin ligase CHIP/STUB1. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955821PMC
May 2018

Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson's disease trial.

NPJ Parkinsons Dis 2017 23;3:10. Epub 2017 Mar 23.

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE USA.

A potential therapeutic role for immune transformation in Parkinson's disease evolves from more than a decade of animal investigations demonstrating regulatory T cell (Treg) nigrostriatal neuroprotection. To bridge these results to human disease, we conducted a randomized, placebo-controlled double-blind phase 1 trial with a well-studied immune modulator, sargramostim (granulocyte-macrophage colony-stimulating factor). We enrolled 17 age-matched non-Parkinsonian subjects as non-treated controls and 20 Parkinson's disease patients. Both Parkinson's disease patients and controls were monitored for 2 months for baseline profiling. Parkinson's disease patients were then randomized into two equal groups to self-administer placebo (saline) or sargramostim subcutaneously at 6 μg/kg/day for 56 days. Adverse events for the sargramostim and placebo groups were 100% (10/10) and 80% (8/10), respectively. These included injection site reactions, increased total white cell counts, and upper extremity bone pain. One urticarial and one vasculitis reaction were found to be drug and benzyl alcohol related, respectively. An additional patient with a history of cerebrovascular disease suffered a stroke on study. Unified Parkinson's disease rating scale, Part III scores in the sargramostim group showed modest improvement after 6 and 8 weeks of treatment when compared with placebo. This paralleled improved magnetoencephalography-recorded cortical motor activities and Treg numbers and function compared with pretreated Parkinson's disease patients and non-Parkinsonian controls. Peripheral Treg transformation was linked to serum tryptophan metabolites, including L-kynurenine, quinolinic acid, and serotonin. These data offer a potential paradigm shift in modulating immune responses for potential therapeutic gain for Parkinson's disease. Confirmation of these early study results requires larger numbers of enrolled patients and further clinical investigation.
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http://dx.doi.org/10.1038/s41531-017-0013-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445595PMC
March 2017

Interaction of CD14 haplotypes and soluble CD14 on pulmonary function in agricultural workers.

Respir Res 2017 03 16;18(1):49. Epub 2017 Mar 16.

Department of Internal Medicine and Veterans Nebraska Western Iowa Healthcare System, Omaha, NE, USA.

Background: Agricultural environments are contaminated with organic dusts containing bacterial components. Chronic inhalation of organic dusts is implicated in respiratory diseases. CD14 is a critical receptor for gram-negative lipopolysaccharide; however, its association with respiratory disease among agricultural workers is unknown. The objective of this study was to determine if serum soluble CD14 (sCD14) levels are associated with lung function among agricultural workers and if this association is modified by genetic variants in CD14.

Methods: This cross-sectional study included 584 veterans with >2 years of farming experience and that were between the ages of 40 and 80 years. Participants underwent spirometry and were genotyped for four tagging CD14 polymorphisms (CD14/-2838, rs2569193; CD14/-1720, rs2915863; CD14/-651, rs5744455; and CD14/-260, rs2569190). Serum sCD14 was assayed by ELISA.

Results: Subjects were 98% white males with a mean age 64.5 years. High soluble CD14 levels (> median sCD14) were associated decreased lung function (FEV/FVC, p = 0.011; % predicted FEV, p = 0.03). When stratified by COPD (yes/no) and smoking status (ever/never), high sCD14 levels (> median sCD14) were associated with low lung function among ever smokers with COPD (% predicted FEV, p = 0.0008; FEV/FVC, p = 0.0002). A similar trend was observed for never smokers with COPD; however, results did not reach statistical significance due to small sample size. There was a significant sCD14 x COPD/smoking interaction with lung function (% predicted FEV, p = 0.0498; FEV/FVC, p = 0.011). Regression models were adjusted for age, body mass index, education, sex, race and years worked on a farm. No association was found between CD14 polymorphisms/haplotypes (CD14/-2838; CD14/-1720; CD14/-651; CD14/-260) and sCD14 levels. The final model included the variables sCD14 and haplotypes and a haplotype x sCD14 interaction term. Individuals with the GTTG haplotype (CD14/-2838 → CD14/-260) and high sCD14 levels (> median sCD14) had on average 6.94 lower % predicted FEV than individuals with the GCCA haplotype and low sCD14 levels (≤ median sCD14, p = 0.03).

