Protective effect of a brisk tumor infiltrating lymphocyte infiltrate in melanoma: An EORTC melanoma group study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8519-8519 ◽  
Author(s):  
A. Spatz ◽  
P. A. Gimotty ◽  
M. G. Cook ◽  
J. J. van den Oord ◽  
N. Desai ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Cox Model ◽  
Tumor Infiltrating Lymphocytes ◽  
Good Prognosis ◽  
Small Population ◽  
Independent Prognostic Factor ◽  
Anatomic Site ◽  
Chi Square ◽  
Cox Models ◽  
Vertical Growth Phase

8519 Background: Tumor-infiltrating lymphocytes (TILs) in melanoma are responsible for tumor killing and may induce spontaneous regression. Brisk TILs in the melanoma vertical growth phase (VGP) is a strong, albeit not independent, prognostic factor associated with superior survival. This study investigated whether more detailed classes of TIL patterns, based on topography and intensity, are independent prognostic factors and identify patients with good prognosis. Methods: The study included 1,171 patients with cutaneous VGP melanoma with at least 3 years of follow up for whom slides were available for review. TIL infiltrate was assessed for pattern (absent, non brisk, brisk), intensity (scanty, moderate, dense), and topography (peripheral, central, both). Pattern was assessed qualitatively: brisk TIL infiltrate was defined as a continuous band of lymphocytes at the base of the melanoma, or throughout the tumor. Other studied variables were: thickness, mitotic count (MC), ulceration, gender, age, anatomic site, melanoma-related death (MRD). Subsequently, Chi-square tests, Kaplan-Meier curves (KM), logrank tests, and Cox models were applied to examine the relation between MRD, TIL categories and interaction with other variables. Results: A brisk infiltrate was observed in 21.2% of the cases. Adjusted hazard ratio for MRD as compared to the absent category was 0.82 (95% CI=0.64–1.06) in the non-brisk category, and 0.43 (95% CI=0.28–0.68) in the brisk category. Based on the Cox model, brisk TIL was an independent prognostic factor for MRD (p<0.001) controlling for thickness, MC, ulceration, gender, age and site. Intensity was significantly associated with MRD for melanomas with peripheral and central brisk TILs (p=0.027) but not for other melanomas. Remarkably, no death was observed in the 5.5% of melanomas with dense, brisk TIL infiltrate at ten years. Conclusions: A brisk TIL pattern was shown to have prognostic value for MRD underscoring the importance of TILs in the outcome of VGP melanoma patients. Furthermore, we identified a small population of “super-responder” patients whose tumor was characterised by a continuous and dense TIL infiltrate and who did not display signs of tumor progression. No significant financial relationships to disclose.

Ki67 as a prognostic biomarker for patients with vertical growth phase (VGP) melanomas

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9043-9043
Author(s):  
P. Gimotty ◽  
D. Guerry ◽  
P. VanBelle ◽  
K. Montone ◽  
M. Guerra ◽  
...  
Keyword(s):  
Cross Validation ◽  
Tumor Infiltrating Lymphocytes ◽  
Roc Curves ◽  
Mitotic Rate ◽  
Net Benefit ◽  
Anatomic Site ◽  
Logistic Regression Models ◽  
Misclassification Rates ◽  
Vertical Growth Phase ◽  
A Prospective Study

9043 Background: In VGP melanomas proliferation is reflected in dermal mitotic figures (“mitogenic” VGP) and/or tumor cell nests larger than any epidermal nest. An alternative to mitotic rate (MR) to characterize cell proliferation is the expression of Ki67 protein. Since Ki67 is expressed in all phases of the cell cycle except G0, it is potentially a more robust biomarker for proliferation and prognosis than mitoses. Methods: To test the hypothesis that Ki67 would replace MR as a prognostic factor, we did a retrospective cohort study of 432 patients with Stage I/II primary VGP melanomas who had at least 10 years of follow up. Tissue sections were stained using the monoclonal antibody MIB-1 to Ki67 and the % of positive melanoma cells were evaluated by two readers. ROC curves for Ki67 and MR were computed. Predicted probabilities (PP) of 10-year melanoma-specific death were computed from 3 multivariate logistic regression models, one for each biomarker (Models 1 and 2) and one with both (Model 3), controlling for established melanoma prognostic factors (thickness, gender, anatomic site, ulceration, regression and tumor infiltrating lymphocytes), and compared. Cross-validation was used to assess differences between using Ki67 and using MR including the differences in PP, Brier scores and the misclassification rates. A decision curve analysis was done to assess the clinical net benefit of the two. Results: The areas under the ROC curve (AUCs) for Ki67 and MR, both continuous factors, were 0.69 and 0.79, respectively. In the multivariate analysis, Ki67 expression was significant in Model 1 (OR=1.03, 95% CI: 1.01–1.05), mitotic rate was not significant in Model 2 (1.05, 0.99–1.1), and only Ki67 was significant in Model 3 (1.03, 1.01–1.05). The AUCs for the three models were 0.84, 0.84, and 0.85, respectively. Based on cross-validation, there was no difference between the two biomarkers in PP, Brier scores, or misclassification rates. The decision cost analysis demonstrated the same net benefit for the two. Conclusions: A prospective study needs to be conducted to confirm that Ki67 and MR are equivalent. No significant financial relationships to disclose.

