Elin Richardsen

Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non–Small Cell Lung Cancer

Purpose: Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, which appears to be superior to the tumor–node–metastasis (TNM) classification in colorectal cancer. In non–small cell lung cancer (NSCLC), no immunoscore has been established, but in situ tumor immunology is recognized as highly important. We have previously evaluated the prognostic impact of several immunological markers in NSCLC, yielding the density of stromal CD8+ tumor-infiltrating lymphocytes (TIL) as the most promising candidate. Hence, we validate the impact of stromal CD8+ TIL density as an immunoscore in NSCLC. Experimental Design: The prognostic impact of stromal CD8+ TILs was evaluated in four different cohorts from Norway and Denmark consisting of 797 stage I–IIIA NSCLC patients. The Tromso cohort (n = 155) was used as training set, and the results were further validated in the cohorts from Bodo (n = 169), Oslo (n = 295), and Denmark (n = 178). Tissue microarrays and clinical routine CD8 staining were used for all cohorts. Results: Stromal CD8+ TIL density was an independent prognostic factor in the total material (n = 797) regardless of the endpoint: disease-free survival (P < 0.001), disease-specific survival (P < 0.001), or overall survival (P < 0.001). Subgroup analyses revealed significant prognostic impact of stromal CD8+ TIL density within each pathologic stage (pStage). In multivariate analysis, stromal CD8+ TIL density and pStage were independent prognostic variables. Conclusions: Stromal CD8+ TIL density has independent prognostic impact in resected NSCLC, adds prognostic impact within each pStage, and is a good candidate marker for establishing a TNM-Immunoscore. Clin Cancer Res; 21(11); 2635–43. ©2015 AACR.

Significant expression of IGFBP2 in breast cancer compared with benign lesions.

Background/Aim: Insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) play a role in the normal development of breast tissue, and possibly in breast cancer aetiology. IGFBP2, one of six members of the IGFBP superfamily, acts as regulator of the IGFs and has pleiotropic effects in normal and neoplastic tissues. Because IGFs have mitogenic effects on mammary epithelia, this study investigated IGFBP2 expression in mammary tissues of different benign and malignant entities. Methods: Immunohistochemistry was used to study correlations between the presence and intensity of IGFBP2 staining and tumour type and grade, in addition to steroid hormone receptor status, in 120 breast specimens. Expression was measured by quantitative colour video image analysis and semiquantitative evaluation, and the measurements correlated well (r = 0.92; p<0.05). Results: Both methods found no significant expression of IGFBP2 in normal glandular cells and hyperplasia (group I). Atypical hyperplasia showed a slightly increased cytoplasmic expression of IGFBP2, and carcinoma in situ showed a distinctive, membrane associated and cytoplasmic expression (group II). Infiltrating carcinomas strongly expressed cytoplasmic IGFBP2 (group III). There were significant differences between group I and II, and between group II and III. There were no significant differences between invasive lobular and invasive ductal carcinoma, or between grades I, II, and III within these entities. There was no significant correlation between IGFBP2 immunostaining and oestrogen or progesterone receptor positivity within the malignant group. Conclusions: IGFBP2 mitogenic signals of autocrine/paracrine regulatory mechanisms may be responsible for the growth of breast carcinomas and IGFBP2 may be an independent indicator of malignancy.

The Role of Tumor-Infiltrating Lymphocytes in Development, Progression, and Prognosis of Non-Small Cell Lung Cancer.

ABSTRACT A malignant tumor is not merely an accumulation of neoplastic cells, but constitutes a microenvironment containing endothelial cells, fibroblasts, structural components, and infiltrating immune cells that impact tumor development, invasion, metastasis, and outcome. Hence, the evolution of cancers reflects intricate cellular and molecular interactions between tumor cells and constituents of the tumor microenvironment. Recent studies have shed new light on this complex interaction between tumor and host immune cells and the resulting immune response. The composition of the immune microenvironment differs across patients as well as in cancers of the same type, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid‐derived suppressor cells, neutrophils, and macrophages. The type, density, location, and organization of immune cells within solid tumors define the immune contexture, which has proved to be a major determinant of tumor characteristics and patient outcome. Lung cancer consists mostly of non–small cell lung cancer (85%); it is our most deadly malignant disease, with the 5‐year survival rate being merely 15%. This review focuses on the immune contexture; the tumor‐suppressing roles of tumor‐infiltrating lymphocytes; and the relevance of this immune contexture for cancer diagnostics, prognostication, and treatment allocation, with an emphasis on non–small cell lung cancer.

