Risk Of Tumor Relapse Research Articles

Surveillance Strategy after Complete Ablation of Initial Recurrent Hepatocellular Carcinoma: A Risk-Based Machine Learning Study

PurposeTo investigate surveillance strategies for initial recurrent hepatocellular carcinoma (irHCC) after ablation to support clinical decision making, as there is no consensus regarding the monitoring strategy for irHCC after ablation. Materials and MethodsData from patients with irHCC who received ablation were retrospectively collected at 2 medical centers. The risk of tumor relapse in each month was calculated through random survival forest methodology, and follow-up schedules were arranged thereafter to maximize the capability of relapse detection at each visit. ResultsThe cumulative 0.5-, 1-, 1.5-, and 2-year risk-adjusted probabilities in the training/validation cohorts were 26.2%/21.5%, 42.3%/39.4%, 55.5%/52.6%, and 61.3%/63.2%, respectively, with the highest recurrence rate occurring in the second month (maximum, 7.9%/7.4%). The surveillance regime primarily concentrated on the first year after treatment, especially the initial 6 months. The delay in detecting tumor recurrence gradually decreased when the total number of follow-up visits increased from 4 to 8. Compared with the control strategies, this schedule (follow-up visits at 2, 4, 6, 9, 12, and 18 months) reduced the delay in detection. The benefits of this surveillance regime were evident when the patients were followed up 6 times. The proposed 6-visit surveillance strategy significantly decreased the delay in detection compared with the control 7-visit approach (1.32 months vs 1.82 months, respectively; P < .001). ConclusionsThe proposed new surveillance schedule minimized the delay in detecting recurrence in patients with irHCC after ablation. The risk-related machine learning method described in this study could be applied to develop follow-up strategies for other patients with hepatocellular carcinoma.

Hormone receptor status influences the impact of body mass index and hyperglycemia on the risk of tumor relapse in early-stage HER2-positive breast cancer patients.

Background:High body mass index (BMI) has been associated with worse clinical outcomes in patients with early-stage breast cancer (BC), and its negative effects could be mediated by hyperglycemia/diabetes. However, the prognostic impact of high BMI in early-stage HER2-positive (HER2+) BC patients remains controversial.Methods:We conducted a retrospective study to investigate the impact of baseline BMI or glycemia on relapse-free survival (RFS) and overall survival (OS) in patients with surgically resected, stage I–III HER2+ BC treated with standard-of-care, trastuzumab-containing adjuvant biochemotherapy. The optimal BMI and glycemia cut-off values for RFS were identified through maximally selected rank statistics. Cox regression models were used to assess the impact of BMI, glycemia and other relevant variables on clinical outcomes.Results:Among 505 patients included in the study, a BMI cut-off of 27.77 kg/m2 was identified as the best threshold to discriminate between patients with low BMI (n = 390; 77.2%) or high BMI (n = 115; 22.8%). At multivariable analysis, higher BMI was associated with significantly worse RFS [hazard ratio 2.26; 95% confidence interval (CI): 1.08–4.74, p = 0.031] and worse OS (hazard ratio 2.25, 95% CI 1.03–4.94, p = 0.043) in the whole patient population. The negative impact of high BMI was only observed in patients with hormone receptor (HR)-negative/HER2+ BC (hazard ratio 2.29; 95% CI: 1.01–5.20; p = 0.047), but not in patients with HR-positive (HR+)/HER2+ BC (hazard ratio 1.36; 95% CI: 0.61–3.07, p = 0.452). By contrast, hyperglycemia (⩾109 mg/dl) at baseline was associated with a trend toward significantly worse RFS at multivariable analysis only in patients with HR+/HER2+ BC (hazard ratio 2.52; 95% CI: 0.89–7.1; p = 0.080).Conclusions:High BMI is associated with worse clinical outcomes in early-stage HR−/HER2+ BC patients treated with trastuzumab-containing adjuvant biochemotherapy, while baseline hyperglycemia could be a predictor of worse RFS in HR+/HER2+ BC patients. Prospective studies are needed to investigate if modifying patient BMI/glycemia during treatment can improve clinical outcomes.

ROLE OF AGE, GENDER, AND TOBACCO IN CAUSING BLADDER CANCER AND PATHOLOGICAL STUDY OF BLADDER CANCER IN KPK.

