Intraepithelial Lymphocytes are Indicators of Better Prognosis in Surgically Resected Endometrioid-Type Endometrial Carcinomas at Early and Advanced Stages

2021 ◽  
Author(s):  
Takako Kono-Sato ◽  
Kosuke Miyai ◽  
Yoji Yamagishi ◽  
Morikazu Miyamoto ◽  
Masashi Takano ◽  
...  
Keyword(s):  
Quantitative Methods ◽  
Multivariate Analyses ◽  
Tumor Infiltrating Lymphocytes ◽  
Intraepithelial Lymphocytes ◽  
Prognostic Indicators ◽  
Stage Iiic ◽  
Tissue Samples ◽  
Stage Ib ◽  
Endometrial Carcinomas ◽  
Worse Prognosis

Abstract Background: Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) may be useful prognostic indicators in endometrial cancer. However, standardized assessment methods and the prognostic roles of these cells in different stage groups are unclear.Methods: Formalin-fixed paraffin-embedded tissue samples of 107 endometrioid-type endometrial carcinomas (EECs) comprising 60 stage IB and 47 stage IIIC or IVB cases were evaluated. CD3+ TILs, CD8+ TILs, CD68+ TAMs, and CD163+ TAMs were detected by immunohistochemistry, and their densities were evaluated by semiquantitative and quantitative methods. TILs within tumor epithelial cell nests (E-TILs) and those within the stroma at the invasive front (S-TILs) were evaluated separately for CD3+ and CD8+ cells. The “TIL score” was defined as the sum of semiquantitative scores of CD3+ E-TILs, CD3+ S-TILs, CD8+ E-TILs, and CD8+ S-TILs. For TAMs, the area of CD68+ and CD163+ cells in the invasive margin were semiquantitatively and quantitatively evaluated. Clinicopathological and prognostic implications of TILs and TAMs in stage IB and IIIC/IVB EECs were examined by Cox univariate and multivariate analyses.Results: By Cox univariate analyses, semiquantitatively low CD3+ E-TILs, low CD8+ E-TILs, and low “TIL score” were significantly correlated with worse prognosis in stage IB patients (P = 0.011, 0.040, and 0.039, respectively). Likewise, low CD3+ E-TILs and low CD8+ E-TILs, by both semiquantitative (P = 0.011 and 0.0051) and quantitative evaluations (P < 0.0001, and P = 0.0015) and low “TIL score” (P = 0.020) were significantly correlated with worse prognosis in stage IIIC/IVB patients. By Cox multivariate analyses, semiquantitatively low CD3+ E-TILs in stage IB (P = 0.030) and semiquantitatively low CD3+ E-TILs or “TIL score” in stage IIIC/IVB (P = 0.022 and 0.049, respectively) were independent worse prognostic factors. CD68+ or CD163+ TAMs were not correlated with prognosis in any patients.Conclusions: Semiquantitatively low E-TILs, possibly representing low degree of TILs, are correlated with prognosis in both early and advanced stage patients with EEC. In particular, CD3+ E-TILs and CD8+ E-TILs are potentially useful prognostic markers in patients with EEC regardless of the stage.

scholarly journals iNOS Expression by Tumor-Infiltrating Lymphocytes, PD-L1 and Prognosis in Non-Small-Cell Lung Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3276
Author(s):  
Alexandra Giatromanolaki ◽  
Avgi Tsolou ◽  
Eleftheria Daridou ◽  
Maria Kouroupi ◽  
Katerina Chlichlia ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Small Cell Lung Carcinoma ◽  
Expression Patterns ◽  
Tumor Infiltrating Lymphocytes ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tissue Samples ◽  
Cell Lung Carcinoma ◽  
Infiltrating Lymphocytes

Background: Inducible Nitric Oxygen Synthase (iNOS) promotes the generation of NO in tissues. Its role in tumor progression and immune response is unclear. Methods: The immunohistochemical expression patterns of iNOS were studied in a series of 98 tissue samples of non-small-cell lung carcinoma (NSCLC), in parallel with the expression of hypoxia and anaerobic metabolism markers, PD-L1 and tumor-infiltrating lymphocytes (TILs). Results: iNOS is expressed by cancer cells in 19/98 (19.4%), while extensive expression by cancer-associated fibroblasts occurs in 8/98 (8.2%) cases. None of these patterns relate to stage or prognosis. Extensive infiltration of the tumor stroma by iNOS-expressing TILs (iNOS+TILs) occurs in 47/98 (48%) cases. This is related to low Hypoxia-Inducible Factor 1α (HIF1α), high PD-L1 expression and a better overall survival (p = 0.002). Expression of PD-L1, however, mitigates the beneficial effect of the presence of iNOS+TIL. Conclusions: Extensive expression of iNOS by TILs occurs in approximately 50% of NSCLCs, and this is significantly related to an improved overall survival. This brings forward the role of iNOS in anti-neoplastic lymphocyte biology, supporting iNOS+TILs as a putative marker of immune response. The value of this biomarker as a predictive and treatment-guiding tool for tumor immunotherapy demands further investigation.

