Prognostic Marker For Survival Research Articles

The Value of Early Tumor Size Response to Chemotherapy in Pediatric Rhabdomyosarcoma.

Simple SummaryRhabdomyosarcoma is the most common soft tissue sarcoma in childhood. At diagnosis, tumor and patient characteristics determine the prognosis and subsequent treatment stratification. There are currently no early biomarkers that identify good or poor responders to chemotherapy regimens, survival being the only valid endpoint. Early tumor size response, which is assessed by imaging, could be such a marker. We performed a systematic assessment of literature to November 2020. Six studies were included describing 2010 patients; quality assessment showed methodological limitations. We conclude that there is evidence that early progressive disease is associated with poorer survival compared to patients with non-progressive disease, being either stable disease, partial, or complete response. However, for the vast majority of patients with non-progressive disease, we found no evidence that the degree of response is prognostic for survival. Therefore, the value of early tumor size response as a prognostic marker, and its translation into treatment modifications on an individual patient or trial level should be reconsidered.Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood. Results of clinical trials, with three-year event-free and overall survival as primary outcomes, often take 7 to 10 years. Identification of an early surrogate biomarker, predictive for survival, is therefore crucial. We conducted a systematic review to define the prognostic value of early tumor size response in children with IRSG group III rhabdomyosarcoma. The search included MEDLINE/EMBASE from inception to 18 November 2020. In total, six studies were included, describing 2010 patients, and assessed by the Quality in Prognosis Studies (QUIPS) instrument. Four studies found no prognostic value for tumor size response, whereas two studies reported a prognostic effect. In these two studies, the survival rate of patients with progressive disease was not separately analyzed from patients with stable disease, potentially explaining the difference in study outcome. In conclusion, our findings support that early progression of disease is associated with poorer survival, justifying adaptation of therapy. However, in patients with non-progressive disease, there is no evidence that the degree of response is a prognostic marker for survival. Because the vast majority of patients do not have progressive disease, early tumor size response should be reconsidered for assessment of treatment efficacy. Therefore, at present, early surrogate biomarkers for survival are still lacking.

Prognostic Value of Antithrombin Levels in COVID-19 Patients and Impact of Fresh Frozen Plasma Treatment: A Retrospective Study

Objective:The defective interplay between coagulation and inflammation may be the leading cause of intravascular coagulation and organ dysfunction in coronavirus disease-19 (COVID-19) patients. Abnormal coagulation profiles were reported to be associated with poor outcomes. In this study, we assessed the prognostic values of antithrombin (AT) activity levels and the impact of fresh frozen plasma (FFP) treatment on outcome.Materials and Methods:Conventional coagulation parameters as well as AT activity levels and outcomes of 104 consecutive critically ill acute respiratory distress syndrome (ARDS) patients with laboratory-confirmed COVID-19 disease were retrospectively analyzed. Patients with AT activity below 75% were treated with FFP. Maximum AT activity levels achieved in those patients were recorded.Results:AT activity levels at admission were significantly lower in nonsurvivors than survivors (73% vs. 81%). The cutoff level for admission AT activity was 79% and 58% was the lowest AT for survival. The outcome in those patients who had AT activity levels above 75% after FFP treatment was better than that of the nonresponding group. As well as AT, admission values of D-dimer, C-reactive protein, and procalcitonin were coagulation and inflammatory parameters among the mortality risk factors.Conclusion:AT activity could be used as a prognostic marker for survival and organ failure in COVID-19-associated ARDS patients. AT supplementation therapy with FFP in patients with COVID-19-induced hypercoagulopathy may improve thrombosis prophylaxis and thus have an impact on survival.

Galectins-1, -3, -7, -8 and -9 as prognostic markers for survival in epithelial ovarian cancer: A systematic review and meta-analysis.

Galectins are a family of proteins that have recently emerged as regulators of cancer biology. To investigate the impact of peritumoral and tumoral galectin expression on ovarian cancer prognosis. We searched Medline, Cochrane, and EMBASE databases from inception until March 22, 2020. All studies correlating galectins and ovarian cancer prognosis were selected. The literature search presented 11 studies, which contained 1034 patients. Meta-analysis was performed with RevMan 5.3 software. Studies were stratified into two groups depending on the location of galectin expression (peritumoral stroma or nucleus/cytoplasm of tumor cells). Tumoral galectin-7 and galectin-9 expression was significantly associated with poor overall survival (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.32-3.21, P=0.001; OR 1.71, 95% CI 1.27-2.30, P<0.001, respectively). The total effect of high tumoral expression of galectins in overall survival and progression-free survival was significant (OR 1.51, 95% CI 1.02-2.23, P=0.04; OR 2.76, 95% CI 1.73-4.40, P<0.001, respectively). Our results suggest that galectins are implicated in ovarian cancer prognosis; however, further research is needed to ascertain their actual importance as well as their diagnostic accuracy.

