Better Overall Survival In Patients Research Articles

The prognostic impact of GSTM1/GSTP1 genetic variants in bladder Cancer

BackgroundThe glutathione S-transferases (GSTs) are a superfamily of phase II detoxifying enzymes that inactivates a wide variety of potential carcinogens through glutathione conjugation. Polymorphic changes in the GST genes have been reported to be associated with increased susceptibility to cancer development and anticancer drug resistance. In this study, we investigated the association between genetic variants in GSTM1 and GSTP1 and patients’ clinicopathological parameters. The prognostic values of such associations were evaluated among bladder cancer patients.MethodsGenotyping of GSTM1 and GSTP1 in bladder cancer patients was assessed using polymerase chain reaction followed by DNA sequencing. Overall survival was estimated using the Kaplan-Meier method and multiple logistic regression and correlation analysis were performed.ResultsThe GSTM1 null genotype was significantly associated with poor overall survival compared with the wild-type GSTM1 genotype. There was a trend towards better overall survival in patients with wild-type GSTP1 allele (AA) compared with GSTP1 (AG/GG) genotype. Interestingly, Kaplan-meier survival curve for GSTM1 null patients adjusted for sub-cohort with amplified HER2 gene showed poor survival compared with the GSTM1 null/ non-amplified HER2 gene. Also the same population when adjusted with HER2 protein expression, data showed poor survival for patients harboring GSTM1 null/high HER2 protein expression compared with low protein expression.ConclusionThis study focuses on the impact of GSTM1 null genotype on bladder cancer patients’ outcome. Further investigations are required to delineate the underlying mechanisms of combined GSTM−/− and HER2 status in bladder cancer.

Implication of Rituximab Infusion Reactions on Clinical Outcomes in Patients With Diffuse Large B-cell Lymphoma: A Single Institution Experience

BackgroundThe addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy for diffuse large B-cell lymphoma (DLBCL) has led to improvements in progression-free survival and overall survival, although the exact mechanism of rituximab is not known. Rituximab administration often results in transient, non–life-threatening infusion reactions (IRs). We report a retrospective cohort of patients with DLBCL who received rituximab to determine the significance of IRs on clinical outcomes. Patients and MethodsWe identified and analyzed a retrospective cohort of 229 patients with DLBCL. They were stratified into 2 cohorts; those who did and did not have an IR. Univariate and multivariate analyses were performed to evaluate the prognostic significance of rituximab-related IRs relative to DLBCL subtype, International Prognostic Index score, c-Myc translocations or amplifications, chemotherapy regimen, and Ki-67 proliferative index. ResultsBaseline characteristics did not differ significantly between the 2 groups. Rituximab was included as initial treatment in all patients. Patients with an IR had a significantly higher overall survival (hazard ratio, 0.26; 95% confidence interval, 0.07-0.95) at 5 years. In addition, subgroup analysis showed a significantly higher progression-free survival in patients with the germinal center subtype of disease and c-Myc alterations who had a rituximab-related IR (log-rank P < .0001). ConclusionsThe presence of a rituximab-related IR is associated with a better overall survival in patients with DLBCL. Although limited by the small sample size and retrospective nature, these results provide rationale for further investigation into the mechanism of action of rituximab in order to optimize the efficacy of CD20 monoclonal antibodies.

Immunohistochemical profiling of liver metastases and matched-pair analysis in patients with metastatic pancreatic ductal adenocarcinoma

BackgroundThe purpose of the current study was to investigate the immunohistochemical (IHC) profile of liver metastases (LM) in patients with pancreatic ductal adenocarcinoma (PDAC). MethodsExpression of 15 IHC markers in liver biopsies from 77 patients with PDAC, who were diagnosed between 2010 and 2014, were evaluated. In a separate subgroup analysis (n = 12), paired samples (LM and primary tumor) from the same patient were investigated for IHC profile differences. ResultsLM samples were classified as pancreatobiliary-type (PB-type) in 72 patients (93.5%), intestinal-type (INT-type) in four patients (5.2%), and squamous in one patient (1.3%). There was no significant difference in overall survival (OS) between LM of the PB-type or INT-type (p = 0.097). In a multivariate analysis, age <70 years (p = 0.047), absence of SMAD4 mutation (p = 0.026), absence of CDX2 expression (p = 0.003), and well to moderate differentiation were significant prognostic factors for better OS in patients with LM (p = 0.031). Analysis of paired tissue samples from LM and the primary tumor revealed a difference in CDX2 (50% increase, p = 0.125) and SMAD4 (33% loss of SMAD4, p = 0.375). ConclusionsCDX2 expression and SMAD4 mutation indicate a poor outcome in patients with LM of PDAC. Matched-pair analysis revealed differences in distinct IHC marker expression.

