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Emerick B.,Trinity College at Hartford | Schleiniger G.,University of Delaware | Boman B.M.,University of Delaware | Boman B.M.,Helen aham Cancer Center And Research Institute
Journal of Mathematical Biology | Year: 2017

The Wnt/(Formula presented.)-catenin pathway plays a crucial role in stem cell renewal and differentiation in the normal human colonic crypt. The balance between (Formula presented.)-catenin and APC along the crypt axis determines its normal functionality. The mechanism that deregulates this balance may give insight into the initiation of colorectal cancer. This is significant because the spatial dysregulation of (Formula presented.)-catenin by the mutated tumor suppressor gene/protein APC in human colonic crypts is responsible for the initiation and growth of colorectal cancer. We consider a regulatory function that promotes APC synthesis within the cell and its effect on the accumulation of the Wnt target protein, (Formula presented.)-catenin. It is evident that an APC gradient exists along the crypt axis; however, the mechanism by which APC expression is regulated within the cell is not well known. We investigate the dynamics of an APC regulatory mechanism with an increased level of Axin at the subcellular level. Model output shows an increase of APC for a diminished Wnt signal, which explains the APC gradient along the crypt. We find that the dynamic interplay between (Formula presented.)-catenin, APC, and Axin produces oscillatory behavior, which is controlled by the Wnt stimulus. In the presence of reduced functional APC, the oscillations are amplified, which suggests that the cell remains in a more proliferative state for longer periods of time. Increased Axin levels (typical of mammalian cells) reduce oscillatory behavior and minimize the levels of (Formula presented.)-catenin within the cell while raising the levels of APC. © 2017 Springer-Verlag Berlin Heidelberg


Jacob D.,Helen aham Cancer Center and Research Institute | Lamberto M.,Pinnacle Health System | DeSouza Lawrence L.,Helen aham Cancer Center and Research Institute | Mourtada F.,Thomas Jefferson University
Brachytherapy | Year: 2017

Purpose: To retrospectively compare clinical dosimetry of CT-based tandem-ring treatment plans using a model-based dose calculation algorithm (MBDCA) with the standard TG-43-based dose formalism. Methods and Materials: A cohort of 10 cervical cancer cohorts treated using the tandem and ring high-dose-rate applicators were evaluated. The original treatment plans were created using the department CT-based volume optimization clinical standards. All plans originally calculated with TG-43 dose calculation formalism were recalculated using the MBDCA algorithm. The gross target volume and organs at risk (OARs) were contoured on each data set along with significant heterogeneities like air in cavity and high-density plastic tandem and ring components. The patient tissue was modeled as homogenous liquid water. D 90, D 95, and D 100 for gross target volume, D 0.1cm3, D 1.0cm3, and D 2.0cm3 for bladder, rectum, and sigmoid were extracted from dose-volume histograms for TG-43 and MBDCA calculated plans. Mean absolute difference ± 2σ in the above metrics was calculated for each plan. Results: Using the manual applicator contouring method, MBDCA plans (n = 10) showed 2.1 ± 1.1% reduction in dose to Point A average, 2.6 ± 0.9% reduction in Target D 90 dose, and 2.1 ± 0.3% dose reduction to OARs. Results from plans using vendor supplied solid applicator models (n = 5) showed 2.2 ± 1.10% reduction in dose to Point A average, 2.7 ± 0.2% reduction in Target D 90 dose, and 2.7 ± 1.0% dose reduction on average to OARs. Conclusion: For unshielded plastic gynecologic applicators, minimal dosimetric changes (<5%) were found using MBDCA relative to standard TG-43. Use of solid applicator model is more efficient than manual applicator contouring and also yielded similar MBDCA dosimetric results. Currently, TG-186 dose calculations should be reported along TG-43 until we obtain studies with larger cohorts to fully realize the potential of MBDCA dosimetry. © 2017 American Brachytherapy Society.


PubMed | Cancer Program of Our Lady of the Lake and Mary Bird Perkins, University of Houston, Dana-Farber Cancer Institute, National Cancer Institute and 10 more.
Type: Journal Article | Journal: JAMA oncology | Year: 2015

