DataSheet_1_Efficacy of pembrolizumab in advanced cancer of the vulva: a systematic review and single-arm meta-analysis.docx

IntroductionVulvar cancer carries a favourable prognosis in early stages. However, therapeutic options for advanced or recurrent cases are limited despite a variety of therapeutic modalities, such as extensive surgical resection, chemotherapy, and radiotherapy. The most important emerging treatment modalities are immune checkpoint inhibitors. This systematic review and meta-analysis aims to assess the efficacy and safety of pembrolizumab, an immune checkpoint inhibitor, in women with advanced vulvar cancer.Materials and methodsFollowing a comprehensive search, review, and appraisal, two relevant single-arm studies were included. Meta-analysis was conducted using R4.3.0 software and RStudio 2023.03.0, presenting the overall effect size with a 95% confidence interval. Heterogeneity was assessed using I2 and the Cochrane Q χ2 statistics.ResultsOut of 154 studies screened for eligibility, two single-arm studies involving 119 patients receiving pembrolizumab for advanced vulvar cancer were included. The pooled objective response rate (ORR) was overall 10% (95% CI: 0.00-0.84) and 9% (95% CI: 0.00-0.89) in the PD-L1 positive subgroup. In the intention-to-treat (ITT) population, 31% (95% CI: 0.04-0.85) exhibited any clinical benefit (complete response, partial response, or stable disease). In the ITT population at six months, progression-free survival (PFS) was 19% (95% CI: 0.01-0.82), and overall survival (OS) was 48% (95% CI: 0.08-0.90). At 12 months, PFS decreased to 9% (95% CI: 0.00-0.85), and OS was 33% (95% CI: 0.04-0.85). No statistically significant heterogeneity was observed in PFS and OS analyses.Discussion and conclusionThis study suggests that one-third of women with advanced or recurrent vulvar cancer may, without the influence of PD-L1 status, benefit from pembrolizumab treatment despite a decline in both PFS and OS at 12 months. These findings provide support for considering pembrolizumab in the treatment paradigm for this specific subset of cancer patients.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42023391888</p

Loss of circadian clock gene expression is associated with tumor progression in breast cancer

<div><p>Several studies suggest a link between circadian rhythm disturbances and tumorigenesis. However, the association between circadian clock genes and prognosis in breast cancer has not been systematically studied. Therefore, we examined the expression of 17 clock components in tumors from 766 node-negative breast cancer patients that were untreated in both neoadjuvant and adjuvant settings. In addition, their association with metastasis-free survival (MFS) and correlation to clinicopathological parameters were investigated. Aiming to estimate functionality of the clockwork, we studied clock gene expression relationships by correlation analysis. Higher expression of several clock genes (e.g., <i>CLOCK</i>, <i>PER1</i>, <i>PER2</i>, <i>PER3</i>, <i>CRY2</i>, <i>NPAS2</i> and <i>RORC</i>) was found to be associated with longer MFS in univariate Cox regression analyses (HR<1 and FDR-adjusted <i>P</i> < 0.05). Stratification according to molecular subtype revealed prognostic relevance for <i>PER1</i>, <i>PER3</i>, <i>CRY2</i> and <i>NFIL3</i> in the ER+/HER2- subgroup, <i>CLOCK</i> and <i>NPAS2</i> in the ER-/HER2- subtype, and <i>ARNTL2</i> in HER2+ breast cancer. In the multivariate Cox model, only <i>PER3</i> (HR = 0.66; P = 0.016) and <i>RORC</i> (HR = 0.42; P = 0.003) were found to be associated with survival outcome independent of established clinicopathological parameters. Pairwise correlations between functionally-related clock genes (e.g., PER2-PER3 and CRY2-PER3) were stronger in ER+, HER2- and low-grade carcinomas; whereas, weaker correlation coefficients were observed in ER- and HER2+ tumors, high-grade tumors and tumors that progressed to metastatic disease. In conclusion, loss of clock genes is associated with worse prognosis in breast cancer. Coordinated co-expression of clock genes, indicative of a functional circadian clock, is maintained in ER+, HER2-, low grade and non-metastasizing tumors but is compromised in more aggressive carcinomas.</p></div

Effect of Surface Properties on the Microstructure, Thermal, and Colloidal Stability of VB₂ Nanoparticles

Recent years have seen an increasing research effort focused on nanoscaling of metal borides, a class of compounds characterized by a variety of crystal structures and bonding interactions. Despite being subject to an increasing number of studies in the application field, comprehensive studies of the size-dependent structural changes of metal borides are limited. In this work, size-dependent microstructural analysis of the VB₂ nanocrystals prepared by means of a size-controlled colloidal solution synthesis is carried out using X-ray powder diffraction. The contributions of crystallite size and strain to X-ray line broadening is separated by introducing a modified Williamson–Hall method taking into account different reflection profile shapes. For average crystallite sizes smaller than ca. 20 nm, a remarkable increase of lattice strain is observed together with a significant contraction of the hexagonal lattice decreasing primarily the cell parameter <i>c</i>. Exemplary density-functional theory calculations support this trend. The size-dependent lattice contraction of VB₂ nanoparticles is associated with the decrease of the interatomic boron distances along the <i>c</i>-axis. The larger fraction of constituent atoms at the surface is formed by boron atoms. Accordingly, lattice contraction is considered to be a surface effect. The anisotropy of the size-dependent lattice contraction in VB₂ nanocrystals is in line with the higher compressibility of its macroscopic bulk structure along the <i>c</i>-axis revealed by theoretical calculations of the respective elastic properties. Transmission electron microscopy indicates that the VB₂ nanocrystals are embedded in an amorphous matrix. X-ray photoelectron spectroscopy analysis reveals that this matrix is mainly composed of boric acid, boron oxides, and vanadium oxides. VB₂ nanocrystals coated with these oxygen containing amorphous species are stable up to 789 °C as evidenced by thermal analysis and temperature dependent X-ray diffraction measurements carried out under Ar atmosphere. Electrokinetic measurement indicates that the aqueous suspension of VB₂ nanoparticles with hydroxyl groups on the surface region has a good stability at neutral and basic pH arising from electrostatic stabilizatio