Objective:&#x0D; To determine assocation of age, gender &amp; tabbaco in causing bladder carcinoma and its causative factors. &#x0D; Materials and Methods:&#x0D; This was a retrospective audit on individuals suffering from bladder carcinoma. All the enrolled individuals in our research study were diagnosed and treated in our set up under strict criteria.&#x0D; Results:&#x0D; Total 156 affected individuals suffering from bladder cancer were diagnosed and treated in our setup. Out of 156 patients, 111 were characterized by isolated painless total hematuria. Bladder carcinoma is associated with age so in 70 patients (age &gt; 60 year) were characterized by high grade cancer with a p = 0.04, while the remaining patients (age &lt;60 years), were characterized by both high and low-grade cancers. The risk of tumor relapse is considerably less in those individuals who take adjuvant BCG therapy or mitomycin C therapy, and the difference between the two groups is statistically significant, with a P &lt; 0.0001.&#x0D; Conclusion:&#x0D; The incidence rate of bladder carcinoma is increasing. Tobacco is one of the most common causative factors for bladder carcinoma in kpk.

Abstract 403: COX-2 expression on circulating tumor cells in nasopharyngeal carcinoma predicts a worse survival: A prospective analysis

Abstract COX-2 expression on circulating tumor cells in nasopharyngeal carcinoma predicts a worse survival: A prospective analysis Yong-Jiang Li1, Xiao-Qi Xie2, Feng Wang1* 1Department of Oncology, West China Hospital, Sichuan University, Chengdu, PR China 2Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, PR China *Corresponding author Short title: COX-2 Expression on CTCs in NPC patients Abstract Background and purpose: The prognostic significance of circulating tumor cells (CTCs) in head and neck cancer is still under debate, as only a few studies have been reported and limited conclusions are reached. Besides, CTCs count alone was utilized as an indicator in the previous researches. As a form of ‘liquid biopsy’, the further identification of genetic or phenotypic biomarkers on CTCs could possibly provide further clinical significance. Materials and methods: The prospective study enrolled 131 patients with nasopharyngeal carcinoma (NPC). CTCs were isolated at baseline and at the end of concurrent chemoradiotherapy, and cyclooxygenase-2 (COX-2) expression status of CTCs was detected by RNA-in situ hybridization (ISH) method. Results were correlated with patient’s clinicopathological parameters and treatment outcomes. Univariate and multivariate survival analysis were performed to determine the prognostic significance. Results: COX-2 expression was found in 87/131 (66.4%) patients at baseline and 53/115 (46.1%) patients at the end of concurrent chemoradiotherapy. Patients with post-therapeutic COX-2 expression had significantly poorer treatment response (P=0.011) and higher risk of tumor relapse (P=0.026) and metastasis (P=0.007). Besides, multivariate analysis revealed that post-therapeutic COX-2 expression on CTCs remained an independent prognostic indicator for poorer progression-free survival (HR 2.17, P=0.019) and overall survival (HR 2.41, P=0.024). Conclusion: The study demonstrated that post-therapeutic COX-2 expression on CTCs was a novel and promising prognostic indicator for NPC patients. Future studies are needed to validate our findings and further clarify the value of integrating the indicator with current clinical strategies in improving survival of NPC patients. Note: This abstract was not presented at the meeting. Citation Format: Yongjiang Li, Xiaoqi Xie, Feng Wang. COX-2 expression on circulating tumor cells in nasopharyngeal carcinoma predicts a worse survival: A prospective analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 403.

COX-2 expression and mesenchymal-transition status on circulating tumor cells to predict survival in patients with nasopharyngeal carcinoma: A prospective analysis.

6042 Background: The prognostic significance of circulating tumor cells (CTCs) in head and neck cancer is still under active investigation. It remains unclear whether just CTC count alone is sufficient to predict outcomes or whether the functional status of the CTCs is also needed. We investigated the clinical significance of determining epithelial-to-mesenchymal transition status and geno-/pheno-typic biomarkers of aggressiveness of CTCs in predicting outcomes in nasopharyngeal carcinoma (NPC). Methods: The prospective study enrolled 131 patients with NPC. CTCs were isolated at baseline and at the end of concurrent chemoradiotherapy using the CanPatrol system. Subsequently, the epithelial-mesenchymal transition (EMT) biomarkers and cyclooxygenase-2 (COX-2) expression status of the CTCs were identified by RNA-in situ hybridization (ISH) method. Results: COX-2 expression was found in 87/131 (66.4%) patients at baseline and 53/115 (46.1%) patients post-treatment. Independent of initial COX-2 expression status, the patients with post-treatment COX-2 expression on CTCs had significantly poorer treatment response (P = 0.011), and higher risk of tumor relapse (P = 0.026) and metastasis (P = 0.007). Similarly, post-treatment mesenchymal transition was also associated with higher risk of tumor relapse and metastasis. In multivariate analysis, post-treatment COX-2 expression on CTCs remained an independent prognostic indicator of poorer overall survival (HR 2.41, 95% CI 1.12-5.19; P = 0.024). Post-treatment COX-2 expression and mesenchymal transition in CTCs was the strongest prognostic indicator of overall survival on multivariate analysis (HR 2.73, 95% CI 1.28-5.83; P = 0.009). Conclusions: Post-treatment COX-2 expression on CTCs, especially on the mesenchymal subtype, is a novel and promising prognostic indicator for NPC patients treated with chemoradiation therapy. Future studies are needed to validate our findings and further clarify the value of integrating the indicators with current clinical strategies in improving survival of NPC patients.