Abstract PO-033: Metabolic differences between human papillomavirus-related and smoking-related squamous cell carcinoma of the head and neck independently predict overall patient survival

Abstract Background: Human papillomavirus (HPV) status and tobacco use are the strongest prognostic factors of survival for squamous cell carcinoma of the head and neck (SCCHN). Patients with HPV-related SCCHN live more than twice as long as patients with tobacco-related SCCHN. The underlying metabolic dysregulation characterizing these two clinically distinct groups may pose exciting translational targets that are yet unknown. Using a metabolome-wide approach, we investigated the metabolic differences of HPV vs smoking-related SCCHN in a large patient population. We then linked those metabolic differences to patient survival. Methods: We recruited 137 patients from Emory University hospitals and clinics: 55 HPV-positive never smokers (i.e., HPV-related SCCHN) and 82 HPV-negative current or former smokers (i.e., smoking-related SCCHN). We performed untargeted high-resolution metabolomics using liquid chromatography-mass spectrometry on pre-treatment patient plasma at the Emory Clinical Biomarkers Laboratory. Our statistical approach has three steps. 1) Metabolite feature selection: We aggregated the results from two selection algorithms (5-fold cross-validated partial least squares discriminant analysis and support vector machine) to determine the metabolites that differentiated HPV vs smoking-related SCCHN. 2) Metabolic pathway analysis (Mummichog): We identified statistically significant (P&amp;lt;0.05) metabolic pathways stemming from the step 1 metabolites. 3) Metabolic profile and survival analysis: We created a metabolite-based linear principal component using the significant pathway metabolites in step 2 and estimated its association with overall survival using adjusted Cox models. Results: Of the 9,640 extracted metabolites, the two models found 229 that differentiated HPV vs smoking-related SCCHN. Metabolic pathway analysis found fatty acid and steroid metabolism was significantly upregulated in HPV patients: bile acid biosynthesis (P&amp;lt;0.0001), 21-carbon steroid hormone metabolism (P=&amp;lt;0.0001), fatty acid beta-oxidation (P=0.04). Pathways related to sugar metabolism were significantly upregulated in smoking patients: galactose metabolism (P=0.003), starch and sucrose metabolism (P=0.007), hexose phosphorylation (P=0.03), sialic acid metabolism (P=0.03). A principal component comprised of the 16 pathway metabolites was significantly associated with overall survival (HR=1.27 per standard deviation, P=0.01, 95% CI: 1.06-1.51) independent of HPV, smoking, tumor site, age, sex, race, and body mass index. Conclusions: Metabolites corresponding to fatty acid, steroid, and sugar metabolism differentiated HPV-related SCCHN from smoking-related SCCHN. They may be clinically informative as prognostic markers of survival. Our novel findings in patient plasma parallel those from HPV positive vs negative SCCHN cell lines, suggesting that metabolites in blood may be putative biomarkers of tumor metabolic activity and thus potentially useful for drug discovery. Citation Format: Ronald C. Eldridge, Karan Uppal, Jonathan Beitler, Kristin Higgins, Evanthia C. Wommack, Dong M. Shin, Nabil F. Saba, Andrew Miller, Deborah W. Bruner, Canhua Xiao. Metabolic differences between human papillomavirus-related and smoking-related squamous cell carcinoma of the head and neck independently predict overall patient survival [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-033.

The AST/ALT (De Ritis) Ratio Predicts Survival in Patients with Oral and Oropharyngeal Cancer.

