Positive Prognostic Factor For Overall Survival Research Articles

Abstract P4-06-22: Transcription factor T-bet and PD-L1 expression in tumor microenvironment of triple-negative breast cancer

Abstract Background: Many analyzes regarding immunotherapies using checkpoint blockade has made it clear that tumor infiltrating lymphocytes (TILs) plays an important role in treating cancers with high levels of somatic mutations such as triple-negative breast cancer (TNBC). We reported the relationship between TILs and PD-L1 expression, and revealed that high-TILs/positive-PD-L1 expression population in TNBC was associated with better prognosis (Oncotarget 2017). However, its molecular mechanism is still unclear. Meanwhile, T-box transcription factor 21 (T-bet) which regulates effecter T-cells activation is derived by stimulation of T-cell receptor and IL-12. Activated T-cells work as antitumor lymphocytes by enhancing the production of cytokines such as INFγ. We focused on T-bet and examined the function of activated T-cells. Patients and Methods: This study included 242 patients with primary TNBC who underwent resection without neoadjuvant chemotherapy at our three hospitals between January 2004 and December 2014. The immunohistochemistry scoring for CD8 and T-bet expression on TILs was defined as ≥30 per 0.00625mm2. PD-L1 positivity was defined as ≥1% of tumor cells staining positive for PD-L1. Results: Of the 242 TNBC, CD8 on TILs was expressed as positive in 127 (52.5%) tumors, T-bet on TILs was expressed as positive in 67 (27.7%) tumors, and PD-L1 expression on tumor cells was expressed as positive in 99 (40.9%) tumors. T-bet expression was significantly correlated with CD8 expression (P<0.0001) and PD-L1 expression (P=0.0004). There was no significant difference in recurrence free survival (RFS) and overall survival (OS) regardless of CD8 or PD-L1expression level. Meanwhile, the patients with T-bet-positive tumors had a longer OS, compared to those with T-bet-negative tumors (P = 0.13 in RFS and P = 0.047 in OS). The multivariate analysis revealed that T-bet expression on TILswas an independent and positive prognostic factor for OS(HR = 0.5, 95%CI 0.1-0.9, P = 0.035). Conclusion: OS was significantly longer among patients with high T-bet expressing TNBC. These results may validate the significance of T-bet as a biomarker for various immunotherapies in TNBC. Citation Format: Mori H, Kubo M, Kai M, Kurata K, Kawaji H, Kaneshiro K, Motoyama Y, Kuroki R, Yamada M, Nishimura R, Okido M, Oda Y, Nakamura M. Transcription factor T-bet and PD-L1 expression in tumor microenvironment of triple-negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-22.

Unresectable pancreatic ductal adenocarcinoma: Role of CT quantitative imaging biomarkers for predicting outcomes of patients treated with chemotherapy

ObjectivesThe primary aim of this study was to determine if computed tomographic (CT) texture analysis measurements of the tumor are independently associated with progression-free survival (PFS) and overall survival (OS) in patients with unresectable pancreatic ductal adenocarcinoma (PDAC), including both unresectable locally advanced and metastatic PDAC, who were treated with chemotherapy. MethodsAfter an institutional review board waiver was obtained, contrast material-enhanced CT studies in 41 patients with unresectable PDAC who underwent contrast-enhanced CT before chemotherapy between 2014 and 2017 were analyzed in terms of tumor texture, with quantification of mean gray-level intensity (Mean), entropy, mean of positive pixels (MPP), kurtosis, standard deviation (SD), and skewness for fine to coarse textures (spatial scaling factor (SSF) 0–6, respectively). The association between pretreatment and posttreatment texture parameters, as well as Δ value (difference between posttreatment and pretreatment texture parameters), and survival time was assessed by using Cox proportional hazards models and Kaplan-Meier analysis. ResultsFindings from the multivariate Cox model indicated that tumor size, tumor SD (HR, 0.942; 95% CI: 0.898, 0.988) and skewness (HR, 0.407; 95% CI: 0.172, 0.962) measurements with SSF = 3, and tumor SD (HR, 0.958; 95% CI: 0.92, 0.997) measurements with SSF = 4 were significantly and independently associated with PFS, while tumor size and tumor SD (HR, 0.928; 95% CI: 0.882, 0.976) measurements with SSF = 3 were significantly and independently associated with OS. None of the post-therapy texture parameters or Δ value had a significant association with OS or PFS in multivariate Cox regression models. Medium SD (SSF = 3) of more than 38.38 and coarse SD (SSF = 4) of more than 40.67 were associated with longer PFS after chemotherapy (for SSF = 3, median PFS was 10.0 vs 6.0 months [P = 0.024], and for SSF = 4, median PFS was 12.0 vs 6.0 months [P = 0.003]). SD of 38.38 or greater (SSF = 3) as a dichotomized variable was a significant positive prognostic factor for OS (median OS, 20.0 vs 9.0 months [P = 0.04]). Survival models that included a combination of pretreatment SD (SSF = 3) with tumor size, had the potential to perform better than SD alone, while having no statistical significance in this study (area under the ROC curve, 0.756 vs 0.715 [P = 0.066]). ConclusionsPretreatment CT quantitative imaging biomarkers from texture analysis are associated with PFS and OS in patients with unresectable PDAC who were treated with chemotherapy, and the combination of pretreatment texture parameters and tumor size have the potential to perform better in survival models than imaging biomarker alone.

