Survival In Early-stage Patients Research Articles

A novel anti-CD47 antibody with therapeutic potential for NK/T-cell lymphoma

ABSTRACT NK/T-cell lymphoma (NKTCL) is a rare type of non-Hodgkin lymphoma (NHL). Although L-asparaginase-based chemotherapy has significantly improved survival in early-stage patients, the prognosis is poor in advanced and relapsed or refractory patients. CD47 is a promising target for cancer immunotherapy. However, the expression of CD47 in NKTCL and the antitumor effect and mechanism of the anti-CD47 monoclonal antibody (mAb) AK117 in NKTCL remain unclear. Firstly, the expression level of CD47 protein in NKTCL cells was detected by immunoblot and flow cytometry. Secondly, in order to validate the role of CD47 downregulation in the proliferation, apoptosis, and cell cycle of NKTCL cells, we used shRNA transfection to knock down CD47 expression. We determined the effect of knocking down CD47 and the novel anti‐CD47 antibody AK117 on the phagocytosis of NKYS and YTS cells by M2 macrophages in vitro. Finally, we assessed the ability of AK117 to inhibit tumor growth in an NKTCL xenograft model in which YTS cells were engrafted in SCID mice. The results showed that CD47 is relatively highly expressed in NKTCL cells. CD47 knockdown in NKTCL promoted phagocytosis by M2 macrophages in an in vitro coculture assay. The study also demonstrated that anti-CD47 mAb AK117 promoted phagocytosis of NKTCL cells by M2 macrophages. In addition, in vivo experiments showed that the anti-CD47 mAb AK117 significantly inhibited the growth of subcutaneous xenograft tumors in SCID mice compared to the control antibody IgG. Our results indicate that targeting CD47 monoclonal antibodies is a potential therapeutic strategy for NKTCL.

Commercial next generation sequencing in a real-world cohort of patients with metastatic breast cancer.

e13082 Background: Clinicians increasingly order next generation sequencing (NGS) of tissue or liquid (ctDNA) biopsies from patients with metastatic breast cancer. Although some genetic information is clinically actionable, some, particularly non-ERBB2 gene amplifications, is not. We reviewed NGS data from a real-world cohort of metastatic breast cancer patients to evaluate the prevalence of somatic abnormalities using commercial NGS technology. Methods: We evaluated Foundation One NGS data from 44 tissue and 17 liquid biopsies from patients seen in a medical oncology practice between 2016 and 2022. We used KM Plotter to measure overall survival in early-stage patients by relative gene expression. Results: 76% of patients had ductal and 24% had lobular carcinomas. 59% of patients had luminal (ER-positive) and 32% of patients had basal breast cancer (ER-negative). Only 9% of patients had HER2-positive disease. 48% of the tumors had a p53 abnormality, either a point (59%) or frameshift mutation (36%). 50% tumors had a somatic mutation in a tumor suppressor gene such as PTEN, RB or APC. One patient had a germline BRCA1 mutation and 5 patients had germline BRCA2 mutations. 39% of patients carried a somatic mutation in PIK3CA, predominantly H1047R (45%) in the kinase domain or E545X (20%) in the helicase domain. KM plotter showed worse OS in early-stage patients with low p53 gene expression or high PIK3CA expression. 10/11 patients with lobular carcinoma had somatic mutations in CDH1, 70% of which were frameshift mutations. 8/27 patients with luminal cancer had an ESR1 mutation, predominantly Y537 or D538. 9 patients, predominantly luminal, had amplifications of the 11q13 (CCND1). 7 patients had amplifications of 8q24 (MYC). 20q13 (AURKA) amplifications were only seen in luminal cancers. 12p13 (CCND2) amplifications were only seen in basal cancers. 27% of lobular cancers (vs. 6-17% of ductal cancers) demonstrated amplification of the 11q13, 8q24 and/or 8p11 amplicons. 20q13 and 12p13 amplifications were only seen in ductal cancers. Liquid biopsies were more likely to detect point mutations than tissue biopsies. p53 mutations were seen in 65% of liquid vs. 48% of tissue biopsies. 47% of liquid biopsies showed two p53 mutations. PIK3CA mutations were seen in 71% of liquid vs. 39% of tissue biopsies. 18% of liquid biopsies showed two PIK3CA mutations. 93% of basal cancers had at least one p53 mutation. 44% of luminal cancers had a PIK3CA mutation. ESR1, GATA3 and AKT1 mutations were only seen in luminal cancers. While ESR1 mutations were seen in ductal and lobular cancers, GATA3 and AKT1 mutations were only seen in ductal cancers. Conclusions: Commercial NGS testing of a real-world cohort yields actionable mutations that can impact clinical management and outcome of metastatic breast cancer patients. NGS testing demonstrates the range of gene amplifications and corresponds closely with what has been reported in the published literature.