Aminotransaminases, including aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT), are strongly involved in cancer cell metabolism and have been associated with prognosis in different types of cancer. The purpose of the present study was to evaluate the prognostic significance of the pre-treatment AST/ALT ratio in a large European cohort of patients with oral and oropharyngeal squamous cell cancer (OOSCC). Data from 515 patients treated for OOSCC at a tertiary academic center from 2000–2017 were retrospectively analyzed. Levels of AST and ALT were measured prior to the start of treatment. Uni- and multivariate Cox regression analyses were applied to evaluate the prognostic value of the AST/ALT ratio for cancer-specific survival (CSS) and overall survival (OS), survival rates were calculated. Univariate analyses showed a significant association of the AST/ALT ratio with CSS (hazard ratio (HR) 1.71, 95% confidence interval (CI) 1.38–2.12; p < 0.001) and OS (HR 1.69, 95% CI 1.41–2.02; p < 0.001). In multivariate analysis, the AST/ALT ratio remained an independent prognostic factor for CSS and OS (HR 1.45, 95% CI 1.12–1.88, p = 0.005 and HR 1.42, 95% CI 1.14–1.77, p = 0.002). Applying receiver operating characteristics (ROC) curve analysis, the optimal cut-off level for the AST/ALT ratio was 1.44, respectively. In multivariate analysis, an AST/ALT ratio > 1.44 was an independent prognostic factor for poor CSS and OS (HR 1.64, 95% CI 1.10–2.43, p = 0.014 and HR 1.55, 95% CI 1.12–2.15; p = 0.008). We conclude that the AST/ALT ratio is a prognostic marker for survival in OOSCC patients and could contribute to a better risk stratification and improved oncological therapy decisions.

Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients

Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy. There is a clinical need to identify biomarkers to predict outcome. Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma patients we identified pathogenic germline mutations in CDKN2A, CDK4, ATM, POLH, MRE11A, RECQL4 and XPC, affecting 7/44 patients. These mutations were associated with poor OS (p = 0.0082). We confirmed our findings in The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma cohort where we identified pathogenic variants in 40/455 patients (p = 0.0203). Combining these cohorts (n = 499) further strengthened these findings showing germline carriers had worse OS (p = 0.0009). Additionally, we determined whether tumour mutation burden (TMB) or BRAF status were prognostic markers of survival. Low TMB rate (< 20 Mut/Mb; p = 0.0034) and BRAF p.V600 mutation (p = 0.0355) were associated with worse progression-free survival. Combining these biomarkers indicated that V600 mutant patients had significantly lower TMB (p = 0.0155). This was confirmed in the TCGA (n = 443, p = 0.0007). Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72–15.7). Stage IV (HR 2.5, 0.74–8.6) and low TMB (HR 2.3, 0.57–9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44–5.2).

Influences of Semaphorin 3A Expression on Clinicopathological Features, Human Papillomavirus Status, and Prognosis in Oropharyngeal Carcinoma.

Human papillomavirus (HPV) infection is now identified as a major etiologic factor for oropharyngeal cancer (OPC), and HPV positivity is well established better prognostic marker in OPC. Now, predictable markers for the prognosis of the patients who are stratified by HPV has been investigated in. Semaphorin 3A (SEMA3A) is a well-known axon guidance molecule in the nervous system. It is also known as a tumor suppressor in various cancers. In the present study, we examined the relationships between SEMA3A and clinicopathologic features, especially HPV status, and neoangiogenesis, and its prognostic significance for OPC patients. Thirty-two OPC patients and 17 normal patients were analyzed for SEMA3A expression by immunohistochemical analysis. We also analyzed 22 OPC specimens for CD34 expression as a marker of neoangiogenesis. SEMA3A was significantly downregulated in OPC compared with chronic tonsillitis tissues (p = 0.005). SEMA3A expression was negatively correlated with CD34 expression (r = −0.466, p = 0.033). Moreover, the higher SEMA3A expression cohort showed better survival than the lower SEMA3A expression cohort regardless of HPV status (p = 0.035). These results suggest that SEMA3A expression is a prognostic marker for survival regardless of HPV status and is associated with anti-angiogenesis in OPC.

Thrombocytosis as a Prognostic Marker of Survival in Patients with Head and Neck Tumors

Zsuzsanna Szilasi*1, Valéria Jósa2, Zsombor Zrubka3, Tünde Mezei M4, Keresztély Merkel5, Frigyes Helfferich1 and Zsolt Baranyai7 Author Affiliations 1Department of Otorhinolaryngology and Head and Neck Surgery, HDF Medical Centre, Budapest, Hungary 2Department of Otorhinolaryngology and Head and Neck Surgery, Jahn Ferenc Hospital, Budapest, Hungary 3Department of Health Economics, Corvinus University of Budapest, Budapest, Hungary 4Department of Urology, Jahn Ferenc Hospital, Budapest, Hungary 5Department of Surgery, Szent Imre Hospital, Budapest, Hungary 6Department of Surgery, Semmelweis University, Budapest, Hungary Received: August 08, 2020 | Published: August 18, 2020 Corresponding author: Zsuzsanna Szilasi, Department of Otorhinolaryngology and Head and Neck Surgery, HDF Medical Centre, Budapest, Hungary DOI: 10.26717/BJSTR.2020.29.004829