To integrate the patient perspective into adverse event reporting, the National Cancer Institute developed a patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).To assess the construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items.A total of 975 adults with cancer undergoing outpatient chemotherapy and/or radiation therapy enrolled in this questionnaire-based study between January 2011 and February 2012. Eligible participants could read English and had no clinically significant cognitive impairment. They completed PRO-CTCAE items on tablet computers in clinic waiting rooms at 9 US cancer centers and community oncology practices at 2 visits 1 to 6 weeks apart. A subset completed PRO-CTCAE items during an additional visit 1 business day after the first visit.Primary comparators were clinician-reported Eastern Cooperative Oncology Group Performance Status (ECOG PS) and the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30).A total of 940 of 975 (96.4%) and 852 of 940 (90.6%) participants completed PRO-CTCAE items at visits 1 and 2, respectively. At least 1 symptom was reported by 938 of 940 (99.8%) participants. Participants median age was 59 years; 57.3% were female, 32.4% had a high school education or less, and 17.1% had an ECOG PS of 2 to 4. All PRO-CTCAE items had at least 1 correlation in the expected direction with a QLQ-C30 scale (111 of 124, P<.05 for all). Stronger correlations were seen between PRO-CTCAE items and conceptually related QLQ-C30 domains. Scores for 94 of 124 PRO-CTCAE items were higher in the ECOG PS 2 to 4 vs 0 to 1 group (58 of 124, P<.05 for all). Overall, 119 of 124 items met at least 1 construct validity criterion. Test-retest reliability was 0.7 or greater for 36 of 49 prespecified items (median [range] intraclass correlation coefficient, 0.76 [0.53-.96]). Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes were statistically significant for 27 prespecified items (median [range] r=0.43 [0.10-.56]; all P.006).Evidence demonstrates favorable validity, reliability, and responsiveness of PRO-CTCAE in a large, heterogeneous US sample of patients undergoing cancer treatment. Studies evaluating other measurement properties of PRO-CTCAE are under way to inform further development of PRO-CTCAE and its inclusion in cancer trials.


Kumar V.,Wistar Institute | Cheng P.,H. Lee Moffitt Cancer Center and Research Institute | Condamine T.,Wistar Institute | Mony S.,Wistar Institute | And 12 more authors.
Immunity | Year: 2016

Recruitment of monocytic myeloid-derived suppressor cells (MDSCs) and differentiation of tumor-associated macrophages (TAMs) are the major factors contributing to tumor progression and metastasis. We demonstrated that differentiation of TAMs in tumor site from monocytic precursors was controlled by downregulation of the activity of the transcription factor STAT3. Decreased STAT3 activity was caused by hypoxia and affected all myeloid cells but was not observed in tumor cells. Upregulation of CD45 tyrosine phosphatase activity in MDSCs exposed to hypoxia in tumor site was responsible for downregulation of STAT3. This effect was mediated by the disruption of CD45 protein dimerization regulated by sialic acid. Thus, STAT3 has a unique function in the tumor environment in controlling the differentiation of MDSC into TAM, and its regulatory pathway could be a potential target for therapy. © 2016 Elsevier Inc.


Gumireddy K.,Wistar Institute | Li A.,Wistar Institute | Chang D.H.,The Valley Hospital | Liu Q.,Wistar Institute | And 9 more authors.
Oncotarget | Year: 2015

Cancer testis antigens (CTAs) are widely expressed in tumor tissues, circulating tumor cells (CTCs) and in cancer derived exosomes that are frequently engulfed by lymphoid cells. To determine whether tumor derived CTA mRNAs could be detected in RNA from purified peripheral blood mononuclear cells (PBMC) of non-small cell lung cancer (NSCLC) patients, we assayed for the expression of 116 CTAs in PBMC RNA in a discovery set and identified AKAP4 as a potential NSCLC biomarker. We validated AKAP4 as a highly accurate biomarker in a cohort of 264 NSCLCs and 135 controls from 2 different sites including a subset of controls with high risk lung nodules. When all (264) lung cancers were compared with all (135) controls the area under the ROC curve (AUC) was 0.9714. When 136 stage I NSCLC lung cancers are compared with all controls the AUC is 0.9795 and when all lung cancer patients were compared to 27 controls with histologically confirmed benign lung nodules, a comparison of significant clinical importance, the AUC was 0.9825. AKAP4 expression increases significantly with tumor stage, but independent of age, gender, smoking history or cancer subtype. Follow-up studies in a small number of resected NSCLC patients revealed a decrease of AKAP4 expression post-surgical resection that remained low in patients in remission and increased with tumor recurrence. AKAP4 is a highly accurate biomarker for the detection of early stage lung cancer.


PubMed | Helen aham Cancer Center And Research Institute, Michigan State University, Rutgers Cancer Institute of New Jersey and Fox Chase Cancer Center
Type: | Journal: Psycho-oncology | Year: 2016

There has been little attention paid to the role of therapeutic processes in group therapy outcomes for cancer patients participating in group. The goal was to evaluate the contribution of 3 group processes-group climate (conflict, engagement, and avoidance) working alliance and therapeutic realizations-to the outcomes of 2 couple-focused approaches to group treatment.Three hundred and two women with early stage breast cancer and their partners were randomized to one of 2 conditions: an 8-session enhanced couple-focused group (ECG) intervention or a couples support group participated. Couples completed measures of depressive symptoms and well-being before and 6months after group. Group process measures were completed after sessions 4 and 8.Support group participants (both patients and partners) perceived higher engagement and less avoidance than ECG participants. Conflict, working alliance, and therapeutic realizations did not differ. Group engagement, working alliance, and therapeutic realizations increased, and group conflict decreased over the course of both treatments. Greater conflict was associated with more posttreatment anxiety and lower well-being, and engagement was associated with higher posttreatment well-being. Patients whose partners reported higher conflict reported greater posttreatment anxiety. Working alliance was associated with posttreatment anxiety for ECG patients and with well-being among participants whose partners reported higher working alliance.Fostering a positive group environment bolsters treatment efficacy for women with early stage breast cancer and their partners attending couple-focused groups. Facilitating the leader-member alliance bolsters treatment efficacy. Improving engagement with one member of a couple impacts the other member.