Response to Immunosuppressive Therapy in Acquired Aplastic Anaemia: Experience of a Tertiary Care Centre from Eastern India.

The current study was conducted to assess response to immunosuppressive therapy (IST) in acquired aplastic anaemia (AA). It was a retrospective and prospective observational study. Patients were diagnosed as per standard international guidelines and IST was started as per standard protocol. Patients were followed up at 3months and 6months for assessment of response as per published standard guidelines. Total 76 cases were included in the study. The median age of the study population was 36years with a range of 6-66years with a male to female ratio of 2.04:1. Most common clinical presentation was pallor followed by bleeding. Commonest type of disease in the study group was severe AA. Among total 76 patients, 32 patients received Atgam and 44 patients received Thymogam. Within 3months of ATG administration, 4 patients died and 1 patient was lost to follow up. At 3months, 2 (2.63%) patients were on complete response (CR), 32 (42.10%) patients were in partial response (PR) and 37 (48.68%) patients were on no response (NR). Overall response (OR) at 3months was 44.73%. At 6months 5 (6.57%) patients were in CR, 43 (56.57%) patients in PR and 23 (30.26%) patients in NR; the OR was 63.14%. Overall response at 3months was 44.73% and overall response at 6months was 63.14%. The study revealed better overall survival for patients with ATGAM treatment than THYMOGAM treatment arm.

Abstract 3547: MicroRNA-496 inhibits triple negative breast cancer cell proliferation by targeting DEL-1

Abstract Background and Objectives: Del-1 is linked to the pathogenesis of various cancers including breast cancer; however, the regulation of Del-1 expression remains unclear. The current study investigated how microRNA-496 (miR-496) regulates Del-1 expression in triple negative breast cancer (TNBC). Methods: Del-1 mRNA and miR-496 were measured by quantitative PCR in breast cancer cells (MDA-MB-231, MCF7, SK-BR3, and T-47D) and tissues from 30 patients with TNBC. The effects of miR-496 on cell proliferation, migration, and invasion were determined in MTT, wound healing, and Matrigel Transwell assays, respectively. Results: In MDA-MB-231, miR-496 levels were remarkably low and Del-1 mRNA was higher compared to other breast cancer cell lines. Luciferase reporter assays revealed that miR-496 binds the 3′-UTR of Del-1 and that Del-1 expression is downregulated by miR-496 mimics. Furthermore, miR-496 inhibited the proliferation, migration, and invasion of MDA-MB-231 cells. The effects of miR-496 on cell proliferation were additive with those of miR-137, another miRNA that regulates Del-1 expression. Moreover, in the 30 TNBC specimens, miR-496 was downregulated (P &amp;lt; 0.005) and the levels of Del-1 in the plasma was significantly elevated as compared to normal controls (P = 0.0142). TCGA data showed the correlation of miR-496 expression with better overall survival in patients with early TNBC. Conclusions: In in silico and in vitro analyses, we showed that Del-1 is a target of miR-496 in TNBC and thereby affects cancer progression. Our findings suggest that miR-496 and Del-1 might act as modulating factors in TNBC and are new biomarkers for patients with TNBC. Citation Format: Dong Won Baek, Jae-Hwan Jeong, Soo Jung Lee, Jiyeon Lee, Yee Soo Chae, Wan WooK Kim, Jieun Kang, Ho Yong Park, Jin Hyang Jung, Ji Yun Jeong, Ji Young Park, Keon Uk Park. MicroRNA-496 inhibits triple negative breast cancer cell proliferation by targeting DEL-1 [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 3547.

Abstract 1501: Clinical significance of tumor immune microenvironment in soft tissue sarcoma