CD103+ tumor-infiltrating lymphocytes predict favorable prognosis in patients with esophageal squamous cell carcinoma.

As an indispensable factor in preventing the recirculation of tissue lymphocytes to the lymphatic and blood systems, the integrin CD103 has enabled the characterization of lymphocyte populations in non-lymphoid tissues and organs. However, the expression, distribution, and clinical significance of CD103+ tumor-infiltrating lymphocytes (TILs) in esophageal squamous cell carcinoma (ESCC) remain unclear. In the present study, we included tumor and adjacent non-tumor tissue specimens from 198 patients with ESCC who had undergone surgical resection. Immunohistochemistry and immunofluorescence were used to detect CD103+ TIL distribution, as well as the co-expression of CD103 and T cell markers and functional molecules. Kaplan-Meier analysis and the Cox proportional hazards model were used to estimate the prognostic value of CD103+ TILs. The results showed that CD103+ TILs were predominantly located in adjacent non-tumor tissues compared with tumor tissues (P < 0.0001). Immunofluorescence double staining revealed that CD8+ T cells, but not CD4+ T cells, comprised the majority of CD103-expressing cells. Most of these CD103-expressing cells co-expressed CTLA-4 and granzyme B rather than the exhaustion marker PD-1. High density of intratumoral CD103+ TIL is associated with longer overall survival (OS) and disease-free survival (DFS) in both the internal (OS, P = 0.0004 and DFS, P = 0.0002) and external (OS, P = 0.038 and DFS, P = 0.12) cohorts. Multivariate Cox analysis showed the density of CD103+ TILs was an independent positive prognostic factor for OS (hazards ratio [HR] = 0.406; P = 0.0003 in the internal cohort; HR = 0.328, P = 0.01, in the external cohort) and DFS (HR = 0.385; P = 0.0002 in the internal cohort; HR = 0.270, P = 0.003, in the external cohort). Our findings indicate that CD103+ TILs might play an important role in the tumor microenvironment, and intratumoral CD103+ TILs could serve as a promising prognostic marker in ESCC.

Positive effect of single nucleotide RAD51 135G>C polymorphism and low Ku70 protein expression on female rectal cancer patients survival after preoperative radiotherapy.

This is a retrospective analysis of 103 patients having locally advanced rectal cancer who received short-course radiotherapy (SCRT). The objective of the study was to check whether a polymorphism in the RAD51 gene (135 G>C), Ku70 protein expression, and tumor microenvironment: proliferation rate measured by BrdUrdLI and Ki-67LI, hypoxia (glucose transporter-1 expression), P53 protein expression, and DNA ploidy can influence DNA repair capacity, the factors contributing to patient overall survival (OS) and the incidence of recurrences and metastases. RAD51 (135 G>C) polymorphism was evaluated using restriction fragment length polymorphism polymerase chain reaction, and proteins were identified using immunohistochemistry. There were 3 (2.9%) tumors with RAD51 CC, 75 (72.8%) with GG, and 25 (24.3%) with GC genotypes. The median follow-up time was 63.1 months (range 2-120). Patients with CC genotype survived significantly longer than those with GG and GC genotypes and did not develop any recurrences or distant metastases. Female patients with Ku70 expression (<75.1) or RAD51CC genotype (impaired DNA damage repair and radiosensitive) had significantly longer OS (p=0.013) than those with Ku70>75.1 % or RAD51GG,GC (radioresistant phenotype) and male patients in the log-rank test. In multivariate analysis, positive prognostic factors for OS in the male patients were grade=1 and <17 days break in the treatment, whereas in the female subgroup, only radiosensitive phenotype (Ku70 <75.1% or RAD51CC genotype). To the best of our knowledge, this is the first study to provide evidence for the positive effect of CC genotype of RAD51 or low Ku70 expression on OS in females with rectal cancer after SCRT.