Adjuvant Tyrosine Kinase Inhibitors in Treatment of Renal Cell Carcinoma: A Meta-Analysis of Available Clinical Trials.

Although tyrosine kinase inhibitors (TKIs) are widely used in the metastatic setting, they have shown more limited effectiveness in the adjuvant setting. Despite multiple clinical trials, there has been no improvement in overall survival (OS) with the use of these agents as adjuvant therapy, and conflicting data on disease-free survival (DFS). We carried out a meta-analysis of available phase III randomized clinical trials on adjuvant TKIs in clear-cell renal cell carcinoma (RCC). Primary end points of our study were the effect of adjuvant TKIs on OS and DFS in the overall population. Furthermore, we investigated if use of adjuvant TKIs resulted in improved DFS among patients with different risk of tumor relapse. Higher-risk patients were patients with 1 or more of the following features: positive nodes (N+), T4 tumors and T3 tumors, with higher Fuhrman grades (3-4). We adopted Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to carry out our study. In the overall population, the pooled hazard ratio (HR) of OS and DFS was 0.89 (95% confidence interval [CI], 0.76-1.04) and 0.84 (95% CI, 0.76-0.93), respectively. In the low- and high-risk populations, the pooled DFS HR was 0.98 (95% CI, 0.82-1.17) and 0.85 (95% CI, 0.75-0.97), respectively. Adjuvant use of TKIs do not appear to provide a statistically significant OS benefit. However, a benefit in DFS has been observed in overall and high-risk populations, suggesting that better selection of patients might be important for the evaluation of adjuvant therapies in RCC.

Abstract CT127: Phase I adoptive cellular therapy trial with actively personalized, multi-targeted CD8+ T-cells in patients with relapsed and/or refractory solid cancers (ACTologIMA101-101)

Abstract Introduction: Adoptive cellular therapy (ACT), which includes the administration of autologous or allogenic anti-tumor T lymphocytes after ex vivo manipulation and expansion, has demonstrated substantial clinical benefit in some hematological cancer types. Particularly for solid cancers, only a relatively small proportion of patients has benefited from these advances due in part to i) lack of suitable immunotherapy targets with high specificity in solid cancers and ii) frequent relapse following immunotherapy to single targets often associated with loss of target expression in the tumor. The actively personalized IMA101 (ACTolog®) process, utilizing autologous antigen-specific T cells to multiple selected tumor targets, is intended to address these limitations. IMA101-101 is a first-in-human clinical trial in patients, with relapsed or refractory solid cancers, whose tumors express at least one target from a pre-defined warehouse of 8 cancer-specific targets. These targets were identified using Immatics' mass spectrometry (MS)-guided XPRESIDENT technology, and carefully selected for their highly tumor-associated expression profile. As such, ACTolog is a multi-target approach where up to four products with four different tumor-specificities will be infused per patient. Methods: One key defining feature of the approach used in this trial is the generation of robust T cells following a proprietary process, where autologous T cells are specifically primed against the expressed ACTolog targets in the presence of IL-21 followed by HLA tetramer-guided cell sorting and rapid expansion. This process has been shown to result in T-cell products with higher frequencies of central memory T cells, extended in vivo persistence and clinical response1,2. Patients are enrolled depending on their HLA-A*02:01 positivity and the expression of warehouse target(s) in the tumor. As the patients participating in this trial have a high unmet medical need (e.g. very poor prognosis and/or refractory or recurrent disease following multiple lines of therapy), treatment with IMA101 T cell products will take place when patients experience recurrence or progressive disease or when therapy is no longer warranted. It is planned that the first-in-human trial will enroll up to 20 patients. Results: Initial data from the patients enrolled in this ongoing Phase 1 clinical trial will be presented at the meeting with a focus on feasibility, safety, and T cell persistence and functionality. Conclusions: The actively personalized ACTolog® approach is unique in that it addresses the scarcity of suitable tumor antigens by using novel tumor targets identified via the MS-guided XPRESIDENT® technology. In addition, it is a multi-target approach intended to generate broad anti-tumor activity with decreased risk of tumor relapse due to loss of target expression.