Conclusion: CD14 haplotypes and sCD14 are important mediators of lung function among those with COPD in this occupationally-exposed population.
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http://dx.doi.org/10.1186/s12931-017-0532-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5353891PMC
March 2017

Empirical Study on the Impact of a Tactical Biosurveillance Information Visualization on Users' Situational Awareness.

Mil Med 2017 03;182(S1):322-329

Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, 42nd and Emily Street, Omaha, NE 68198-4375.

Decisions on antibiotic-resistant infection (ARI) prevention in dynamic health care settings should be agile and target the right process at the right time. Health information technologies can aid the recognition of high-risk situations for ARI transmission and timely facilitate operators' situational awareness (SA) in various military and civilian health care locations or transport platforms. High SA is one of the significant predictors of better performance. The objective of this study was to evaluate the impact of the developed health information visualization (VIZ) on the users' SA regarding situations when risks of ARI transmission and exposure are high. The enrolled 19 subjects assessed the proposed VIZ artifacts representing 1 scenario, compared the VIZ effectiveness against the currently employed local methods, and reported their SA (perception and comprehension) with the use of a pre- and post-self-rating questionnaire. The results showed that the VIZ significantly increased SA in the study subjects and revealed the importance of communicating the risk of exposure to ARIs. The VIZ enabled the participants to quickly acknowledge the high-risk individuals (super-spreaders), locations (hot spots), and biosafety (deficient infection prevention). The study concluded that SA-oriented technologies may be promising for promoting better infection prevention practices.
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http://dx.doi.org/10.7205/MILMED-D-16-00143DOI Listing
March 2017

Reduction of cyclophosphamide dose for patients with subset 2 low-risk rhabdomyosarcoma is associated with an increased risk of recurrence: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

Cancer 2017 Jun 17;123(12):2368-2375. Epub 2017 Feb 17.

Division of Hematology/Oncology, Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.

Background: Failure-free survival (FFS) and overall survival (OS) rates were found to improve on Intergroup Rhabdomyosarcoma Study (IRS) IV (IRS-IV) compared with IRS-III for patients with subset 2 (IRS stage 1, group III nonorbit or stage 3, group I/II) low-risk embryonal rhabdomyosarcoma with the addition of cyclophosphamide (total cumulative cyclophosphamide dose of 26.4 g/m ) to the combination of vincristine and dactinomycin (VAC). The goal of Children's Oncology Group ARST0331 for subset 2 low-risk patients was to reduce the total cumulative cyclophosphamide dose without compromising FFS.

Methods: Therapy included 4 cycles of VAC (total cumulative cyclophosphamide dose of 4.8 g/m ) followed by 12 cycles of vincristine and dactinomycin over 46 weeks. Patients with group II or III tumors received radiotherapy, except for girls with group III vaginal tumors who enrolled before September 2009 and achieved a complete response with chemotherapy with or without delayed surgical resection.

Results: Among 66 eligible patients who were followed for a median of 3.5 years, there were 20 failures versus 10.53 expected failures. The estimated 3-year FFS and OS rates were 70% (95% confidence interval [95% CI], 57%-80%) and 92% (95% CI, 83%-97%), respectively. The estimated 3-year FFS rate was 57% (95% CI, 33%-75%) for girls with subset 2 genital tract embryonal rhabdomyosarcoma (21 patients) and 77% (95% CI, 61%-87%) for all other subset 2 patients (45 patients) (P = .02).

Conclusions: The authors observed suboptimal FFS among patients with subset 2 low-risk rhabdomyosarcoma using reduced total cyclophosphamide. Eliminating radiotherapy for girls with group III vaginal tumors in combination with reduced total cyclophosphamide appeared to contribute to the suboptimal outcome. Cancer 2017;123:2368-2375. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662934PMC
June 2017

Lack of Benefit With Combination Therapy for Clostridium difficile Infection.

