Breast carcinomas are often infiltrated by inflammatory cells, particularly macrophages and T lymphocytes, but the significance of these cells remains unclear. One possible role of these inflammatory ...cells is that they represent a cell-mediated immune response against the carcinoma. CD8(+) lymphocytes are a known crucial component of cell-mediated immunity. The purpose of this study was to explore the prognostic value of tumor-infiltrating CD8(+) cytotoxic lymphocytes in breast cancer. Tumor-infiltrating CD8(+) lymphocytes were assessed by immunohistochemical staining of tissue microarray cores from 1,334 unselected breast tumors from patients with long-term follow-up. The number of CD8(+) T cells was counted in tumor nests (intratumoral), in stroma adjacent to tumor cells, and in stroma distant to tumor cells, and their relationship with clinical outcome was determined. The total number of CD8(+) cells was positively correlated with tumor grade (r(s) = 0.20; P < .001) and inversely correlated with patient's age at diagnosis, estrogen receptor-alpha (ER-α), and progesterone receptor (PgR) expression (Mann-Whitney U test, P < .001). The total patient cohort was randomly divided into two separate training and validation sets before performing univariate survival analysis. Total number and distant stromal CD8(+) lymphocytes were associated with better patient survival (P = .041 and P < .001, respectively) in the training set. In multivariate analysis, total CD8(+) T-cell count was an independent prognostic factor in both training and validation sets. These results suggest that tumor-infiltrating CD8(+) T lymphocytes have antitumor activity as judged by their favorable effect on patients' survival and could potentially be exploited in the treatment of breast cancer.
Abstract Objectives To identify and summarize published systematic reviews that report results of meta-analyses that combined direct and indirect comparisons. Study Design and Setting Narrative ...review of mixed treatment comparisons (MTCs) reported in systematic reviews of health interventions. MEDLINE, MEDLINE In-Process, Embase, CINAHL, DARE, the Cochrane Database of Systematic Reviews, and SIGLE were searched for reviews published up to June 2012 in which a meta-analysis had been conducted that combined direct and indirect comparisons among more than two interventions. Results Reviews reporting MTCs are difficult to identify when searching major databases. These databases offer no way to identify MTCs, and authors use various names when reporting them. Of the 201 eligible reviews identified, more than three-quarters had been published in full. MTC methods have been used to study a wide range of clinical topics. The reported use of these methods has increased rapidly since 2009, and results from MTCs are commonly used in health policy decisions, through the evidence considered in health technology assessments. Conclusion In view of the increasing use of MTCs, indexing of this study type in databases and a consensus on terminology and standards for conduct and reporting would be timely.
Osteoarthritis afflicts millions of individuals across the world resulting in impaired quality of life and increased health costs. To understand this disease, physicians have been studying risk ...factors, such as genetic predisposition, aging, obesity, and joint malalignment; however have been unable to conclusively determine the direct etiology. Current treatment options are short-term or ineffective and fail to address pathophysiological and biochemical mechanisms involved with cartilage degeneration and the induction of pain in arthritic joints. OA pain involves a complex integration of sensory, affective, and cognitive processes that integrate a variety of abnormal cellular mechanisms at both peripheral and central (spinal and supraspinal) levels of the nervous system Through studies examined by investigators, the role of growth factors and cytokines has increasingly become more relevant in examining their effects on articular cartilage homeostasis and the development of osteoarthritis and osteoarthritis-associated pain. Catabolic factors involved in both cartilage degradation in vitro and nociceptive stimulation include IL-1, IL-6, TNF-α, PGE2, FGF-2 and PKCδ, and pharmacologic inhibitors to these mediators, as well as compounds such as RSV and LfcinB, may potentially be used as biological treatments in the future. This review explores several biochemical mediators involved in OA and pain, and provides a framework for the understanding of potential biologic therapies in the treatment of degenerative joint disease in the future.
•We explore biochemical mediators involved in osteoarthritis and pain.•Current treatment options are ineffective and fail to address pathophysiological and biochemical mechanisms of osteoarthritis.•The role of growth factors and cytokines are increasingly more relevant in their effects on articular cartilage homeostasis.
Adoptive cell therapy (ACT) using tumor-specific tumor-infiltrating lymphocytes (TILs) has demonstrated success in patients where tumor-antigen specific TILs can be harvested from the tumor, ...expanded, and re-infused in combination with a preparatory regimen and IL2. One major issue for non-immunogenic tumors has been that the isolated TILs lack tumor specificity and thus possess limited in vivo therapeutic function. An oncolytic virus (OV) mediates an immunogenic cell death for cancer cells, leading to elicitation and dramatic enhancement of tumor-specific TILs. We hypothesized that the tumor-specific TILs elicited and promoted by an OV would be a great source for ACT for solid cancer. In this study, we show that a local injection of oncolytic poxvirus in MC38 tumor with low immunogenicity in C57BL/6 mice, led to elicitation and accumulation of tumor-specific TILs in the tumor tissue. Our analyses indicated that IL2-armed OV-elicited TILs contain lower quantities of exhausted PD-1
Tim-3
CD8
T cells and regulatory T cells. The isolated TILs from IL2-expressing OV-treated tumor tissue retained high tumor specificity after expansion ex vivo. These TILs resulted in significant tumor regression and improved survival after adoptive transfer in mice with established MC38 tumor. Our study showcases the feasibility of using an OV to induce tumor-reactive TILs that can be expanded for ACT.