Multimodal treatments combined with gamma knife surgery for primary atypical teratoid/rhabdoid tumor of the central nervous system: a single-institute experience of 18 patients.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly malignant tumor of the central nervous system with poor prognosis. Nowadays, multimodal management, including surgery, chemotherapy (CMT), and radiation therapy (RT), is advocated. However, AT/RT treatment with gamma knife surgery (GKS) was rarely reported. The aim of this study was to assess the efficacy and safety of GKS for the treatment of AT/RT. Medical records of AT/RT patients who underwent surgery from 2007 to 2014 at the West China Hospital were retrospectively reviewed and statistically analyzed. Eighteen patients (12 males and 6 females) were presented with AT/RTs. Median age during presentation was 20.5months (range, 4-179months). Twelve patients were < 3years and six patients were > 3years. Tumor location was supratentorial in seven patients, infratentorial in ten patients, and center area of the brain in one patient. Treatments performed were as follows: surgery alone in two patients, surgery+RT in two patients, surgery+CMT in five patients, surgery+CMT+RT in two patients, and surgery+CMT+RT+GKS in seven patients. The 2-year overall survival (OS) rate and event-free survival (EFS) rate for all 18 consecutive patients were 33.3 and 27.8%, respectively. Cox regression analyses showed that multimodal management combined with GKS was an independent positive prognostic factor for OS. Although AT/RTs are lethal cancer types, the OS of the disease was improved by using multimodal therapeutic strategies, including surgery, CMT, and RT, combined with GKS.

Impact of clinicopathological parameters on survival after multiorgan resection among patients with T4 gastric carcinoma: a systematic review and meta-analysis.

The prognostic factors which can improve the overall survival (OS) of patients with T4 gastric carcinoma (GC) are still controversial: a meta-analysis was conducted to analyze the impact of clinicopathological parameters on survival after MOR among patients with T4 GC. A systematic search was performed. Odd risks (ORs) of patients with T4 GC were used to calculate the relationship between clinicopathological parameters and OS. Nine studies involving 941 patients with T4 GC were identified. Well-moderate differentiation led to increased 1-, 3-, 5-year OS with an OR of 2.63, 1.58 and 1.45. Borrmann type I-II led to increased 1-, 3-year OS with an OR of 1.67 and 2.08. No lymph node metastasis led to increased 1-, 3-, 5-year OS with an OR of 7.16, 3.18 and 3.71. Total gastrectomy led to increased 1-, 3-year OS with an OR of 2.01 and 1.79. ≥2 Organs resected led to increased 1-, 3-year OS with an OR of 2.19 and 2.19. TNM stage II-III led to increased 1-, 3-year OS with an OR of 3.68 and 5.75. Curative resection led to increased 1-, 3-, 5-year OS with an OR of 4.46, 5.80 and 5.98. Well-moderate differentiation, Borrmann type I-II, no lymph node metastasis, total gastrectomy, ≥2 organs resected, TNM stage II-III and curative resection were positive prognostic factors for OS of patients with T4 GC.