Infect Control Hosp Epidemiol 2017 05 6;38(5):602-605. Epub 2017 Feb 6.

3Department of Pharmacy Practice, University of Nebraska Medical Center,Omaha,Nebraska.

Limited data exist regarding combination therapy for Clostridium difficile infection (CDI). After adjusting for confounders in a cohort of patients with CDI and≥1 year old, combination therapy was not associated with significant differences in clinical outcomes, but it was associated with prolonged duration of therapy (1.22 days; 95% confidence interval, 1.03-1.44 days; P=.02). Infect Control Hosp Epidemiol 2017;38:602-605.
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http://dx.doi.org/10.1017/ice.2016.320DOI Listing
May 2017

An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance.

Development 2017 03 18;144(6):1072-1086. Epub 2017 Jan 18.

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA

The ubiquitin ligases CBL and CBL-B are negative regulators of tyrosine kinase signaling with established roles in the immune system. However, their physiological roles in epithelial tissues are unknown. Here, we used MMTV-Cre-mediated gene deletion on a null background, as well as a tamoxifen-inducible mammary stem cell (MaSC)-specific and double knockout ( DKO) using Lgr5-EGFP-IRES-CreERT2, to demonstrate a mammary epithelial cell-autonomous requirement of CBL and CBL-B in the maintenance of MaSCs. Using a newly engineered tamoxifen-inducible and deletion model with a dual fluorescent reporter (), we show that DKO in mammary organoids leads to hyperactivation of AKT-mTOR signaling with depletion of MaSCs. Chemical inhibition of AKT or mTOR rescued MaSCs from DKO-induced depletion. Our studies reveal a novel, cell-autonomous requirement of CBL and CBL-B in epithelial stem cell maintenance during organ development and remodeling through modulation of mTOR signaling.
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http://dx.doi.org/10.1242/dev.138164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358102PMC
March 2017

Weekly vinorelbine and paclitaxel in older patients with advanced non-small cell lung cancer: A phase II Fred and Pamela Buffet Cancer Center Clinical Trials Network study.

J Geriatr Oncol 2017 01 1;8(1):18-22. Epub 2016 Aug 1.

Department of Medicine, VA Nebraska Western Iowa Health Care System, Omaha, NE, United States; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States; Early Phase Therapeutic Clinical Trial Unit, Fred and Pamela Buffett Cancer Center, Omaha, NE, United States. Electronic address:

Objective: Platinum-based doublet chemotherapy is the standard for most patients with advanced non-small cell lung cancer (NSCLC). Toxicity concerns limit chemotherapy for patients over 70years. Vinorelbine and paclitaxel are effective as single agents in advanced NSCLC. This phase II study evaluates safety and efficacy of a combination of these two agents in patients >70years with advanced NSCLC.

Materials And Methods: Patients with treatment naïve metastatic NSCLC received two cycles comprising 6 weekly doses of vinorelbine and paclitaxel, with restaging scans at week 8. Patients with radiographic progression came off study. The estimated sample size was 29. Toxicity analyses were conducted after 10 patients and again after 19 patients were enrolled. Outcomes were safety and efficacy, progression free (PFS) and overall survival (OS) and quality of life (QOL).

Results: The study closed at second interim analysis as 6/19 patients had ≥grade 4 non-hematologic toxicity (respiratory failure, sepsis, ischemic encephalopathy, pneumonia, hypoxemia, cardiopulmonary arrest, neutropenic fever, death). Of the 16 evaluable patients, 7 completed the study. Disease control rate (partial response+stable disease) was 47% (n=9); 37% (n=7) progressed. No complete responses were seen. Median PFS was 3.5months (95% CI: 1.4, 5.5) and OS 7.8months (95% CI: 1.9, 13.6). QOL did not change compared to baseline, at week 9, but increased at week 17.

Conclusions: Although the combination met its response end points, increased toxicity makes this combination unsuitable for older patients. While QOL improved over the study, the small sample hinders interpretation.
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http://dx.doi.org/10.1016/j.jgo.2016.07.006DOI Listing
January 2017

Higher levels of serum lycopene are associated with reduced mortality in individuals with metabolic syndrome.

