Favorable Prognostic Effect Research Articles

CTLA-4 in mesothelioma patients: tissue expression, body fluid levels and possible relevance as a prognostic factor.

CTLA-4 function as a negative regulator of T cell-mediated immune response is well established, whereas much less is known about the immunoregulatory role of its soluble isoform (sCTLA-4). No data are available on CTLA-4 expression and prognostic impact in malignant pleural mesothelioma (MPM). We investigated, by immunohistochemistry, CTLA-4 expression in tumor tissues and, by ELISA, sCTLA-4 levels in sera and matched pleural effusions from 45 MPM patients. Prognostic effect of CTLA-4 expression on overall survival (OS) was assessed through Cox regression and prognostic significance expressed as death rate ratio (HR). We found that 56.0% of MPM tissues expressed CTLA-4 with variable intensity and percentage of positive cells estimated by the immunoreactive score. sCTLA-4 levels were significantly higher in sera (S-sCTLA-4) than in pleural effusions (PE-sCTLA-4) (geometric mean ratio=2.70, P value=0.020). CTLA-4 expression at the tissue level was higher in the epithelioid histological subtype than in the sarcomatoid, whereas at the serum level, it was higher in the sarcomatoid subtype. A homogeneous favorable prognostic effect was found for CTLA-4 overexpression in tissue, serum and pleural effusion. Interestingly, only the PE-sCTLA-4 was found to be a statistically significant positive prognostic factor (HR=0.37, 95% CI=0.18-0.77, P value=0.007). Indeed, PE-sCTLA-4 correlated with CTLA-4 expression in tissues, whereas this latter expression showed a weak association with OS. To confirm our findings, further experimental evidences obtained from a larger cohort of MPM patients are required. However, our results would indicate a positive correlation of PE-sCTLA-4 levels and OS in MPM patients.

RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications.

Despite therapeutic improvements, a sizable number of patients with T-cell acute lymphoblastic leukemia still have a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 cases of refractory/early relapsed T-cell acute lymphoblastic leukemia (discovery cohort) by performing RNA-sequencing on diagnostic material. The incidence and prognostic impact of the most frequently mutated pathways were validated by Sanger sequencing on genomic DNA from diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in patients with chemorefractory disease or early relapse, frequently in association with NOTCH1/FBXW7 mutations. The analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in patients with JAK/STAT or RAS/PTEN alterations. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells demonstrated sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways.

CD74 and intratumoral immune response in breast cancer.

CD74 (invariant chain) plays a role in MHC class II antigen presentation. We assessed CD74 and MHCII expression in tumor cells, as well as CD8, CD4, and CD68 tumor infiltrating leucocyte (TIL) density by immunohistochemistry in a cohort of 492 breast cancer patients. CD74 expression was associated with poor prognostic markers including patient age, tumor grade, ER status, non-Luminal A subtypes, and with MHCII expression and higher TIL densities, particularly in the Basal-like subgroup. Univariate analysis showed a favorable prognostic effect of CD74 (Hazard ratio = 0.46, 95% CI = 0.26–0.89, p = 0.022) and for combined CD74/MHCII (Hazard ratio = 0.26, 95% CI = 0.17–0.81, p = 0.014) positive status for overall survival that was only manifested in the Basal-like subgroup. CD74 and MHCII expression is associated with patient survival in Basal-like breast cancer, and the association with TIL may reflect an effective intratumoral immune response.

Prognostic role of gastrectomy in patients with gastric cancer with positive peritoneal cytology.

This retrospective study identified the optimal treatment strategy for patients with gastric cancer with positive peritoneal cytology. We analyzed clinicopathologic and survival data for 54 patients who had undergone gastrectomy and/or chemotherapy for treatment of gastric cancer with positive peritoneal cytology with (n = 40) or without (n = 14) metastatic disease. The median overall survival did not differ significantly between patients with gastric cancer with positive peritoneal cytology with and without metastatic disease (19 versus 13 months, respectively). Among 14 clinicopathologic variables, the lack of gastrectomy was the only significant independent unfavorable factor for survival (odds ratio, 1.64; 95% confidence interval, 1.04-2.57; P = 0.03). The median overall survival significantly differed among patients who had undergone gastrectomy plus chemotherapy, chemotherapy alone, and gastrectomy alone (25, 10, and 17 months, respectively; P < 0.01). Gastrectomy may be optimal for patients with (gastric cancer with positive peritoneal cytology), considering its favorable prognostic effect with respect to perioperative chemotherapy.