Increased serum carcinoembryonic antigen level can predict poor survival of patients with small cell lung cancer

Increased serum tumor biomarkers are usually associated with huge tumor burden, but the prognostic value of these markers remains controversial. The serum levels of carcinoembryonic antigen (CEA), nerve cell-specific enolase, and lactate dehydrogenase in 281 patients with small cell lung cancer (SCLC) were analyzed in this study. Increased serum CEA levels were observed in 92 (32.7%) patients. Survival was superior in patients with normal serum CEA levels compared with those with increased serum CEA levels. The median survival time, 2-year overall survival (OS) rate, and 3-year OS rate were 19.1 months vs 14.6 months, 42.7% vs 28.3%, and 30.6% vs 14.1%, respectively (P = 0.002). In multivariate analysis, extensive-stage (ES)-SCLC (hazard ratio [HR] = 1.936, P = 0.001), an increased serum CEA level (HR = 1.432, P = 0.021) at diagnosis, and <4 cycles of chemotherapy (ChT) (HR = 0.432, P = 0.001) were independent negative prognostic factors for the OS. Additionally, normal CEA level (HR = 1.678, P = 0.012), treatment modalities including surgery (HR = 1.595, P = 0.049), and ≥ 4 cycles of ChT (HR = 1.880, P = 0.004) were independent positive prognostic factors for OS in patients with local disease. In the subgroup with ES-SCLC, normal serum CEA level (HR = 1.608, P = 0.043), thoracic radiation therapy (HR = 1.744, P = 0.005), and ≥ 4 cycles of ChT (HR = 2.626, P = 0.001) were independent positive prognostic factors for OS.

The prognostic value of preoperative helicobacter pylori infection in resected gastric cancer.

137 Background: Limited data exist on the prognostic implication of pre-operative Helicobacter pylori (H. pylori) infection in gastric adenocarcinoma (GAC). Our aim was to assess the association of H. pyloriwith recurrence and survival in patients undergoing resection of GAC. Methods: All patients who underwent curative intent resection for GAC from 2000 to 2012 at seven academic institutions comprising the US Gastric Cancer Collaborative were included. 30-day mortalities were excluded. Survival analyses were conducted with Kaplan Meier log rank and multivariate Cox regression. Primary endpoints were recurrence-free survival (RFS) and overall survival (OS). Results: Of 965 patients, 559 met inclusion criteria and had documented pre-operative H. pylori testing. 18.6% (n=104) of patients tested positive for H. pylori pre-operatively. Data regarding treatment of H. pylori was not available. H. pylori infection was associated with younger age (62.1 vs 65.1 years; p=0.041), distal tumor location (82.7% vs 71.9%; p=0.033), and receipt of adjuvant radiation therapy (47.0% vs 34.9%; p=0.032). There were no significant differences in ASA class, margin status, Grade, PNI, LVI, or nodal metastases. The distribution of TNM stage I-III was similar between the two groups. H. pylori status was not associated with tumor recurrence. However, pre-operative H. pylori infection was associated with longer OS (84.3 mo vs 44.2 mo; p=0.008). When accounting for differences in age, tumor location, and delivery of radiation therapy, H. pylori infection persisted as a positive prognostic factor for OS (HR 0.60; CI 0.40-0.91; p = 0.016). Conclusions: Patients with and without preoperative H. pylori infection had no significant differences in adverse pathologic factors including positive margin, high grade, lymph node metastases, or advanced TNM stage. Despite similar disease presentation, pre-operative H. pylori infection was independently associated with improved overall survival. Further studies examining the interaction between H. pylori and tumor immunology and genetics are needed to better understand the relationship between H. pylori and survival in gastric cancer.

Additional prognostic role of EGFR activating mutations in lung adenocarcinoma patients with brain metastasis: Integrating with lung specific GPA score

ObjectiveWhile several prognostic models have been presented in NSCLC patients with brain metastasis, none of these models have included molecular markers as an index. The aim of our study was to evaluate the prognostic value of EGFR mutations and to integrate these EGFR mutations into the prognostic index in NSCLC patients with brain metastasis. Materials and methodsWe analyzed retrospectively 292 lung adenocarcinoma patients with brain metastasis. Clinico-pathological features and overall survival (OS) were compared between patients with EGFR mutations and patients with EGFR wild type. EGFR mutation status was integrated with lung specific graded prognostic assessment (GPA) score. ResultsAmong 292 patients, EGFR mutation status was tested in 183 patients. One hundred and five patients (57.4%) had EGFR activating mutations, 14 (7.7%) had EGFR non-activating mutations and 64 (35.0%) had EGFR wild type. OS was significantly longer in patients with EGFR activating mutations than in those with EGFR wild type patients (20.4 vs. 10.1 months, p=0.002). However, patients with EGFR non-activating mutations did not show superior OS compared with EGFR wild type patients (14.6 vs. 10.1 months, p=0.83). Multivariate analysis revealed that the presence of EGFR activating mutation is an independent positive prognostic factor for OS (adjusted hazard ratio 0.56, p=0.002). ConclusionsEGFR activating mutations have a prognostic role in lung adenocarcinoma patients with brain metastasis that is independent of other known prognostic factors. The frequency of EGFR mutation was higher than expected. The presence of EGFR activating mutations should be included as an index in the prognostic models for lung adenocarcinoma patients with brain metastasis.