Nutr Res 2016 May 9;36(5):402-7. Epub 2016 Jan 9.

Department of Epidemiology, College of Public Health, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address:

Metabolic syndrome increases the risk of mortality. Increased oxidative stress and inflammation may play an important role in the high mortality of individuals with metabolic syndrome. Previous studies have suggested that lycopene intake might be related to the reduced oxidative stress and decreased inflammation. Using data from the National Health and Nutrition Examination Survey, we examined the hypothesis that lycopene is associated with mortality among individuals with metabolic syndrome. A total of 2499 participants 20 years and older with metabolic syndrome were divided into 3 groups based on their serum concentration of lycopene using the tertile rank method. The National Health and Nutrition Examination Survey from years 2001 to 2006 was linked to the mortality file for mortality follow-up data through December 31, 2011, to determine the mortality rate and hazard ratios (HR) for the 3 serum lycopene concentration groups. The mean survival time was significantly higher in the group with the highest serum lycopene concentration (120.6 months; 95% confidence interval [CI], 118.8-122.3) and the medium group (116.3 months; 95% CI, 115.2-117.4), compared with the group with lowest serum lycopene concentration (107.4 months; 95% CI, 106.5-108.3). After adjusting for possible confounding factors, participants in the highest (HR, 0.61; P = .0113) and in the second highest (HR, 0.67; P = .0497) serum lycopene concentration groups showed significantly lower HRs of mortality when compared with participants in the lower serum lycopene concentration. The data suggest that higher serum lycopene concentration has a significant association with the reduced risk of mortality among individuals with metabolic syndrome.
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http://dx.doi.org/10.1016/j.nutres.2016.01.003DOI Listing
May 2016

The influence of BMI on the association between serum lycopene and the metabolic syndrome.

Br J Nutr 2016 Apr 9;115(7):1292-300. Epub 2016 Feb 9.

1Department of Epidemiology,College of Public Health,University of Nebraska Medical Center,Omaha,NE 68198USA.

Overweight and obese individuals have an increased risk of developing the metabolic syndrome because of subsequent chronic inflammation and oxidative stress, which the antioxidant nutrient lycopene can reduce. However, studies indicate that different BMI statuses can alter the positive effects of lycopene. Therefore, the purpose of this study was to examine how BMI influences the association between serum lycopene and the metabolic syndrome. The tertile rank method was used to divide 13 196 participants, aged 20 years and older, into three groups according to serum concentrations of lycopene. The associations between serum lycopene and the metabolic syndrome were analysed separately for normal-weight, overweight and obese participants. Overall, the prevalence of the metabolic syndrome was significantly higher in the first tertile group (OR 38·6%; 95% CI 36·9, 40·3) compared with the second tertile group (OR 29·3%; 95% CI 27·5, 31·1) and the third tertile group (OR 26·6%; 95% CI 24·9, 28·3). However, the associations between lycopene and the metabolic syndrome were only significant for normal-weight and overweight participants (P0·05), even after adjusting for possible confounding variables. In conclusion, BMI appears to strongly influence the association between serum lycopene and the metabolic syndrome.
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http://dx.doi.org/10.1017/S0007114516000179DOI Listing
April 2016

A phase 1 clinical trial of sequential pralatrexate followed by a 48-hour infusion of 5-fluorouracil given every other week in adult patients with solid tumors.

Cancer 2015 Nov 4;121(21):3862-8. Epub 2015 Aug 4.

Section of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.

Background: Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU).

Methods: Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m(2) on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m(2) /48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase.

Results: Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression-free survival (PFS) was 112 days (range, 28-588 days). Seven patients (26%) had a PFS of >180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity.

Conclusions: The recommended dose of PDX was 148 mg/m(2) . A subset of heavily pretreated patients had PFS durations of ≥6 months with this regimen.
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http://dx.doi.org/10.1002/cncr.29504DOI Listing
November 2015

Loss of Cbl and Cbl-b ubiquitin ligases abrogates hematopoietic stem cell quiescence and sensitizes leukemic disease to chemotherapy.