The importance of controlling PaCO₂ throughout long-term noninvasive ventilation.

The significance of changes in P(aCO2) during long-term noninvasive ventilation (NIV) on prognosis remains unclear. We aimed to clarify whether stabilizing P(aCO2) during NIV had a favorable prognostic effect. Data from 190 subjects with restrictive thoracic disease and who received long-term NIV were studied retrospectively. The annual change in P(aCO2) during NIV was determined using a simple linear regression method for each subject who had at least 4 6-month intervals of P(aCO2) data. Annual changes in P(aCO2) during long-term NIV and possible confounders were analyzed with discontinuation of long-term NIV as the main outcome. One hundred and twenty-five subjects who had > 4 6-month intervals of P(aCO2) data were included in the study. P(aCO2) during long-term NIV decreased in 41 subjects (group 1; < 0 mm Hg/y), increased slightly in 42 subjects (group 2; between 0 and 1.85 mm Hg/y), and increased significantly in 42 subjects (group 3; > 1.85 mm Hg/y). Smaller annual changes in P(aCO2) (P < .001) and a control ventilator mode (P = .008) were associated with a significantly higher probability of continuing NIV, compared with decreased P(aCO2) 3-6 months after the start of long-term NIV (P = .11). The 10-y probability of continuing NIV was 69% in group 1, 39% in group 2, and 12% in group 3. A decrease in the annual change of P(aCO2) during long-term NIV was shown to be a significantly prognostically favorable factor. Efforts to reduce P(aCO2) should be made if P(aCO2) increases at a greater rate during long-term NIV.

GM-CSF Production by Tumor Cells Is Associated with Improved Survival in Colorectal Cancer

Colorectal cancer infiltration by CD16(+) myeloid cells correlates with improved prognosis. We addressed mechanistic clues and gene and protein expression of cytokines potentially associated with macrophage polarization. GM-CSF or M-CSF-stimulated peripheral blood CD14(+) cells from healthy donors were cocultured with colorectal cancer cells. Tumor cell proliferation was assessed by (3)H-thymidine incorporation. Expression of cytokine genes in colorectal cancer and autologous healthy mucosa was tested by quantitative, real-time PCR. A tumor microarray (TMA) including >1,200 colorectal cancer specimens was stained with GM-CSF- and M-CSF-specific antibodies. Clinicopathological features and overall survival were analyzed. GM-CSF induced CD16 expression in 66% ± 8% of monocytes, as compared with 28% ± 1% in cells stimulated by M-CSF (P = 0.011). GM-CSF but not M-CSF-stimulated macrophages significantly (P < 0.02) inhibited colorectal cancer cell proliferation. GM-CSF gene was expressed to significantly (n = 45, P < 0.0001) higher extents in colorectal cancer than in healthy mucosa, whereas M-CSF gene expression was similar in healthy mucosa and colorectal cancer. Accordingly, IL1β and IL23 genes, typically expressed by M1 macrophages, were expressed to significantly (P < 0.001) higher extents in colorectal cancer than in healthy mucosa. TMA staining revealed that GM-CSF production by tumor cells is associated with lower T stage (P = 0.02), "pushing" growth pattern (P = 0.004) and significantly (P = 0.0002) longer survival in mismatch-repair proficient colorectal cancer. Favorable prognostic effect of GM-CSF production by colorectal cancer cells was confirmed by multivariate analysis and was independent from CD16(+) and CD8(+) cell colorectal cancer infiltration. M-CSF expression had no significant prognostic relevance. GM-CSF production by tumor cells is an independent favorable prognostic factor in colorectal cancer.

High Expression of AT-Rich Interactive Domain 3A (ARID3A) is Associated with Good Prognosis in Colorectal Carcinoma