scholarly journals Combined Effect of IL-12Rβ2 and IL-23R Expression on Prognosis of Patients with Laryngeal Cancer

2018 ◽  
Vol 50 (3) ◽  
pp. 1041-1054 ◽  
Author(s):  
Ye Tao ◽  
Tianchang Tao ◽  
Neil Gross ◽  
Xuyun Peng ◽  
Ying Li ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Laryngeal Cancer ◽  
Cox Regression ◽  
Tumor Infiltrating Lymphocytes ◽  
Combined Effect ◽  
Interleukin 12 ◽  
Rank Test ◽  
Tissue Samples ◽  
Functional Studies

Background/Aims: This study aimed to pathologically elucidate the roles of interleukin-12 receptor (IL-12R) β2 and interleukin-23 receptor (IL-23R) expression in tumor cells and tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment and to determine their combined effect on prognosis of laryngeal cancer (LC). Methods: The tumor-cell expression scores and TIL positivity ratiosof IL-12Rβ2 and IL-23R in matched LC and normal laryngeal tissue samples from 61 LC patients were measured via immunohistochemistry (IHC). We adopted a linear regression model to analyze the correlation between IL-12Rβ2 and IL-23R expression in tumor cells and TIL ratios. TheKaplan-Meier log-rank test and Cox regression hazard ratios were used to analyze survival. Results: LC tumor cells had a higher IL-12Rβ2 expression and TIL ratio than IL-23R expression and TIL ratio. The significant correlations between IL-12Rβ2 and IL-23R expression and TIL ratios were identified in LC tissues, particularly in well-differentiated LC. Furthermore, either high tumor cell IL-12Rβ2 or low IL-23R expression had better survival than its corresponding low or high expression, respectively. Similar results did for IL-12Rβ2 ratio and IL-23R ratio. Finally, patients with both high IL-12Rβ2 and low IL-23R had the best prognosis among any other combined groups with both gene expression (HR, 0.1; 95% CI, 0.0-0.8). Likewise, patients with positive ratios of high IL-12Rβ2 and low IL-23R TILs had the best survival (HR, 0.1; 95% CI, 0.0-0.4). Conclusion: IL-12Rβ2 and IL-23R create a homeostasis within the tumor cells and TILs, and this homeostasis affects prognosis. While the intrinsic mechanisms of epigenetic immunoediting for IL-12Rβ2 and IL-23R remain unknown, additional larger and functional studies are warranted for validation.

Expression of survivin, PTEN and p27 in normal, hyperplastic, and carcinomatous endometrium

2006 ◽  
Vol 16 (3) ◽  
pp. 1412-1418 ◽  
Author(s):  
S. Erkanli ◽  
F. Kayaselcuk ◽  
E. Kuscu ◽  
T. Bagis ◽  
F. Bolat ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Endometrial Hyperplasia ◽  
Survivin Expression ◽  
Myometrial Invasion ◽  
Immunohistochemical Analysis ◽  
Endometrioid Adenocarcinoma ◽  
Tissue Samples ◽  
Proliferative Endometrium ◽  
Endometrial Carcinomas ◽  
First Time