Cancer Stem Cells and Cell Cycle Genes as Independent Predictors of Relapse in Non-small Cell Lung Cancer: Secondary Analysis of a Prospective Study.

PurposeCancer stem cells (CSCs) are described as resistant to chemotherapy and radiotherapy. It has been shown that CSCs influence disease-free survival in patients undergoing surgery for lung cancer (NCT04634630). We recently described an overexpression of CSCs recurrence-related genes (RG) in lung cancer. This study aims to investigate CSC frequency and RG expression as predictors of disease-free survival in lung cancer.Experimental DesignThis secondary analysis of a prospective cohort study involved 22 surgical tumor specimens from 22 patients harboring early (I-II) and locally advanced (IIIA) stages ACL and SCCL. Cell population frequency analysis of ALDHhigh (CSCs) and ALDHlow (cancer cells) was performed on each tumor specimen. In addition, RG expression was assessed for 31 target genes separately in ALDHhigh and ALDHlow populations. CSCs frequency and RG expression were assessed as predictors of disease-free survival by Cox analysis.ResultsCSCs frequency and RG expression were independent predictors of disease-free survival. CSC frequency was not related to disease-free survival in early-stage patients (HR = 0.84, 95%CI = 0.53-1.33, P = .454), whereas it was a risk factor for locally advanced-stage patients (HR = 1.22, 95%CI = 1.09-1.35, P = .000). RG expression—if measured in CSCs—was related to a higher risk of recurrence (HR = 1.19, 95%CI = 1.03-1.39, P = .021). The effect of RG expression measured in cancer cells on disease-free survival was lower and was not statistically significant (HR = 1.12, 95%CI = 0.94-1.33, P = .196).ConclusionsCSCs frequency and RG expression are independent predictors of relapse in lung cancer. Considering these results, CSCs and RG may be considered for both target therapy and prognosis.

Role of radiation therapy in primary tonsil large B cell lymphoma: a SEER-based analysis

BackgroudPrimary tonsil diffuse large B cell lymphoma (PT-DLBCL) is an uncommon disease entity. The role of radiation therapy (RT) in PT-DLBCL is debatable in both the pre- and post- rituximab era. The purpose of this study was to evaluate the treatment outcome and establish a prognostic model in PT-DLBCL based on the Surveillance, Epidemiology, and End Results (SEER) database.Materials and methodsData of 1214 PT-DLBCL patients diagnosed between 1975 and 2016 were extracted from SEER 18. The effect of RT was assessed for the entire cohort and subgroups by stages using univariate, multivariate Cox regression analyses and propensity score matching (PSM).ResultsThe entire cohort included 1043 patients with early-stage (ES) PT-DLBCL and 171 patients with advanced-stage (AS) disease. A decreasing trend of RT utilization in the ES cohort after 2002 was observed. 47.4% of patients in ES received RT, whereas 25.1% in AS underwent RT. RT significantly improved overall survival in both univariate (P < 0.001) and multivariate (P = 0.002) analyses. PSM analysis further validated the survival advantage of RT (P = 0.002). A nomogram was established to predict the potential survival benefit. Subgroup analysis revealed RT was significantly associated with overall survival in ES patients of PT-DLBCL (P = 0.001) and in the rituximab era (P = 0.001) but not in those with AS disease (P = 0.241).ConclusionsThis population-based study encloses the largest sample of PT-DLBCL to date and demonstrates a favorable survival role of RT in early stages rather than advanced stages. The established nomogram helps to identify high risk patients to improve prognosis.

Re-thinking the prognostic significance of positive peritoneal cytology in endometrial cancer