Oncotarget 2015 Apr;6(12):10498-509

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Cbl and Cbl-b are tyrosine kinase-directed RING finger type ubiquitin ligases (E3s) that negatively regulate cellular activation pathways. E3 activity-disrupting human Cbl mutations are associated with myeloproliferative disorders (MPD) that are reproduced in mice with Cbl RING finger mutant knock-in or hematopoietic Cbl and Cbl-b double knockout. However, the role of Cbl proteins in hematopoietic stem cell (HSC) homeostasis, especially in the context of MPD is unclear. Here we demonstrate that HSC expansion and MPD development upon combined Cbl and Cbl-b deletion are dependent on HSCs. Cell cycle analysis demonstrated that DKO HSCs exhibit reduced quiescence associated with compromised reconstitution ability and propensity to undergo exhaustion. We show that sustained c-Kit and FLT3 signaling in DKO HSCs promotes loss of colony-forming potential, and c-Kit or FLT3 inhibition in vitro protects HSCs from exhaustion. In vivo, treatment with 5-fluorouracil hastens DKO HSC exhaustion and protects mice from death due to MPD. Our data reveal a novel and leukemia therapy-relevant role of Cbl and Cbl-b in the maintenance of HSC quiescence and protection against exhaustion, through negative regulation of tyrosine kinase-coupled receptor signaling.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496370PMC
http://dx.doi.org/10.18632/oncotarget.3403DOI Listing
April 2015

Amyloid precursor-like protein 2 (APLP2) affects the actin cytoskeleton and increases pancreatic cancer growth and metastasis.

Oncotarget 2015 Feb;6(4):2064-75

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA.

Amyloid precursor-like protein 2 (APLP2) is aberrantly expressed in pancreatic cancer. Here we showed that APLP2 is increased in pancreatic cancer metastases, particularly in metastatic lesions found in the diaphragm and intestine. Examination of matched human primary tumor-liver metastasis pairs showed that 38.1% of the patients had positive APLP2 expression in both the primary tumor and the corresponding liver metastasis. Stable knock-down of APLP2 expression (with inducible shRNA) in pancreatic cancer cells reduced the ability of these cells to migrate and invade. Loss of APLP2 decreased cortical actin and increased intracellular actin filaments in pancreatic cancer cells. Down-regulation of APLP2 decreased the weight and metastasis of orthotopically transplanted pancreatic tumors in nude mice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385836PMC
http://dx.doi.org/10.18632/oncotarget.2990DOI Listing
February 2015

Observed and expected incidence of cervical cancer in lusaka and the southern and Western provinces of Zambia, 2007 to 2012.

Int J Gynecol Cancer 2015 Jan;25(1):98-105

*Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE; †Cancer Diseases Hospital, Lusaka, Zambia; ‡Faculty of Medical Radiation Sciences, Lusaka Apex Medical University, Lusaka, Zambia; §Department of Epidemiology, College of Public Health, University of Nebraska Medical Center, Omaha; ∥Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE; and ¶Department of Epidemiology, MD Anderson Cancer Center, University of Texas, Houston, TX.

Objectives: Cervical cancer is increasing but underestimated in developing countries. We calculated the observed and expected incidence of cervical cancer in Lusaka and Southern and Western provinces of Zambia.

Methods/materials: Data for 2007 to 2012 were obtained for the 3 provinces. Data included age, residence, year of diagnosis, marital status, occupation, human immunodeficiency virus (HIV), stage, radiotherapy, and chemotherapy. Expected incidence in Southern and Western provinces was calculated based on observed incidence for Lusaka province, adjusting for HIV.

Results: Crude and age-standardized incidence rates (ASRs) in Lusaka were 2 to 4 times higher than incidence in the other 2 provinces. Lusaka had a rate of 54.1 per 10(5) and ASR of 82.1 per 10(5) in the age group of 15 to 49 years. The Southern province had a rate of 17.1 per 10(5) and ASR of 25.5 per 10(5); the Western province had a rate of 12.3 per 10(5) and ASR rate of 17.2 per 10(5). The observed cervical cancer incidence rates in the Southern and Western provinces were lower than the rate in Lusaka, possibly because of the uncertainty of underreporting/underdiagnosis or actual lower risk for reasons yet unclear. The HIV seroprevalence rates in patients from the 3 provinces were 46% to 93% higher than seroprevalence in the respective general populations.

