Prognostic Value Of Molecular Markers Research Articles

Extent of resection, molecular signature, and survival in 1p19q-codeleted gliomas.

Genomic analysis in neurooncology has underscored the importance of understanding the patterns of survival in different molecular subtypes within gliomas and their responses to treatment. In particular, diffuse gliomas are now principally characterized by their mutation status (IDH1 and 1p/19q codeletion), yet there remains a paucity of information regarding the prognostic value of molecular markers and extent of resection (EOR) on survival. Furthermore, given the modern emphasis on molecular rather than histological diagnosis, it is important to examine the effect of maximal resection on survival in all gliomas with 1p/q19 codeletions, as these will now be classified as oligodendrogliomas under the new WHO guidelines. The objectives of the present study were twofold: 1) to assess the association between EOR and survival for patients with oligodendrogliomas in the National Cancer Database (NCDB), which includes information on mutation status, and 2) to demonstrate the same effect for all patients with 1p/19q codeleted gliomas in the NCDB. The NCDB was queried for all cases of oligodendroglioma between 2004 and 2014, with follow-up dates through 2016. The authors found 2514 cases of histologically confirmed oligodendrogliomas for the final analysis of the effect of EOR on survival. Upon further query, 1067 1p/19q-codeleted tumors were identified in the NCDB. Patients who received subtotal resection (STR) or gross-total resection (GTR) were compared to those who received no tumor debulking surgery. Univariable and multivariable analyses of both overall survival and cause-specific survival were performed. EOR was associated with increased overall survival for both histologically confirmed oligodendrogliomas and all 1p/19q-codeleted-defined tumors (p < 0.001 and p = 0.002, respectively). Tumor grade, location, and size covaried predictably with EOR. When evaluating tumors by each classification system for predictors of overall survival, facility setting, age, comorbidity index, grade, location, chemotherapy, and radiation therapy were all shown to be significantly associated with overall survival. STR and GTR were independent predictors of improved survival in historically classified oligodendrogliomas (HR 0.83, p = 0.18; HR 0.69, p = 0.01, respectively) and in 1p/19q-codeleted tumors (HR 0.49, p < 0.01; HR 0.43, p < 0.01, respectively). By using the NCDB, the authors have demonstrated a side-by-side comparison of the survival benefits of greater EOR in 1p/19q-codeleted gliomas.

Current opinion in otolaryngology and head and neck surgery: clival chordoma and its management.

Chordomas of the clival region are challenging tumors to treat due to their location and infiltrative behavior. The primary goal of treatment remains a gross total resection (GTR). Advances in surgical techniques, especially the adoption of endoscopic endonasal techniques, provide improved rates of surgical resection while minimizing secondary surgical morbidities. Advances in the management of clival chordomas include further development of endoscopic endonasal approaches to the clivus and petroclival region, enhanced understanding of the biologic behavior of chordomas and prognostic value of molecular markers, and increased experience with newer radiation therapy modalities such as proton beam therapy. Improved surgical techniques enhance our ability to achieve a GTR while minimizing morbidity of surgery. Molecular markers may allow stratification of patients into prognostic groups and help direct further therapy. A combination of surgery with GTR and proton beam or intensity modulated radiotherapy currently offers the best potential for cure. Therapy with new immune system modulators is promising but is reserved for clinical trials.

Prognostic Value of Next-Generation Sequencing Data in Patients with Myelodysplastic Syndrome