Intrahepatic cholangiocarcinoma accounts for 5% to 30% of all primary liver cancers, and its incidence has increased in the last 3 decades. Surgical resection remains the only potentially curative ...treatment but is associated with high tumor recurrence rates. The 7th edition of the American Joint Committee on Cancer (AJCC) Staging Manual introduced a new staging system for intrahepatic cholangiocarcinoma, which was previously staged the same as hepatocellular carcinoma. The recently published 8th edition has subdivided the T1 category to T1a and T1b based on a size cutoff of 5 cm, removed periductal invasion from the T4 category, and downstaged T4 tumors and regional lymph node metastasis from stage IV to IIIB. Continued international efforts to accurately stratify prognosis are important to counsel patients and guide treatment decisions.
The International Academy of Cytology (IAC) gathered together a group of cytopathologists expert in breast cytology who, working with clinicians expert in breast diagnostics and management, have ...developed the IAC Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy (FNAB) Cytology. The project was initiated with the first cytopathology group meeting in Yokohama at the 2016 International Congress of Cytology. This IAC Yokohama System defines five categories for reporting breast cytology, each with a clear descriptive term for the category, a definition, a risk of malignancy (ROM) and a suggested management algorithm. The key diagnostic cytopathology features of each of the lesions within each category will be presented more fully in a subsequent atlas. The System emphasizes that the crucial requirements for diagnostic breast FNAB cytology are a high standard for the performance of the FNAB and for the making of direct smears, and well-trained experienced cytopathologists to interpret the material. The performance indicators of breast FNAB, including specificity and sensitivity, negative predictive value, positive predictive value and ROM stated in this article have been derived from the recent literature. The current practice of breast FNAB has evolved with the increasing use of ultrasound guidance and rapid on-site evaluation. Two recent publications have shown a range of ROM for the insufficient/inadequate category of 2.6-4.8%, benign 1.4-2.3%, atypical 13-15.7%, suspicious of malignancy 84.6-97.1%, and malignant 99.0-100%. The management algorithm in the System provides options because there are variations in the management of breast lesions using FNAB and core-needle biopsy in those countries utilizing the "triple test" of clinical, imaging, and FNAB assessment, and also variations in the availability of CNB and imaging in low- and middle-income countries. The System will stimulate further discussion and research, particularly in the cytological diagnostic features of specific lesions within each category and in management recommendations. This will lead to continuing improvements in the care of patients with breast lesions and possible modifications to the IAC Yokohama System.
Human pluripotent stem cells (PSCs) are a leading candidate for cell-based therapies because of their capacity for unlimited self renewal and pluripotent differentiation. These advances have recently ...culminated in the first-in-human PSC clinical trials by Geron, Advanced Cell Technology and the Kobe Center for Developmental Biology for the treatment of spinal cord injury and macular degeneration. Despite their therapeutic promise, a crucial hurdle for the clinical implementation of human PSCs is their potential to form tumors in vivo. In this Perspective, we present an overview of the mechanisms underlying the tumorigenic risk of human PSC-based therapies and discuss current advances in addressing these challenges.
The three strongest prognostic determinants in operable breast cancer used in routine clinical practice are lymph node (LN) stage, primary tumor size, and histologic grade. However, grade is not ...included in the recent revision of the TNM staging system of breast cancer as its value is questioned in certain settings.
This study is based on a large and well-characterized consecutive series of operable breast cancer (2,219 cases), treated according to standard protocols in a single institution, with a long-term follow-up (median, 111 months) to assess the prognostic value of routine assessment of histologic grade using Nottingham histologic grading system.
Histologic grade is strongly associated with both breast cancer-specific survival (BCSS) and disease-free survival (DFS) in the whole series as well as in different subgroups based on tumor size (pT1a, pT1b, pT1c, and pT2) and LN stages (pN0 and pN1 and pN2). Differences in survival were also noted between different individual grades (1, 2, and 3). Multivariate analyses showed that histologic grade is an independent predictor of both BCSS and DFS in operable breast cancer as a whole as well as in all studied subgroups.
Histologic grade, as assessed by the Nottingham grading system, provides a strong predictor of outcome in patients with invasive breast cancer and should be incorporated in breast cancer staging systems.
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