PubMed | Helen aham Cancer Center And Research Institute, Massachusetts General Hospital, Mayo Medical School and Vanderbilt University
Type: Journal Article | Journal: Annals of surgical oncology | Year: 2016

More than 50% of states have state-mandated density notification for patients with heterogeneously or extremely dense breasts. Increased breast density carries a risk of masking a cancer and delaying diagnosis. Supplemental imaging is optional and often recommended for certain patients. There are no evidence-based consensus guidelines for screening patients with density as their only risk factor. Breast cancer risk assessment and breast cancer prevention strategies should be discussed with women with dense breasts.


PubMed | Helen aham Cancer Center And Research Institute and Ohio State University
Type: Journal Article | Journal: Surgical oncology clinics of North America | Year: 2015

The role of the cancer genetic counselor in the management of patients with cancer is discussed in this article. This includes explaining what a genetic counselor is trained to do and how they are credentialed and licensed. In addition, the article explains who to refer for cancer genetic counseling. Once referred, the article describes what actually happens in a pretest and posttest cancer genetic counseling session. Use of a cancer genetic registry and how it can help in practice is discussed. Finally, several mechanisms for identifying a cancer genetic counselor at ones institution or nearby are outlined.


PubMed | University of Houston, Fox Chase Cancer Center, New York University, Indiana University and 7 more.
Type: Clinical Trial, Phase II | Journal: The oncologist | Year: 2016

Effective new agents for patients with colorectal cancer (CRC) with disease progression during standard therapy regimens are needed. We hypothesized that poly ADP ribose polymerase (PARP) inhibitor therapy in patients with CRC and inefficient tumor DNA repair mechanisms, such as those with high-level microsatellite instability (MSI-H), would result in synthetic lethality.This was an open-label phase II trial testing olaparib 400 mg p.o. b.i.d. for patients with disseminated, measurable CRC failing standard therapies with centrally confirmed tumor MSI status. The primary endpoint was the tumor response, assessed by RECIST, version 1.0. The secondary endpoints were safety/toxicity, progression-free survival (PFS), and overall survival (OS).Thirty-three patients (20 microsatellite stable [MSS], 13 MSI-H) were enrolled. The median age for all patients was 57 years and for MSS and MSI-H patients was 51 and 61 years, respectively. All patients received at least one 28-day cycle of olaparib. No patient had a complete or partial response. Nausea (48%), fatigue (36%), and vomiting (33%) were the most commonly reported treatment-related adverse events. The median PFS for all patients was 1.84 months. No statistically significant differences were found in the median PFS or OS for the MSS group compared with the MSI-H group.Single-agent olaparib delivered after failure of standard systemic therapy did not demonstrate activity for CRC patients, regardless of microsatellite status. Future trials, testing PARP inhibitors in patients with CRC should focus on the use of DNA-damaging chemotherapy and/or radiation therapy, combined with PARP inhibitors, remembering the toxicity reported in the present study.Microsatellite instability (MSI-H) colorectal tumors exhibit hypermethylation in tumor mismatch repair genes, or have mutations in one or more of these genes resulting from a germ-line defect (Lynch syndrome). PARP inhibitors such as olaparib are most effective in tumors associated with inability to repair DNA damage. However, in this trial, single agent olaparib failed to elicit responses in patients with MSI-H colorectal tumors, and in those with microsatellite-stable tumors. It is possible that by adding olaparib to radiation therapy, or to a systemic DNA damaging agent, tumor lethality could be obtained. However, the price would be increased toxicity.


Sims-Mourtada J.,Christiana Care Health Services Inc | Niamat R.A.,Delaware State University | Samuel S.,Helen aham Cancer Center and Research Institute | Eskridge C.,Helen aham Cancer Center and Research Institute | And 2 more authors.
International Journal of Nanomedicine | Year: 2014

A small population of highly tumorigenic breast cancer cells has recently been identified. These cells, known as breast-cancer stem-like cells (BCSC), express markers similar to mammary stem cells, and are highly resistant to chemotherapy. Currently, study of BCSC is hampered by the inability to propagate these cells in tissue culture without inducing differentiation. Recently, it was reported that proliferation and differentiation can be modified by culturing cells on electrospun nanofibers. Here, we sought to characterize the chemoresistance and stem-like properties of breast cancer cell lines grown on nanofiber scaffolds. Cells cultured on three-dimensional templates of electrospun poly(?-caprolactone)-chitosan nanofibers showed increases in mammary stem cell markers and in sphere-forming ability compared with cells cultured on polystyrene culture dishes. There was no increase in proliferation of stem cell populations, indicating that culture on nanofibers may inhibit differentiation of BCSC. The increase in stemness was accompanied by increases in resistance to docetaxel and doxorubicin. These data indicate that BCSC populations are enriched in cells cultured on electrospun poly(?-caprolactone)-chitosan nanofibers, scaffolds that may provide a useful system to study BCSC and their response to anticancer drug treatment. © 2014 Sims-Mourtada et al.

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