Aim. To assess the prognostic value of the mutation of DNA methylation genes, SF3B1, and TP53 in patients with myelodysplastic syndrome (MDS). Materials &amp; Methods. Out of 35 MDS patients included into the trial 2 had multilineage dysplasia, 13 with excess blasts-I, 19 with excess blasts-II, and 1 had 5q-syndrome (criteria WHO 2016). In 30 patients primary MDS was identified, in 5 patients it was detected after prior chemo- or radiotherapy. 25 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). According to IPSS-R there were 1 low-risk, 5 intermediate risk, 17 high-risk, and 12 very highrisk patients. Hypomethylating agents were administered to 28 patients. Median age of patients was 49 years (range 18-80 years). Next-generation sequencing was applied for identifying somatic mutations in DNA methylation genes (TET2, IDH1/2, ASXL1, and DNMT3A) as well as in SF3B1, TP53, and RUNX1. Time to progression (TTP) was defined as the time from the initial diagnosis to the date of acute leukemia diagnosis. Allo-HSCT- or antitumor therapy-associated death was considered as competing risk. Results. Methylation gene analysis showed no mutation in 37 % of patients, in 40 % mutation was detected only in one of the genes, in 23 % mutation was identified in &gt; 2 genes. SF3B1 mutations were reported in 23 % and TP53 in 11 % of patients. Median follow-up was 25 months (range 5-116 months). Univariate analysis showed no considerable differences in overall survival depending on mutation status. Median TTP in the group with allo-HSCT was not achieved, in the group without allo-HSCT it was 6 months (p = 0.0001). In patients with no SF3B1 mutation median TTP was 35 months, in patients with this mutation it was not achieved (p = 0.043). With ≥ 2 mutations in methylation genes median TTP was 12 months, in other cases it was not achieved (p = 0.024). In cases of TP53 mutation median TTP was 6 months, in cases without this mutation it was 43 months (p = 0.023). Multivariate analysis confirmed unfavorable prognostic value of TP53 mutation or ≥ 2 mutations in methylation genes in terms of TTP regardless of the drug treatment or allo-HSCT performed (hazard ratio 7.1; 95% confidence interval 2.6-19.6; p = 0.0001). Conclusion. The analysis of molecular markers yields additional data concerning the MDS prognosis. Further research is required to determine the prognostic value of molecular markers in clinical practice which will enable to individualize approaches to MDS treatment.

LRIG1‑2 and LMO7 immunoreactivity in vulvar squamous cell carcinoma: Association with prognosis in relation to HPV‑DNA and p16INK4a status.

The present study was conducted to investigate the possible prognostic value of molecular markers LRIG1-2 and LIM domain 7 protein (LMO7) in vulvar squamous cell carcinoma (VSCC) and their possible correlation to human papilloma virus (HPV)- and p16INK4a-status of the tumors. Patients diagnosed with VSCC at the University Hospital of Umeå, Sweden, during the years 1990–2013 were selected. Tumor blocks were retrieved from tissue archives and clinical data were collected from the records of patients. HPV-PCR analysis, HPV genotyping and immunohistochemistry were performed. In total, 112 patients were included. Forty percent of the tumors were HPV-positive, 27% were p16INK4a-positive and 23% were positive for both HPV and p16INK4a (considered HPV-driven). HPV-positivity and p16INK4a-positivity were associated with prolonged disease-free survival (DFS) in Kaplan-Meier survival analysis. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) immunoreactivity was not significantly associated with survival. High leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2) immunoreactivity was associated with a prolonged overall survival (OS) (P=0.001). By analyzing HPV-negative cases only, it was determined that high LRIG2 immunoreactivity was associated with both favorable OS (P=0.008) and DFS (P=0.031). LRIG2 immunoreactivity was also an independent prognostic factor in multivariate analysis of OS (P=0.002, HR=0.41; 95% CI, 0.24-0.71). High immunoreactivity with LMO7-1250 antibody was associated with survival benefits in the whole cohort (OS; P=0.011) although DFS was only prolonged in HPV-negative and not HPV-driven tumors (P=0.038 and 0.042, respectively). The present study indicated that LRIG2 and LMO7 may be useful prognostic markers in VSCC, particularly for patients without HPV-driven tumors or with advanced tumors at diagnosis. In contrast to earlier observations regarding other types of squamous cell carcinoma, LRIG1 was not a significant prognostic factor in VSCC.

Clinical and Prognostic Value of Molecular Markers of Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid tumor in adults which is associated with approximately 30-40 % of all non-Hodgkin’s lymphomas. Diagnostic criteria include diffuse growth of large anaplastic tumor cells, expression of В-cell markers, and a high proliferative index. Due to the development of molecular genetic technologies it became obvious that underlying cause of clinical diversity is a huge amount of genetic failures which determine epigenetic modification of gene expression, activation variability of certain signaling pathways, and immunological properties of tumor cells. The study and systemization of molecular markers present a significant trend in DLBCL diagnosis and treatment. This review discusses most important molecular markers and current view on their clinical value.