Abstract Background: The prognosis of patients with metastatic soft tissue sarcoma (STS) remain poor. Although immunotherapies have been attempted in patients with STS, the prognostic significance of the immune status within the tumor microenvironment in STS is not well understood. The purpose of this study is to investigate the tumor immune microenvironment and evaluate its prognostic impact for patients with STS. Material and Methods: We retrospectively evaluated the tumor immune microenvironment in 116 primary untreated STS patients with five subtypes: synovial sarcoma (SS: n=36), myxoid liposarcoma (MLS: n=32), undifferentiated pleomorphic sarcoma (UPS: n=27), leiomyosarcoma (LMS: n=11), and dedifferentiated liposarcoma (DDLS: n=10). The infiltration of CD8+ and FOXP3+ lymphocytes, CD163+ macrophages, and the expression of HLA class I and PD-L1 in the tumor were evaluated by immunohistochemistry. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Results: UPS had a higher infiltration of CD8+ and FOXP3+ lymphocytes than SS and MLS. Infiltration of CD163 + macrophages were higher in UPS, LMS, and DDLS than in SS and MLS. HLA class I expression was detected in all of UPS, LMS, and DDLS. However, HLA class I was negative in 17% of SS and 69% of MLS. Although no PD-L1 expression was observed in SS and MLS, PD-L1 expression was detected in 36% of UPS, 28% of LMS, and 25% of DDLS. Moreover, PD-L1 expression was associated with poor outcome in these subtypes. Increasing number of CD8+ lymphocytes was associated with a better OS in patients with SS. A higher infiltration of FOXP3+ lymphocytes was associated with an unfavorable OS in patients with MLS but favorable outcome in SS. Moreover, a higher infiltration of CD163+ macrophages showed a significantly worse OS and PFS in patients with SS and MLS. Conclusion: Lymphocytes and macrophages were variably infiltrated across STS subtype. UPS, LMS and DDLS, which have numerous genetic mutations, demonstrated high infiltration of lymphocytes, HLA class I and PD-L1 expression. These suggest that T-cell based immunotherapy such as immune checkpoint inhibitors may be effective in these tumor subtypes. Although the SS and MLS are less mutated and do express cancer-testis antigen NY-ESO-1 in common, expression level of HLA class I is significantly different between SS and MLS. In addition, infiltration of FOXP3+ lymphocytes have opposite effect in these tumors. These suggests different immunotherapeutic strategy might be required in these subtypes. Our results might be useful in the clinical strategy of immunotherapy in STS. Citation Format: Naoki Oike, Hiroyuki Kawashima, Akira Ogose, Hiroshi Hatano, Takashi Ariizumi, Taro Sasaki, Tetsuro Yamagishi, Hajime Umezu, Naoto Endo. Clinical significance of tumor immune microenvironment in soft tissue sarcoma [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 1501.

The prognostic significance of PD-L1 and PD-1 expression in patients with nasopharyngeal carcinoma: a systematic review and meta-analysis

BackgroundWhether PD-L1/PD-1 expression plays a significant role in the prognosis of NPC is still controversial. The present study mainly aimed to investigate the prognostic significance of PD-L1/PD-1 expression in patients with NPC.MethodsA systematical research was performed in the PubMed, Web of Science, EMBASE, and the Cochrane Library databases up to January 06, 2019. Eighteen studies met eligible criteria were included in the meta-analysis. Quality assessment of included articles was evaluated by Newcastle–Ottawa quality assessment scale (NOS). Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) were used to elucidated the primary endpoint, overall survival (OS), and the secondary endpoints. Furthermore, the relationship between clinicopathological features of NPC and PD-L1/PD-1 expression was estimated by relative ratios (RRs) and 95% CIs.ResultsA total of 1836 patients from 15 included studies concerning PD-L1 and 678 patients from six studies regarding PD-1 were included in the meta-analysis. Pooled results revealed that PD-L1 expression in NPC did not correlate with OS (HR 1.34 95% CI 0.93–1.93, p = 0.11), DFS (HR 1.82, 95% CI 0.86–3.85, p = 0.12), PFS (HR 1.19, 95% CI 0.46–3.08, p = 0.72), and DMFS (HR 2.26, 95% CI 0.60–8.56, p = 0.23). Meanwhile, no statistically significant differences existed between the expression level of PD-1 in tumor infiltrating lymphocytes (TILs) and the OS in NPC, with the pooled HR 1.29 (95% CI 0.68–2.42, p = 0.44). In subgroup analysis, higher expression of PD-L1 in immune cells correlated with better OS in patients with NPC, with a pooled HR 0.68 (95% CI 0.47–0.99, p = 0.04). Among the clinicopathological features included in our study, we found that the positive expression of PD-L1 in NPC associated with the higher expression of PD-1 (RR 1.25, 95% CI 1.02–1.52, p = 0.03).ConclusionsOur meta-analysis indicated that higher/positive expression of PD-L1/PD-1 may not serve as suitable biomarkers for the prognosis of NPC, which was not in consistent with some previous studies about the prognostic value of PD-L1/PD-1 in other types of tumors. Despite the positive results in subgroup analysis and study about clinicopathological features, it may still need corroboration of prospective and large-scale studies.

Prognostic values of preoperative platelet-to-lymphocyte ratio, albumin and hemoglobin in patients with non-metastatic colon cancer.