Conclusions: Cervical cancer is significantly underestimated in Zambia, and HIV has a significant role in pathogenesis. Future studies should establish methods for case ascertainment and better utilization of hospital- and population-based registries in Zambia and other similar developing countries.
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http://dx.doi.org/10.1097/IGC.0000000000000325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272632PMC
January 2015

Weight change during childhood acute lymphoblastic leukemia induction therapy predicts obesity: a report from the Children's Oncology Group.

Pediatr Blood Cancer 2015 Mar 18;62(3):434-9. Epub 2014 Nov 18.

Children's Cancer Center, Palmetto Health, Columbia, South Carolina.

Background: Obesity is a well documented problem associated with childhood acute lymphoblastic leukemia (ALL) with increasing body mass index often observed during therapy. This study aims to evaluate if weight gain, early in therapy, is predictive of obesity at the end of treatment.

Procedure: In this secondary analysis, data from 1,017 high-risk ALL patients previously treated on a Children's Oncology Group protocol (CCG study 1961) were reviewed. Logistic regression was used to examine whether change in BMI z-score at Induction or Delayed Intensification (DI) 1 were predictive of obesity at the end of therapy.

Results: The BMI z-score at the beginning of Induction and the change in BMI z-score during Induction were both significant predictors of obesity at the end of therapy. The change in BMI z-score during cycle 1 of DI was not found to be associated with obesity.

Conclusions: It is well know that obesity at the beginning of therapy is predictive of obesity at the end of ALL therapy. The new, and more important, finding from this study is that even after adjusting for baseline weight, the increase in BMI z-scores during induction was an independent predictor of obesity at the end of therapy. Most researchers agree that prevention is the best form of treatment for obesity as it is difficult to reverse once it is present. This study suggests that monitoring weight trends during Induction may be useful in guiding healthcare practitioners in identifying which patients are at highest risk for obesity development so that early intervention may occur.
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http://dx.doi.org/10.1002/pbc.25316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304977PMC
March 2015

Shorter-duration therapy using vincristine, dactinomycin, and lower-dose cyclophosphamide with or without radiotherapy for patients with newly diagnosed low-risk rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

J Clin Oncol 2014 Nov 29;32(31):3547-52. Epub 2014 Sep 29.

David O. Walterhouse, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL; Alberto S. Pappo, Saint Jude Children's Research Hospital, Memphis, TN; Jane L. Meza, James R. Anderson, University of Nebraska Medical Center College of Public Health, Omaha, NE; John C. Breneman, Children's Hospital Medical Center, Cincinnati; Timothy P. Cripe, Nationwide Children's Hospital, Columbus, OH; Andrea Hayes-Jordan, MD Anderson Cancer Center, Houston, TX; David M. Parham, William H. Meyer, University of Oklahoma School of Medicine, Oklahoma City, OK; Douglas S. Hawkins, Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA.

Purpose: Intergroup Rhabdomyosarcoma Study Group (IRSG) studies III and IV showed improved failure-free survival (FFS) rates with vincristine, dactinomycin, and cyclophosphamide (VAC; total cumulative cyclophosphamide dose, 26.4 g/m(2)) compared with vincristine and dactinomycin (VA) for patients with subset-one low-risk embryonal rhabdomyosarcoma (ERMS; stage 1/2 group I/II ERMS or stage 1 group III orbit ERMS). The objective of Children's Oncology Group ARST0331 was to reduce the length of therapy without compromising FFS for this subset of low-risk patients by using VA in combination with lower-dose cyclophosphamide (total cumulative dose, 4.8 g/m(2)) plus radiotherapy (RT).

Patients And Methods: This noninferiority prospective clinical trial enrolled newly diagnosed patients with subset-one clinical features. Therapy included four cycles of VAC followed by four cycles of VA over 22 weeks. Patients with microscopic or gross residual disease at study entry received RT.