BackgroundWhether abnormal peritoneal cytology (PC) is an independent prognostic factor in endometrial cancer (EC) remains controversial. This study aimed to re-think the prognostic significance of PC in not only all EC patients but also in various subgroups with similar clinicopathological and biological characteristics. MethodsEC patients who underwent primary surgery of at least a hysterectomy and were pathologically diagnosed with EC in four hospitals affiliated with the Jikei University School of Medicine were retrospectively reviewed. The prognostic significance of PC was evaluated with univariate and multivariate analyses in the entire cohort and subgroups stratified by surgical stages (early/advanced stages), tumor types (types 1/2), and risk classifications (low/intermediate/high). ResultsOf 1963 EC cases, 1616 met the inclusion criteria. Positive PC was identified as an adverse prognostic factor in analyses of all EC cases and in all subgroup analyses stratified by surgical stages and tumor types. In survival curve comparisons, the progression-free survival (PFS) and disease-specific survival in early-stage patients with positive PC were clearly located between those of stage II patients with negative PC and stage III patients. In the subgroup analyses stratified by risk classification in early-stage EC, positive PC was related to poorer PFS in the intermediate- and high-risk groups but not in the low-risk group. ConclusionPC status was an independent prognostic factor of EC in all stages and tumor types. Early PC-positive cases, except for the low-risk group, may be recommended for upstaging and should be carefully managed compared with PC-negative cases.

Abstract B20: Hypopharyngeal carcinoma management: 25-year experience from a tertiary care medical center in United States

Abstract Introduction: The purpose of this study is to evaluate the incidence, management, and prognosis of hypopharyngeal carcinoma in a tertiary care institution over the past 25 years. Methods: We retrospectively analyzed patients from 1995 to 2019 from the head and neck cancer data base of our institution. The data regarding the demographics, stage, treatment, and follow-up were collected. Outcomes including median survival and overall survival were evaluated using the Kaplan Meier method. All analyses were performed using SPSS version 24. Results: We identified 144 hypopharyngeal carcinoma patients, and the incidence was almost 4% of all head and neck cancers. All patients had squamous cell carcinoma. Sixty-one percent of patients were African Americans and 36% were Caucasians. Ninety percent of the patients were males, and 10% were females. Pyriform sinus was the subsite most commonly affected (67%), followed by posterior pharyngeal wall (10%) and postcricoid area (5%). Ninety-six percent of patients presented with advanced-stage disease (stages III and IV), with only 4% of patients presenting with early-stage disease (Stages I and II). Fifty-one percent of patients underwent definitive chemoradiotherapy with or without induction chemotherapy and 23% of patients underwent surgical management, followed by adjuvant radiation or chemoradiation, depending on risk factors. Ten percent of patients received only palliative chemotherapy and 15% did not receive any treatments. Induction chemotherapy was used in 31% of patients prior to initiation of definitive chemoradiation treatment. The median overall survival of early-stage patients and of advanced-stage patients was 56 months and 15 months, respectively. The median survival of the patients with advanced-stage patients who received definitive treatment was 26 months. The patients who underwent definitive operative management followed by adjuvant treatments had an improved median survival as compared to those undergoing definitive chemoradiation treatment (38 months vs. 16 months, p=0.05). Similarly, the overall survival at 3 years (30% vs. 54%, p=0.05) and 5 years (13% vs. 34%, p=0.05) was also better for surgery patients. The patients who received induction chemotherapy had clinically worse median survival as compared to those who did not, but this was not statistically significant (14 months vs. 21 months, p=0.2). Conclusions: Our results agree with the published literature regarding the low incidence of hypopharyngeal cancer, presentation in advanced stages, and poor long-term outcomes. Selection of patients for laryngeal preservation should be done very carefully. Our results suggest that trimodality treatment may be more efficacious than definitive chemoradiotherapy for locally advanced disease. Future studies are warranted to evaluate if neoadjuvant chemoradiotherapy followed by surgery might be able to improve the current poor outcomes for advanced hypopharyngeal cancer patients who are not eligible for laryngeal preservation. Citation Format: Toms Vengaloor Thomas, Mary R. Nittala, Divyang Mehta, Madhava Rao Kanakamedala, Anu Abraham, Lacey Weatherall, Eldrin Bhanat, Ashley A. Albert, Srinivasan Vijayakumar. Hypopharyngeal carcinoma management: 25-year experience from a tertiary care medical center in United States [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B20.

Effects of Surgery on Survival of Early-Stage Patients With SCLC: Propensity Score Analysis and Nomogram Construction in SEER Database.