Purpose: Preoperative platelet-to-monocyte ratio (PLR), albumin and hemoglobin are suggested prognostic indicators in various malignancies. However, the prognostic values of PLR, albumin and hemoglobin remain elusive. The objective of the present study was to evaluate the prognostic values of PLR, albumin and hemoglobin in stage I-III colon cancer.Patients and methods: A total of 312 patients with non-metastatic colon cancer undergoing curative resection were enrolled in this study. The prognostic values of PLR, albumin and hemoglobin were identified by receiver operating characteristics, and univariate and multivariate analyses.Results: Univariate analysis revealed that preoperative PLR, albumin and hemoglobin were significantly associated with overall survival (OS) and that preoperative PLR and albumin were significantly associated with progression-free survival (PFS). Multivariate analysis revealed that preoperative PLR was significantly associated with OS.Conclusion: Reduced preoperative PLR was significantly associated with better OS in patients with stage I-III colon cancer. Preoperative PLR was an independent prognostic indictor for OS in patients with colon cancer undergoing curative resection.

CADM1 is a TWIST1-regulated suppressor of invasion and survival

Metastatic cancer remains a clinical challenge; however, patients diagnosed prior to metastatic dissemination have a good prognosis. The transcription factor, TWIST1 has been implicated in enhancing the migration and invasion steps within the metastatic cascade, but the range of TWIST1-regulated targets is poorly described. In this study, we performed expression profiling to identify the TWIST1-regulated transcriptome of melanoma cells. Gene ontology pathway analysis revealed that TWIST1 and epithelial to mesenchymal transition (EMT) were inversely correlated with levels of cell adhesion molecule 1 (CADM1). Chromatin immunoprecipitation (ChIP) studies and promoter assays demonstrated that TWIST1 physically interacts with the CADM1 promoter, suggesting TWIST1 directly represses CADM1 levels. Increased expression of CADM1 resulted in significant inhibition of motility and invasiveness of melanoma cells. In addition, elevated CADM1 elicited caspase-independent cell death in non-adherent conditions. Expression array analysis suggests that CADM1 directed non-adherent cell death is associated with loss of mitochondrial membrane potential and subsequent failure of oxidative phosphorylation pathways. Importantly, tissue microarray analysis and clinical data from TCGA indicate that CADM1 expression is inversely associated with melanoma progression and positively correlated with better overall survival in patients. Together, these data suggest that CADM1 exerts tumor suppressive functions in melanoma by reducing invasive potential and may be considered a biomarker for favorable prognosis.

Fumarate hydratase expression in localized, radically-resected clear cell renal cell carcinoma and its association with clinical outcomes.

620 Background: Prognostic stratification of localized clear cell renal cell carcinoma (lccRCC) mainly relies on clinical characteristics and TNM staging system, while biological biomarkers are currently lacking. We previously showed that reduced expression of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) was associated with better clinical outcomes in patients (pts) with metastatic ccRCC. In the present study we aimed at assessing the association between intratumor FH expression and clinical outcomes in pts with radically-resected lccRCC. Methods: Pts with radically-resected lccRCC and available formalin-fixed, paraffin-embedded (FFPE) primary (renal) tumor tissue were included. FH protein expression was assessed by means of immunohistochemistry (IHC) and defined as normal (comparably to non-neoplastic tubular cells) or low (lower than in non-neoplastic tubular cells). Results: Out of 50 pts included, we found a normal FH expression in 20 cases (40%) and a low FH expression in 30 cases (60%). Median age was 57 years (interquartile range 49-68) and 48 pts (96%) had pN0 disease, while 2 pts (4%) had pN1 disease. Low FH expression was associated with pT ( P= .003) but not with sex, age, Fuhrman grade or pN. After a median follow-up of 76.9 months, low FH expression was associated with a lower relapse rate (13% vs 50%; odds ratio for relapse 0.16; 95% confidence interval [CI] 0.04-0.62; P= .005), longer relapse-free survival (RFS) (5-years RFS rate 90% vs 50%; HR 0.20; 95% CI 0.06-0.63; P= .006) and a trend toward a better overall survival (OS) (5-years OS rate 100% vs 77.3%; HR 0.14; 95% CI 0.02-1.23; P= .07) when compared with normal FH expression. In the multivariable model including other characteristics associated with RFS, low FH expression confirmed an independent association with RFS (adjusted HR 0.25; 95% CI 0.06-0.91; P= .03). Conclusions: In our study, low intratumor FH, as detected by IHC, was associated with lower relapse rate, better RFS and a trend toward a better OS in patients with lccRCC when compared with normal FH levels. The role of FH expression as a prognostic biomarker in this setting warrants further investigation.

Attenuated ZHX3 expression serves as a potential biomarker that predicts poor clinical outcomes in breast cancer patients.