Abstract 6616: Functional hotness score generated by representative functional cytotoxic T-lymphocytes predicts long-term survival of triple-negative breast cancer independently to the tumor mutational burden

Abstract Background: Cytotoxic T-lymphocytes (CTLs) infiltration in a bulk tumor is a positive prognostic factor in breast cancer. CTL recognition is believed to react to mutation-induced neoantigens, thus, higher tumor mutation burden (TMB) is considered as an important predictor of tumor immunogenicity and response to immunotherapy. Although majority of breast cancer have low tumor mutation burden (TMB), triple-negative breast cancer (TNBC) has higher TMB compared to other breast cancer subtypes. However, it is unclear if the prognostic value high CTL infiltration depends on the TMB as the primary driver of enhanced anti-cancer immunity or represents an independent prognostic marker which can be used as a complement to TMB to predict patients' outcomes. CTLs are identified by CD8 marker, is encoded by CD8A. Granzyme B (GZMB) is a serine protease that is secreted by functionally-active CTLs to induce apoptosis of the target cells. CXCL10 is a chemokine which selectively attracts activated CTLs into subsets of other cancers; but its role in breast cancer remains unknown. We investigated if TNBC infiltrated with high levels of functional CTLs, so called “hot tumors”, have improved survival independently of their TMB. Methods: Utilizing The Cancer Genome Atlas (TCGA) breast cancer cohort, we established Functional Hotness Score (FHS), based on the CD8A, GZMB and CXCL10 gene expression levels of bulk tumors. Total of 4149 breast cancer patients from publicly available multiple cohorts were analyzed to assess FHS and breast cancer patient prognosis as well as distinct immunity markers. Results: FHS predicted the breast cancer patient survival better than each consisting gene. The breast cancer patients with high FHS tumors showed significantly better survival in the testing cohort (TCGA), which was further confirmed in the validation cohort (METABRIC). FHS was higher in the primary breast cancer tissues with metastasis compared to that without metastasis in TCGA. Further, FHS was higher in the metastatic tumors compared to the primary tumors in GSE110590. Among breast cancer subtypes, TNBC showed highest FHS compared to other subtypes in testing TCGA, which was validated in the METABRIC cohort. The patients with high FHS tumor demonstrated significantly better long-term survival than that with low FHS only in the hormone receptor (HR)-negative breast cancers, but not in the HR-positive tumors. The high FHS TNBCs showed higher not only CD8-positive T cell infiltration, but also a broader type-1 anti-cancer immunity. To investigate if FHS predicts patient survival independent of TMB, the patients were divided into high and low TMB groups. Interestingly, the higher FHS patients showed better prognosis not only in the high TMB group but also in the low TMB among TNBC patients. The combination of high TMB with high FHS identified the unique subset of the patients who did not recur over time. Conclusion: In conclusion, TNBC with higher FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with higher anti-cancer immunity regardless of TMB, and constituting an independent prognostic marker of survival, particularly when combined with TMB. Citation Format: Eriko Katsuta, Li Yan, Mateusz Opyrchal, Pawel Kalinski, Kazuaki Takabe. Functional hotness score generated by representative functional cytotoxic T-lymphocytes predicts long-term survival of triple-negative breast cancer independently to the tumor mutational burden [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6616.

Factors predicting survival in thick melanoma: Do all thick melanomas have the same prognosis?

BackgroundIt is unknown whether all thick melanomas share the same prognostic features. We present a large, multi-institutional study on thick melanoma, evaluating for factors prognostic of survival. MethodsWe queried the database of the Sentinel Lymph Node Working Group for patients with thick melanoma (>4 mm) who had a sentinel lymph node biopsy from 1993 to 2018. Clinicopathologic characteristics were correlated with overall survival. ResultsThere were 1,235 patients with a median follow-up of 28 months. Median thickness was 5.9 mm, with 713, 356, and 166 cases having a thickness of >4 to 6, >6 to 10, and >10 mm, respectively. Ulceration was seen in 51.2% of cases, while sentinel lymph node metastases were seen in 439 of 1,235 (35.5%) cases. For melanomas >4 to 6 mm, age, thickness, ulceration, lymphovascular invasion, and sentinel lymph node metastasis were correlated with overall survival (all P < .05), but for melanomas >6 to 10 mm, only sex and sentinel lymph node metastasis were prognostic of overall survival (both P < .05). For melanomas >10 mm, only sentinel lymph node metastasis predicted overall survival on multivariable analyses (P < .05). ConclusionPrognostic markers of overall survival for thick melanoma include thickness, ulceration, and sentinel lymph node metastasis, but also include other unique factors such as lymphovascular invasion. Moreover, certain prognostic markers for survival are associated with different subgroups of thick melanoma, which vary based on thickness group.