AT-rich interactive domain 3A (ARID3A) is a member of the ARID family of DNA-binding proteins. Previous reports have shown that ARID3A controls cell growth in a p53-dependent manner. Recently, it has been reported that expression of the ARID3A protein was markedly increased in colon cancer tissue compared with matched normal colonic mucosa. However, little is currently known about the role of ARID3A in colorectal cancer (CRC). The aim of this study was to investigate the clinical significance of ARID3A expression in CRC. We examined ARID3A expression in 690 CRC patients using tissue microarray and immunohistochemistry. Kaplan-Meier analysis and Cox proportional hazard models were used to estimate the impact of ARID3A expression on overall survival. Of the 690 cases, 195 tumors were strongly positive for ARID3A, 187 were weakly positive, and 308 were negative. ARID3A expression in CRC was significantly correlated with age, degree of differentiation, depth of invasion, lymph node metastasis, distant metastasis, tumor-node-metastasis stage, status of microsatellite instability, and carcinoembryonic antigen levels. The overall survival of CRC patients with strong ARID3A expression was significantly longer than that of patients with weak or negative ARID3A expression. We also performed an additional survival analysis on 388 colon cancer patients and 302 rectal cancer patients. In doing so, a favorable prognostic effect of ARID3A expression was revealed only in the colon cancer group (p = 0.002), not in rectal cancer. Moreover, we showed that the effect of ARID3A on the survival was correlated with p53 status. Using multivariate analysis, we found that strong expression of ARID3A was an independent predictor for better prognosis in CRC. Our data suggested that strong expression of ARID3A may predict a good prognosis in patients with CRC.

Potential Benefits of Weight Loss in Coronary Heart Disease

The prevalence of overweight, obesity and insulin resistance in patients with coronary heart disease (CHD) exceeds that of the general population. Obesity is associated with a constellation of coronary risk factors that predispose to the development and progression of CHD. Intentional weight loss, accomplished through behavioral weight loss and exercise, improves insulin sensitivity and associated cardio-metabolic risk factors such as lipid measures, blood pressure, measures of inflammation and vascular function both in healthy individuals and patients with CHD. Additionally, physical fitness, physical function and quality of life all improve. There is evidence that intentional weight loss prevents the onset of CHD in high risk overweight individuals. While weight loss associated improvements in insulin resistance, fitness and related risk factors strongly supports favorable prognostic effects in individuals with established CHD, further study is needed to determine if long-term clinical outcomes are improved.

Clinicopathologic implication of A20/TNFAIP3 deletion in diffuse large B-cell lymphoma: an analysis according to immunohistochemical subgroups and rituximab treatment

We analyzed the clinicopathologic implication of A20/tumor necrosis factor α-induced protein 3 deletion in diffuse large B-cell lymphoma (DLBCL) using fluorescence in situ hybridization, according to germinal center B-cell (GCB) versus non-GCB/activated B-cell (ABC) phenotypes and rituximab treatment. Excluding primary central nervous system (CNS) and Epstein–Barr virus (EBV)-positive lymphomas, 134 DLBCLs were analyzed. A20 was deleted in 23.1% (31/134) of DLBCLs including 21.6% (29/ 134) of monoallelic and 1.5% (2/134) of biallelic deletion, with no predilection for GCB versus non-GCB/ABC. In univariate analysis, A20 deletion was marginally associated with favorable prognosis in the rituximab-treated subgroup (n = 109; p = 0.0454), non-gastrointestinal lymphoma (n = 108; p = 0.0320) and nodal lymphoma (n = 46; p = 0.0411). In multivariate analysis in rituximab-treated DLBCL, MUM1 and international prognostic index (IPI) were independent prognostic factors (p = 0.021 [IPI]; p = 009 [MUM1]) with a marginally favorable prognostic effect for A20 deletion (p = 0.047). Taken together, A20 deletion was observed in similar frequencies in GCB and non-GCB/ABC, and was not a poor prognostic factor in DLBCL.

Patients with SF3B1 Mutation Have Good Prognosis Even in the Presence of Other Poor Prognostic MDS Features and Have Better Outcomes During Treatment with Low Intensity Chemotherapy