BackgroundThe ZHX family has recently been in the spotlight as an integrator and an indispensable node in carcinogenesis, whose expression is frequently dysregulated in multiple cancers. The current study provides a novel investigation of the expression profiles of ZHX factors in breast cancer.Materials and methodsThe mRNA levels of ZHXs and follow-up periods in breast cancer patients were mined through the Oncomine, Cancer Cell Line Encyclopedia, bc-GenExMiner, cBioPortal and Kaplan–Meier plotter databases. In addition, ZHX3 protein expression was examined in 98 primary tumor samples by immunohistochemistry to investigate its association with clinicopathological parameters and patient outcomes.ResultsWe found that the transcriptional levels of ZHX1, ZHX2 and ZHX3 were not significantly altered in tumor tissues compared with those in nontumor tissues. ZHX2 and ZHX3 mRNA levels were observed to be positively correlated with estrogen receptor and progesterone receptor expression, while ZHX2 mRNA levels were negatively associated with HER2 expression. Survival analyses revealed that high mRNA levels of ZHX2 and ZHX3 correlated with better overall survival in patients with breast cancer. Immunohistochemical analysis revealed that patients with decreased ZHX3 protein levels had poorer outcomes. Multivariate analysis exhibited that ZHX3 expression may serve as an independent high-risk prognostic predictor.ConclusionDysregulated expression of ZHXs may be involved in the progression of breast cancer and could serve as a novel biomarker and potential target for breast cancer.

Microwave Ablation Provided Better Overall Survival Than Liver Resection For Small Hepatocellular Carcinoma In Patients With Borderline Liver Function

Background: Microwave ablation (MWA) is showed to be at least as effective as, if not superior than, radiofrequency ablation in treating HCC. Studies comparing MWA and liver resection are lacking. The aim of this study is to evaluate the survival of patients who were treated with liver resection and MWA and to evaluate if the newly developed Albumin-Bilirubin (ALBI) grade can help in patient selections for liver resection or ablation. Methods: This is a retrospective analysis on patients who received curative liver resection and MWA for primary HCC from March 2009 to December 2015. Baseline clinical and laboratory parameters were retrieved and reviewed from the hospital database. Propensity score matching was used at 1:1 ratio. The ALBI grade was evaluated for their abilities of patient selection. Results: A total of 442 patients underwent MWA and liver resection for primary HCC during the study period. Propensity scoring matching was used and resulted in 63 matched pairs for further analysis. While liver resection still offered better overall and disease-free survivals in patients with ALBI grade 1, MWA provided a significantly better overall survival in patients with ALBI grade 2 or 3. (p=0.025). Conclusion: Microwave ablation, as a treatment for HCC, offered superior overall survival to liver resection in patients ALBI grade 2 or 3.

Microwave ablation provided better overall survival than liver resection for small hepatocellular carcinoma in patients with borderline liver function

Background: Microwave ablation (MWA) is showed to be at least as effective as, if not superior than, radiofrequency ablation in treating HCC. Studies comparing MWA and liver resection are lacking. The aim of this study is to evaluate the survival of patients who were treated with liver resection and MWA and to evaluate if the newly developed Albumin-Bilirubin (ALBI) grade can help in patient selections for liver resection or ablation. Methods: This is a retrospective analysis on patients who received curative liver resection and MWA for primary HCC from March 2009 to December 2015. Baseline clinical and laboratory parameters were retrieved and reviewed from the hospital database. Propensity score matching was used at 1:1 ratio. The ALBI grade was evaluated for their abilities of patient selection. Results: A total of 442 patients underwent MWA and liver resection for primary HCC during the study period. Propensity scoring matching was used and resulted in 63 matched pairs for further analysis. While liver resection still offered better overall and disease-free survivals in patients with ALBI grade 1, MWA provided a significantly better overall survival in patients with ALBI grade 2 or 3. (p=0.025) Conclusion: Microwave ablation, as a treatment for HCC, offered superior overall survival to liver resection in patients ALBI grade 2 or 3.

Survival Impact of Locoregional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancers in a Large Multicentric Cohort Study: A Propensity Score-Matched Analysis

Improvement in overall survival (OS) by locoregional treatment (LRT) of the primary tumor in de novo metastatic breast cancer (MBC) patients remains controversial. The aim of our study was to evaluate the impact of LRT on OS in a large retrospective cohort of de novo MBC patients, with regard to immunohistochemical characteristics and pattern of metastatic dissemination. We conducted a multicentric retrospective study of patients diagnosed with de novo MBC selected from the French Epidemiological Strategy and Medical Economics MBC database (NCT03275311) between 2008 and 2014. Overall, 4276 women were included in the study. LRT comprised either radiotherapy, surgery, or both. LRT was used in 40% of patients. Compared with no LRT, patients who received LRT were younger (p < 0.0001) and were more likely to have only one metastatic site (p < 0.0001) or bone-only metastases (p < 0.0001). LRT was associated with a significantly better OS based on landmark multivariate analysis at 1-year (hazard ratio 0.65, 95% confidence interval 0.55-0.76, p < 0.001). Similar results were observed in all sensitivity analyses, including propensity score matching. In subgroup analysis, LRT was associated with better OS in patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (61.6 vs. 45.9months, p < 0.001) and HER2-positive tumors (77.2 vs. 52.6months, p = 0.008), but not in triple-negative tumors (19 vs. 18.6months, p = 0.54), and was also associated with a reduction in the risk of death in visceral metastatic patients (p < 0.001). LRT was associated with a significantly better OS in de novo MBC patients, including patients with visceral involvement at diagnosis; however, LRT did not impact OS in triple-negative MBC.

