Effect of PDL-1 expression on prognosis in head and neck squamous cell carcinoma.
Maria VasilakopoulouVamsidhar VelchetiΘεόδωρος ΡάμπιαςClarence T. SasakiDavid L. RimmGeorge FountzilasAmanda Psyrri
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6012 Background: The recent demonstration that immunotherapeutic approaches may be clinically effective for cancer patients has renewed the interest for this therapeutic strategy. Engagement of programmed death-1 receptor (PD-1), expressed on activated T-cells, by its ligands, results in a negative regulatory effect, with inhibition of downstream cellular signaling events. Our aim was to investigate the expression and prognostic significance of immunoresistance molecule PDL-1 (the negative regulator programmed death-1-ligand 1) on an annotated HNSCC tissue microarray. Methods: A tissue array composed of 400 larynx cancers treated with surgery followed by radiotherapy was constructed. PDL-1 protein expression levels were assessed using automated quantitative protein analysis (AQUA). The objectives of this analysis were to determine the association of PDL-1 with efficacy outcomes ( overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) ). The univariate and multivariate Cox proportional hazards models were used to evaluate the relationship between PDL-1 and event-time distributions. Event-time distributions were estimated by the Kaplan-Meier method and compared by the log-rank test. Results: Mean follow-up time for the entire cohort was 39.34 months. Two-hundred thirty eight of 400 cases had sufficient tissue for AQUA analysis. High tumor PDL-1 expression was associated with favorable outcome for OS (P=0.029) and trended towards improved DFS (P=0.06) at 5 years. In multivariable analysis, adjusting for well-characterized prognostic variables, PDL-1 expression status retained its prognostic significance for OS and there was again a trend for PFS (p=0.05). Conclusions: This paradoxical result is in accordance with reported studies in HPV-associated HNSCC where PD-1(+) T cells were associated with favorable clinical outcome. It is possible that PDL-1 detection may reflect a previous immune response against tumors. Further work will determine whether PD-1/PD-L1 blockade induces tumor regression in HNSCC.Keywords:
Tissue microarray
Univariate analysis
Morphologic assessment of lung tumors is informative but insufficient to adequately predict patient outcome. We previously identified transcriptional profiles that predict patient survival, and here we identify proteins associated with patient survival in lung adenocarcinoma. A total of 682 individual protein spots were quantified in 90 lung adenocarcinomas by using quantitative two-dimensional polyacrylamide gel electrophoresis analysis. A leave-one-out cross-validation procedure using the top 20 survival-associated proteins identified by Cox modeling indicated that protein profiles as a whole can predict survival in stage I tumor patients ( P = 0.01). Thirty-three of 46 survival-associated proteins were identified by using mass spectrometry. Expression of 12 candidate proteins was confirmed as tumor-derived with immunohistochemical analysis and tissue microarrays. Oligonucleotide microarray results from both the same tumors and from an independent study showed mRNAs associated with survival for 11 of 27 encoded genes. Combined analysis of protein and mRNA data revealed 11 components of the glycolysis pathway as associated with poor survival. Among these candidates, phosphoglycerate kinase 1 was associated with survival in the protein study, in both mRNA studies and in an independent validation set of 117 adenocarcinomas and squamous lung tumors using tissue microarrays. Elevated levels of phosphoglycerate kinase 1 in the serum were also significantly correlated with poor outcome in a validation set of 107 patients with lung adenocarcinomas using ELISA analysis. These studies identify new prognostic biomarkers and indicate that protein expression profiles can predict the outcome of patients with early-stage lung cancer.
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Objective To search a simple making mothd of tissue microarray and evaluate its validation. Methods A new, simple and easy method was designed to improve the technology of TMA during the experiment. Tissue microarrays with 1.6 mm in diameter tissue core were constructed from 124 cases of breast cancer. The tissue microarrays were stained for oestrogen receptor(ER),progesterone receptor(PR)and c-erBb2 using immunohistochemistry.At the same time the stains on the tissue microarrays were compared with that from the full tissue sections. Results A highly significant association was observed between the staining scores(0 ～ 7)obtained from the full tissue sections and from the tissue microarrays. Concordance for the receptor status(positive / negative)of the whole section and the tissue core were 94.35% for ER,93.55% for PR.and 91.94% for c-erBb2.The discordance between full section and tissue microarrays was studied using Two - Related - Samples tests and the result had no statistical significance(P0.05) . Conclusion Tissue microarays with 1.6 mm in diameter tissue core made by simple method can represent full tissue section on immunohistochemistry study.We believe our method of tissue microarray is a reliable and valid
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Background/Aim: Previously, we identified predictors of survival after irradiation of grade II-IV cerebral gliomas. In this supplementary analysis, survival was calculated in a more appropriate way than the original study. Patients and Methods: Ten factors were re-evaluated for survival in patients of the original study including pre-radiotherapy seizures. In the original study, survival was calculated from the end of the last radiotherapy course (primary or re-irradiation). After re-review, this approach was considered inappropriate. Survival should have always been calculated from the first radiotherapy course, as done in this supplementary analysis. Results: On multivariate analysis, WHO-grade II (p=0.006) and upfront resection (p=0.001) were associated with better survival. Unifocal glioma was significant on univariate analysis (p=0.001), where a trend could be identified for age ≤59 years (p=0.057) and seizures (p=0.060). Conclusion: The findings of this supplementary analysis regarding the identification of prognostic factors for survival agree with the results of the original study.