A failure-type specific risk prediction tool for selection of head-and-neck cancer patients for experimental treatments

ObjectivesThe objective of this work was to develop a tool for decision support, providing simultaneous predictions of the risk of loco-regional failure (LRF) and distant metastasis (DM) after definitive treatment for head-and-neck squamous cell carcinoma (HNSCC). Materials and MethodsRetrospective data for 560HNSCC patients were used to generate a multi-endpoint model, combining three cause-specific Cox models (LRF, DM and death with no evidence of disease (death NED)). The model was used to generate risk profiles of patients eligible for/included in a de-intensification study (RTOG 1016) and a dose escalation study (CONTRAST), respectively, to illustrate model predictions versus classic inclusion/exclusion criteria for clinical trials. The model is published as an on-line interactive tool (https://katrin.shinyapps.io/HNSCCmodel/). ResultsThe final model included pre-selected clinical variables (tumor subsite, T stage, N stage, smoking status, age and performance status) and one additional variable (tumor volume). The treatment failure discrimination ability of the developed model was superior of that of UICC staging, 8th edition (AUCLRF=72.7% vs 64.2%, p<0.001 and AUCDM=70.7% vs 58.8%, p<0.001). Using the model for trial inclusion simulation, it was found that 14% of patients eligible for the de-intensification study had>20% risk of tumor relapse. Conversely, 9 of the 15 dose escalation trial participants had LRF risks<20%. ConclusionA multi-endpoint model was generated and published as an on-line interactive tool. Its potential in decision support was illustrated by generating risk profiles for patients eligible for/included in clinical trials for HNSCC.

Sequential endoscopic ultrasound identifies predictive variables for relapse-free follow-up after neoadjuvant chemotherapy in gastric cancer

Background: The accuracy of endosonographic tumor staging after neoadjuvant therapy is less reliable than in primary staging. Therefore, the value of sequential endosonographic examinations after neaodjuvant chemotherapy in gastro-esophageal cancer is discussed controversially. Previous data suggest, that endoscopic ultrasound (EUS) after neoadjuvant treatment using other variables than classic uTN-criteria may identify patients with a better prognosis.Methods: In 67 patients with locally advanced gastric cancer treated in curative intent, we performed EUS before and after neoadjuvant chemotherapy. Endosonographic yTN-stage was compared to pathohistological yTN-stage after curative resection. The uTN-stage, yuTN-stage, maximal tumor thickness and maximal lymph node diameter as well as the shift of these variables after neoadjuvant therapy were analyzed for their usefulness to predict recurrence-free follow-up.Results: Accuracy of EUS for yTN-staging after neoadjuvant therapy was poor, especially in lower tumor stages. However, three heavily correlated variables analyzed by sequential EUS could be used for the prediction of prognosis: low endosonographic tumor stage (yuT0–2) after neoadjuvant chemotherapy, a decrease of two or more steps in uT-stage and a maximal tumor thickness of <15 mm after chemotherapy were significantly associated with recurrence-free follow-up. Endosonographic T-stage before neoadjuvant therapy, as well as lymph node variables before or after chemotherapy, were of no predictive value.Conclusion: In spite of poor concordance between endosonographic and pathohistological TN-stage after neoadjuvant treatment, sequential EUS, performed before and after neoadjuvant therapy, possibly identify patients at risk for tumor relapse after multimodal treatment in gastric cancer. This finding should be validated in a larger patient cohort.

Abstract IA06: Serum contains enough information for early detection of pancreatic cancer

Abstract One of the driving forces in personalized medicine is the search for protein patterns that can be utilized for improved diagnosis, assessing the risk for tumor relapse and disease progression. Affinity proteomics, a high-throughput technology for protein expression profiling, is now generating data for improved diagnosis and patient stratification, which has been demonstrated in several clinical studies. Pancreatic ductal adenocarcinoma (PDAC) is such a disease where detection preceding clinical symptoms significantly increases the life expectancy of patients. Based on multiparametric microarray analysis of over 2500 patient samples, serum protein signatures have for the first time been identified that could discriminate between pancreatic cancer patients with stage I, II, III and IV, which indicates a possibility for early diagnosis and an increased detection rate of surgically resectable tumors, which significantly would increase the life expectancy of pancreatic cancer patients. Citation Format: Carl A. K. Borrebaeck.{Authors}. Serum contains enough information for early detection of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA06.