Results: With a median follow-up of 4.3 years, we observed 35 failures among 271 eligible patients versus 48.4 expected failures, calculated using a fixed outcome based on the FFS expected for similar patients treated on the IRSG D9602 protocol. The estimated 3-year FFS rate was 89% (95% CI, 85% to 92%), and the overall survival rate was 98% (95% CI, 95% to 99%). Patients with paratesticular tumors had the most favorable outcome. Three-year cumulative incidence rates for any local, regional, or distant failures were 7.6%, 1.5%, and 3.4%, respectively.

Conclusion: Shorter-duration therapy that included lower-dose cyclophosphamide and RT did not compromise FFS for patients with subset-one low-risk ERMS.
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http://dx.doi.org/10.1200/JCO.2014.55.6787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209105PMC
November 2014

The Association Between Dietary Intake and Phenotypical Characteristics of COPD in the ECLIPSE Cohort.

Chronic Obstr Pulm Dis 2014 May 6;1(1):115-124. Epub 2014 May 6.

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha.

: Diet is a potentially modifiable risk factor in the development and progression of many diseases, and there is evidence that diet plays a role in COPD. : Evaluate the relationship between dietary intake and clinical characteristics of COPD in a large and well-characterized population of COPD patients and controls who were part of the ECLIPSE study. Limited diet records were available from 2,167 participants at 8 time points over a 3-year period. Participants reported the amount they had consumed over the last 24 hours for 8 food categories. Intake of each food group was handled as a dichotomous variable (Yes/last 24 hours at any of the 8 follow-up points vs. No at all 8 points). These 2 groups were then compared using clinical outcome measures at the last available follow-up that included lung function, emphysema, 6-minute walk, St. George's Respiratory Questionaire (SGRQ) scores, the change in these scores over a 3-year period, and inflammatory biomarkers. Multivariate models for each food group and each outcome measure were run to adjust for confounding factors of age, sex, body mass index (BMI), and smoking. : Participants who demonstrated recent consumption of foods associated with a healthful diet, including fish, fruit, tea, and dairy products, had greater lung function measures and less decline over time, less emphysema and emphysema progression, greater 6-minute walk and SGRQ scores, and lower levels of certain inflammatory markers. Increasing the number of diet record time points that were included in the analysis improved ability to detect significant associations. : Diet as a possible modifiable risk factor in COPD continues to warrant investigation.
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http://dx.doi.org/10.15326/jcopdf.1.1.2014.0113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559148PMC
May 2014

Pilot study of younger and older HIV-infected adults using traditional and novel functional assessments.

HIV Clin Trials 2013 Jul-Aug;14(4):165-74

Department of Internal Medicine and Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE, USA.

Objectives: Emerging data suggest that HIV disease and its treatment affect the aging process. Accurate and reliable measures of functional status are needed to investigate this further.

Design: A pilot study in groups of younger and older HIV-infected adults using objective measures of function.

Methods: Evaluations included neuropsychological testing, grip strength, balance assessed by the Wii Balance Board, and actigraphy. Surveys were used for depression, fatigue, loneliness, self-reported activity level, and sexual function. Two-samplet test or Wilcoxon rank sum tests were used for continuous variables and exact chi-square tests were used for comparison between groups.

Results: Twenty-one participants were 20 to 40 years old (younger; mean age, 31.5), and 20 were more than 50 years old (older; mean age, 56.5). There was no difference between groups for depression, fatigue, or loneliness. Overall, there was a trend to lower scores in the older age group for neuropsychologicalz score (P = .11) and for verbal learning (P = .09). Functioning in the memory domain was significantly lower in older subjects (P = .007). There was no difference in executive function, speed of processing, memory, motor skills, or total activity. Gender differences in sexual function were observed. Four older and 3 younger participants met the definition of frailty. Total activity by actigraphy did not correlate well with self-reported activity.

Conclusions: Objective tests were well accepted and feasible to perform, although not all are suitable for widespread clinical or research use. Objective measurements of activity did not correlate well with patient self-report, which has implications for future studies in this area.
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http://dx.doi.org/10.1310/hct1404-165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931515PMC
September 2013
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