AbstractAbstract 3831The discovery of mutations in components of the RNA splicing machinery has underlined the importance of this pathogenetic mechanism in MDS biology. We and others reported that mutations in SF3B1 are frequent in refractory anemia with ring sideroblasts (RARS) and RARS associated with thrombocytosis (RARS-T). We recently reported good survival outcomes in a large cohort of SF3B1 mutant patients similar to the findings of Papaemmanuil et al, NEJM< 2011. Here, we aimed to evaluate the correlation between SF3B1 mutations in association with other poor prognostic clinical and pathologic factors in MDS. We focused on a large cohort of patients with several myeloid malignancies (n=340). Patients were grouped in MDS (n=176), MDS/MPN (n=88) and secondary AML (sAML) from a previous MDS (n=76). Diseases were classified according to the 2008 WHO classification. Survival outcomes (overall survival [OS], progression free survival [PFS] and event free survival [EFS]) were defined according to MDS IWG criteria. We studied a total of 340 patients with myeloid malignancies. median age, 69 years old (range 19–92), sex (Male, n=222; females, n=118). We performed direct sequencing for SF3B1 (exon 13–16) on a large cohort of MDS, MDS/MPN and sAML patients and found 11.8% SF3B1 mutants. The outcomes of SF3B1 mutant vs WT patients were compared based on the presence of poor clinicopathologic factors associated with MDS like RBC transfusion dependence, presence of SNP-A lesions, presence of acquired somatic uniparental disomy (AS-UPD), Age ≥ 60 years, presence of reticulin fibrosis in the bone marrow. We also assessed the effects of therapies in the prognostic effect of SF3B1 mutations. We previously reported that the presence of new SNP-A lesions in myeloid malignancies including MDS and AML are associated with poor prognostic outcomes. However, the good prognostic effects of SF3B1 mutation is still apparent even in the patients with new SNP-A abnormalities (OS: 40 vs 16 mos, p=.003; PFS: 40 vs 10 mos, p=.003, 40 vs 10 mos, p=.0007. However, when analysis is limited to acquired somatic uniparental disomy defects which we recently reported as the worst lesion among SNP-A abnormalities, the good prognostic effect of SF3B1 is lost (OS: 19 vs 9 mos, p=.29, PFS: 18 vs 7 mos, p=.20, EFS: 19 vs 8 mos, p=.17). Age is an important predictor of outcomes in MDS with higher age associated with worse outcomes. SF3B1 remained predictive of good outcomes in patients ≥ 60 years of age (OS: 40 vs 16, p=.002; PFS: 40 vs 11 mos, p=.003; EFS: 40 vs 10 mos, p=.0005). Persistent RBC transfusions are also associated with inferior survival in MDS, yet SF3B1 mutant patients continued to have good outcomes (OS 34 vs 13, p=.002; PFS: 27 vs 8 mos, p=.004; EFS: 14 vs 9 mos, p=.001). Reticulin fibrosis in the bone marrow is a characteristic feature of myeloproliferative neoplasms but their presence in MDS is associated with unfavorable results, SF3B1 mutant retain their good outcomes even in the presence of reticulin fibrosis in the BM (OS: 40 vs 15 mos, p=.09; PFS: 47 vs 12 mos, p=.04; EFS: 75 vs 13 mos, p=.008). Patients screened for SF3B1 were also further stratified according to treatments received. No patients with SF3B1 mutations underwent allogeneic hematopoietic stem cell transplantation and high intensity chemotherapy specifically induction chemotherapy or high dose cytarabine. However based on treatment with LIC, SF3B1 mutant patients have better survival outcomes compared to WT patients (OS: 61 vs 17 mos, p=.004; PFS: not reached [NR] vs 7 mos; p=.009; EFS: 61 vs 10 mos, p=.001). These observed survival outcomes remain significant when patients were stratified according to disease subtypes. MDS and MDS/MPN patients treated with LIC have better outcomes if they have SF3B1 mutation (OS: 61 vs 23 mos, p=.005; PFS: NR vs 16 mos, p=.01; EFS: 61 vs 16 mos, p=.001). A high number of TET2/DNMT3A mutations are found in SF3B1 mutants. TET2/DNMT3A mutations have been previously association with improved response to hypomethylating agents which is one of the possible reasons why SF3B1 mutants treated with LIC did better than their WT counterpart. In conclusion, SF3B1 retains its favorable prognostic effect even in the face of poor prognostic factors such as RBC transfusion dependence, presence of SNP-A lesions, Age ≥ 60 years, presence of reticulin fibrosis in the bone marrow except in the presence of AS-UPD. SF3B1 mutants treated with LIC also have better outcomes. Disclosures:No relevant conflicts of interest to declare.