We aimed to investigate if expressions of survivin and p27 proteins are involved in the development of endometrioid carcinoma, along with whether there are any correlations between these proteins and loss of wild-type PTEN that is found in up to 80% of endometrial carcinomas. We also studied their correlations with classical prognostic factors and survival in endometrial carcinoma. To our knowledge, this is the first time survivin expression is investigated in endometrial hyperplasia along with endometrioid adenocarcinoma. For immunohistochemical analysis, 29 endometrioid adenocarcinoma, 38 endometrial hyperplasia, and 10 proliferative endometrium tissue samples were selected in the pathology archives. Staining of cells was scored as +2 if >50%, +1 if <50%, and negative if none were stained positive. Survivin expression increased from proliferative to hyperplasia to carcinoma cases. PTEN and p27 expressions decreased in hyperplasia and carcinoma cases with respect to proliferative endometrium. All these differences were statistically significant (P < 0.05). PTEN positively correlated to p27 (P < 0.05); however, neither was correlated with survivin. None of these genes were correlated with classical prognostic factors such as grade and myometrial invasion in endometrioid adenocarcinoma. However, mean survival was statistically significantly higher in PTEN-positive cases (46.6 vs 16.4 months) (P < 0.05). Survivin overexpression might be one of the important mechanisms in the development of endometrioid adenocarcinoma along with lost or decreased activity of PTEN and p27. However, survivin seems to exert its role in ways different from those of PTEN or p27 in the development of endometrioid adenocarcinoma. These findings on the role of survivin in endometrioid adenocarcinoma should be confirmed and the pathways through which survivin acts in endometrioid adenocarcinoma studied further with a larger sample size.

scholarly journals Analysis of DNA Methylation of Multiple Genes in Microdissected Cells From Formalin-fixed and Paraffin-embedded Tissues

2009 ◽  
Vol 57 (5) ◽  
pp. 477-489 ◽  
Author(s):  
Dimo Dietrich ◽  
Ralf Lesche ◽  
Reimo Tetzner ◽  
Manuel Krispin ◽  
Jörn Dietrich ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Ductal Carcinoma ◽  
Treatment Protocol ◽  
Tumor Infiltrating Lymphocytes ◽  
Tissue Samples ◽  
Bisulfite Treatment ◽  
Pcr Product ◽  
Reliable Quantification ◽  
Infiltrating Lymphocytes ◽  
Formalin Fixed

A procedure for simultaneous quantification of DNA methylation of several genes in minute amounts of sample material was developed and applied to microdissected formalin-fixed and paraffin-embedded breast tissues. The procedure is comprised of an optimized bisulfite treatment protocol suitable for samples containing only few cells, a multiplex preamplification and subsequent locus specific reamplification, and a novel quantitative bisulfite sequencing method based on the incorporation of a normalization domain into the PCR product. A real-time PCR assay amplifying repetitive elements was established to quantify low amounts of bisulfite-treated DNA. Ten prognostic and diagnostic epigenetic breast cancer bio-markers ( PITX2, RASSF1A, PLAU, LHX3, PITX3, LIMK1, SLITRK1, SLIT2, HS3ST2, and TFF1) were analyzed in tissue samples obtained from two patients with invasive ductal carcinoma of the breast. The microdissected samples were obtained from several areas within the tumor tissue, including intraductal and invasive carcinoma, adenosis, and normal ductal epithelia of adjacent normal tissue, as well as stroma, tumor infiltrating lymphocytes, and adipose tissue. Overall, reliable quantification was possible for all genes. For most genes, increased DNA methylation in invasive and intraductal carcinoma cells compared with other tissue components was observed. For TFF1, decreased methylation levels were observed in tumor cells. (J Histochem Cytochem 57:477–489, 2009)

Overexpression of the osteopontin correlates with the aggressiveness of endometrial cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5038-5038
Author(s):  
C. Cho ◽  
S. Kwon ◽  
S. Ramachandran ◽  
S. Kwon ◽  
K. Kwon ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Correlation Coefficient ◽  
Statistical Significance ◽  
Endometrial Adenocarcinoma ◽  
Clinicopathologic Characteristics ◽  
Tissue Samples ◽  
The Status ◽  
Endometrial Carcinomas ◽  
Spearman’S Correlation ◽  
Coefficient Method

5038 Background: To test the hypothesis that expression of osteopontin (OPN), an integrin-binding glycoprotein, can independently predict the potential aggressiveness of endometrial cancer. We studied OPN expression in endometrial cell carcinomas and correlated OPN expression levels with clinicopathologic tumor features. Methods: The status of OPN expression in benign and malignant endometrial cancer cell lines and tissues was analyzed by Western blot and immunohistochemistry. Nonparametric Spearman’s correlation coefficient method was used to assess the statistical significance of the correlation between clinicopathologic characteristics of tumor and OPN expression. Results: An increased expression of OPN was observed in the endometrial cancer compared to normal endometrial tissue samples. When the level of OPN in normal tissue was set at 1, its level in benign endometrial hyperplasia was slightly increased at 1.2, whereas the OPN level in the highly malignant endometrial carcinoma tissue was greatly increased by nearly 3- 5 folds. Amongst the 70 cases examined immunocytochemically, of the 23 grade 1 endometrial carcinomas, 6 were unstained and 12 stained weakly positive (+). For the 20 grade 3 or serous type endometrial carcinomas analyzed, 8 (40%) stained strongly positive (+++), 8 (40%) stained moderately positive (++) and 1 stained weakly positive (+). These results showed that the level of OPN expressed between grade 1 and grde 3 or more was significantly different (Spearman’s correlation coefficient method, p = 0.001). Kaplan-Meier survival analysis showed that the increased level of OPN expression was significantly associated with reduced survival time of the patients. Conclusions: The results suggest that the increased OPN level may be involved in the malignant transformation of endometrial adenocarcinoma cells and OPN expression level is an important determinant for patient survival. No significant financial relationships to disclose.