Presence of tumor-infiltrating lymphocytes is an independent prognostic factor in type I and II endometrial cancer

2009 ◽  
Vol 114 (1) ◽  
pp. 105-110 ◽  
Author(s):  
R.A. de Jong ◽  
N. Leffers ◽  
H.M. Boezen ◽  
K.A. ten Hoor ◽  
A.G.J. van der Zee ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Prognostic Factor ◽  
Tumor Infiltrating Lymphocytes ◽  
Independent Prognostic Factor ◽  
Type I ◽  
Infiltrating Lymphocytes

The biology and prognostic value of lymphatic vessel density (LD) and lymphatic invasion (LI) in regression in melanoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9017-9017
Author(s):  
S. Yun ◽  
P. Gimotty ◽  
W. Hwang ◽  
P. Dawson ◽  
P. VanBelle ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Prognostic Value ◽  
Lymphatic Vessels ◽  
Tumor Infiltrating Lymphocytes ◽  
Lymphocytic Infiltration ◽  
Melanoma Cells ◽  
Lymphatic Invasion ◽  
Complete Regression ◽  
Cox Models ◽  
Vertical Growth Phase

9017 Background: Regression in melanoma is characterized by increased vascularity, lymphocytic infiltrate and fibroplasia in the papillary dermis, accompanied by the absence (complete regression, CoR) or presence (partial regression, PaR) of melanoma cells in the epidermis. The prognostic value of regression is controversial. We noticed that LD and LI were increased in the areas of regression (AR) or areas with brisk lymphocytic infiltration (AB). Our goal was to clarify the prognostic value of regression in melanoma. Methods: Dual immunohistochemical staining was done using antibodies to podoplanin (lymphatic vessels) and S100 (melanoma cells) on paraffin tissues from 321 patients with vertical growth phase (VGP) primary melanomas who had 10 years or more of follow-up. LD in AR (both CoR and PaR) was compared with that of normal dermis adjacent and distant, as well as LD in the AB. LI in these areas was also scored. Unadjusted and adjusted hazard rates were obtained from univariate and multivariate Cox models for time to melanoma-specific death using established melanoma prognostic factors. Results: 116 patients (36%) had regression: 75 CoR (23%) and 41 PaR (13%). LD significantly decreased stepwise from CoR (mean ± se, 23.7 ± 2.7) to PaR (15.5 ± 1.1), adjacent normal dermis (7.3 ± 0.28) and distant normal dermis (5.4±0.31) and it was significantly elevated in the AB (18.5±0.78). Melanomas with CoR had the highest percentage of LI in both AR and AB. In addition, the percentage of LI in AB was highest for men and for those with VGP tumor infiltrating lymphocytes (TILs). Both high LD in AR and more LI in AB were associated with poor prognosis (p=0.004 and p=0.002, respectively). Six factors were significant in the final multivariate model: LI in AB (HR=2.3), LD in AR (HR=1.04), thickness (HR=1.44), axial (HR=7.7), ulceration (HR=2.5) and no VGP TILs (HR=2.8). Conclusions: AR and AB were associated with increased LD and higher incidence of LI in primary melanomas. LD and LI in AR or AB are independent prognostic factors. Our data suggest that the effects of regression on prognosis are mediated at least in part through lymphangiogenesis and LI. No significant financial relationships to disclose.