Safety and efficacy of cytotoxic chemotherapy in hepatocellular carcinoma after first-line treatment with sorafenib

BackgroundBefore the targeted therapies era, cytotoxic chemotherapy (CCT) was an option for advanced hepatocellular carcinoma (HCC), even with the lack of supporting evidence. Since the last decade, sorafenib has been established as the first-line therapy. Although new agents are being incorporated, CCT is still considered in regions where new drugs are not available or for patients who progressed through the approved therapies and remain in good clinical condition. We aimed to describe our experience regarding the use of CCT as second-line treatment after sorafenib.MethodsA database of 273 patients was evaluated. Patients that received CCT after sorafenib progression were selected for the analysis. Descriptive statistics was used for categorical and continue variables. Median survival was estimated with Kaplan-Meier curves. Variables were found to be significant if the two-sided p value was ≤ 0.05 on multivariate testing using the Cox regression model.ResultsForty-five patients received CCT; 33 (73.3%) had Child-Pugh classification A, and 34 (75.6%) had stage C according to the Barcelona Clinic Liver Cancer (BCLC) staging system. The most used regimen was doxorubicin in 25 patients (55.6%). Median overall survival (OS) was 8.05 months (95% confidence interval [CI] 2.73 – 9.88 months). The 6-month and 1-year survival probability was 52.4% and 27.36%, respectively. Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 and disease control with sorafenib was independently associated with better OS in patients treated with CCT. Any-grade toxicities were observed in 82.2% and grade 3–4 in 44.4% of the patients.ConclusionIn accordance with previous studies, CCT had a notable rate of adverse events. The poor prognosis of this cohort suggests that CCT may not alter the natural history of HCC after sorafenib progression.

Impact of Rituximab Infusion Reactions on Clinical Outcomes in Patients with Diffuse Large B-Cell Lymphoma

Introduction: Rituximab is a chimeric mouse/human monoclonal antibody that binds to CD20, which is expressed on both normal and neoplastic B-lymphocytes. The addition of rituximab to standard chemotherapy regimens has led to improvements in progression-free survival and overall survival for diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma (NHL). Despite the widespread clinical success of rituximab, its mechanism of action is not clear. However, evidence from pre-clinical models and clinical observations suggest complement-mediated cytotoxicity (CMC) and/or antibody-dependent cell mediated cytotoxicity (ADCC) may both play a role.Clinically, the most common complication of rituximab is mild infusion reactions (IR), characterized by fevers, rigors, flushing, dyspnea, and mild hypotension, which are typically limited to the first infusion. Complement activation has been suggested as an underlying mechanism for rituximab-related IR, though the exact nature or implications of such reactions are not known. Since complement activation is also a potential mechanism of rituximab-related anti-lymphoma activity, we aimed to determine whether an association exists between rituximab associated IR and outcomes in patients with DLBCL. These results would help guide future studies on the mechanism of monoclonal antibody therapy for NHL.Methods: We identified and analyzed a retrospective cohort of 229 patients with DLBCL. They were stratified into two cohorts, based on the presence or absence of an infusion reaction during the first cycle of rituximab. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 was used to grade the severity of rituximab-associated IR. Univariate and multivariate analyses were performed to evaluate the prognostic significance of rituximab-related infusion reactions relative to DLBCL subtype, IPI score, c-Myc mutational status, chemotherapy regimen, and Ki-67 proliferative index.Results: Baseline characteristics did not differ significantly between the two groups. Rituximab was included as initial treatment in all patients studied. Among 226 patients, 68 (30.1%) had a grade 1-2 IR, all of whom were able to receive subsequent rituximab therapy. In comparing outcomes between the two cohorts, those with an IR had a significantly greater overall survival (HR 0.26, 95% CI 0.07-0.95) at five years (Figure 1). Multivariate analysis showed that patients with c-Myc alterations or higher IPI scores were more likely to experience a rituximab associated IR (Table 1). Furthermore, subgroup analysis showed that among patients with either c-Myc alterations or GCB subtype of DLBCL, those who experienced an IR had a statistically significant increase in progression-free survival (p-value of 0.01 and 0.03, respectively).Conclusion: Rituximab associated IR occurs commonly and is associated with better overall survival in patients with DLBCL. Subgroup analyses suggest that this benefit is largely restricted to patients with c-Myc alterations or the GCB subtype. While these data are limited by the small sample size and retrospective nature, they do generate some intriguing hypotheses related to underlying mechanism of action of rituximab in a subset of DLBCL patients. These data have potential implications in augmenting the efficacy of CD20-directed monoclonal antibody therapy in these patients that should be further validated in subsequent prospective studies. [Display omitted] DisclosuresBartlett:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Affimed: Research Funding; Forty Seven: Research Funding; ImaginAB: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Immune Design: Research Funding; Millennium: Research Funding; Merck & Co: Research Funding. Wagner-Johnston:JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Novartis: Research Funding; Celgene: Research Funding; ASTEX: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Endometriosis-Associated Ovarian Cancer: Population Characteristics and Prognosis.