Purpose: We aimed to assess the survival benefit of surgery for patients with stage IA–IIB small cell lung cancer (SCLC) and construct a nomogram for predicting overall survival (OS).Methods: Patients who had been diagnosed with stage IA–IIB SCLC between 2004 and 2014 and who had received active treatment were selected from the Surveillance, Epidemiology, and End Results database. The primary endpoint was OS. Cox proportional hazards models and propensity score (PS) analyses were used to compare the associations between surgery and OS. The probability of 1- and 3-year OS was predicted using a nomogram.Results: We reviewed 2,246 patients. The median OS of the surgery and non-surgery groups was 35 months and 19 months, respectively. Multivariable Cox proportional hazards models showed a survival benefit in the surgery group (hazards ratio [HR], 0.642; 95% confidence interval [CI], 0.557–0.740; P < 0.001). To balance the between-group measurable confounders, the impact of surgery on OS was assessed using PS matching. After PS matching, OS analysis still favored surgical resection. The PS-stratification, PS-weighting, and PS-adjustment models showed similar results to demonstrate a statistically significant benefit for surgery. Further, the nomogram was well calibrated and had good discriminative ability (Harrell's C-index = 0.645).Conclusion: Our analysis suggests that surgery is a viable option for patients with early-stage SCLC. Our nomogram is a viable tool for quantifying treatment trade-off assumptions and may assist clinicians in decision-making. Future work is needed to validate our results and improve our tools.

Decreased cytokeratin 7 expression correlates with the progression of cervical squamous cell carcinoma and poor patient outcomes

To identify potential biomarkers for tumor progression and patient outcomes in cervical squamous cell carcinoma. We examined the expressions of CK7 and CK17 as potential markers of the squamo-columnar junction, and podoplanin as a basal cell marker using surgical and biopsy samples of patients in grade 3 cervical intraepithelial neoplasia (n = 30), operable invasive carcinoma (OP group, n = 53) and inoperable invasive carcinoma before radiotherapy and/or chemotherapy (RC group, n = 76). The positive rates of CK7 and podoplanin in invasive carcinoma were significantly lower than those in grade 3 cervical intraepithelial neoplasia (P = 0.001, P < 0.0001). The positive rates of CK7 and podoplanin in the RC group were significantly lower than those in the OP group (P < 0.0001, P = 0.04), while CK17 expression showed significantly higher positivity in the RC group than in the OP group (P < 0.0001). Negative CK7 expression showed a potential impact on overall survival in early-stage patients. In the RC group, the prevalence of cases with post-therapeutic residual carcinoma cells was higher in the CK7-negative group than in the positive group (P = 0.003). We found that decreased expression of CK7 could be a prognostic factor in early-stage cervical cancer patients. This result may provide strategies and suggestions for new treatment options and follow-up practices in managing patients with cervical cancer.

RETRACTED ARTICLE: Comparison of minimally invasive Ivor Lewis esophagectomy and left transthoracic esophagectomy in esophageal squamous cell carcinoma patients: a propensity score-matched analysis

BackgroundTo investigate the long-term efficacy of the minimally invasive Ivor Lewis esophagectomy (MIILE) in esophageal squamous cell carcinoma (ESCC) patients, a retrospective comparison of the quality of life (QOL) and survival between patients who underwent MIILE and left transthoracic esophagectomy (Sweet approach) was conducted.MethodsA detailed database search identified 614 patients who underwent MIILE and 243 patients who underwent Sweet esophagectomy between January 2011 and December 2017. After propensity score matching, 216 paired cases were selected for statistical analysis. Survival was evaluated with Kaplan-Meier curves or Cox models.ResultsMIILE was associated with a longer duration, less blood loss and more lymph node dissected than Sweet esophagectomy. MIILE patients suffered from less pain, less frequently developed pneumonia, and had fewer postoperative complications. Additionally, MIILE patients began oral intake earlier and had a shorter postoperative hospital stay, and enhanced recovery of QOL. There was no significant difference between the approaches regarding the recurrence pattern, 2-year and 5-year overall survival (OS) or disease-free survival (DFS), except that patients with tumor-node-metastasis (TNM) stage I in the MIILE group demonstrated superior OS and DFS. Pathological TNM stage and postoperative complications were determined to be independent prognostic factors based on the multivariate analysis.ConclusionMIILE is a safe and feasible approach for treating ESCC patients. MIILE approach may provide more postoperative advantages, enhanced QOL improvement, and more favorable long-term survival in early stage patients than the Sweet procedure.