Abstract 358: In vitro assessment of tumor relapse in a 3D tumor microtissue model

Abstract One of the most pressing problems in the treatment of cancer is tumor relapse. Although many tumors regress in response to neoadjuvant chemotherapy, residual tumor cells are detected in most cancer patients post-treatment. These residual tumor cells are thought to remain dormant for years before resuming growth, resulting in tumor recurrence. Considering that recurrent tumors are most often responsible for patient mortality, there exists an urgent need to study signaling pathways that drive tumor dormancy/recurrence. Current in vitro assays based on monolayer cultures do not provide the required time frame to study tumor recurrence. We developed a new method to study tumor relapse in a 3D in vitro tumor microtissue model. HCT116 colorectal tumor microtissues were produced and dosed with 3 reference compounds, Taxol (cell division inhibitor), Staurosporine (protein kinase inhibitor) and Doxorubicin (DNA synthesis inhibitor). Based on an initial range finding to determine IC20 and IC50 values, tumor growth was monitored via size profiling and viability (intra-tissue ATP content) over 10 days. Three different conditions were tested: (i) continuous treated tumor microtissues, (ii) microtissues which were supplemented with the drug for 5 days and (iii) non-treated tumor microtissues. Growth differences couldn't be observed comparing IC20 concentrations, however growth profiles significantly varied comparing IC50 concentrations. Whereas a 5-day treatment of Taxol was leading to a complete growth inhibition after removing the drug, Staurosporine treated tumor microtissues relapsed even with a similar growth kinetic as the untreated control group. Pulsed treatment of Doxorubicin was leading to a slower growth kinetic as compared to the control but not to a complete reminiscence. Based on the individual growth profiles relative to the continuous treated and non-treated groups we calculated a relapse index (ReI, patent pending) to enable classification of compounds and compound combinations according to their risk for tumor relapse. Here we present a novel in vitro tumor relapse assay method based on a 3-dimensional tumor microtissue model, to enable compound classification based on their efficiency to prevent tumor relapse. Citation Format: Sumeer Dhar. In vitro assessment of tumor relapse in a 3D tumor microtissue model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 358.

Sarcopenia as a marker for prediction of long-term survival following radical cystectomy.

435 Background: Patients undergoing radical cystectomy (RC) face a relevant risk of tumor relapse and mortality based on variable factors. Risk stratification may be enhanced by objective measures such as sarcopenia (loss of skeletal muscle mass) which has been described as a potential biomarker associated with survival after radical cystectomy. However, data on this highly interesting biomarker in conjunction with urothelial carcinoma of the bladder are sparse. Methods: A retrospective study including patients that were treated with RC at Hannover Medical School between 2005 and 2011 were included. The lumbar skeletal muscle index (SMI) was measured on preoperative computed tomography (CT) which was performed within 60 days prior to surgery. MeVisLab 2.7 was used to perform calculations. The fat mass index (FMI) was calculated based on the same CT slides. The body mass index (BMI) was used as a comparative value. Cut off points were developed for men and women separately. Results: Indices were measured on 103 patients (79 men, 24 women, mean age: 67.5 yrs). 72 (70%) pts. had muscle-invasive disease, 21 (20%) pts. were lymph node positive and 6 (6%) pts. had synchronous metastasis. Median follow-up time was 39 months. SMI (cm2/m2), FMI (kg/m2) and BMI (kg/m2) for men were calculated with mean scores of 51.2, 9.6 and 27.0, respectively. The corresponding calculated means for women were 38.7, 10.0 and 25.3. None of the stratification markers correlated with overall survival (OS) using Kaplan-Meier plots. However when applied on patients that survived at least 12 months, the sarcopenia index (SMI) became statistically significant (p &lt; 0.05). Conclusions: The presence of sarcopenia may be predictor of poor overall survival later than 12 months after radical cystectomy. BMI and FMI may not be used in risk stratification models. Further research is needed to validate the current findings.