The aim of this study was to analyze and compare the clinicopathologic features and prognosis of clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (EOC) associated or not with endometriosis. This was a reconstituted cohort study from a single-institution Brazilian cancer center approved under review board no. 68150617.7.0000.5404 with 50 patients with CCOC and EOC diagnosed between 1995 and 2016, followed up until 2017. Clinicopathologic characteristics and survival outcomes were analyzed. There were 23 women (46%) with CCOC and 27 with EOC (54%); 80% of those women had histologic confirmation of endometriosis; 42% were nulliparous, and 42% were premenopausal; and cancer antigen 125 was elevated in both International Federation of Gynecology and Obstetrics stages I-II disease (mean, 614.7 Ui/mL; range, 3-6030 Ui/mL) or International Federation of Gynecology and Obstetrics stages III-IV disease (mean, 2361.2 Ui/mL; range, 8-12771 Ui/mL). Women with EOC were 7 years younger than those with CCOC. When associated with endometriosis, CCOCs were more likely diagnosed at earlier stages. Endometrioid ovarian carcinoma and CCOC at initial stage and EOC at advanced stage share similar good prognosis. Univariate analysis showed that CCOC not associated with endometriosis has worse overall survival (OS). However, multivariate analysis showed that only abnormally elevated levels of cancer antigen 125 and advanced stage at diagnosis were significantly associated with reduced progression-free survival. Tumor stage remains the only prognostic factor for OS. The presence of coexisting endometriosis did not change the prognosis of EOC but was associated with better OS in patients with CCOC. Patients with CCOC and EOC at initial stages and EOC at advanced stages have a good prognosis; however, CCOC at advanced stages had a sooner recurrence and shorter OS.

Comparison of extracorporeal membrane oxygenation outcome for influenza-associated acute respiratory failure in Japan between 2009 and 2016.

BackgroundSince the 2009 pandemic influenza, we have nationally established a committee of the extracorporeal membrane oxygenation (ECMO) project. This project involves adequate respiratory management for severe respiratory failure using ECMO. This study aimed to investigate the correlations between changes in respiratory management using ECMO in Japan and outcomes of patients with influenza-associated acute respiratory failure between 2009 and 2016.MethodsWe investigated the incidence, severity, characteristics, and prognosis of influenza-associated acute respiratory failure in 2016 by web-based surveillance. The correlations between clinical characteristics, ventilator settings, ECMO settings, and prognosis were evaluated.ResultsA total of 14 patients were managed with ECMO in 2016. There were no significant differences in age, sex, and the acute physiology and chronic health evaluation II score between 2009 and 2016. The maximum sequential organ failure assessment score and highest positive end-expiratory pressure were lower in 2016 than in 2009 (p = 0.03 and p = 0.015, respectively). Baseline and lowest partial pressure of arterial oxygen (PaO2)/fraction of inspiratory oxygen (FIO2) ratios were higher in 2016 than in 2009 (p = 0.009 and p = 0.002, respectively). The types of consoles, circuits, oxygenators, centrifugal pumps, and cannulas were significantly changed between 2016 and 2009 (p = 0.006, p = 0.003, p = 0.004, p < 0.001, respectively). Duration of the use of each circuit was significantly longer in 2016 than in 2009 (8.5 vs. 4.0 days; p = 0.0001). Multivariate analysis showed that the use of ECMO in 2016 was an independent predictor of better overall survival in patients with influenza-associated acute respiratory failure (hazard ratio, 7.25; 95% confidence interval, 1.35–33.3; p = 0.021).ConclusionsRespiratory management for influenza-associated acute respiratory failure using ECMO was significantly changed in 2016 compared with 2009 in Japan. The outcome of ECMO use had improved in 2016 compared with the outcome in 2009 in patients with influenza-associated acute respiratory failure.