Prognostic Value of the VHL, HIF-1α, and VEGF Signaling Pathway and Associated MAPK (ERK1/2 and ERK5) Pathways in Clear-Cell Renal Cell Carcinoma. A Long-Term Study.

The prognostic value of molecular markers in renal cell carcinoma has been investigated in several studies. Although their value is still not confirmed, various proteins are important. We describe the effect on long-term survival of the status of the von Hippel-Lindau (VHL) hypoxia-inducible factor 1-α (HIF1-α) signaling pathway as well as associated mitogen-activated protein kinase (extracellular signal-regulated kinase [ERK]1/2 and ERK5). A prospective, longitudinal cohort study was conducted with 50 patients diagnosed with clear-cell renal cell carcinoma to analyze VHL mutations and hypermethylation as well as VHL, HIF1-α, vascular endothelial growth factor (VEGF), ERK1/2, and ERK5 protein expression. Overall survival (OS), disease-specific survival (DSS), and progression- or recurrence-free survival (PFS) were analyzed using the Kaplan-Meier method. Mantel-Haenszel was used for comparisons, and Cox proportional risk models were also constructed. Follow-up was 66.9 months. There were 23 (46.0%) deaths, of which 17 (73.9%) were caused by the tumor. Mean periods were 85.6 months for OS and 94.3 months for DSS. A total of 22 (44.0%) patients showed progression (PFS, 78.1 months). VHL expression (P= .045) and > 10% of HIF1-α expression (P= .034) were associated with greater OS. DSS was greater in patients without VHL methylation (P= .012), with > 10% HIF1-α expression (P= .037), or with ERK5 protein underexpression. Greater PFS was associated with absence of VHL methylation (P= .045), presence of VHL expression (P< .0001), HIF1-α expression > 10% (P= .04), and ERK5 protein underexpression (P= .011). The presence of VHL mutation and/or methylation and VEGF expression had no prognostic value. Fuhrman nuclear grade and Tumor, Node, Metastases (TNM) stage were the only variables that remained in the Cox model. The HIF1-α and ERK5 pathway has prognostic value. Patients with no VHL or HIF1-α expression and ERK5 overexpression had a worse course of disease. VHL or VEGF status had no prognostic value. Only TNM stage and Fuhrman nuclear grade remained in the Cox model and, therefore, are still essential in prognostic biomarker panels.

Prognostic Value of Molecular Markers and Implication for Molecular Targeted Therapies in Nasopharyngeal Carcinoma: An Update in an Era of New Targeted Molecules Development.

The aim of the study was to evaluate the prognostic significance of molecular biomarkers which could provide information for more accurate prognostication and development of novel therapeutic strategies for nasopharyngeal carcinoma (NPC). NPC is a unique malignant epithelial carcinoma of head and neck region, with an intimate association with the Epstein-Barr virus (EBV). Currently, the prediction of NPC prognosis is mainly based on the clinical TNM staging; however, NPC patients with the same clinical stage often present different clinical outcomes, suggesting that the TNM stage is insufficient to precisely predict the prognosis of this disease. In this review, we give an overview of the prognostic value of molecular markers in NPC and discuss potential strategies of targeted therapies for treatment of NPC. Molecular biomarkers, which play roles in abnormal proliferation signaling pathways (such as Wnt/β-catenin pathway), intracellular mitogenic signal aberration (such as hypoxia-inducible factor (HIF)-1α), receptor-mediated aberrations (such as vascular endothelial growth factor (VEGF)), tumor suppressors (such as p16 and p27 activity), cell cycle aberrations (such as cyclin D1 and cyclin E), cell adhesion aberrations (such as E-cadherin), apoptosis dysregualtion (such as survivin) and centromere aberration (centromere protein H), are prognostic markers for NPC. Plasma EBV DNA concentrations and EBV-encoded latent membrane proteins are also prognostic markers for NPC. Implication of molecular targeted therapies in NPC was discussed. Such therapies could have potential in combination with different cytotoxic agents to combat and eradicate tumor cells. In order to further improve overall survival for patients with loco-regionally advanced NPC, the development of innovative strategies, including prognostic molecular markers and molecular targeted agents is needed.