Patient-reported outcomes as a prognostic marker of survival in patients with advanced nonsmall cell lung cancer treated with immunotherapy.

There has been minimal research on the prognostic value of patient-reported outcomes (PROs) for immune checkpoint inhibitors (ICIs). The relative performance of PROs compared to established markers such as Eastern Cooperative Oncology Group Performance Status (ECOG-PS) and the Lung Immune Prognostic Index (LIPI) is unknown. In our study, data from the advanced nonsmall cell lung cancer (NSCLC) single-arm atezolizumab trials BIRCH, FIR and randomised-trials OAK, POPLAR (atezolizumab vs docetaxel) were pooled. The study included 1548 participants who initiated atezolizumab. The associations between pretreatment PROs and overall survival (OS) and progression-free survival (PFS) were modelled using Cox proportional hazards regression. Prediction performance was assessed using the C-statistic (c). PROs were recorded via the EORTC QLQ-C30 and QLQ-LC13. Patient-reported physical function, fatigue, global health, appetite, role function, pain, dyspnoea, social function, constipation, nausea-vomiting, emotional function and coughing were significantly associated with OS and PFS on univariable and adjusted analysis (P < .05). Physical function (c = 0.654), fatigue (c = 0.653) and global health (c = 0.650) were the most predictive variables for OS. Comparatively, the OS prediction performance of physical function (c = 0.65) was superior to ECOG-PS (c = .59) and LIPI (c = 0.63). On multivariable analysis physical function, ECOG-PS and LIPI were all significant (P < .001). In conclusion, PROs were identified as independent prognostic factors for OS and PFS in advanced NSCLC patients receiving ICI therapy. Further, patient-reported physical function was more predictive of OS than ECOG-PS and LIPI and contained independent information. This highlights the value of PROs as prognostic and stratification factors for clinical use and research trials of ICIs.

Level of tumor-infiltrating lymphocytes and PD status as potential prognostic markers of survival and therapy effectiveness in triple-negative breast cancer

In breast cancer, genetic profile and expression of immunohistochemical markers determine prognosis and treatment scheme. Triple-negative breast cancer is characterized by absence of hormone receptor expression and negative HER2 status, as well as high proliferative index. These features of the tumor tissue limit doctors» selection of antitumor drugs. Development of triple-negative variant of tumor tissue is associated with a mutation in the BRCA1/2 gene. Consequently, determination of BRCA1/2 mutations is a prognostic biomarker, and in triple-negative cancer presence of expression of immune checkpoint proteins, multiprotein receptors on the surface of immune cells and tumor tissue play an important role in prognosis and selection of treatment strategy. Additionally, some studies demonstrate existence of multiple prognostic markers which allow to divide patients with triple-negative breast cancer into subgroups facilitating prognosis and selection of treatment strategy.

Functional hotness score based on three genes predicts long-term survival of triple-negative breast cancer independent from tumor mutational burden.

e12583 Background: Cytotoxic T-lymphocytes (CTLs) infiltration into tumor is a positive prognostic factor in breast cancer. Infiltration of CTLs are believed to be driven by mutation-induced neoantigens, thus, higher tumor mutation burden (TMB) is considered an important predictor of tumor immunogenicity and response to immunotherapy, but the association between intratumoral CTL counts and TMB in the overall cancer prognosis remains unclear. Methods: Utilizing publicly available breast cancer cohorts, we established Functional Hotness Score (FHS), based on CD8A, GZMB and CXCL10 gene expression levels of bulk tumors. The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed. Results: Breast cancer patients with high-FHS tumors demonstrated significantly better survival. FHS was lower in metastatic breast cancer. Among breast cancer subtypes, triple-negative breast cancer (TNBC) showed the highest FHS. FHS predicted patient survival not in hormone receptor (HR)-positive but in HR-negative, especially TNBCs. The high-FHS TNBCs enhanced not only CD8+ T cell infiltration, but also a broader type-1 anti-cancer immunity. The patients with the high-FHS patients showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified the unique subset of patients who did not recur over time. Conclusions: In conclusion, TNBCs with high-FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with higher anti-cancer immunity regardless of TMB, and constituting an independent prognostic marker of survival, particularly robust when combined with TMB.