Abstract 105: CADM1 is a TWIST1-regulated suppressor of melanoma invasion and survival

Abstract Metastatic melanoma is the deadliest form of skin cancer; however, patients diagnosed and treated prior to metastatic dissemination have a good prognosis. The transcription factor, TWIST1 has been implicated in enhancing the migration and invasion of melanoma cells but the range of TWIST1-regulated targets is poorly described. In this study, we performed expression profiling to identify the TWIST1-regulated transcriptome. Gene ontology pathway analysis revealed that TWIST1 and epithelial to mesenchymal transition (EMT) were inversely correlated with levels of cell adhesion molecule 1 (CADM1). Chromatin immunoprecipitation (ChIP) studies and promoter assays demonstrated that TWIST1 physically interacts with the CADM1 promoter, suggesting TWIST1 directly represses CADM1 levels. Modulation of CADM1 resulted in significant effects on the migration and invasion of melanoma cells. In addition, elevated CADM1 elicited cell death in non-adherent conditions, an effect that could not be rescued with a pan-caspase inhibitor. Analyses suggest that CADM1 directed non-adherent cell death is associated with loss of mitochondrial membrane potential and subsequent failure of oxidative phosphorylation pathways. Furthermore, clinical data from TCGA indicates that CADM1 expression is correlated with better overall survival in patients. Together, these data suggest that CADM1 exerts tumor suppressive functions in melanoma by reducing invasive potential and may be a biomarker for improved survival of melanoma patients. Citation Format: Edward J. Hartsough, Michele B. Weiss, Shea A. Heilman, Timothy J. Purwin, Curtis H. Kugel, Sheera R. Rosenbaum, Dan A. Erkes, Manoela Tiago, Inna Chervoneva, Andrew E. Aplin. CADM1 is a TWIST1-regulated suppressor of melanoma invasion and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 105.

Abstract 3797: Chromosome instability as a prognostic factor&amp; an immunotherapeutic target in acute myeloid leukemia

Abstract Chromosome instability (CIN) is an increased rate of chromosome mis-segregation due to errors in mitosis. CIN generates genetic and karyotypic diversity and is common in hematological malignancies. Low to moderate levels of CIN are well tolerated, and moderate levels can promote cancer proliferation by generating genetic diversity for tumor evolution. However, very high levels of CIN are lethal and enhancing CIN can be therapeutic. Therefore, CIN status could be prognostic for clinical outcomes as well as a therapeutic target. Despite its promise, little is known about CIN in AML. We first determined if CIN is correlated with clinical outcome in patients with acute myeloid leukemia (AML). We quantified the chromosome mis-segregation frequency (lagging chromosomes and chromatin bridges) in dividing AML cells on bone marrow core biopsies. Our study reveals a wide distribution of CIN in AML core biopsy specimens, ranging from 20% to 67%. High CIN correlates with a better overall survival in patients with AML. Recent data suggest that chromosome mis-segregation promotes senescence and initiates immune clearance. Our hypothesis is that chromosome instability is immunogenic due to DNA damage, proteotoxic/oxidative stress with a high mutagenic potential, which can be recognized by immune system. To test this, we used an inhibitor of Monopolar spindle 1 (Mps1) to enhance CIN and tested if that altered immunogenicity. Mps1 is a key component of the mitotic checkpoint and is also involved with chromosome alignment. Inhibition of Mps1 by AZ3146 results in severe chromosome mis-segregation, micronuclei formation, and apoptosis in AML cell lines. In addition, AZ3146 treatment causes activation of γH2AX due to DNA damage, and calreticulin exposure from endoplasmic reticulum stress. This generates danger signals to activate innate immune system (natural killer cells and dendritic cells) and induces immunogenic cell death (ICD) through priming of cytotoxic T cells. This effect is mainly seen in synchronized mitotic cells, suggesting AZ3146 acts specifically on mitosis. Additionally, we observed the overexpression of programed death ligand-1 (PD-L1) after the treatment of AZ3146 in AML cells. As evidence showed, PD-L1 participates in the immune evasion and protects AML blasts from cytotoxic T cells in mouse models of leukemia. Taken together, our observations in Mps1 inhibitor treatment indicate the immunogenicity of CIN in AML. Additionally, these data support combination treatment of mitotic checkpoint inhibitor with immunotherapy to improve therapeutic efficacy in AML patients. Citation Format: Ning Jin, Mark Burkard. Chromosome instability as a prognostic factor&amp; an immunotherapeutic target in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3797.