The prognostic impact of M-CSF, CSF-1 receptor, CD68 and CD3 in prostatic carcinoma

Aims:  Macrophage colony‐stimulating factor (M‐CSF) binds to colony‐stimulating factor‐1 receptor (CSF‐1R) and stimulates proliferation and differentiation of monocytes, macrophages and their bone marrow progenitors. M‐CSF, CSF‐1R, the macrophage marker CD68, and the pan T‐lymphocyte marker CD3 are increased in many human cancers. Their prognostic importance in primary prostatic carcinoma has not been fully delineated. The aim was to compare the expression of M‐CSF, CSF‐1R, CD68 and CD3 in metastatic and non‐metastatic prostatic cancer.

COX-2 is overexpressed in primary prostate cancer with metastatic potential and may predict survival. A comparison study between COX-2, TGF-β, IL-10 and Ki67

BACKGROUND The immune modulating molecules cyclooxygenase-2 (COX-2), transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) have regulatory roles in cancer progression. There are conflicting data regarding the roles of these molecules in prostate cancer. To elucidate the prognostic impact of these proteins and provide information on prognosis and treatment, we compared the expression of COX-2, TGF-beta, and IL-10 in prostate cancer specimens with or without metastases. Ki67 was included as a measure of growth fraction of tumor cells. METHODS Digital video analysis images from tumor cell areas and tumor stromal areas were analyzed on formalin fixed, paraffin-embedded and immunohistochemical stained cancer specimens from 59 patients: 32 patients with metastases and 27 patients without clinical, biochemical, or radiological evidence of metastases within 10 years after diagnosis. The expression of COX-2 was scored as negative, weak, moderate, or strong. The expressions of TGF-beta and IL-10 were assessed as proportions of moderately or strongly stained cells. Ki67 was detected as strong nuclear staining in proliferating cells. RESULTS In primary cancers in the metastatic group, COX-2, TGF-beta and Ki67 were stronger expressed in epithelial tumor cell and tumor stromal areas compared with non-metastatic cancers (for all markers, p<0.0001). High intensity of COX-2 staining in tumor areas was strongly associated with death from prostate cancer in univariate analyses (hazard ratio [HR] 95% CI, 4.0 (1.1-14.5)). In multivariate analyses, the risk estimate was strengthened but did not reach significance. No associations to death were found for the other markers. CONCLUSION High expression of COX-2, TGF-beta and Ki67 were in metastatic primary prostate carcinoma compared to non-metastatic cancers. High expression of COX-2 was associated to death from prostate carcinoma.

Overexpression of IGBFB2 is a marker for malignant transformation in prostate epithelium

Insulin-like growth factor binding protein 2 (IGFBP2) has been shown to be overexpressed in prostatic intraepithelial neoplasia (PIN) and invasive cancer and the serum level to parallel that of prostate-specific antigen (PSA) in prostate cancer. A combination of cDNA and tissue microarray results recently demonstrated overexpression of IGFBP2 in hormone refractory prostate cancer, indicating that the IGF system may be part of a key growth regulatory pathway in prostate cancer. The present study reexamines the immunohistochemical expression of IGFBP2 and its relationship to grade in tissue from 193 radical prostatectomy specimens from patients with localized prostate adenocarcinoma. We found a significant overexpression of IGFBP2 in all instances of PIN and in more than 90% of cancers regardless of the grade. An intense overexpression was noted in the neuroendocrine cells in normal glands as well as in cancer. The IGFBP2 expression was also analyzed in 18 cases of biopsy diagnosed prostate cancer. In all these cases, the glands interpreted as invasive cancer in hematoxylin-eosin stained sections overexpressed IGFBP2, without a significant correlation to grade. We conclude that overexpression of IGFBP2 is a powerful marker for malignant transformation in the prostate epithelium and suggest that optimized immunohistochemical detection of IGFBP2 expression may be an adjunct tool in the diagnosis of prostate cancer.