Prognostic Relevance of Integrated Genetic Profiling in Adult T-Cell Acute Lymphoblastic Leukemia

AbstractAbstract 294▪▪This icon denotes a clinically relevant abstractT-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic tumor associated with poor prognosis. Over the last decade, microarray gene expression studies have shown that T-ALL encompasses distinct molecular groups defined by characteristic gene expression signatures and molecular studies have uncovered major mechanisms of T-cell transformation and numerous oncogenes and tumor suppressors involved in the pathogenesis of T-ALL. This molecular and genetic heterogeneity suggests that distinct groups of T-ALL may respond differently to chemotherapy. However, today there are no well established prognostic markers for patient stratification in this disease and all T-ALL patients are treated under the same therapeutic scheme.To overcome this obstacle here we performed a comprehensive analysis of the prognostic significance of molecular groups defined gene microarray expression profiling, copy number alterations identified by array-Comparative Genomic Hybridization, immunophenotypic markers and mutation analysis of all major adult T-ALL oncogenes (NOTCH1, IL7R, FLT3, NRAS) and tumor suppressor genes (FBXW7, PTEN, DNM2, PHF6, BCL11B, WT1, EZH2, ETV6, IDH1, IDH2, DNMT3A, GATA3 and RUNX1) in a clinical series of 53 primary leukemia samples uniformly treated according to the Eastern Cooperative Oncology Group (ECOG) E2993 protocol.Unsupervised analysis of gene expression oligonucleotide microarrays in this series revealed the presence of 2 stable gene expression clusters corresponding to early immature (n = 28) and cortical/mature (n = 25) adult T-ALLs respectively. Early immature T-ALLs show gene expression signatures related to hematopoietic stem cells and myeloid progenitors and are associated with poor prognosis and reduced overall survival compared with cortical/mature adult T-ALLs (P = 0.011). Immunophenotypic analysis showed that CD13 expression was strongly associated with poor survival in our patient series (P=0.002), whereas other early immature or myeloid antigens including CD34 and CD33 showed no clinical impact. Array comparative genomic hybridization (aCGH) analysis in this series identified absence of biallelic deletion of TCRγ, a cytogenetic feature associated with early induction failure and inferior overall survival rates in pediatric T-ALL (Gutierrez et al., JCO, 2010), in 27 out of 53 (51%) adult T-ALL samples analyzed. Notably, 22 of 27 T-ALLs with absence of biallelic deletion of TCRγ were found in the early immature adult T-ALL group, and as in pediatric T-ALL, this molecular marker was associated with inferior overall survival (P = 0.022). In addition, heterozygous deletions of the short arm of chromosome 17 encompassing the TP53 tumor suppressor gene predicted for worse clinical outcome (P = 0.0005); while, homozygous deletions of the CDKN2A/CDKN2B locus on the short arm of chromosome 9 was associated with favorable prognosis (P = 0.012). Most notably, the favorable prognostic effect of homozygous CDKN2A/CDKN2B deletions in our series was restricted to the good prognostic subtype of leukemia samples with a mature/cortical gene expression profile. Finally, comprehensive mutation analysis of adult T-ALL oncogenes and tumor suppressors demonstrated a favorable prognosis for patients with activation of NOTCH1 signaling as result of mutations in NOTCH1 and/or FBXW7 (P = 0.021) and for those harboring heterozygous inactivating mutations or deletions in the BCL11B tumor suppressor gene (P = 0.041). In contrast, somatic mutations in genes targeting the epigenetic regulators DNMT3A (P = 0.003) and IDH1/2 (P = 0.011) were associated with adverse prognosis.Multivariate analyses highlighted the association of NOTCH1 and/or FBXW7 mutations with favorable outcome and that of TP53 deletions and DNMT3A mutations with poor prognosis in adult T-ALL. Importantly, homozygous CDKN2A/CDKN2B deletions and CD13 expression may serve as prognostic markers to further stratify low-risk cortical/mature adult T-ALL leukemias, whereas DNMT3A mutations might be useful for risk stratification within high-risk early immature adult T-ALLs. Overall, our comprehensive analysis of molecular prognostic markers identify for the first time a subset of adult T-ALLs with very poor response to intensified chemotherapy, highlighting the need to introduce alternative therapies aiming to improve the therapeutic outcome in this group. Disclosures:No relevant conflicts of interest to declare.

CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer

IntroductionTumor infiltrating lymphocytes may indicate an immune response to cancer development, but their significance remains controversial in breast cancer. We conducted this study to assess CD8+ (cytotoxic T) lymphocyte infiltration in a large cohort of invasive early stage breast cancers, and to evaluate its prognostic effect in different breast cancer intrinsic subtypes.MethodsImmunohistochemistry for CD8 staining was performed on tissue microarrays from 3992 breast cancer patients. CD8+ tumor infiltrating lymphocytes were counted as intratumoral when in direct contact with tumor cells, and as stromal in adjacent locations. Kaplan-Meier functions and Cox proportional hazards regression models were applied to examine the associations between tumor infiltrating lymphocytes and breast cancer specific survival.ResultsAmong 3403 cases for which immunohistochemical results were obtained, CD8+ tumor infiltrating lymphocytes were identified in an intratumoral pattern in 32% and stromal pattern in 61% of the cases. In the whole cohort, the presence of intratumoral tumor-infiltrating lymphocytes was significantly correlated with young age, high grade, estrogen receptor negativity, human epidermal growth factor receptor-2 positivity and core basal intrinsic subtype, and was associated with superior breast cancer specific survival. Multivariate analysis indicated that the favorable prognostic effect of CD8+ tumor infiltrating lymphocytes was significant only in the core basal intrinsic subgroup (Hazard ratio, HR = 0.35, 95% CI = 0.23-0.54). No association with improved survival was present in those triple negative breast cancers that lack expression of basal markers (HR = 0.99, 95% CI = 0.48-2.04) nor in the other intrinsic subtypes.ConclusionsCD8+ tumor infiltrating lymphocytes are an independent prognostic factor associated with better patient survival in basal-like breast cancer, but not in non-basal triple negative breast cancers nor in other intrinsic molecular subtypes.

Clinical implication of nucleophosmin gene mutation and Flt-3 internal tandem duplication in a cohort of Egyptian AML patients

Nucleophosmin (NPM) gene mutations are the most frequent genetic abnormality in adult AML. NPM gene mutation (NPM1) leads to aberrant localization of the NPM protein into the cytoplasm. As NPM1 mutation is frequently associated with FMS-like tyrosine kinase 3—internal tandem duplication (FLT3-ITD) that appears to abrogate its favorable prognostic effect. This study aimed at detecting the frequency of NPM1 exon-12 gene mutation and FLT3-ITD in 62 de novo AML patients by reverse-transcriptase polymerase chain reaction and immunocytochemical staining. Twenty age- and sex-matched healthy volunteers were included in the current study as a control group. NPM1 mutation was detected in 30/62 (48.3%) of cases, while 27/62 (43.5%) of cases were FLT3-ITD-positive. All the control subjects were negative for the studied genetic mutations. Immunostaining for NPM revealed cytoplasmic positivity (NPMc+) in 32/62 (51.6%) of case. NPM1 mutation was significantly higher in patients with normal karyotype, FAB-M4 subtype, low expression of CD34 and favorable response to induction therapy. FLT3-ITD was higher among female patients and was associated with poor response to induction therapy. Patients harboring both mutations showed unfavorable response as the presence of FLT3-ITD abolished the favorable effect of NPM1. In conclusion, all AML cases should be screened prior to therapy for both mutations as two important prognostic markers that can be valuable in predicting the response to therapy, in addition to their role in monitoring minimal residual disease and early detection of relapse. Furthermore, they represent potential therapeutic targets.

CRIP1 expression is correlated with a favorable outcome and less metastases in osteosarcoma patients

Predicting the clinical course of osteosarcoma patients is a crucial prerequisite for a better treatment stratification in these highly aggressive neoplasms of bone. In search of new and reliable biomarkers we recently identified cysteine-rich intestinal protein 1 (CRIP1) to have significant prognostic impact in gastric cancer and therefore decided to investigate its role also in osteosarcoma. For this purpose we analyzed 223 pretherapeutic and well characterized osteosarcoma samples for their immunohistochemical expression of CRIP1 and correlated our findings with clinico-pathological parameters including follow‑up, systemic spread and response to chemotherapy. Interestingly and contrarily to gastric cancer, we found CRIP1 expression more frequently in patients with long‑term survival (10-year survival 73% in positive vs. 54% in negative cases, p = 0.0433) and without metastases (p = 0.0108) indicating a favorable prognostic effect. CRIP1 therefore seems to represent a promising new biomarker in osteosarcoma patients which should be considered for a prospective validation.

Advances in the management of recurrent or metastatic squamous cell carcinoma of the head and neck

Most patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) undergo definitive therapy, yet locoregional recurrence and metastasis are common. Most patients ultimately require systemic treatment. Platinum/5-fluorouracil (5-FU) has been the standard of care for patients with good performance status (median survival, 6-8 months). Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), significantly improved median survival in combination with platinum/5-FU compared with chemotherapy alone, establishing it as a new standard for patients with recurrent or metastatic disease. Cetuximab is also active in platinum-refractory disease. Ongoing trials are exploring other EGFR inhibitors as well as the use of biologic agents in combination (eg, cetuximab + bevacizumab). Predictive biomarkers may help personalize therapy for SCCHN, and it is unclear whether the favorable prognostic effect of p16 or human papillomavirus in locally advanced oropharyngeal cancer is relevant for advanced disease.