Overexpression of the osteopontin correlates with the aggressiveness of endometrial cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 16048-16048
Author(s):  
C. Cho ◽  
S. Cha ◽  
S. Kwon ◽  
Y. Kwon ◽  
S. Kang ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Correlation Coefficient ◽  
Statistical Significance ◽  
Endometrial Adenocarcinoma ◽  
Clinicopathologic Characteristics ◽  
Tissue Samples ◽  
Grade 3 ◽  
Endometrial Carcinomas ◽  
Spearman’S Correlation ◽  
Coefficient Method

16048 Background: To test the hypothesis that expression of osteopontin (OPN), an integrin-binding glycoprotein, can independently predict the potential aggressiveness of endometrial cancer. Methods: The status of OPN expression in benign and malignant endometrial cancer cell lines and tissues was analyzed by real time PCR, Western blot, and immunohistochemistry. Nonparametric Spearman's correlation coefficient method was used to assess the statistical significance of the correlation between clinicopathologic characteristics of tumor and OPN expression. Results: An increased expression of OPN was observed in the endometrial cancer compared to normal endometrial tissue samples. When the level of OPN in normal tissue was set at 1, its level in benign endometrial hyperplasia was slightly increased at 1.2, whereas the OPN level in the highly malignant endometrial carcinoma tissue was greatly increased by nearly 3–5 folds. Amongst the 160 cases examined immunohistochemically, of the 43 grade 1 endometrial carcinomas, 31 were unstained and 12 stained weakly positive (+). For the 41 grade 3 or serous type endometrial carcinomas analyzed, 25 (60%) stained strongly positive (+++), 8 (19%) stained moderately positive (++) and 4 (9%) stained weakly positive (+). These results showed that the level of OPN expressed between grade 1 and grade 3 or more was significantly different (Spearman's correlation coefficient method, p = 0.001). However, Kaplan-Meier survival analysis showed that the increased level of OPN expression was not significantly associated with reduced survival time of the patients. Conclusion: The results suggest that the increased OPN level may be involved in the malignant transformation of endometrial adenocarcinoma cells. No significant financial relationships to disclose.

Recurrence-free survival (RFS) and objective response rate (ORR) phase 1/2 study of intralesional (IL) neoadjuvant (neo) anti-PD1 agents (aPD1) for stage IIIB-IV melanoma (MEL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14171-e14171
Author(s):  
Igor Samoylenko ◽  
Olga V. Korotkova ◽  
Ekaterina Shakhray ◽  
Tatiana Zabotina ◽  
Sergey Berdnikov ◽  
...  
Keyword(s):  
Phase 1 ◽  
Objective Response ◽  
Tumor Infiltrating Lymphocytes ◽  
Residual Tumor ◽  
Primary Analysis ◽  
Stage Iiic ◽  
Unresectable Stage ◽  
Biomarker Analysis ◽  
Expansion Cohort ◽  
Infiltrating Lymphocytes