Abstract 4751: APOBEC3A inhibits tumor immune response independent of deamination in a novel genetic model of pancreatic cancer

Abstract Introduction: Apolipoprotein B mRNA Editing enzyme, Catalytic polypeptide 3A (A3A) is a C to U cytidine deaminase, preferentially deaminating the lagging strand of double-stranded DNA at specific sequence motifs. A3A is overexpressed across multiple tumor types, and in pancreatic ductal adenocarcinoma (PDA), high expression is associated with significantly decreased survival in early stage patients. Large scale sequencing studies of various human tumors (TCGA and ICGC), including PDA, have implicated A3A as a potential driver of tumor mutagenesis. However, the biological relevance of the deamination function of A3A has not yet been shown. Here, we utilize a novel genetically engineered mouse model to show that A3A supports the development of aggressive PDA independent of mutagenic capabilities. Methods: As opposed to humans, mice only contain one APOBEC3 isoform which has limited to no deaminating activity on genomic DNA. Thus, to dissect the function of A3A on PDA initiation and progression, we made mice with a germline knockin for the coding sequence for human A3A and bred to a well-established GEMM of PDA to yield LSL-KrasG12D; p53fl/+; Pdx1-Cre; RosaLSL-YFP; A3A+/- (KPCY;A3A) mice and compared to KPCY mice. We genotyped tumors from both cohorts using VarScan after exome capture sequencing. Tumor and immune cells were FACS sorted comparative RNAseq performed. The immune contexture of murine and 155 untreated and treated human PDAs was analyzed by performing 7-color multiplex staining and immune cell spatial interaction analysis. Results: All KPCY;A3A (n=11) mice developed tumors and expired significantly faster compared to KPCY (n=18) controls (3.9 v. 7.0 mo; p&amp;lt;0.01). One third of the KPCY; A3A mice developed macrometastatic disease compared to 3/12 in the KPCY control. Whole exome sequencing of tumors revealed no significant difference in the number of point mutations or neoantigen load between KPCY;A3A and KPCY tumors. However, histologically, KPCY;A3A tumors contained significantly more desmoplasia and altered immune cell infiltrates. Specifically, comparative RNAseq and IHC analyses revealed dramatic differences in the number and distribution of various T-cell and B-cell subsets in KPCY;A3A mice. Moreover, A3A expression led to abrogation of CD8+ T cell activation and proliferation. Concomitantly, a panel of immune checkpoint-related genes were upregulated in A3A high expressing tumors and cell lines compared to non-A3A expressing controls. This was confirmed in a panel of resected human PDA. Conclusions: Counter to our hypothesis, A3A supports the initiation and growth of PDA in vivo through effects independent of deamination or mutagenesis of cancer cell genomes but rather indirectly through suppression of the tumor immune response. Future studies will address the precise mechanisms underlying A3A-mediated tumor immune evasion. Citation Format: Sonja Woermann, Robert Cowan, Susan M. Ross, Andrew D. Rhim. APOBEC3A inhibits tumor immune response independent of deamination in a novel genetic model of pancreatic cancer [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 4751.

Deviations from Expected Treatment of Pancreatic Cancer in Octogenarians: Analysis of Patient and Surgeon Factors.

Morbidity and mortality of pancreatectomy has improved and chemotherapeutic options for pancreatic cancer (PC) are growing, yet there is reluctance to treat octogenarians. This study examined the reasons for failure to treat and analyzes outcomes in octogenarians with PC. Retrospective chart review 2005-2013. Demographics, tumor characteristics, treatment, reason for lack of treatment, Charlson comorbidity index (CCI), and survival were analyzed. Expected treatment for early-stage patients (I/II) included surgery±chemotherapy±radiation. Expected treatment for advanced stage patients (III/IV) was chemotherapy. A total of 431 octogenarians were analyzed. Mean age was 84.0±3.4, 59.6% female, and 44.1% received no treatment. Patients with operable tumors (I=31 [7.2%]/II=214 [49.7%]) had surgery 39.2% of the time. Age was a predictor of not receiving surgery (odds ratio [OR] 0.78; 95% confidence interval [CI] 0.70-0.86; p=0.0001), whereas CCI was not. The most common reason for no surgery was contraindication despite similar CCI. Median overall survival for early-stage patients was better in the surgical group (15.8 vs. 5.5months) than nonsurgical group (p<0.0001). Advanced patients (III=54 [12.5%]/IV=132 [30.6%]) had similarly low treatment rates (n=65 [34.9%]). Survival for advanced disease was best for treated patients (6.9 vs. 1.8months; p<0.0001). CCI did not differ between those receiving chemotherapy and not, although age was significantly different (p<0.0001). There is significant deviation from expected treatment for octogenarians with PC. While no correlation existed between CCI and treatment, age correlated with therapy for nearly all stages. Chronological age, not comorbidity, may drive recommendation for treatment in elderly patients.

Clinicopathologic analysis and prognostic factors for survival in early stage patients with ampullary carcinoma.

e15666Background: In this study we aimed to evaluate the possible important clinicopathological features and adjuvant treatment approaches in terms of prognosis in patient with early stage ampullar...