Prognostic value of flare-up phenomenon after discontinuation of sunitinib (SU) or pazopanib (PA) in metastatic renal cell carcinoma (mRCC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 448-448
Author(s):  
Roberto Iacovelli ◽  
Francesco Massari ◽  
Laurence Albiges ◽  
Bernard Escudier
Keyword(s):  
Prognostic Factor ◽  
Cox Model ◽  
Univariate Analysis ◽  
Complete Response ◽  
Independent Prognostic Factor ◽  
Tumor Growth Rate ◽  
Severe Toxicity ◽  
Risk Of Death ◽  
Kaplan Meier ◽  
The Difference

448 Background: SU and PA are VEGFR inhibitors, approved for the treatment of mRCC. Cessation of treatment has been reported to induce flare-up, with increased tumor growth rate (TGR). We aimed to investigate this phenomenon and its prognostic role in mRCC. Methods: Patients who discontinued first line SU or PA with available data about CT scans performed before (t-1), at the time of discontinuation (t0) and after (t+1), were included in this analysis. TGR was evaluated as the difference between the sum of longest diameters (SLD) of the target lesions during the interval time between the CTs (TGR1=SLD0–SLD-1/t0-t-1 and TGR2=SLD+1-SLD0/t+1-t0) and expressed in cm/month. Flare-up was evaluated as the difference between the TGRs. Median overall survival was evaluated from t0 (OS0) to death by the Kaplan-Meier method and correlation with variables was evaluated with Cox model. Results: Sixty-three patients treated from Oct 2006 to Nov 2012 at the Institut Gustave Roussy were eligible. Median age was 57.1 y, 81% were males, 89% had SU and 11% PA. Heng prognostic groups were good in 33% and intermediate in 67% of the pts. Median OS0 was 24.1 months (95%CI, 8.3 – 40.0). Major reasons for discontinuation were durable partial/complete response (16%), severe toxicity (22%) and progression of disease (62%). The median TGR1 and TGR2 were 0.2 and 0.7 cm/month, respectively (p=0.001), no correlation was found (p=0.33) and no differences were found between SU and PA in TGR1 (p=0.95) and TGR2 (p=0.53). Median flare-up was 0.5 cm/month (IQR: 0.1 – 1.2); in pts who discontinued for response, toxicity, or PD it was 0.1 (IQR: -0.2 – 0.6), 0.5 (IQR; 0.2 – 2.0) and 0.8 (0.1 – 1.7), respectively. At the univariate analysis flare-up was a prognostic factor for OS0 (HR: 1.13, 95%CI: 1.02 – 1.24; p=0.018). When compared to Heng criteria in the multivariate analysis, it was confirmed to be an independent prognostic factor: each increase of 1 cm in flare-up increases the risk of death by 11% (HR: 1.11, 95%CI: 1.00 – 1.23; p=0.048). Conclusions: Flare-up is an independent prognostic factor present in patients affected by mRCC who discontinued SU or PA. This is independent by the reason for discontinuation and the type of therapy.

Time from nephrectomy (Nx) as an independent prognostic factor in metastatic renal cell carcinoma (mRCC) patients treated with targeted therapies (TTs).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 517-517
Author(s):  
Giuseppe Procopio ◽  
Roberto Iacovelli ◽  
Elena Verzoni ◽  
Paolo Grassi ◽  
Isabella Testa ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Metastatic Disease ◽  
Prognostic Value ◽  
Performance Status ◽  
Multivariable Analysis ◽  
Final Analysis ◽  
Good Prognosis ◽  
Independent Prognostic Factor ◽  
Rank Test ◽  
Ecog Performance Status