Prognostic value of molecular markers and cytogenetic alterations that characterize breast cancer precursor lesions (Review)

The understanding of the molecular mechanisms that underlie all stages of tumor progression in breast cancer (BC) represents an important goal in the biomedical research of this disease, particularly for the identification of more specific targeted therapies. In this context, BC preinvasive and precursor lesions represent a major dilemma. These lesions are well characterized under the phenotypic and genotypic profile, but it is not clear if they represent obligatory passages of a multistep process determining breast cancer evolution. In fact, the numerous cytogenetic and molecular alterations identified are not always representative of the progression into invasive phenotypes.

Prognostic value of CD44 expression in penile squamous cell carcinoma: a pilot study

Several studies have reported on the prognostic value of molecular markers for metastasis risk and survival in penile squamous cell carcinoma (SCC) patients. The usefulness of CD44 expression as such a marker has been studied in different tumors, but not in penile SCC. Our aim was to determine whether CD44 expression may serve as a prognostic marker for lymph node metastasis and survival in penile SCC patients. CD44 immunoistochemical expression was investigated in tissue specimens from 39 patients with penile SCC. CD44 cell positivity, staining intensity and distribution were analyzed and correlated with tumor stage, grade, lymph node status and disease-specific survival. CD44 expression was detected in epithelial cells of both intratumoral and normal tissues with different intensities and staining distributions. In normal tissues CD44 protein was mainly detected in cell membranes, whereas in the tumor compartments it was found in both the cell membranes and the cytoplasm. The intensities and percentages of CD44 expressing cells did not correlate with tumor stage and/or grade. Seventy-three percent of the patients with lymph node metastasis showed high intensities of CD44 staining, as compared to 44% of the patients without lymph node metastasis (P = 0.03). Lymph node-positive patients showed both cytoplasmic and membranous CD44 expression. High CD44 expression was found to be significantly correlated with a decreased 5 year overall survival (P = 0.01). CD44 levels and patterns of expression can be considered as markers for penile SCC aggressiveness and, in addition, may serve as predictive markers for lymph node metastasis, also in patients with clinically negative lymph nodes. CD44 expression may provide prognostic information for penile SCC patients, next to classical clinical-pathological factors.

Prognostic histopathological and molecular markers in feline mammary neoplasia

Feline mammary tumours comprise approximately 11% of feline non-integumentary neoplasms, are more commonly malignant than benign, and carry a poor prognosis attributable to a high probability of local recurrence and metastasis. This review discusses histopathological and molecular markers that could aid in prognostic discrimination, and draws comparisons with studies examining prognostic markers in breast cancer. Tumour grade and mitotic index correlate with survival data and could be useful for prognostication. Although assessment of Ki67 expression might have prognostic potential, further studies are required to corroborate the correlation between expression and clinical outcome. Additional molecular markers that have been investigated for prognostic potential can be grouped according to the 'hallmarks of cancer'. Many studies utilise 'surrogate markers' of clinical outcome, such as correlation with histological grade, to assess the prognostic value of molecular markers, and further investigation is therefore necessary before reaching firm conclusions regarding the prognostic value of some markers. Feline mammary tumours have been proposed as spontaneous models of breast cancer but might only be suitable models for certain molecular sub-types. Compared to humans, cats tend to have a high percentage of mammary tumours which are oestrogen receptor-negative and they might therefore be suitable models for late stage oestrogen receptor-negative breast cancer. The basal-like properties of feline mammary carcinomas offer another avenue for future research in this field of comparative oncology.