High Pretreatment D-Dimer Levels Correlate with Adverse Clinical Features and Predict Poor Survival in Patients with Natural Killer/T-Cell Lymphoma.

Pretreatment plasma D-dimer levels have been reported to predict survival in several types of malignancies. The aim of this study was to evaluate the prognostic value of D-dimer levels in patients with newly diagnosed natural killer/T-cell lymphoma (NKTCL). The cut-off value of D-dimer to predict survival was set as 1.2 μg/mL based on the receiver operating curve analysis. Patients with a D-dimer level ≥ 1.2 μg/mL had significantly more adverse clinical features, including poor performance status, advanced stage diseases, B symptoms, elevated serum lactic dehydrogenase levels, involvement of regional lymph nodes, more extranodal diseases, and higher International Prognostic Index and natural killer/T-cell lymphoma prognostic index scores. A D-dimer level ≥ 1.2 μg/mL was significantly associated with inferior 3-year overall survival (OS, 13.0 vs. 68.5%, P < 0.001). In the multivariate analysis, a D-dimer level ≥ 1.2 μg/mL remained an independent predictor for worse OS (HR: 3.13, 95% CI: 1.47–6.68, P = 0.003) after adjusting for other confounding prognostic factors. Among patients with Ann Arbor stage I-II diseases, those with a D-dimer level ≥ 1.2 μg/mL had a significantly worse survival than those with a D-dimer level < 1.2 μg/mL (3 year-OS: 76.2 vs. 22.2%, P < 0.001). Survival of early-stage patients with a high D-dimer level was similar to that of the advanced-stage patients. In conclusion, pretreatment plasma D-dimer level may serve as a simple but effective predictor of prognosis in patients with NKTCL.

Treatment patterns, outcomes and long-term toxicity among patients with Hodgkin’s lymphoma in real world: results of a hospital based registry

Data on treatment results and long-term toxicity of patients with Hodgkin’s lymphoma in Russian Federation are scarce. We present analysis of the S. P. Botkin Hospital based registry. Six hundreds nine patients were identified since 01.01.2006 to 31.12.2015, among them there were 374 (61 %) women and 235 (39 %) men. The median age was 31 years (range, 15–85). One hundred sixty four patients (29 %) had Cotswolds stage IV, 128 (22,5 %) – stage III, 256 (45 %) – stage II, and 20 (3,5 %) – stage I. Among first-line regimens ABVD was received by 26 % of patients, AVD – 1,2 %, COPP/ABVD – 5,6 %, BEACOPP-14 – 22 %, BEACOPP-21 – 19 %, BEACOPP escalated – 2,8 %, EACOPP – 2,6 %, ABVD-BEACOPP – 2,9 %. Sixty seven (11 %) patients received other regimens, including MOPP-ABVD, LABO, LOPP, CEA/ABVD, CHOP and irradiation only. Radiotherapy was given to 81 % of patients. Long-term remission after first-line therapy was achieved in 432 patients (75,2 %). Second-line treatment was required in 117 patients (20,4 %). Twenty five patients (4,4 %) died before second-line therapy. High dose therapy with autologous stem cells rescue (HDCT-ASCT) was conducted in 26 of 117 (22 %) patients with relapse after first-line treatment. Five-year overall survival in early stage patients, receiving ABVD was 96 % and 85 % in those, receiving other regimens. In patients with advanced stages no differences in overall survival were found when comparing BEACOPP modifications with other regimens. Time to next treatment (TTNT) was different: 5-year TTNT rate was 71 % in BEACOPP group compared to 56 % in patients, receiving other regimens. BEACOPP-escalated and BEACOPP-14 had an advantage over BEACOPP-21: 5-year TTNT rate was 80, 77 and 63 %, respectively. Long-term toxicity was analyzed by comparing HL patients with age and sex-matched control group, consisting of patients, hospitalized to S. P. Botkin City Hosiptal betwen 01.01.2008 and 01.01.2009 for trauma or infection (n = 555). Standardized incidence ratio (SIR) of developing secondary malignancies was 3,56. SIR of developing all cardiac events, including myocardial infarction, heart failure or cardiac arrhythmia was 2,97. The implications of these findings suggests several ways in which quality of care of HL patients can be improved. These measures include widespread use of PET for precise staging, improvement in integrated care pathways, education of patients, the abandonment of radiotherapy or reduction of volumes and doses of irradiation, greater use of HDCT-ASCT and targeted agents.