Neutrophil-To-Lymphocyte and Platelet-To-Lymphocyte Ratios as Prognostic Markers of Survival in Patients with Head and Neck Tumours-Results of a Retrospective Multicentric Study.

Background: The neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) may be useful for drawing conclusions about the survival of head and neck squamous cell carcinoma (HNSCC) patients. Methods: Clinical data of 156 patients managed for HNSCC at two head and neck surgery centres were analyzed retrospectively. We studied the relationships between survival and PLR as well as NLR. Results: With regards to 5-year survival, the difference between the two groups with PLR values lower or higher than the threshold was statistically significant (p = 0.004), and we found the same for disease-free survival (p = 0.05), and tumour-specific mortality (p = 0.009). Concerning NLR, the difference in tumour-specific survival was statistically significant (p = 0.006). According to the multivariate analysis, NLR values higher than the threshold indicated an enhanced risk for overall as well as for tumour-specific mortality. Conclusion: In HNSCC patients, a high NLR may be considered as an independent risk factor for 5-year overall survival.

Controlling Nutritional Status score does not predict patients' overall survival or hepatocellular carcinoma recurrence after deceased donor liver transplantation.

The Controlling Nutritional Status (CONUT) score is a newly developed laboratory-derived immunonutritional score which has been validated as prognostic marker for survival and tumor recurrence in surgically treated patients with various tumor types, including hepatocellular carcinoma (HCC). The aim of the present study was to test the CONUT score performance in HCC patients treated with liver transplantation (LT). A retrospective study on a bi-centers cohort of 280 HCC patients submitted to LT between 2006 and 2017 was performed. Indication to LT was limited to Milan criteria or UCSF criteria, defined by preoperative imaging. Median pre-LT CONUT score was 5 (interquartile range 3-7). Overall patients' survival at 1, 3, and 5years was 84%, 76.6%, and 68.3%, respectively. Multivariate analysis showed that HCC recurrence (hazard ratio [HR]=1.987, P=.012] and pre-LT neutrophil to lymphocyte ratio (NLR) (HR=1.064, P=.003) were independent risk factors for reduced survival. Cumulative incidence of HCC recurrence at 1, 3, and 5years was 5.1%, 11.5%, and 15.5%, respectively. Pre-LT platelet-to-lymphocyte ratio (PLR) (subdistribution hazard ratio [SHR]=1.086, P=.044], tumor max diameter (SHR=1.695, P<.001), and bilobar tumor distribution (SHR=6.892, P=.006) were independent risk factors for tumor recurrence. The CONUT score did not show any prognostic value. The CONUT score did not predict poor survival or tumor recurrence in LT recipients.

Unmet Clinical Needs in the Treatment of Patients with Thyroid Cancer.

The increased incidence of thyroid cancer is a worldwide phenomenon; however, the issue of overdiagnosis has been most prominent in South Korea. The age-standardized mortality rate of thyroid cancer in Korea steeply increased from 1985 to 2004 (from 0.17 per 100,000 to 0.85 per 100,000), and then decreased until 2015 to 0.42 per 100,000, suggesting that early detection reduced mortality. However, early detection of thyroid cancer may be cost-ineffective, considering its very high prevalence and indolent course. Therefore, risk stratification and tailored management are vitally important, but many prognostic markers can only be evaluated postoperatively. Discovery of preoperative marker(s), especially for small cancers, is the most important unmet clinical need for thyroid cancer. Herein, we discuss some such factors that we recently discovered. Another unmet clinical need is better treatment of radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) and undifferentiated cancers. Although sorafenib and lenvatinib are available, better drugs are needed. We found that phosphoglycerate dehydrogenase, a critical enzyme for serine biosynthesis, could be a novel therapeutic target, and that the lymphocyte-to-monocyte ratio is a prognostic marker of survival in patients with anaplastic thyroid carcinoma or RAIR DTC. Deeper insights are needed into tumor-host interactions in thyroid cancer to improve treatment.