Prognostic value of molecular markers, sub‐stage and European Organisation for the Research and Treatment of Cancer risk scores in primary T1 bladder cancer

What's known on the subject? and What does the study add? The stakes are high when making treatment decisions in T1 bladder cancer (BC). Conservative management may lead to progression and possibly death from BC. Conversely, radical cystectomy could be over-treatment of non-progressive disease. The problem for clinicians is that reliable prognostic indices are lacking. We performed a head-to-head comparison of two substaging systems, European Organisation for the Research and Treatment of Cancer (EORTC) risk scores and four molecular markers in T1 carcinomas of the bladder treated conservatively with BCG. T1 sub-stage according to a new system (micro-invasive [T1m] and extensive-invasive [T1e]) was the most important clinical variable for predicting progression to carcinoma invading bladder muscle. The performance of the EORTC risk scores was disappointing for this T1 sub-group. Molecular markers were not significant in multivariable analysis for predicting progression. Future studies may lead to the incorporation of sub-stage (T1m/T1e) in the TNM classification system for urinary BC to guide clinical decision-making in T1 BC. To evaluate the prognostic significance of four molecular markers, sub-stage and European Organisation for the Research and Treatment of Cancer (EORTC) risk scores in primary T1 bladder cancer (BC) treated with adjuvant bacille Calmette-Guérin. The slides of 129 carcinomas of the bladder from two university hospitals were reviewed and the T1 diagnosis was confirmed. T1 sub-staging was done in two separate rounds, using a new system that identifies micro-invasive (T1m) and extensive-invasive (T1e) T1BC, and then according to invasion of the muscularis mucosae (T1a/T1b/T1c). The EORTC risk scores for recurrence and progression were calculated. Uni- and multivariable analyses for recurrence and progression were performed using clinicopathological variables, T1 sub-stage, EORTC risk scores and molecular markers (fibroblast growth factor receptor 3 gene mutation and Ki-67, P53, P27 expression). The median follow-up was 6.5 years. Forty-two patients remained recurrence-free (33%). Progression to T2 or metastasis was observed in 38 (30%) patients. In multivariable analysis for recurrence, multiplicity was significant. In multivariable analysis for progression, female gender, sub-stage (T1m/T1e) and carcinoma in situ (CIS) were significant. Molecular markers were significant in univariable and in multivariable analyses for recurrence. EORTC risk scores were not significant. CIS, female gender and sub-stage (T1m/T1e) were the most important variables for progression. The additional value of molecular markers was modest. Sub-stage (T1m/T1e) could potentially be incorporated in future tumour-node-metastasis classifications.

Tissue Biomarkers for Prognosis in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis

The management of pancreatic ductal adenocarcinoma (PDAC) continues to present a great challenge particularly with regard to prediction of outcome following pancreaticoduodenectomy. Molecular markers have been extensively investigated by numerous groups with the aim of enhancing prognostication; however, despite hundreds of studies that have sought to assess the potential prognostic value of molecular markers in predicting the clinical course following resection of PDAC, at this time, no molecular marker assay forms part of recommended clinical practice. We conducted a systematic review and meta-analysis of the published literature for immunohistochemistry-based biomarkers of PDAC outcome. A dual search strategy was applied to the PubMed database on January 6, 2010, to identify cohort studies that reported associations between immunohistochemical biomarker expression and survival outcomes in PDAC, and conformed to the REMARK (REporting recommendations for tumor MARKer prognostic studies) criteria. A total of 103 distinct proteins met all inclusion criteria. Promising markers that emerged for the prediction of overall survival included BAX (HR = 0.31, 95% CI: 0.71-0.56), Bcl-2 (HR = 0.41, 95% CI: 0.27-0.63), survivin (HR = 0.46, 95% CI: 0.29-0.73), Ki-67: (HR = 2.42, 95% CI: 1.87-3.14), COX-2 (HR = 1.39, 95% CI: 1.13-1.71), E-cadherin (HR = 1.80, 95% CI: 1.33-2.42), and S100 calcium-binding proteins, in particular S100A2 (HR = 3.23, 95% CI: 1.58-6.62). We noted that that there was incomplete adherence to the REMARK guidelines with inadequate methodology reporting as well as failure to perform multivariate analysis. Addressing the persistent incomplete adoption of these criteria may eventually result in the incorporation of molecular marker assessment within PDAC management algorithms.