Prognostic Influence of Pre-Operative C-Reactive Protein in Node-Negative Breast Cancer Patients

<div><p>The importance of inflammation is increasingly noticed in cancer. The aim of this study was to analyze the prognostic influence of pre-operative serum C-reactive protein (CRP) in a cohort of 148 lymph node-negative breast cancer patients. The prognostic significance of CRP level for disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS) was evaluated using univariate and multivariate Cox regression, also including information on age at diagnosis, tumor size, tumor grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, proliferation index (Ki67) and molecular subtype, as well as an assessment of the presence of necrosis and inflammation in the tumor tissue. Univariate analysis showed that CRP, as a continuous variable, was significantly associated with DFS (P = 0.002, hazard ratio [HR]  = 1.04, 95% confidence interval [CI]  = 1.02–1.07) and OS (P = 0.036, HR  = 1.03, 95% CI  = 1.00–1.06), whereas a trend was observed for MFS (P = 0.111). In the multivariate analysis, CRP retained its significance for DFS (P = 0.033, HR  = 1.01, 95% CI  = 1.00–1.07) as well as OS (P = 0.023, HR  = 1.03, 95% CI  = 1.00–1.06), independent of established prognostic factors. Furthermore, large-scale gene expression analysis by Affymetrix HG-U133A arrays was performed for 72 (48.6%) patients. The correlations between serum CRP and gene expression levels in the corresponding carcinoma of the breast were assessed using Spearman's rank correlation, controlled for false-discovery rate. No significant correlation was observed between CRP level and gene expression indicative of an ongoing local inflammatory process. In summary, pre-operatively elevated CRP levels at the time of diagnosis were associated with shorter DFS and OS independent of established prognostic factors in node-negative breast cancer, supporting a possible link between inflammation and prognosis in breast cancer.</p></div

Spearman's rank correlation between pre-operative CRP level in peripheral blood and metagene expression in the tumor tissue.

<p>Spearman's rank correlation between pre-operative CRP level in peripheral blood and metagene expression in the tumor tissue.</p

Association of CRP with survival in node-negative breast cancer (n = 148).

<p>CRP dichotomized using values above upper limit normal (>5 mg/l; n = 31) shows no significant association with disease-free survival (A), metastasis-free survival (B) and overall survival (C), respectively. The numbers below the diagrams represent patients at risk at the time point indicated on the x-axis.</p

Multivariate Cox regression analysis for disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS).

<p>HR: Hazard Ratio; CI: 95% Confidence Interval; Luminal A: ER+ and/or PR+, HER2−, Ki67≤20%; Luminal B: ER+ and/or PR+, HER2−, Ki67>20%; Basal-like: ER− and PR−, HER2−; HER2: ER+/−, PR+/−, HER2+.</p><p>Multivariate Cox regression analysis for disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS).</p

Clinicopathological characteristics for node-negative breast cancer patients.

<p>Clinicopathological characteristics for node-negative breast cancer patients.</p

Intermediate-Valence Ytterbium Compound Yb₄Ga₂₄Pt₉: Synthesis, Crystal Structure, and Physical Properties

The title compound was synthesized by a reaction of the elemental educts in a corundum crucible at 1200 °C under an Ar atmosphere. The excess of Ga used in the initial mixture served as a flux for the subsequent crystal growth at 600 °C. The crystal structure of Yb₄Ga₂₄Pt₉ was determined from single-crystal X-ray diffraction data: new prototype of crystal structure, space group <i>C</i>2<i>/m</i>, Pearson symbol <i>mS</i>74, <i>a</i> = 7.4809(1) Å, <i>b</i> = 12.9546(2) Å, <i>c</i> = 13.2479(2) Å, β = 100.879(1)°, <i>V</i> = 1260.82(6) ų, <i>R</i>_<i>F</i> = 0.039 for 1781 observed reflections and 107 variable parameters. The structure is described as an <i>ABABB</i> stacking of two slabs with trigonal symmetry and compositions Yb₄Ga₆ (<i>A</i>) and Ga₁₂Pt₆ (<i>B</i>). The hard X-ray photoelectron spectrum (HAXPES) of Yb₄Ga₂₄Pt₉ shows both Yb²⁺ and Yb³⁺ contributions as evidence of an intermediate valence state of ytterbium. The evaluated Yb valence of ∼2.5 is in good agreement with the results obtained from the magnetic susceptibility measurements. The compound is a bad metallic conductor

Validated early- and late-type genes.

<p>Kaplan-Meier plots representing validated late-type (A) and early-type (B) genes, for each showing one examples of one gene associated with better prognosis and one gene associated with worse prognosis. The median was used to differentiate between patients with low and high expression. Overlap between early-type and late-type genes with the previously described proliferation metagene (C). Overlap between early-type and late-type genes with genes associated with MFS in a conventional Cox model that considers the entire follow-up period (‘non-time restricted’) (D).</p