Circulating micrornas associated with the systemic immune-inflammation index and prognosis in resectable pancreatic cancer

Background: The systemic immune-inflammation index (SII) is an inflammatory marker, calculated as the neutrophil-to-lymphocyte ratio multiplied by the platelet count. It is a prognostic marker of survival and recurrence in patients with resectable pancreatic cancer (PDAC). Cell-free circulating microRNAs (miRNAs), small non-coding RNAs that regulate gene expression, are highly expressed by blood cells, including leukocytes and platelets. Circulating miRNAs can reflect the status of the immune system. This study aims to identify circulating miRNAs associated with a high SII (≥900) in order to explore underlying mechanisms of an altered immune system, associated with a worse prognosis in PDAC patients. Material & Methods: In the discovery cohort, preoperative serum miRNAs from twelve patients with treatment naive resectable PDAC were analyzed. Six patients with a low SII (range 320-449) and six patients with a high SII (range 1831-3433) were compared. MiRNAs were isolated from serum samples and measured with RT-qPCR using the ID3EAL 384 miRNA Panel (MiRXES). Differentially expressed miRNAs were selected for validation, based on a fold change of ≥2 and P<0.05. In the validation cohort, preoperative serum samples from 19 patients with a low SII (range 455-876) and 11 patients with a high SII (range 945-1491) were measured using miRNA-specific ID3EAL RT-qPCR assays (MiRXES). Results: Four serum miRNAs were differentially expressed between the low SII and high SII group. All four were upregulated in the high SII patient group. These were then measured in serum from patients of the validation cohort. MiRNA analyses in the circulation and immune cells, as well as the long term clinical follow-up are currently ongoing and the Results will be presented. Conclusion: Circulating miRNAs may reflect the systemic immune-inflammation index and elucidate the underlying mechanism of the altered immune status in PDAC patients with worse outcome, which is currently being validated.

Abstract AP15: IDENTIFICATION OF P53 PRIONS AS AN INDEPENDENT PROGNOSTIC MARKER FOR SURVIVAL IN HIGH-GRADE SEROUS OVARIAN CANCER

Abstract PURPOSE: Although the discovery of prions was rewarded with a Nobel Prize, their existence was only attributed to a limited number of diseases. Recent evidence suggests that their role has been underestimated and several other proteins carry prion-like properties, like ß-amyloid, and most recently p53. High-grade serous ovarian cancers (HGSOC) harbor TP53 mutations in about 96% of cases. These mutations promote p53 aggregation, which might be responsible for complete abrogation of tumor suppressor functions, resulting in dominant-negative activity and oncogenic gain-of-function. Here, we describe the use of an ELISA-based technology for p53 prion detection in fresh-frozen tumor tissue and their clinical relevance in ovarian cancer. EXPERIMENTAL PROCEDURES: Fresh-frozen tumor tissue specimens of 81 HGSOC patients, who previously had been included in the EU-funded OVCAD study, were analyzed. For each of these patients at least 5-year follow-up data were available. For the detection of p53 prions the Seprion-ELISA, previously designed for the detection of BSE and scrapie was adapted and optimized. To investigate the impact of p53 aggregation on clinical outcomes (overall survival and progression-free survival), we performed a complete-case analysis. In a subset of patients the Ki67 proliferation index and a homologous recombination deficiency (HRD) score, based on the Myriad score, were available. Correlations were analyzed using ANOVA and t-test. RESULTS: In 39 of 46 (84.8%) patients with missense mutated cancers a p53 prion specific signal was observed. The aggregation propensity varied considerably within samples carrying the same mutations. Multivariable Cox regression models, with respect to other prognostic factors significantly associated with overall survival in patients with late-stage serous epithelial ovarian cancer (age, FIGO stage and presence of a residual tumor), show superiority of the group with extensive p53 aggregation in overall survival and in progression-free survival. No and moderate p53 aggregation are associated with a worse overall survival in contrast to high p53 aggregation (P values 0.025 and 0.011). Similar results in these groups are assessed for progression-free survival (P values 0.030 and 0.008). Interestingly, the group with extensive p53 aggregation was associated with a non-significant trend toward higher HR deficiency. Furthermore, this group had a significantly higher Ki67 index compared to patients with moderate p53 aggregation (P value 0.033). CONCLUSIONS: This study reports the first specific and quantitative screening for p53 prions in patient material. We were able to demonstrate that the p53-Seprion-ELISA is a robust and highly sensitive detection tool for p53 prions. Our data show that the aggregation propensity is not only depending on the TP53 mutation and that other cofactors may be involved. Moreover, we show that p53 aggregation is an independent prognostic marker for survival. The higher Ki67 proliferation index and the trend towards higher genomic instability in patients with extensive p53 aggregation suggest that these tumors have an increased likelihood of response to platinum-containing therapy. To conclude, we demonstrated the high potential of p53 aggregation as a biomarker for patients' survival, suggesting that classification of patients based on the amount of aggregated p53 could allow therapy decisions. Citation Format: Nicole Heinzl, Elisabeth Maritschnegg, Katarzyna Koziel, Stuart Wilson, Georg Heinze, Christine Wallisch, Reinhard Horvat, Jalid Sehouli, Ioana Braicu, Ignace Vergote, Els van Nieuwenhuysen, Sven Mahner, Eva Obermayr, Eva Schuster, Barbara Holzer, Nicole Concin, Robert Zeillinger. IDENTIFICATION OF P53 PRIONS AS AN INDEPENDENT PROGNOSTIC MARKER FOR SURVIVAL IN HIGH-GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP15.