517 Background: Nx has been established as a prognostic factor in mRCC and included in current prognostic classifications. Despite this, the prognostic value of time from Nx has not well established in patients (pts) treated with TTs. We aim to investigate if the time from Nx to diagnosis of metastatic disease is a prognostic factor in mRCC pts treated with TTs. Methods: Database of pts treated at Istituto Nazionale Tumori of Milan, was reviewed. Only pts who received an Nx were included in the final analysis. For each pt time from Nx to diagnosis of metastatic disease was collected and pts were divided in three groups based on time ≥ 1 year (A), < 1 year (B) or Nx performed at diagnosis of metastatic disease (C, cytoreductive). Age, sex, ECOG performance status and MSKCC prognostic group were also collected. Overall survival was calculated from the start of therapy to death or last follow-up. Median OSs were estimated with Kaplan-Meier method and compared with log-rank test; association of factors with survival was evaluated with Cox-analysis. Results: A total of 285 pts meet the inclusion criteria: median age was 60.8 y (IQR: 52.5 – 68), 73% were males; ECOG-PS was 0 in 61%, 1 in 34% and 2 in 5%. Prognosis based on MSKCC classification was good in 36%, intermediate in 49% and poor in 15%, and its prognostic value was confirmed (HR: 2.7; 95%CI, 2.1 – 3.4, p<0.001). Time from Nx was ≥ 1 year in 25%, < 1 year in 26% and concomitant to diagnosis of metastatic disease in 49% of cases. The median survival was 44.5 (95%CI, 35.6 – 53.5), 22.3 (95%CI, 16.1 – 28.5), 18.1 months (95%CI, 11.5 – 24.6) for the group A, B and C, respectively with a significant differenced for every comparison (A vs. B: p=0.041; A vs. C p<0.001 and B vs. C p=0.016). When time from Nx was compared to MSKCC in the multivariable analysis, this remain an independent prognostic factor (HR: 0.7; 95%CI, 0.6 – 0.9, p<0.001). Conclusions: In mRCC pts treated with Nx and targeted therapy, time from Nx is an independent prognostic factor. Pts with good prognosis based on MSKCC criteria who had Nx more than 1 year before the diagnosis of metastatic disease have better prognosis compared to a pts with the same MSKCC risk that receive Nx with cytoreductive intent.

scholarly journals Necroptosis in Esophageal Squamous Cell Carcinoma: An Independent Prognostic Factor and Its Correlation with Tumor-Infiltrating Lymphocytes

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4473
Author(s):  
Takuro Yamauchi ◽  
Fumiyoshi Fujishima ◽  
Masatoshi Hashimoto ◽  
Junichi Tsunokake ◽  
Ryujiro Akaishi ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Prognostic Factor ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Therapeutic Efficacy ◽  
Tumor Infiltrating Lymphocytes ◽  
Independent Prognostic Factor ◽  
Biopsy Specimens ◽  
Infiltrating Lymphocytes

Necroptosis is a pivotal process in cancer biology; however, the clinical significance of necroptosis in esophageal squamous cell carcinoma (ESCC) has remained unknown. Therefore, in this study, we aimed to verify the potential involvement of necroptosis in the clinical outcome, chemotherapeutic resistance, and tumor microenvironment of ESCC. Mixed lineage kinase domain-like protein (MLKL) and phosphorylated MLKL (pMLKL) were immunohistochemically examined in 88 surgically resected specimens following neoadjuvant chemotherapy (NAC) and 53 pre-therapeutic biopsy specimens, respectively. Tumor-infiltrating lymphocytes (TILs) were also evaluated by immunolocalizing CD3, CD8, and forkhead box protein 3 (FOXP3) in the residual tumors after NAC. High pMLKL status in the post-NAC resected specimens was significantly correlated with worse prognosis in ESCC patients. Multivariate analysis demonstrated that a high pMLKL status was an independent prognostic factor. In pre-NAC biopsy specimens, a high pMLKL status was significantly associated with a lower therapeutic efficacy. CD8+ TILs were significantly lower in the high-pMLKL group. FOXP3+ TILs were significantly higher in both high-MLKL and high-pMLKL groups. We first demonstrated pMLKL status as an independent prognostic factor in ESCC patients. Our study revealed the possible involvement of necroptosis in the immunosuppressive microenvironment, resulting in the attenuated therapeutic efficacy of NAC and eventual adverse clinical outcomes in ESCC.

