Re-interpretation of PAM50 gene expression as quantitative tumor dimensions shows utility for clinical trials: application to prognosis and response to paclitaxel in breast cancer

Background

We recently showed PAM50 gene expression data can be represented by five quantitative, orthogonal, multi-gene breast tumor traits. These novel tumor ‘dimensions’ were superior to categorical intrinsic subtypes for clustering in high-risk breast cancer pedigrees, indicating potential to represent underlying genetic susceptibilities and biological pathways. Here we explore the prognostic and predictive utility of these dimensions in a sub-study of GEICAM/9906, a Phase III randomized prospective clinical trial of paclitaxel in breast cancer.

Methods

Tumor dimensions, PC1–PC5, were calculated using pre-defined coefficients. Univariable and multivariable Cox proportional hazards (PH) models for disease-free survival (DFS) were used to identify associations between quantitative dimensions and prognosis or response to the addition of paclitaxel. Results were illustrated using Kaplan–Meier curves.

Results

Dimensions PC1 and PC5 were associated with DFS (Cox PH p = 6.7 \(\times\) 10⁻⁷ and p = 0.036), remaining significant after correction for standard clinical–pathological prognostic characteristics. Both dimensions were selected in the optimal multivariable model, together with nodal status and tumor size (Cox PH p = 1.4 \(\times\) 10⁻¹²). Interactions with treatment were identified for PC3 and PC4. Response to paclitaxel was restricted to tumors with low PC3 and PC4 (log-rank p = 0.0021). Women with tumors high for PC3 or PC4 showed no survival advantage.

Conclusions

Our proof-of-concept application of quantitative dimensions illustrated novel findings and clinical utility beyond standard clinical–pathological characteristics and categorical intrinsic subtypes for prognosis and predicting chemotherapy response. Consideration of expression data as quantitative tumor dimensions offers new potential to identify clinically important patient subsets in clinical trials and advance precision medicine.

     

Inhibition of urinary bladder cancer cell proliferation by silibinin

Silibinin, a natural compound extracted from milk thistle, has demonstrated antitumor properties in urinary bladder cancer cells; however, the role of TP53 gene in these effects is unclear. In order to better understand the molecular and antiproliferative mechanisms of this compound, urinary bladder cancer cells with different TP53 gene status, RT4 (low-grade tumor, wild TP53 gene), 5637 (high-grade tumor, Grade 2, mutated TP53 gene), and T24 (high-grade tumor, Grade 3, mutated TP53 gene) were treated with several concentrations of silibinin (1, 5, 10, 50, 100, and 150 μM). Cytotoxicity, prooxidant effect, morphological changes, cell migration, cell cycle progression, global methylation profile, and relative expression of HOXB3, c-MYC, PLK1, SMAD4, SRC, HAT, HDAC, and RASSF1A genes were evaluated. The silibinin presented cytotoxic and prooxidant effects in the three cell lines. In mutated TP53 cells, significant interference in cell migration and cell cycle arrest at the G2/M phase was observed. Additionally, silibinin induced global DNA hypomethylation in the highest grade tumor cells. For wild-type TP53 cells, a sub-G1 apoptotic population was present. Furthermore, there was modulation of gene expression responsible for cell growth (SMAD and c-MYC), migration (SRC), cell cycle kinetics (PLK1), angiogenesis (HOXB3), and of genes associated with epigenetic events such as DNA acetylation (HAT) and deacetylation (HDAC). In conclusion, the silibinin inhibited the urinary bladder tumor cell proliferation independently of TP53 status; however, cell cycle effects, gene expression changes, and alteration of cell migration are dependent on TP53 status. © 2020 Wiley Periodicals, Inc.     

Efectividad de la técnica de resolución de problemas aplicada por enfermeras: disminución de la ansiedad y la depresión en cuidadoras familiares

ObjectiveTo determine the effectiveness of Problem Solving Technique in reducing anxiety and depression, and increased perceived well-being in women family caregivers of chronic patients.DesignA clinical trialField of studyHealth centres in Tarragona, Spain, during 2007-2011.ParticipantsA sample 122 caregivers of patients in home care programs that met the inclusion criteria, were assigned to intervention or control group according to a simple random process.InterventionsIn the experimental group, the nurses applied the Problem Solving Technique to the caregiver according to a four-session protocol. The nurses provided the usual care to the caregivers In the control group. One month after intervention, the dependent vriables were measured again in both groups.Principal measurementThe dependent variables of anxiety and depression were measured using the Goldberg scale, and the emotional well-being variable by the scale of emotional health of the primary caregiver.ResultsA statistically significant improvement was detected in the anxiety and depression symptoms, as well as the perceived well-being in the intervention group compared to the control group.ConclusionsImplementation of the Problem Solving Technique is a useful therapeutic tool for reducing symptoms of distress in family caregivers of chronic patients.     

Narrow-diameter implants: Are they a predictable treatment option? A literature review

Objective: To evaluate the predictability of narrow-diameter implants as a treatment option in routine clinical practice. A literature review was performed of studies reporting clinical results obtained with these implants. Survival rates, peri-implant bone loss and related complications were evaluated. The working hypothesis was that narrow-diameter implants offer clinical results similar to those obtained with implants of greater diameter. Material and Methods: A Medline-PubMed search covering the period between 2002 and 2012 was carried out. Studies published in English and with a follow-up period of at least 12 months were considered for inclusion. A manual search was also conducted in different journals with an important impact factor. Results: Twenty-one studies meeting the screening criteria were included in the literature review. A total of 2980 narrow-diameter implants placed in 1607 patients were analyzed. Conclusions: The results obtained from the literature indicate that narrow-diameter implants are a predictable treatment option, since they afford clinical results comparable to those obtained with implants of greater diameter. Key words:Narrow implant, survival rate, peri-implant bone loss, related complications.