Prognostic Significance of Pretreatment Plasma Fibrinogen and Platelet Levels in Patients with Early-Stage Cervical Cancer

Background: Hyperfibrinogenaemia and thrombocytosis, which usually occur in cancer patients, have been shown to contribute to cancer cell growth, progression, and metastasis. The aims of the present study were to assess the prognostic significance of pretreatment plasma fibrinogen and platelet levels in early-stage cervical cancer patients. Methods: The present study was a retrospective analysis of 220 cervical cancer patients with stage I-IIA disease. The pretreatment plasma fibrinogen and platelet levels were investigated along with clinicopathological findings and survival data. Results: The incidences of hyperfibrinogenaemia and thrombocytosis were 11.8 and 25.5%, respectively. Elevated fibrinogen levels were associated with advanced tumour stage, older age, large tumour size, deep stromal invasion, and tumour recurrence, whereas higher platelet levels correlated significantly with advanced tumour stage, large tumour size, and tumour recurrence. Kaplan-Meier analysis showed that hyperfibrinogenaemia and thrombocytosis were significantly associated with shorter disease-free and overall survival. Furthermore, patients with hyperfibrinogenaemia and thrombocytosis may suffer from a higher risk of recurrence. Multivariate survival analyses showed that fibrinogen levels, but not platelet levels, were an independent prognostic factor for poor survival in early-stage patients. Conclusion: Hyperfibrinogenaemia and thrombocytosis may be valuable biomarkers for predicting recurrence in patients with early-stage cervical cancer.

Do HIV-infected Non–Small Cell Lung Cancer Patients Receive Guidance-concordant Care?

The incidence of lung cancer cases among HIV-infected individuals is increasing with time. It is unclear whether HIV-infected individuals receive the same care for lung cancer as immunocompetent patients because of comorbidities, the potential for interaction between antiretroviral agents and cancer chemotherapy, and concerns regarding complications related to treatment or infection. The objective of this study was to assess the effect of HIV infection on receipt of guidance-concordant care, and its impact on overall survival among non-small cell lung cancer Medicare beneficiaries. The study design was a matched case-control design where each HIV patient was matched by age group, sex, race, and lung cancer stage at diagnosis with 20 controls randomly selected among those who were not HIV infected. The patients included in this study were Medicare beneficiaries diagnosed with non-small cell lung cancer between 1998 and 2007, who qualified for Medicare on the basis of age and were 65 years of age or older at the time of lung cancer diagnosis. HIV infection status was based on Medicare claims data. A total of 174 HIV cases and 3480 controls were included in the analysis. Odds ratios for receiving guidance-concordant care and hazard ratios for overall survival were estimated. HIV infection was not independently associated with the receipt of guidance-concordant care. Among stage I/II patients, median survival times were 26 and 43 months, respectively, for those with and without HIV infection (odds ratio=1.48, P=0.021). HIV infection was not associated with receipt of guidance-concordant care but reduced survival in early-stage patients.

Abstract C22: Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma

Abstract Metastasis accounts for the vast majority of cancer related deaths, yet the molecular mechanisms that drive metastatic spread remain poorly understood. Here we report that Tks5, which has been linked to formation of proteolytic cellular protrusions known as invadopodia, undergoes an isoform switch during metastatic progression in a genetically-engineered mouse model of lung adenocarcinoma. Non-metastatic primary tumor-derived cells predominantly expressed a short isoform Tks5short, while metastatic primary tumor- and metastasis-derived cells acquired increased expression of the full-length isoform Tks5long. This elevation of Tks5long-to-Tks5short ratio correlated with a commensurate increase in invadopodia activity in metastatic cells compared to non-metastatic cells. Further characterization of these isoforms by knockdown and over-expression experiments demonstrated that Tks5long promoted invadopodia in vitro and increased metastasis in transplant models and an autochthonous model of lung adenocarcinoma. Conversely, Tks5short decreased invadopodia stability and proteolysis, acting as a natural dominant-negative inhibitor to Tks5long. Importantly, high Tks5long and low Tks5short expressions in human lung adenocarcinomas correlated with metastatic disease and predicted worse survival of early-stage patients. These data indicate that tipping the Tks5 isoform balance to a high Tks5long-to-Tks5short ratio promotes invadopodia-mediated invasion and metastasis. Citation Format: Carman Man-Chung Li, Guoan Chen, Talya Dayton, Caroline Kim-Kiselak, David Beer, Monte Winslow, Tyler Jacks. Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C22.

Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma

Metastasis accounts for the vast majority of cancer-related deaths, yet the molecular mechanisms that drive metastatic spread remain poorly understood. Here we report that Tks5, which has been linked to the formation of proteolytic cellular protrusions known as invadopodia, undergoes an isoform switch during metastatic progression in a genetically engineered mouse model of lung adenocarcinoma. Nonmetastatic primary tumor-derived cells predominantly expressed a short isoform, Tks5short, while metastatic primary tumor- and metastasis-derived cells acquired increased expression of the full-length isoform Tks5long. This elevation of Tks5long to Tks5short ratio correlated with a commensurate increase in invadopodia activity in metastatic cells compared with nonmetastatic cells. Further characterization of these isoforms by knockdown and overexpression experiments demonstrated that Tks5long promoted invadopodia in vitro and increased metastasis in transplant models and an autochthonous model of lung adenocarcinoma. Conversely, Tks5short decreased invadopodia stability and proteolysis, acting as a natural dominant-negative inhibitor to Tks5long. Importantly, high Tks5long and low Tks5short expressions in human lung adenocarcinomas correlated with metastatic disease and predicted worse survival of early stage patients. These data indicate that tipping the Tks5 isoform balance to a high Tks5long to Tks5short ratio promotes invadopodia-mediated invasion and metastasis.

ERCC1 expression as a prognostic and predictive factor in patients with non-small cell lung cancer: a meta-analysis

It is hypothesized that high expression of the excision repair cross-complementation group 1 (ERCC1) gene might be a positive prognostic factor, but predict decreased sensitivity to platinum-based chemotherapy. Results from the published data are inconsistent. To derive a more precise estimation of the relationship between ERCC1 and the prognosis and predictive response to chemotherapy of non-small cell lung cancer (NSCLC), a meta-analysis was performed. An electronic search of the PubMed and Embase database was performed. Hazard ratio (HR) for overall survival (OS) was pooled in early stage patients received surgery alone to analyze the prognosis of ERCC1 on NSCLC. HRs for OS in patients received surgery plus adjuvant chemotherapy and in patients received palliative chemotherapy and relative risk (RR) for overall response to chemotherapy were aggregated to analyze the prediction of ERCC1 on NSCLC. The pooled HR indicated that high ERCC1 levels were associated with longer survival in early stage patients received surgery alone (HR, 0.69; 95% confidence interval (CI), 0.58-0.83; P = 0.000). There was no difference in survival between high and low ERCC1 levels in patients received surgery plus adjuvant chemotherapy (HR, 1.41; 95% CI, 0.93-2.12; P = 0.106). However, high ERCC1 levels were associated with shorter survival and lower response to chemotherapy in advanced NSCLC patients received palliative chemotherapy (HR, 1.75; 95% CI, 1.39-2.22; P = 0.000; RR, 0.77; 95% CI, 0.64-0.93; P = 0.007; respectively). The meta-analysis indicated that high ERCC1 expression might be a favourable prognostic and a drug resistance predictive factor for NSCLC.

Identification of a 7-gene signature that predicts relapse and survival for early stage patients with cervical carcinoma

There is no gene signature for predicting relapse and survival of cervical cancer with early stage currently. In this study, we investigate whether gene expression profiling of cervical cancer could be used to predict the prognosis of patient. A series of 100 primary cervical cancer patients who underwent radical hysterectomy between January 2001 and October 2006 were analyzed for gene expression profiles by using a custom oligonucleotide microarray containing probes for 1440 human tumor-related gene transcripts. Supervised analysis of gene expression data identified 19 genes that exhibited differential expression between cervical cancer and normal cervix. Then, all 100 patients were divided into the training (n=50) and testing sets (n=50). Using Cox regression and risk-score analysis, we identified a 7-gene (UBL3, FGF3, BMI1, PDGFRA, PTPRF, RFC4, and NOL7) signature for predicting relapse of patient in the training set. The 7-gene signature was validated by the testing set (sensitivity, 84.6%; specificity, 91.9%; positive predictive value, 78.6%; negative predictive value, 94.4%). Patients with high-risk 7-gene signature had poor relapse-free survivals (RFS) than patients with low-risk 7-gene signature in both training set (P=0.026) and testing set (P=0.042). Multivariate analysis showed that the FIGO stage and 7-gene signature are independent prognostic factors associated with RFS of cervical cancer patients. The 7-gene signature can predict cancer recurrence and survival of cervical cancer patients. This may have prognostic or therapeutic implications for the future management of cervical cancer patients.