The prognostic significance of lymphatic invasion in primary melanoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9050-9050
Author(s):  
X. Xu ◽  
L. Chen ◽  
W. Hwang ◽  
P. Dawson ◽  
D. Guerry ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Prognostic Significance ◽  
Primary Melanoma ◽  
Risk Groups ◽  
Lymphatic Invasion ◽  
Independent Prognostic Factor ◽  
Rank Test ◽  
Survival Curves ◽  
Cox Models ◽  
Log Rank Test

9050 Background: Lymphatic invasion (LI) is an under-observed phenomenon in primary malignancies that can be better detected by immunostaining and that may associate with prognosis. In this study we sought to test the hypothesis that LI was associated with melanoma-specific survival (MSS) and was an independent prognostic factor. Methods: This study included 277 patients with stage I/II melanomas in vertical growth phase (VGP) who had at least 10 years of follow up. The log-rank test was used to test the study hypothesis - 72 melanoma-specific deaths were needed for 80% power to detect an odds ratio of 2.1. Paraffin sections were stained with antibodies to podoplanin (lymphatic vessels) and S-100 (melanoma cells) to identify LI. Univariate and multivariate Cox models were used to evaluate the prognostic significance of LI. An independent cohort of 106 similar patients was used for validation of the 10-year MSS rates. Results: LI was observed in 44.5% (95% CI: 38.6% - 50.4%) of the melanomas and its presence was significantly associated with thickness, mitotic rate, gender, age, and ulceration (U). The Kaplan-Meier survival curves for those with and without LI were significantly different (log-rank test p=0.022). The final multivariate model for time to MSD identified 4 independent prognostic factors: thickness (HR=1.5, p<0.001), U (HR=2.2 p=0.013), site (HR=3.9, p<0.001) and LI (HR=1.9, p=0.015). These factors were used to define a prognostic tree with 5 risk groups defined by melanomas that were thin (≤1.0mm) with no LI or U; thin with LI but no U; 1–3mm with no U; 1–3mm with U; and >3mm. Respectively, MSS rates were 100%, 88.6%, 77%, 48% and 42%. In the validation set, observed 10-year MSS rates in each risk group were not significantly different from those predicted from the survival curves for the tree-based risk groups. Conclusions: LI is an independent prognostic factor for MSS. Among patients with thin melanomas without U the 10-year MSS was lower for those patients with LI (89%, 95% CI=78% - 99%; n=41) compared to those without (100%, n=78). LI is an important prognostic factor that needs further validation in a population of patients from the sentinel node biopsy era. No significant financial relationships to disclose.

scholarly journals Lectin-Like Transcript 1 (LLT1) Checkpoint: A Novel Independent Prognostic Factor in HPV-Negative Oropharyngeal Squamous Cell Carcinoma

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 535
Author(s):  
Mario Sanchez-Canteli ◽  
Francisco Hermida-Prado ◽  
Christian Sordo-Bahamonde ◽  
Irene Montoro-Jiménez ◽  
Esperanza Pozo-Agundo ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Squamous Cell ◽  
Nk Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Independent Prognostic Factor ◽  
Rank Test ◽  
Prognostic Impact ◽  
Mrna Levels ◽  
Primary Tumors ◽  
Hpv Status

Lectin-like transcript 1 (LLT1) expression by tumor cells contributes to immune evasion, thereby emerging as a natural killer (NK) cell-mediated immunotherapeutic target. This study is the first to investigate LLT1 expression (encoded by CLEC2D gene) in head and neck cancers to ascertain its impact on patient prognosis. LLT1 expression was analyzed by immunohistochemistry in a homogeneous cohort of human papillomavirus (HPV)-negative oropharyngeal squamous cell carcinomas (OPSCC), and correlated with clinical data. Results were further validated using transcriptomic data from the TCGA database. Tumoral LLT1 expression was detected in 190/221 (86%) OPSCC specimens, whereas normal pharyngeal epithelium was negative. Patients harboring LLT1-positive tumors showed significantly lower disease-specific (DSS) and overall survival (OS) (p = 0.049 and p = 0.036, respectively, log-rank test). High density of LLT1-positive tumor-infiltrating lymphocytes (TIL) was also frequently detected in 160 (73%) OPSCC samples, and significantly associated with better DSS and OS (p < 0.001 and p = 0.007, respectively). Multivariate Cox analysis further revealed that tumoral LLT1 expression and infiltration of LLT1-positive TIL were independent prognostic factors for DSS and OS. CLEC2D mRNA levels are also significantly increased in primary tumors compared to normal tissue. Strikingly, the prognostic impact of CLEC2D mRNA levels varied depending on HPV status in OPSCC, and among distinct cancer types. CLEC2D expression was significantly correlated with NK cell infiltration using the MCP-counter model. These findings uncover LLT1/CLEC2D as an independent prognostic factor in HPV-negative OPSCC, and a potential novel target for immunotherapy.

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