Factors that predict early treatment failure for patients with locally advanced (T4) breast cancer

Locally advanced breast cancer (LABC) is associated with dire prognosis despite progress in multimodal treatments. We evaluated several clinical and pathological features of patients with either noninflammatory (NIBC, cT4a-c) or inflammatory (IBC, cT4d) breast cancer to identify subset groups of patients with high risk of early treatment failure. Clinical and pathological features of 248 patients with LABC, who were treated with multimodality treatments including neoadjuvant chemotherapy followed by radical surgery and radiotherapy were reassessed. Tumour samples obtained at surgery were evaluated using standard immunohistochemical methods. Overall, 141 patients (57%) presented with NIBC (cT4a-c, N0-2, M0) and 107 patients (43%) with IBC (cT4d, N0-2, M0). Median follow-up time was 27.5 months (range: 1.6–87.8). No significant difference in terms of recurrence-free survival (RFS) (P=0.72), disease-free survival (DFS) (P=0.98) and overall survival (OS) (P=0.35) was observed between NIBC and IBC. At the multivariate analysis, patients with ER- and PgR-negative diseases had a significantly worse RFS than patients with ER- and/or PgR-positive diseases (hazard ratio: 2.47, 95% CI: 1.33–4.59 for overall). The worst RFS was observed for the subgroup of patients with endocrine nonresponsive and HER2-negative breast cancer (2-year RFS: 57% in NIBC and 57% in IBC) A high Ki-67 labelling index (>20% of the invasive tumour cells) and the presence of peritumoral vascular invasion (PVI) significantly correlated with poorer RFS in overall (HR 2.69, 95% CI: 1.61–4.50 for Ki-67>20% and HR 2.27, 95% CI: 1.42–3.62 for PVI). Patients with endocrine nonresponsive LABC had the most dire treatment outcome. High degree of Ki-67 staining and presence of PVI were also indicators of higher risk of early relapse. These factors should be considered in therapeutic algorithms for LABC

Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families

Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which highlights the need for accurate identification and interpretation of novel variants. In a large Mendelian cohort of 4577 molecularly characterized families, numerous scenarios in which variant identification and interpretation can be challenging are encountered. We describe categories of challenges that cover the phenotype (e.g. novel allelic disorders), pedigree structure (e.g. imprinting disorders masquerading as autosomal recessive phenotypes), positional mapping (e.g. double recombination events abrogating candidate autozygous intervals), gene (e.g. novel gene-disease assertion) and variant (e.g. complex compound inheritance). Overall, we estimate a probability of 34.3% for encountering at least one of these challenges. Importantly, our data show that by only addressing non-sequencing-based challenges, around 71% increase in the diagnostic yield can be expected. Indeed, by applying these lessons to a cohort of 314 cases with negative clinical exome or genome reports, we could identify the likely causal variant in 54.5%. Our work highlights the need to have a thorough approach to undiagnosed diseases by considering a wide range of challenges rather than a narrow focus on sequencing technologies. It is hoped that by sharing this experience, the yield of undiagnosed disease programs globally can be improved

FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy

<p>Abstract</p> <p>Background</p> <p>Recent studies have demonstrated a direct involvement of B7-H1, PD-1 and FOXP3 molecules in the immune escape of cancer. B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (T_regs). We have previously demonstrated the association of B7-H1-expressing T infiltrating lymphocytes (TIL) with high-risk breast cancer patients while other studies reported the involvement of FOXP3+ T_regsas a bad prognostic factor in breast tumors. Although the co-existence between the two types of cells has been demonstrated <it>in vitro </it>and animal models, their relative infiltration and correlation with the clinicopathological parameters of cancer patients have not been well studied. Therefore, we investigated TIL-expressing the B7-H1, PD-1, and FOXP3 molecules, in the microenvironment of human breast tumors and their possible association with the progression of the disease.</p> <p>Methods</p> <p>Using immunohistochemistry, tumor sections from 62 breast cancer patients were co-stained for B7-H1, PD-1 and FOXP3 molecules and their expression was statistically correlated with factors known to be involved in the progression of the disease.</p> <p>Results</p> <p>A co-existence of B7-H1⁺T lymphocytes and FOXP3⁺T_regswas evidenced by the highly significant correlation of these molecules (<it>P </it>< .0001) and their expression by different T lymphocyte subsets was clearly demonstrated. Interestingly, concomitant presence of FOXP3⁺T_regs, B7-H1⁺and PD-1⁺TIL synergistically correlated with high histological grade (III) (<it>P </it>< .001), estrogen receptor negative status (<it>P </it>= .017), and the presence of severe lymphocytic infiltration (<it>P </it>= .022).</p> <p>Conclusion</p> <p>Accumulation of TIL-expressing such inhibitory molecules may deteriorate the immunity of high-risk breast cancer patients and this should encourage vigorous combinatorial immunotherapeutic approaches targeting T_regsand B7-H1/PD-1 molecules.</p