Positive prognostic impact of miR-210 in non-small cell lung cancer.

OBJECTIVES miR-210 is an important regulator of the cellular response to hypoxia. Therefore, we aimed to explore the prognostic significance of miR-210 in non-small cell lung cancer (NSCLC) patients with stage I-IIIA disease. MATERIALS AND METHODS In addition to clinicopathological and demograpic information, tumor tissues were collected and tissue micro arrays (TMAs) were constructed from 335 patients with stage I-IIIA NSCLC. Expression of miR-210 in cancer cells and stromal cells of the tumor was assessed by in situ hybridization. RESULTS In univariate analyses, high cancer cell (p=0.039) and high stromal cell expression (p=0.008) of miR-210 were both significantly associated with an improved disease-spesific survival (DSS). High co-expression of miR-210 in cancer and stromal cells was also a positive prognostic factor for DSS (p=0.010). In multivariate analysis, miR-210 in stromal cells (p=0.011), and miR-210 co-expressed in cancer and stromal cells was an independent prognosticator for DSS (p=0.011). CONCLUSIONS We show that miR-210 in stromal cells, and co-expressed in cancer cells and stromal cells mediates an independent prognostic impact. It is a candidate marker for prognostic stratification in NSCLC.

Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer.

Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates and appears highly promising as a supplement to the tumor-node-metastasis (TNM) classification of various tumors. In colorectal cancer, an international task force has initiated prospective multicenter studies aiming to implement TNM-Immunoscore (TNM-I) in a routine clinical setting. In breast cancer, recommendations for the evaluation of tumor-infiltrating lymphocytes (TILs) have been proposed by an international working group. Regardless of promising results, there are potential obstacles related to implementing TNM-I into the clinic. Diverse methods may be needed for different malignancies and even within each cancer entity. Nevertheless, a uniform approach across malignancies would be advantageous. In nonsmall-cell lung cancer (NSCLC), there are several previous reports indicating an apparent prognostic importance of TILs, but studies on TILs in a TNM-I setting are sparse and no general recommendations are made. However, recently published data is promising, evoking a realistic hope of a clinical useful NSCLC TNM-I. This review will focus on the TNM-I potential in NSCLC and propose strategies for clinical implementation of a TNM-I in resected NSCLC.

Infiltration of CD8+ lymphocytes is an independent prognostic factor of biochemical failure‐free survival in prostate cancer

The adaptive immune system can potentially have dual roles in cancer development and progression by contributing to or suppressing tumor progression and metastasis. The aim of this study was to evaluate the prognostic impact of adaptive immune cells residing in different tumor compartments in prostate cancer.

Do cancer patients benefit from short-term contact with a general practitioner following cancer treatment? A randomised, controlled study.

Goals of workTo investigate whether increased contact with the patient’s general practitioner (GP) soon after cancer treatment can increase patient quality of life (QoL) and satisfaction with follow-up.Patients and methodsA randomised controlled study with 91 patients from one Norwegian municipality. The intervention group got a 30-min invited consultation with the patient’s GP and an invitation to further GP follow-up. Quality of life and patient satisfaction with diagnosis, treatment and overall care were measured with validated instruments.Main resultsRelatives’ satisfaction with care increased over 6 months in the intervention group (P=0.018), but otherwise, there was no difference between the intervention and control groups concerning QoL, satisfaction with care or number of consultations. Patient satisfaction with care showed a tendency to increase when treatment intent was curative. Some functional QoL measures and satisfaction tended to increase during the first 6 months after treatment. Free text comments suggested that some patients appreciated the contact with their GP.ConclusionSome cancer patients benefit from follow-up by their GP. The way to perform this kind of follow-up in primary care, and who these cancer patients are, should be further studied. Short follow-up time and an urban setting may have contributed to the lack of group differences in our study, but patients treated for cancer may have limited need for follow-up as long as they feel well and the situation remains stable.