Ornithine Decarboxylase mRNA Expression in Curatively Resected Non–Small-Cell Lung Cancer

Background The effect of ornithine decarboxylase (ODC) on the pathogenesis of non–small-cell lung cancer (NSCLC) remains poorly investigated. Hence, the aim of this study was to explore the potential role of ODC mRNA expression as a prognostic biomarker in patients with curatively resected NSCLC. Patients and Methods A total of 91 tumor and matching nontumorous lung tissue samples from patients with NSCLC were analyzed using a quantitative real-time reverse-transcriptase polymerase chain reaction method. The relative ODC mRNA expression was measured in tumorous and nontumorous lung tissue using β-actin as a reference gene. Squamous cell carcinoma was found in 43 patients (47%), adenocarcinoma in 33 (36%), and large-cell carcinoma in 15 of the patients (17%). All patients' disease was R0 resected. Results Ornithine decarboxylase was detected in all 91 tumor and nontumorous lung tissue samples. The median tumorous expression of 9.11 (range, 0.92-155.35) was significantly elevated compared with the median ODC expression of 7.89 (range, 0.0-45.8) in nontumorous lung tissue. Ornithine decarboxylase expression levels were not associated with any clinicopathologic parameters. Using an ODC/β-actin ratio of 10 as a cutoff, tumorous ODC (tODC) expression is a significant prognostic factor in NSCLC. The ODC ratio between tumorous and nontumorous expression was even more prognostic. Moreover, Cox proportional hazards model analysis showed ODC expression to be an independent prognostic factor. Conclusion In this study, ODC is shown to have a prognostic potential in NSCLC. Low levels of tODC expression are associated with a more aggressive tumor biology. Also, an increase of ODC mRNA expression during carcinogenesis seems to have a favorable prognostic effect. Measuring the ODC expression in patients with NSCLC could aid in further chemotherapy decisions. Our results suggest that further investigation of ODC mRNA expression in NSCLC may be warranted.

Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer

Mutations in the alpha catalytic subunit of phosphoinositol-3-kinase (PIK3CA) occur in approximately 30% of ER positive breast cancers. We therefore sought to determine the impact of PIK3CA mutation on response to neoadjuvant endocrine therapy. Exons 9 (helical domain) and 20 (kinase domain-KD) mutations in PIK3CA were determined samples from four neoadjuvant endocrine therapy trials.Interactions with clinical, pathological, and biomarker response parameters were examined. A weak negative interaction between PIK3CA mutation status and clinical response to neoadjuvant endocrine treatment was detected(N = 235 P < or = 0.05), but not with treatment-induced changes in Ki67-based proliferation index (N = 418). Despite these findings, PIK3CA KD mutation was a favorable prognostic factor for relapse-free survival (RFS log-rank P = 0.02) in the P024 trial (N = 153). The favorable prognostic effect was maintained in a multivariable analysis(N = 125) that included the preoperative endocrine prognostic index, an approach to predicting RFS based on post neoadjuvant endocrine therapy pathological stage, ER, and Ki67 levels (HR for no PIK3CA KD mutation, 14, CI 1.9-105 P = 0.01). PIK3CA mutation status did not strongly interact with neoadjuvant endocrine therapy responsiveness in estrogen receptor-positive breast cancer. Nonetheless, as with other recent studies, a favorable interaction between PIK3CA KD mutation and prognosis was detected. The mechanism for the favorable prognostic impact of PIK3CA mutation status therefore remains unexplained.

Expression of tumor-associated antigens in acute myeloid leukemia: implications for specific immunotherapeutic approaches