Stage-specific prognostic value of molecular markers in colon cancer: Results of the translational study on the PETACC 3-EORTC 40993-SAKK 60–00 trial

4002 Background: We compared the incidence of molecular markers in stage II (SII) and III (SIII) colon cancer and tested their prognostic value per stage, using PETACC 3, an adjuvant trial with 3,278 patients. We included expression of P53, SMAD4, thymidylate synthetase (TS) and hTERT, mutations of KRAS and BRAF, microsatellite instability (MSI) and 18qLOH. Methods: 1,564 formalin fixed paraffin embedded tissue blocks were prospectively collected and DNA from normal and tumor tissue was extracted after macrodissection. High P53, TS and hTERT expression and SMAD4 loss were assessed by immunohistochemistry. MSI was studied with 10 markers. KRAS exon 2 and BRAF exon 15 mutations were analyzed by allele specific real time PCR. 18qLOH was studied by pyrosequencing 7 SNPs. Prognostic value of the markers was analysed per stage by Cox regression for Relapse Free Survival (RFS). Results: marker frequencies and stage specific p-values in prognostic models in 420 SII and 984 SIII patients are listed in the table . Significant differences in frequency per stage were found for all markers except KRAS and BRAF. An interaction test for differences between marker prognostic value for SII and SIII was significant for MSI (p=0.04) and 18qLOH (p=0.04) in SII. Multivariate analysis including markers, T stage, N stage (for SIII), Tu grade, age &lt;60, sex, treatment arm, and Tu site found T stage (p=0.0001) and MSI (p=0.02) as independently significant clinical predictors in SII; N stage (p&lt;0.0001), T stage (p&lt;0.0001), SMAD4 (p&lt;0.0001) and P53 (p=0.01) in SIII. Conclusions: Molecular markers in colon cancer have a stage specific prognostic value. The possibility that the stages represent different diseases, rather than sequential steps in the evolution of a single disease, needs to be considered. [Table: see text] [Table: see text]

Tissue Biomarkers for Prognosis in Cutaneous Melanoma: A Systematic Review and Meta-analysis

In the clinical management of early-stage cutaneous melanoma, it is critical to determine which patients are cured by surgery alone and which should be treated with adjuvant therapy. To assist in this decision, many groups have made an effort to use molecular information. However, although there are hundreds of studies that have sought to assess the potential prognostic value of molecular markers in predicting the course of cutaneous melanoma, at this time, no molecular method to improve risk stratification is part of recommended clinical practice. To help understand this disconnect, we conducted a systematic review and meta-analysis of the published literature that reported immunohistochemistry-based protein biomarkers of melanoma outcome. Three parallel search strategies were applied to the PubMed database through January 15, 2008, to identify cohort studies that reported associations between immunohistochemical expression and survival outcomes in melanoma that conformed to the REMARK criteria. Of the 102 cohort studies, we identified only 37 manuscripts, collectively describing 87 assays on 62 distinct proteins, which met all inclusion criteria. Promising markers that emerged included melanoma cell adhesion molecule (MCAM)/MUC18 (all-cause mortality [ACM] hazard ratio [HR] = 16.34; 95% confidence interval [CI] = 3.80 to 70.28), matrix metalloproteinase-2 (melanoma-specific mortality [MSM] HR = 2.6; 95% CI = 1.32 to 5.07), Ki-67 (combined ACM HR = 2.66; 95% CI = 1.41 to 5.01), proliferating cell nuclear antigen (ACM HR = 2.27; 95% CI = 1.56 to 3.31), and p16/INK4A (ACM HR = 0.29; 95% CI = 0.10 to 0.83, MSM HR = 0.4; 95% CI = 0.24 to 0.67). We further noted incomplete adherence to the REMARK guidelines: 14 of 27 cohort studies that failed to adequately report their methods and nine studies that failed to either perform multivariable analyses or report their risk estimates were published since 2005.