Compositional, structural, optical and electrical properties of solution grown CdTe thin films

127-132<span style="font-size: 15.0pt;mso-bidi-font-size:11.0pt;font-family:Arial;color:black">CdTe films were prepared by solution growth technique. Influence of the preparation technique on compositional, structural, optical and electrical properties of polycrystalline CdTe films was investigated using energy dispersive spectroscopy (EDS), X-ray diffraction (XRD), scanning electron microscopy (SEM), optical transmission and electrical resistivity. EDS analysis shows that CdTe films are nearly stoichiometric. X-ray studies show that as grown films are composed of zinc blende and wurtzite structure. The films predominately show wurtzite structure. Optical measurements indicate the existence of one direct allowed optical transition with a corresponding energy gap of 1.46 eV. The optical parameters (n. K. α) were evaluated by simple straight forward calculations using the transmission spectrum. The electrical resistivity of solution grown CdTe films was found to be 2.5 x 106 Ωm for film grown on substrate and 5 Ωm for film grown on Ag substrates. The lateral result is attributed to the effect of grain boundary, crystallite size, the degree of preferred orientation, internal micro- strain and stoichiometry of the film.<span style="font-size:15.0pt;mso-bidi-font-size:11.0pt; color:black"> </span

Sociodemographic characteristics and sexual behavior as risk factors for human papillomavirus infection in Saudi Arabia

This article seeks to determine the prevalence and the sociodemographic characteristics and sexual behavior risk factors for human papillomavirus (HPV) infection in a hospital-based cohort of women in Saudi Arabia

Polymorphisms in RAD51 and their relation with breast cancer in Saudi females

Sahar Tulbah,1 Huda Alabdulkarim,2 Mohammad Alanazi,3 Narasimha Reddy Parine,3 Jilani Shaik,3 Akbar Ali Khan Pathan,3 Abdullah Al-Amri,3 Wajahatullah Khan,4 Arjumand Warsy1 1Department of Biochemistry, College of Science, King Saud University, Center of Scientific and Medical Colleges, 2Department of Hematology/Oncology, King Fahad Medical City Hospital, Comprehensive Cancer Center, 3Department of Biochemistry, College of Science, King Saud University, 4Basic Sciences Department, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia Abstract: The present study aimed at investigating the relationship between rs1801320 (G&gt;C), rs1801321 (G&gt;T), and rs2619681 (C&gt;T) RAD51 gene polymorphisms and the risk of breast cancer development in Saudi females. The genotypes were analyzed using TaqMan genotyping assay and polymerase chain reaction-restriction fragment length polymorphism. The genotype and allele frequencies were computed using chi-square or Fisher&rsquo;s exact test (two-tailed) by SPSS 21 software. The results showed that rs1801321G&gt;T GG genotype and G allele frequency were strongly (P&lt;0.0001) related to an elevated risk of breast cancer, while the mutant T allele appeared to provide protection against breast cancer development as observed from the significantly lower (P&lt;0.0001) frequencies of the TT and GT genotypes in cancer patients compared to the healthy controls. The variant rs1801320G&gt;C showed no significant differences in the frequencies of the genotypes and alleles in the patients and the control groups. The CC genotype and C allele frequency of rs2619681 (C&gt;T) variant were significantly (P=0.012) higher in cancer patients, whereas the T allele showed a protective effect against cancer development. The frequencies of the three single-nucleotide polymorphisms did not differ in cancer patients with different tumor grades and human epidermal growth factor receptor 2 status (+ or -). However, the genotype frequency of rs1801320 (135G&gt;C) differed in the patients with estrogen receptor (ER)+ and ER-, where CC genotype showed a significantly higher prevalence in the females with ER- who were suffering from breast cancer. In addition, the frequency of C allele of rs2619681 (C&gt;T) was also significantly higher in the breast cancer patients who were ER+ and progesterone receptor (PR)+ compared to those with ER- and PR-. In the Saudi females, rs1801320 did not show an association with risk of breast cancer. Taken together, the results suggest that RAD51 rs1801321 polymorphism may be involved in the etiology of breast cancer in the Saudi females; however, further studies are necessary to confirm this relation. Keywords: RAD51, breast cancer, Saudi Arabia, single nucleotide polymorphis