e14171 Background: We previously reported that aPD1 agents could be safely administered IL in patients (pts) with metastatic MEL with superficial lesions, providing local and bystander tumor response (Samoylenko, I., et al. (ASCO-SITC 2018)). We present results from an interim 6 mos analysis of RFS and ORR for IL neo aPD1 therapy. Methods: Pts with unresectable stage IIIC/D/IVM1a-c MEL (safety cohort, N = 7) and resectable stage IIIC/D/IVM1a (expansion cohort, N = 18), with ≥ 1 injectable cutaneous, subcutaneous, or nodal lesions ≥ 10 mm were allocated to 6 doses/12 of nivolumab or pembrolizumab before surgery (surg). aPD1 was given at scale-based dosing regimen reported previously. Tumor sampling for biomarker analysis and pCR confirmation (or core-needle biopsy, CNB) was performed prior to treatment and at week 13-18. The analysis was conducted on the ITT basis to estimate RFS at 6 mos and ORR. An RFS event was defined as disease progression or death due to any cause after surg and assessed in the expansion cohort. ORR for the both cohorts was evaluated. Results: Since Apr 2016 to Dec 2018 25 pts were enrolled. Baseline characteristics are summarized in Table. ORR was 47,6% (10/21 pts assessed), with 5 (24%) clinical CR and 4 pathological CR (19%). Among 18 pts considered for surg 2 refused from surg when CNB confirmed no residual tumor. 89% of pts (16/18 pts) from the expansion cohort remained recurrence free at 6 mos FU. Baseline immune phenotype of tumor infiltrating lymphocytes (TILs) was available for 20 of 21 pts assessed. Baseline percent of TILs assessed by flow cytometry (FCT) was higher in responders vs non-responders (7.54±7.51% vs 1.51±2.93, p < .05), whereas CD3-CD16+CD56+ and CD4+CD25+ values were lower in responders vs non-responders (0.94±1.45% vs 7.88±6.84, p < .05, and 6.68±3.46% vs 20.50±16.79, p < 0.05, respectively). PD1, PDL-1 and PDL-2 expression in tumor cells and TILs assessed by FCT did not differ significantly between responders and non-responders. Conclusions: We demonstrated the potential clinical efficacy of IL aPD1 in melanoma pts. Further studies are needed to determine if unsuccessful IL administration could predict failure to adjuvant treatment. Primary analysis of RFS at 1-yr is expected. Clinical trial information: NA. [Table: see text]

Biomarkers of immunotherapy response in rectal adenocarcinoma treated with neoadjuvant chemoradiotherapy.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 593-593
Author(s):  
Gurveen Kaur ◽  
Pritam Tayshetye ◽  
Prashant Mukesh Jani ◽  
Ashten N Omstead ◽  
Paul Renz ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Rectal Adenocarcinoma ◽  
Neoadjuvant Chemoradiotherapy ◽  
Tumor Infiltrating Lymphocytes ◽  
Distant Metastases ◽  
Outcome Data ◽  
Rt Pcr ◽  
High Power Field ◽  
Tissue Samples

593 Background: Immunotherapy (IO) in combination with chemoradiotherapy (CRT) in the neoadjuvant treatment for locally advanced rectal adenocarcinoma (RAC) is an area of active clinical research. There are no well-defined biomarkers in RAC predicting response to neoadjuvant therapy. Increase in tumor PD-L1 expression and tumor infiltrating lymphocytes (TIL) has been observed after neoadjuvant CRT which potentially enhances response to IO. We report herein expression of PD-L1 and CD8+ TIL and other biomarkers of immune activation including CXCL9, TIM3 (HAVCR2), IDO1, IFNG, IL17RE, LAG3 and OX40 (TNFRSF4) pre and post neoadjuvant CRT in RAC. Methods: We retrospectively evaluated 38 RAC patients from 2007-2016 treated with neoadjuvant CRT using 5FU based therapy. Pre and post CRT tissue samples were stained with VENTANA PD-L1 (SP263) rabbit monoclonal antibody to quantify PD-L1 expression. CD8+ TIL were recorded over one high power field (hpf) (40x objective) in the area of densest infiltrate. Additional biomarkers CXCL9, TIM3 (HAVCR2), IDO1, IFNG, IL17RE, LAG3 and OX40 (TNFRSF4) were assayed with RT-PCR. Independent sample and paired sample t-tests were used for statistical analysis of difference in biomarker expression. Relevant clinical endpoints including local relapse, distant metastases and survival were collected. Results: Median age was 60 years (range 32–87). Median follow up was 16.7 months (range 2.6-120.1). Median duration from completion of CRT to resection was 73 days (range 44–315). PD-L1 expression increased from 10% to 23% in pre-CRT versus post-CRT patients. CD8+ TIL increased in 30/39 (83%) patients with an average increase from 66.48 to 129.20 CD8+ TIL/hpf in the pre-CRT versus post-CRT setting. Using RT-PCR, a statistically significant increase in the expression of CXCL9, IFNG and OX40 (TNFRSF4) was found pre-CRT versus post-CRT using paired samples t-test. Conclusions: Neoadjuvant CRT for RAC increased PD-L1 expression and CD8+ TIL along with an increased expression of CXCL9, IFNG and OX40 (TNFRSF4). These data suggest a novel role for IO in neoadjuvant treatment of rectal cancer. Clinical outcome data on these patients will be presented.

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