Prognostic Value of Molecular Markers for Guiding Post-Remission Therapy in Patients with De Novo Acute Myeloid Leukemia (AML) and Intermediate-Risk Cytogenetics

The heterogeneous prognosis of patients with intermediate-risk cytogenetics AML (AML-IR) can be partially clarified by screening of NPM1 mutations (NPMmut) and internal tandem duplication of FLT3 (FLT3-ITD). Nonetheless, additional factors might influence the prognostic effect of these molecular lesions, such as the FLT3-ITD mutant level. Moreover, the optimal post-remission strategy might differ depending on the underlying molecular lesion. In this regard, we analyzed the outcome, according to NPM1 and FLT3 mutations and post-remission therapy given, of a series of patients diagnosed with de novo AML-IR in a single institution who received intensive chemotherapy. Patients were treated following 4 sequential protocols of CETLAM group during the period 1994–2006, consisting of 1 or 2 cycles of standard induction chemotherapy and 1 course of high-dose cytarabine-based consolidation therapy. Thereafter, patients underwent hematopoietic stem cell transplantation (HSCT) according to donor availability and presumed risk (protocols LAM 99 & 2003). NPM1 mutations and FLT3-ITD were screened in diagnostic DNA by PCR amplification followed by Genescan analysis. The ratio between FLT3-ITD and wildtype FLT3 alleles (ITD/wt ratio) was calculated using the area under the peak of corresponding alleles. Overall, 134 patients (51% male; median age, 53; range: 17–70) with AML-IR (normal karyotype, 66%) were studied. NPM1mut and FLT3-ITD were found in 45% and 37% of patients, respectively, with a median ITD/wt ratio of 0.59 (0.045–5.5). After induction regimen, 109 patients (81%) achieved complete response (CR). The only variables predictive of a favorable response were NPMmut (90% vs. 75%; p=0.01) and age <60 (85% vs. 72.5%; p=0.05). After a median follow-up of 69 months, relapse risk (RR) at 5 years was 54% (±5%). RR was higher in patients presenting with hyperleukocytosis (>50 × 109/L), NPMwt, and FLT3-ITD. Interestingly, the prognostic value of FLT3-ITD depended on the relative mutant level, and detection of FLT3-ITD with a low ITD/wt ratio (i.e.,<0.3) did not increase the risk conferred by underlying NPM1 mutational status. In accordance, a composite variable based on NPMmut and quantitative FLT3-ITD was created defining 2 prognostic categories: a low-risk group (LOWmol), constituted by patients with NPMmut and either absence of FLT3-ITD or low ITD/wt ratio, and a high-risk subset (HIGHmol), defined by the absence of NPMmut and/or high ITD/wt ratio. This molecular stratification showed independent prognostic value for RR (5-year RR: 24%±10% vs. 81%±7 in LOWmol vs. HIGHmol patients, respectively; p<0.001), and survival (OS; relative risk: 2.8, 95% CI:1.6-5, p<0.001; figureMoreover, the effect of post-remission therapy varied in both molecular-defined subgroups. Thus, among patients with an age ≤60, 5-year survival in LOWmol patients with a planned autologous HSCT (autoHSCT) was 83%±9%, not differing significantly from that of patients undergoing allogeneic HSCT (intention-to-treat analysis; figureOn the other hand, 5-year OS of HIGHmol patients who underwent allogeneic HSCT in first CR was 73%±13, which compared favorably with other post-remission strategies (5-yr OS: 27%±7%; p=0.019).In conclusion, in patients with intermediate-risk AML, the combined assessment of NPM1 mutations and quantitative estimation of FLT3-ITD allows the distinction of 2 categories of patients with different prognosis. Thus, whereas autoHSCT arises as an effective postremission therapy in patients harboring low-risk molecular features, allogeneic HSCT in first CR seems to overcome adverse prognosis of patients with high-risk disease.Nonetheless, the validity of this molecularly-based therapeutic algorithm warrants confirmation in other studies. [Display omitted]

Prognostic value of clinical, pathological and immunohistochemical markers in stage II colon cancer patients