Abstract 1351: Post-transplantation cyclophosphamide depletes vaccine primed donor T cells and compromises graft-versus-tumor effects in alloBMT model

Abstract Graft-versus-host disease (GVHD) remains a major complication of allogeneic bone marrow transplant (alloBMT) for patients with hematologic malignancies. Donor T cell depletion or recipient immunosuppression reduces GVHD, but may increase the risks of infection and relapse. High doses of cyclophosphamide (Cy) in the early post-transplantation period (PT/Cy) have been shown to reduce GVHD incidence by eliminating alloreactive proliferating cells both in the HLA-matched and -haploidentical settings. Donor vaccination with tumor cells or tumor antigens has been shown to reduce the risk of relapse in syngeneic BMT. We wished to explore whether donor vaccination could increase the frequency of the tumor specific T cells and reduce the risk of relapse in the content of alloBMT with PT/Cy. Donor mice were vaccinated with chicken ovalbumin (OVA) expressing Listeria monocytogenes OVA (Lm-OVA) 7 or 30 days before T cell transfer. Recipients were challenged with thymic lymphoma cells expressing OVA and luciferase (EL4-mOVA-Luci). Splenocytes from naïve or Lm-OVA primed donors were transferred along with T cell depleted bone marrow into lethally irradiated recipients harboring tumor. Half of the recipients were treated with Cy (200 mg/kg IP) on day 2. In the syngeneic setting, we examined anti-tumor immunity after donor/recipient vaccination with tumor antigen and characterized the reconstitution of naïve/memory/effector T cell subsets with or without PT/Cy. Significant numbers of OVA-specific CD8+ effector T cells were found on day 15 after transplantation in mice that did not receive PT/Cy. PT/Cy reduced percentages of KLRG1+ effector CD8+ T cells, but CD27+CD127+ memory T cells were increased in mice receiving vaccine-primed donor cells. Both OVA-specific CD4+ effector and memory T cell numbers increased after PT/Cy. Our data showed that donor vaccination on either day -7 or on day -30 prior to BMT delayed tumor growth and significantly prolonged survival of tumor-bearing mice. In an MHC matched, minor antigen mismatched alloBMT mouse model, we further demonstrated PT/Cy decreased donor T cell mediated graft-versus-tumor (GVT) effects. Among mice receiving PT/Cy, overall and event-free survivals at 120 days after transplantation were 38% (day-30) and 31% (day -7), versus 0% among mice receiving cells from unprimed donors. Among mice treated with PT/Cy, those receiving cells from donors primed on day -7 survived slightly longer than those primed on day -30. All mice receiving PT/Cy were dead of tumor by day 70. In summary, our data demonstrate that PT/Cy compromised the GVT effect of vaccinating donors with tumor antigen and worsened survival. We also showed that there were Cy-resistant OVA-specific T cells found after PT/Cy. Further work is required to reduce the risk of tumor relapse in the content of this alloBMT platform. Citation Format: Han-Hsuan Fu, Jie Fu, Jie Wang, Richard J. Jones, Ephraim Fuchs, Hyam Levitsky. Post-transplantation cyclophosphamide depletes vaccine primed donor T cells and compromises graft-versus-tumor effects in alloBMT model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1351. doi:10.1158/1538-7445.AM2015-1351

Abstract LB-219: Interleukin-8 promotes generation of M2 macrophages and arginase-producing granulocytes: Prognostic significance of interleukin-8 and infiltration of immune cells positive for CD163 and CD66b in tumor tissues in patients with oral squamous cell carcinoma

Abstract Biomarkers are essential for improving the effectiveness of treatments for patients with cancer. The immunological status in a tumor microenvironment is closely associated with the prognosis of cancer patients. Here we investigated whether serum interleukin (IL)-8 reflects the tumor microenvironment and has prognostic value in 50 patients with resectable oral squamous cell carcinoma (OSCC). We found that the relapse-free survival (RFS) was significantly longer in the Stage I/II OSCC patients with low serum IL-8 levels compared to those with high levels (p = 0.001). The tumor expression of IL-8, the infiltration of CD163-positive cells, and of CD66b-positive cells in the tumor tissues were correlated with the serum IL-8 level (p = 0.033, p = 0.038 and p = 0.044, respectively), and they were associated with poor clinical outcome (p = 0.007, p = 0.002 and p = 0.001 respectively, in DFS) in all patients. A multivariate analysis revealed that N status, tumor IL-8 expression, CD163 and CD66b infiltration significantly affected the DFS of the patients. A further analysis suggested that the combination of N status with serum IL-8, tumor IL-8, CD163 and CD66b infiltration in the tumor tissues may be a new criterion for discriminating between OSCC patients at high and low risk for tumor relapse. Finally, the in vitro experiments clearly demonstrated that IL-8 enhanced the generation of CD163-positive M2 macrophages from peripheral blood monocytes, and that the cells produced IL-10 which suppress anti-tumor immunity. Furthermore, IL-8 increased the generation of arginase-producing, CD66b-overexpressing cells from peripheral blood polymorphonuclear cells. These findings indicate that IL-8 may be involved in poor clinical outcomes via the generation of CD163-positive M2 macrophages and CD66b-overexpressing, arginase-producing granulocytes, and that these factors may have prognostic value as well as may be new targets for treatment in patients with resectable OSCC. Citation Format: Masato Okamoto, Yohei Fujita, Hiroyuki Goda, Koh-ichi Nakashiro, Hiroyuki Hamakawa. Interleukin-8 promotes generation of M2 macrophages and arginase-producing granulocytes: Prognostic significance of interleukin-8 and infiltration of immune cells positive for CD163 and CD66b in tumor tissues in patients with oral squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-219. doi:10.1158/1538-7445.AM2015-LB-219