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Objective To explore the prognostic factors of astrocytic tumors as the theoretical reference to the clinical treatment. Methods Data of 89 patients with astrocytic tumors, admitted in Zhujiang Hospital from January to June 2000, were collected and analyzed with regard to patient age, gender, preoperative KPS score, epilepsy before surgery, histologic grade, tumor location and extension, extent of surgery, radiation, date of operation, date of death, physical state in the last follow-up (dead or alive), and cause of death. For the univariate analysis, survival probabilities were estimated based on Kaplan-Meier's survival analysis and Logrank test. Multivariate regression analysis using Cox's proportional-hazards model showed the simultaneous effect of outcome-related variables on survival. Results Univariate analysis demonstrated that patient age, KPS score, epilepsy before surgery, histologic grade and radiation were the significant factors for survival (P0.01). In contrast, multivariate survival analysis showed that patient age, histologic grade and KPS score were independent, statistically significant prognostic factors for patients with astrocytic tumors, whereas preoperative epilepsy and postoperative radiation did not reach the significance level for entry into the stepwise model. And gender, tumor location, tumor extension and extent of sugery had no association with patient survival on both univariate and multivariate analysis. Conclusion Patient age, histologic grade and KPS score are associated strongly with survival, while preoperative epilepsy and postoperative radiation appear to be of limited prognostic value. And there is no correlation among gender, extent of surgery and prognosis. Neither tumor location nor tumor extension is associated with survival.
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Objective To evaluate the validation of tissue microarrays.Methods Tissue microarrays with 2 mm in diameter tissue core were constructed from seventy cases of breast cancer.The tissue microarrays were stained for oestrogen receptor(ER) and progesterone receptor(PR) using immunohistochemistry.At the same time the stains on the tissue microarrays were compared with that from the full tissue sections. Results A highly significant association was observed between the staining scores(0～7) obtained from the full tissue sections and from the tissue microarrays.Concordance for the receptor status(positive/negative) of the whole section and the tissue core were 96.67% for ER,93.93% for PR.The discordance between full section and tissue microarrays was studied using Two-Related-Samples tests and the result had no statistical significance(P0.05). Conclusion Tissue microarays with 2 mm in diameter tissue core can represent full tissue section on immunohistochemistry study,if the tissue microarrays are constructed as standard method.We believe tissue microarray is a reliable and highthroughout tool for research.
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Background: Oral squamous cell carcinoma (OSCC) accounts for more than 90% of all oral cancers. Epidermal growth factor receptor (EGFR) dysregulation is associated with essentially all of the key features of cancer. Tissue microarrays (TMAs) allow the simultaneous analysis of many tumours using small-diameter cores sampled from larger blocks of tissue. Hence present study was taken up to validate TMA technology. Aims and Objectives: To analyse and compare the immunohistochemical (IHC) expression of EGFR in OSCC using TMA technology and in whole tissue sections. Materials and Methods: Study included 34 cases of OSCC.Three tissue cores, each 1 mm in diameter were placed into a recipient paraffin block using a precision microarray instrument finally containing 102 spots. EGFR expression was analysed. Agreement between whole sections and TMA scores was analysed using Cohen's weighted Kappa. Results: EGFR expression was seen in 61.8% of whole section cases. In TMA out of 102 cores 75.50 % of the disks were confirmed to represent an adequate amount of tumor tissue. In TMA 48.5% cases showed EGFR expression. The EGFR expression of whole. Conclusion: Some OSCC express high EGFR and this expression may be an independent Wfactor of certain clinico-pathological variables. TMA may be used as an adjunct with conventional method of evaluation of OSCC especially in larger sample sized studies keeping in mind its limitations.
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HER-2 gene alterations have been shown to have prognostic and predictive value for the treatment of breast cancer with therapeutic agents. As a result, the accurate evaluation of HER-2 status is crucial. HER-2 status is assessed at the protein level by immunohistochemistry and at the DNA level by fluorescence in situ hybridization (FISH). Although the best approach is to combine immunohistochemistry and FISH assays, doing so is not practical or cost-effective for routine histopathologic laboratories. The recent development of tissue microarray technology has allowed large-scale studies using formalin-fixed, paraffin-embedded material. We used this technique to assess HER-2 status in a cohort of 54 invasive breast cancer cases by immunohistochemistry and FISH assays to determine whether the results obtained were representative of the protein and gene expression patterns of the original whole tissue section. Concordance for HER-2 immunohistochemistry between the tissue microarray and full sections was 93%. Concordance for HER-2 FISH between the tissue microarray and full sections was 91%. Concordance between HER-2 FISH and HER-2 immunohistochemistry on the tissue microarray was 98%. We conclude that tissue microarrays provide highly comparable results in the assessment of HER-2 protein levels and allow large-scale analysis of the HER-2 gene by FISH.
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