Stage IE/IIE extranodal NK/T-cell lymphoma arising in the nasal cavity: Analysis of CT findings and their prognostic value

To investigate the computed tomography (CT) findings in patients with stage IE/IIE extranodal natural killer/T-cell lymphoma (ENKTL) arising in the nasal cavity and to evaluate whether imaging findings revealed by CT have prognostic value. The CT findings of 62 patients diagnosed with IE/IIE ENKTL arising in the nasal cavity were retrospectively reviewed. Imaging findings were investigated, and evaluated imaging findings were analysed for the prognostic value of overall survival (OS) and disease-free survival (DFS). Of the 62 patients, 21 (34%) presented with a superficial infiltrative, 38 (61%) with a mass forming, and three (5%) with a combined pattern. Of all imaging findings, local invasiveness (n = 26, 42%), including bony destruction, erosion, or soft-tissue involvement, was the only independent prognostic factor for OS [p = 0.008; hazard ratio (HR): 3.85; 95% confidence intervals (CI): 1.42-10.44] and DFS (p = 0.001; HR: 4.25; 95% CI: 1.72-10.47). In a subgroup analysis of 36 cases with no local invasiveness, a superficial infiltrative pattern in one nasal cavity was a positive prognostic factor for OS (p = 0.028) and DFS (p = 0.008). Imaging findings at CT provided clinically useful predictions for treatment outcomes. Local invasiveness revealed by CT findings was a strong prognostic factor for poor OS and DFS. In addition, in patients with no local invasiveness, a superficial infiltrative pattern in one nasal cavity predicted favourable OS and DFS.

Risk factors of peritoneal recurrence and outcome of resected peritoneal recurrence after liver resection in hepatocellular carcinoma: review of 1222 cases of hepatectomy in a tertiary institution.

BackgroundReports on the risk factors of peritoneal recurrence (PR) after liver resection for hepatocellular carcinoma are lacking. We examined the risk factors of PR after hepatectomy and the outcome of resected PR at our institution.MethodsWe retrospectively reviewed the data from 1,222 patients who underwent hepatectomies for hepatocellular carcinoma in Samsung Medical Center from January 2006 to August 2010. We identified patients with PR and studied the risk factors and outcomes of resected PR.ResultsThe rate of PR was 3.0% (n = 36). The mean ± SD age of patients was 54.0 ± 10.2 years. Among those with PR, 23 patients (63.9%) had unresectable disease and 13 patients (36.1%) had resectable disease. Multivariate analysis found that tumor size >50 mm, presence of microvascular invasion, bile duct invasion, and positive margins were significant risk factors of PR after liver resection. The median overall survival (OS) for resectable PR was 33.0 (28.0–61.6) months compared to 14.0 (6.8–21.2) months for unresectable PR (P = 0.009). Cox regression analysis demonstrated that resected PR [hazard ratio (HR) 0.042, P = 0.001] and interval between hepatectomy and PR (>6months) (HR 0.195, P = 0.016) were positive prognostic factors for OS, while alfa-fetoprotein >200 ng/dl at detection of PR (HR 11.321, P = 0.015) and serosal involvement of primary hepatocellular carcinoma (HR 25.616, P = 0.007) were negative prognostic factors for OS.ConclusionsWe found that tumor size >50 mm, presence of microvascular invasion, bile duct invasion, and positive resection margins were significant risk factors of PR after liver resection. Selected patients with resected PR had significantly better OS.

Prognostic significance of tenascin-C expression in superficial and invasive bladder cancer

Aims: Tenascin-C (Tn-C) is an extracellular matrix glycoprotein that is upregulated in malignant tumours. Tn-C promotes cell growth, cell migration, and angiogenesis. It has been suggested to be a prognostic...