Abstract B12: Synergistic anticancer activity of Aurora A kinase and MDM2 antagonists in melanoma

Abstract Senescence-inducing therapies can block proliferation of malignant cells and promote anti-tumor immune activity. However, the risk of tumor relapse remains high due to the long lifespan of senescence cells with potential to escape senescence. Here our preclinical studies demonstrate that combining a senescent-inducing aurora kinase A (AURKA) inhibitor alisertib (MLN8237) with an MDM2 antagonist [(-)-nutlin 3a] effectively induces robust p53 activation in senescent Tp53WT tumors accompanied by: 1) tumor cell proliferation arrest; 2) mitochondrial depolarization and tumor cell apoptosis; and 3) tumor cell clearance via CCL5-, CCL1- and CCL9-mediated recruitment of anti-tumor leukocytes. This combined therapy shows adequate bioavailability and low toxicity to the host in the mouse model. Moreover, the prominent preclinical response of patient-derived melanoma tumors to the co-targeting of MDM2 and AURKA provides rationale for further investigation of alisertib and MDM2 inhibitors. Citation Format: Anna E. Vilgelm, Jeff S. Pawlikowski, Yan Liu, E. Hawkins Oriana, A. Davis Tyler, Kevin P. Weller, Linda W. Horton, Colt M. McClain, Gregory D. Ayers, David Turner, David C. Essaka, Clinton F. Stewart, Jeffrey A. Sosman, Mark C. Kelley, Jeffrey A. Ecsedy, Jeffrey N. Johnston, Ann Richmond. Synergistic anticancer activity of Aurora A kinase and MDM2 antagonists in melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B12.

Cancer, Aging and Immune Reconstitution

Aging is a complex phenomenon involving multiple physiological functions. Among these, very important are the modifications induced in the immune system; these modifications may be related to cancer development, a disease of older people. We herein describe the age-dependent alterations observed in the various arms of the immune system. Both innate and adaptive immunity are compromised during aging, a condition where an inflammatory status contributes to promote immune suppression and tumour growth. Collectively, aging of the immune system may produce detrimental consequences on the response against tumours in old patients. In fact, preclinical studies and clinical observations in humans have demonstrated age-associated alterations in antitumor immunity. Immunological recovery of old patients after conventional chemotherapy (CT) has not been fully investigated, while several studies conducted in patients undergoing blood stem cell transplantation have demonstrated that a delayed immune reconstitution associated with older age results in increased susceptibility to opportunistic infections and risk of tumour relapse. Cellular immunotherapy and vaccination are becoming viable options for improving survival and quality of life of cancer patients targeting both the host defences and the tumour. The clinical experience in elderly patients is still in its infancy, but available data indicate that these approaches are feasible and promising. A key problem in the studies on aging, immunity and cancer is that it is difficult to distinguish changes related to age from those related to cancer-dependent immunosuppression, but independent from the age of the subject. Longitudinal studies on aged healthy and cancer persons and the use of new immunological techniques may be required to clarify these issues.

Intermediate filament dynamics and breast cancer: Aberrant promoter methylation of the Synemin gene is associated with early tumor relapse