MicroRNA-15a tissue expression is a prognostic marker for survival in patients with clear cell renal cell carcinoma.

None of the currently investigated molecular markers demonstrated sufficient accuracy in prognostication of the renal cell carcinoma (RCC) oncologic outcomes; thus, none of them has been recommended for the application in the routine clinical practice. The role of miR-15a as a potential prognostic marker for RCC is still not unveiled. The aim of our study was to assess the expression of miR-15a in tumor tissues of the patients with RCC and to evaluate the possibility of its usage as a prognostic molecular biomarker of this disease. The retrospective included 64 adult patients with clear cell RCC (ccRCC) in whom radical or partial nephrectomy was conducted. After deparaffinization of formalin-fixed paraffin-embedded (FFPE) ccRCC specimens, the tissue expression of miR-15a was measured using the reverse transcription and quantitative polymerase chain reaction in the real time. For the reference, the expression of miR-15a was estimated in 15 FFPE tissue specimens of the normal renal parenchyma. Survival analysis involved all cases of non-metastatic RCCs (n = 57). Five-year cancer-specific survival (CSS) was estimated by means of the Kaplan-Meier method and was calculated from the date of surgery to the date of death. Patients with the RCC were characterized by significantly upregulated tumor tissue mean levels of miR-15a compared to the healthy controls: 0.10 ± 2.62 relative units (RU) versus 4.84E - 03 ± 3.11E - 03 RU (p < 0.001). Overexpression of miR-15a was strongly associated with poor histologic prognostic features of ccRCC. Poorly differentiated tumors tend to have more pronounced upregulation of miR-15a compared to highly differentiated lesions: Mean expression values were 4.57 ± 3.19 RU for Fuhrman grade 4 versus 0.02 ± 0.01 RU for Fuhrman grade 1 (p < 0.001). The metastatic involvement of the regional lymphatic nodules (N +) was associated with significantly upregulated miRNA-15a in comparison with N - cases: Mean expression values were 4.92 ± 2.80 RU versus 1.10 ± 2.29 RU, respectively (p < 0.001). In patients with miR-15a expression in RCC tissues ≤ 0.10 RU, mean 5-year CSS was significantly longer compared to patients with expression levels above this threshold: 92.31% (mean duration of survival-59.88 ± 0.12months) versus 54.8% (mean duration of survival-49.74 ± 2.16months), respectively (p < 0.001). The tissue expression of miR-15a could be used as a potential prognostic molecular biomarker for conventional RCC.

The effect of antioxidant status on overall survival in renal cell carcinoma.

IntroductionThe oxidative stress contributes to all three phases of carcinogenesis and represents a concomitant condition in renal cell carcinoma (RCC). RCC is the most common type of neoplasm of the kidney, and despite numerous studies the set of predictive and prognostic markers of survival are still unknown. The aim of our study was to examine the relation between antioxidant (AO) status and overall survival (OS) in RCC patients.Material and methodsOur study included 95 patients with RCC, who underwent radical nephrectomy. We analysed the prognostic role of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, glutathione reductase, glutathione, and malondialdehyde) and other clinicopathological factors (size, grade, stage, and histological subtype) on the OS of RCC patients.ResultsThe 5-year OS was 54.6%. The survival analysis related to AO parameters showed no significant difference in survival of RCC patients. The concentration of malondialdehyde, an indicator of lipid peroxidation, also had no significant effect on the survival rate of RCC patients. Univariate and multivariate analysis confirmed the significance of clinicopathological parameters (size, p < 0.001; Fuhrman grade, p = 0.001, and stage, p < 0.001) for patients’ survival.ConclusionsIn our cohort of patients, different antioxidant parameters were not found to be predictors for OS of patients with RCC, who underwent radical nephrectomy.