A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8⁺ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα⁺ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.     

Maximizing Breast Cancer Therapy with Awareness of Potential Treatment-Related Blood Disorders

In this review we summarize the impact of the various modalities of breast cancer therapy coupled with intrinsic patient factors on incidence of subsequent treatment-induced myelodysplasia and acute myelogenous leukemia (t-MDS/AML). It is clear that risk is increased for patients treated with radiation and chemotherapy at younger ages. Radiation is associated with modest risk, whereas chemotherapy, particularly the combination of an alkylating agent and an anthracycline, carries higher risk and radiation and chemotherapy combined increase the risk markedly. Recently, treatment with granulocyte colony-stimulating factor (G-CSF), but not pegylated G-CSF, has been identified as a factor associated with increased t-MDS/AML risk. Two newly identified associations may link homologous DNA repair gene deficiency and poly (ADP-ribose) polymerase inhibitor treatment to increased t-MDS/AML risk. When predisposing factors, such as young age, are combined with an increasing number of potentially leukemogenic treatments that may not confer large risk singly, the risk of t-MDS/AML appears to increase. Patient and treatment factors combine to form a biological cascade that can trigger a myelodysplastic event. Patients with breast cancer are often exposed to many of these risk factors in the course of their treatment, and triple-negative patients, who are often younger and/or BRCA positive, are often exposed to all of them. It is important going forward to identify effective therapies without these adverse associated effects and choose existing therapies that minimize the risk of t-MDS/AML without sacrificing therapeutic gain.

Implications for Practice

Breast cancer is far more curable than in the past but requires multimodality treatment. Great care must be taken to use the least leukemogenic treatment programs that do not sacrifice efficacy. Elimination of radiation and anthracycline/alkylating agent regimens will be helpful where possible, particularly in younger patients and possibly those with homologous repair deficiency (HRD). Use of colony-stimulating factors should be limited to those who truly require them for safe chemotherapy administration. Further study of a possible leukemogenic association with HRD and the various forms of colony-stimulating factors is badly needed.

     

Age-related variations in gene expression patterns of renal cell carcinoma

Background

Clear cell renal cell carcinoma (ccRCC) is known to occur across the adult lifetime traversing the spectrum of age-related organismal changes. Little is known as to how the aging process may affect the course of renal cell carcinoma (RCC) and the repertoire of genes involved.

Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30–100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated.

Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed.

Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.     

A population-based analysis of pediatric breast cancer

Purpose

The purpose of this study was to evaluate trends in demographics and outcomes of pediatric breast cancer in a United States population-based cohort.

Quality of life after single-incision laparoscopic cholecystectomy: A randomized,clinical trial

Background

Controversy continues as to whether single-incision laparoscopic cholecystectomy, with the somewhat larger incision at the umbilicus, may lead to a worse postoperative quality of life and more pain compared with the more classic 4-port laparoscopic cholecystectomy. The aim of this study was to compare single-incision and 4-port laparoscopic cholecystectomy from the perspective of quality of life.

弹性绷带在乳腺癌术后应用的效果观察

目的　观察弹性绷带在乳腺癌术后应用效果。方法　 4 8例乳腺癌根治术后应用弹性绷带包扎为实验组 ,4 5例用普通宽绷带包扎为对照组。然后 ,对两组患者术后并发症进行观察。结果　实验组患者的并发症明显低于对照组 ,两组比较有显著性差异 ,P <0 .0 5。结论　应用弹性绷带包扎 ,能明显减少并发症的发生 ,促进切口愈合 ,使患者术后术侧上肢功能锻炼可以提早进行。     

乳腺癌HSV—1,HSV—2与c—erbB—2关系的免疫组化研究

采用免疫组织化学Ｓ－Ｐ法检测５２例手术切除乳腺癌组织ｃ－ｅｒｂＢ－２蛋白和ＨＳＶ－１、ＨＳＶ－２表达情况。结果发现癌组织中ｃ－ｅｒｂＢ－２阳性３４例（６５．４％）；ＨＳＶ－１阳性３８例（７３．１％）；ＨＳＶ－２阳性１５例（２８．８％）。癌旁组织３２例，阳性分别为３例（９．４％）；１２例（３７．５％）；２例（６．３％）。乳腺癌中ｃ－ｅｒｂＢ－２阳性率明显高于癌旁组织。乳腺癌及癌旁的ＨＳＶ－１阳性率明     

Value of contrast-enhanced MRI of breast after silicone implant

Summary Early recognition of recurrence and work-up of clinically indeterminate lesions may be impaired after reconstruction with silicone implants due to superimposition of the implant or to scarring. This study was undertaken to evaluate the use of contrast-enhanced MRI in patients with silicone implant after breast cancer. Contrast-enhanded MRI was offered to 169 patients. Comparative two- to three-view mammography was also performed in 169 patients, as well as comparative sonography in 144 patients. Conventional imaging and clinical examination detected only 8/13 recurrences, whereas 12/13 were detected by MRI. One recurrence had been visible as a strongly enhancing 2-mm dot in a previous examination (2 years before), but was not called. It was therefore counted as false negative. In addition, multicentricity was detected by MRI alone in two of three cases. MRI correctly diagnosed scar tissue in all cases with indeterminate findings. However, due to false-positive calls caused by enhancing granulomas specificity could not be improved. Contrast-enhanded MRI allowed decisive additional information in our study group and improved the sensitivity significantly (concerning all diagnoses). Contrast-enhanded MRI is recommended in patients with diagnostic problems or high risk of recurrence after silicone implants.