Synemin (SYNM) is a type IV intermediate filament that has recently been shown to interact with the LIM domain protein zyxin, thereby possibly modulating cell adhesion and cell motility. Owing to this multiplicity of potential functions relevant to cancer development, we initiated a study to decipher SYNM expression and regulation in benign human breast tissue and breast cancer. Dot blot array analysis showed significant SYNM mRNA downregulation in 86% (n=100, P<0.001) of breast cancers compared with their normal tissue counterparts, a result that was confirmed by real-time PCR analysis (n=36, P<0.0001). Immunohistochemistry analysis showed abundant SYNM protein expression in healthy myoepithelial breast cells, whereas SYNM expression loss was evident in 57% (n=37, P<0.001) of breast cancer specimens. Next, we analyzed methylation of the SYNM promoter to clarify whether the SYNM gene can be silenced by epigenetic means. Indeed, methylation-specific PCR analysis showed tumor-specific SYNM promoter methylation in 27% (n=195) of breast cancers. As expected, SYNM promoter methylation was tightly associated (P<0.0001) with SYNM expression loss. In-depth analysis of the SYNM promoter by pyrosequencing showed extensive CpG methylation of DNA elements supposed to regulate gene transcription. Demethylating treatment of SYNM methylated breast cancer cell lines with 5-aza-2-deoxycytidine clearly reestablished the SYNM expression. Statistical analysis of the patient cohort showed a close association between SYNM promoter methylation and unfavorable recurrence-free survival (hazard ratio=2.941, P=0.0282). Furthermore, SYNM methylation positively correlated with lymph node metastases (P=0.0177) and advanced tumor grade (P=0.0275), suggesting that SYNM methylation is associated with aggressive forms of breast cancer. This is the first study on the epigenetic regulation of the SYNM gene in a cancer entity. We provide first hints that SYNM could represent a novel putative breast tumor suppressor gene that is prone to epigenetic silencing. SYNM promoter methylation may become a useful predictive biomarker to stratify breast cancer patients' risk for tumor relapse.

Total laryngectomy and T3-T4 laryngeal cancer without other adverse histopathology

We sought to determine the postoperative management, incidence of tumor recurrence in the neck, and outcome in laryngeal cancer patients whose risk for tumor relapse is not clear. Thirty patients (27 of whom had transglottic tumors) met the study criteria (resected T3-T4 laryngeal cancer, histologically negative cervical nodes, and no other adverse histopathology). A group of 12 patients who underwent surgery alone was compared with a second group of 18 patients with similar characteristics but who received postoperative radiotherapy. Overall survival at five years was 50% in the surgery alone group and 61% in the combined therapy group (P=0.63). Among the 28 evaluable patients with a median follow-up of 44 months, the relapse rate in the neck was 25% in the surgery alone group and was 0% in the postoperatively irradiated group (P=0.07). Recurrences in the neck remained uncontrolled in two of the three patients at the time of death. Postoperative radiotherapy deserves consideration in selected cases of T3-T4 laryngeal cancer without adverse histopathology.

Impact of targeting deviations on outcome in medulloblastoma: study of the French society of pediatric oncology (SFOP)

Purpose: To correlate targeting deviation in external beam radiation therapy with site of relapse in a prospective study of 174 patients treated for medulloblastoma.Methods and Materials: Between February 1992 and February 1998 the radiotherapy treatment records were reviewed by a panel of radiation oncologists for 174 children treated with radiation therapy for medulloblastoma. The review was done without knowledge of patient outcome. Patterns of relapse were correlated with the results of the quality control review.Results: Among the 174 patients five relapsed before the start of radiotherapy. One hundred sixty-nine patients were evaluable for correlation between targeting deviation and site of relapse. Number of major deviations in radiation therapy treatment is strongly correlated with the risk of tumor relapse (67% [95% CI: 28–91] of 3-year relapse rate in patient group with 2 major deviations and 78% [95% CI: 35–96] with 3 major deviations). This is particularly correlated with relapse in the frontal region of the brain: 5 relapses occurred in the frontal region in patients with major deviation in this area. An erroneous choice of electron beam energy is also linked with craniospinal fluid (CSF) relapse (3-year relapse rate of 68% [95% CI: 42–86]). Minor deviations in therapy technique are slightly associated with an increased risk of relapse in the same range as the group with only one major deviation.Conclusion: The quality of medulloblastoma radiation therapy technique is strongly correlated with outcome. Pretreatment central quality assurance review or standardized computer-designed blocks would improve survival to an extent equivalent to that attributed to adjuvant chemotherapy.

Detection of early micrometastases in subcutaneous fat of primary malignant melanoma patients by identification of tyrosinase-mRNA

To improve survival following melanoma excision, wide margin resection including subcutaneous fat, is indicated. Subcutaneous fat, resected with primary melanomas, was investigated using the tyrosinase PCR method originally described for detection of melanoma cells in peripheral blood. Identification of tyrosinase transcripts was possible in 4 melanoma patients (3 Clark level IV, 1 level III), while negative results were obtained from 6 other patients (2 level IV, 3 level III and 1 level I). In control experiments, after infiltration of the reference cell line SkMel into normal fat tissue, the PCR was positive in 33% (3/9) with 10’ infiltrated cells, 69% (9/13) with lo4 cells and in 100% (717) with lo6 cells. We conclude that detection of melanoma cells in subcutaneous fat tissue is possible by tyrosinase PCR. Follow-up studies should show whether such positive tyrosinase PCR can define patients at very high risk of tumour relapse. Copyright