AbstractThe expression of tumor-associated antigens (TAAs) might play a critical role in the control of minimal residual disease (MRD) in acute myeloid leukemia (AML), and therefore might be associated with clinical outcome in AML. In a DNA microarray analysis of 116 AML samples, we found a significant correlation between high mRNA levels of G250/CA9 and longer overall survival (P = .022), a similar trend with high mRNA levels of PRAME (P = .103), and a hint for RHAMM/HMMR. In contrast, for other TAAs like WT1, TERT, PRTN3, BCL2, and LAMR1, we found no correlation with clinical outcome. High expression of at least 1 of the 3 TAAs, RHAMM/HMMR, PRAME, or G250/CA9, provided the strongest favorable prognostic effect (P = .005). Specific T-cell responses were detected in 8 (47%) of 17 patients with AML in complete remission for RHAMM/HMMR-R3 peptide, in 7 (70%) of 10 for PRAME-P3 peptide, and in 6 (60%) of 10 for newly characterized G250/CA9-G2 peptide, a significant increased immune response compared with patients with AML patients who had refractory disease (P < .001). Furthermore, we could demonstrate specific lysis of T2 cells presenting these epitope peptides. In conclusion, expression of the TAAs RHAMM/HMMR, PRAME, and G250/CA9 can induce strong antileukemic immune responses, possibly enabling MRD control. Thus, these TAAs represent interesting targets for polyvalent immunotherapeutic approaches in AML.

Expression of Tumor-Associated Antigens (TAAs) in Acute Myeloid Leukemia (AML) Correlated with Specific T Cell Responses and Survival.

Several Tumor-associated antigens (TAAs) are expressed in acute myeloid leukemia (AML) and elicit specific immune responses of CD8 positive T cells. These specific T cell responses against leukemic blasts expressing TAAs might play a critical role in the control of minimal residual disease (MRD) in AML. Therefore, we investigated whether TAAs inducing specific immune responses in AML patients were associated with the clinical outcome. A DNA-microarray analysis of 116 AML samples was performed to correlate expression of TAAs to the clinical outcome. In these AML patients specific T cell responses to TAAs were assessed by ELISPOT analysis, tetramer staining and chromium release assays. Quantitative RT-PCR based validation of our results demonstrated the power of DNA microarray technology. We found a significant correlation of high mRNA expression of the TAA G250/CA9 with a longer overall survival (P=0.022), a trend for better outcome in patients with high expression levels of PRAME (P=0.103), and a hint for RHAMM/HMMR. In contrast, for other TAAs like WT1, TERT, PRTN3, BCL2, and LAMR1 we found no correlation with clinical outcome of AML patients. Moreover, co-expression of RHAMM/HMMR, PRAME and G250/CA9 provided a favorable prognostic effect (P=0.005). We found specific T cell responses at high frequency for these three antigens in AML patients. Positive immune reactions were detected in 8/17 (47%) AML patients for RHAMM/HMMR-R3-derived, in 7/10 (70%) for PRAME-P3-derived, and in 6/10 (60%) for newly characterized G250/CA9-G2-derived peptides. We detected a significant increased immune response of AML patients in complete remission compared to AML patients with refractory disease (P<0.001). Furthermore, we could demonstrate specific lysis of T2 cells and AML blasts presenting these epitope peptides RHAMM/HMMR-R3, PRAME-P3 and G250/CA9-G2. In conclusion, the expression of the TAAs RHAMM/HMMR, PRAME and G250/CA9 can induce strong anti-leukemic immune responses of CD8 positive T cells possibly enabling the control of MRD in AML patients. Thus, the antigens RHAMM/HMMR, PRAME and G250/CA9 represent interesting target structures for polyvalent immunotherapeutic approaches in AML.

Long-Term Prognosis of Dilated Cardiomyopathy Revisited An Improvement in Survival Over the Past 20 Years

Because of their favorable prognostic effects, angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) and beta blockers have become background therapy in dilated cardiomyopathy (DCM). However, there are few reports concerning the long-term prognosis of Japanese patients with DCM in relation to these treatments. One hundred and fifty patients with DCM were divided into 2 groups: group A (n=46) (diagnosis: 1982-1989) and group B (n=104) (diagnosis: 1990-2002). During follow-up period of 6.9+/-4.8 years, 62 patients died and 1 patient had a heart transplant. The survival rate at 5 and 10 years was 60.9% and 34.8%, respectively, in group A patients, and 80.9% and 65.3%, respectively, in group B patients (p=0.0079). In group A patients, ACEI/ARB or beta blockers were less frequently used (p<0.0001), whereas antiarrhythmics (class Ia or Ib) were more often used (p<0.0001). The patients treated with ACEI/ARB and beta blockers showed a better survival rate than those without (p<0.0001). The patients with antiarrhythmics showed a worse survival rate than those without (p<0.0001). The prognosis of Japanese patients with DCM has significantly improved over the past 20 years. This improvement may be explained partly through the increased use of ACEI/ARB and beta blockers and a declining use of antiarrhythmics.