The purpose of our analysis was to determine the prognostic value of molecular markers for identifying high-risk TNM stage II colon cancer patients, the association with various clinical and pathological features, and possible relation to survival. In 191 colon cancer patients who underwent a potentially curative resection, clinical and pathological factors (age, tumour site, histological grade of malignancy, pT stage, presence of venous, lymphatic and perineural invasion) and tumour molecular markers were analysed. Molecular markers were assessed immunohistochemically in sections of paraffin-embedded tissues. Patients were followed for a median of 8.7 years. The 5-year survival rate was estimated using the the Kaplan-Meier statistical method. From 1. Jan. 1994 to 31. Dec. 2000, 191 patients underwent radical resection for T3-4 N0M0 colorectal cancer without adjuvant chemotherapy. A significant decrease in survival was identified in older patients, patients with tumours pT4 and with perineural invasion. We found no significant differences in survival of patients with expression of MLH1, Cyclin D1 and reduced overexpression of E-cadherin. The results of our study indicate that the presence of perineural invasion, pT4 stage and the patient's age are significantly correlated with the expected survival in radically resected TNM stage II colon cancer patients, while immunohistochemical markers are not related to survival.

Cancer mucoépidermoïde des glandes salivaires : signification pronostique des marqueurs tumoraux

Mucoepidermoid carcinoma is one of the most frequent malignant lesions of salivary glands. The treatment is based on clinical, paraclinical and histological data. Several studies on the prognostic value of molecular markers for these cancers were made with contradictory results. The aim of this retrospective study was to analyze the prognostic value of molecular markers of salivary gland mucoepidermoid carcinoma. Sixteen patients were treated for mucoepidermoid carcinoma of principal and/or accessory salivary glands between 1994 and 2003. An immunohistochemical study of archive specimen was performed. Nine markers were specifically studied: 4 proteins/oncoproteins (p53, bcl2, c-erb-B2 and cd117), 2 markers of proliferation (PCNA and Ki67), 1 growing factor receptor (EGFR), 1 epithelial adhesion molecule (E-cadherin), and 1 angiogenic cytokine (PDGF). Nine men and 7 women were included, with a mean age of 43.7 years (14-80). The mean diameter of tumors was 3.1 mm (1-14), and the parotid gland was the most frequent location. The mean global survival rate was 57.3 months with a median of 55 months. The 2 to 5 years survival expectation rate were 82.5% and 46.4% respectively. The mean survival rate for women was superior to that of men (P=0.043). The expression of p53 and the high expression rate of EFGR were bad prognostic factors (respectively P=0.049 and P=0.012). The expression of PCNA was linked to the location (mainly the salivary gland) and to the diameter of the tumor (respectively P=0.037 and P=0.029). The degree of EFGR positivity and the histological grade were linked (P=0.027). The strong expression of EGFR was statistically linked to the histological tumor grade. The degree of PCNA positivity seemed to be associated to the preferential location in the main salivary glands and to the diameter of the tumor. The strong expression of p53 and EGFR were bad prognostic factors. These retrospective results need to be confirmed by prospective randomized and larger studies. EGFR and p53 were significant negative prognostic factors. EGFR was highly correlated to the histological grade, making it an interesting target for further investigation.

Prognostic Impact of Molecular Analyses in Adenoid Cystic Carcinomas of the Salivary Gland

Background: Adenoid cystic carcinoma (ACC) of the salivary gland is a generally slow-growing but highly malignant neoplasm with a remarkable capacity for recurrence. Prognosis is greatly influenced by the histological subtype (tubular, cribriform or solid), presence of tumour at the margins, anatomic size, and lymph node metastases. However, none of these parameters has proven to be an unequivocal predictor of disease activity. Therefore, the current study was undertaken to investigate the prognostic value of molecular markers. Patients and Methods: Samples from 22 patients, including 4 patients with recurrent disease, were included in the study. By means of immunohistochemistry, the staining pattern of p53, bcl-2, P-glycoprotein, glutathione S-transferase, and topoisomerase as well as sequence analyses of p53 were performed. These molecules were chosen because of their proven association with poor prognosis and therapy resistance in other malignancies. Results: Homozygous p53 mutations were found in all of the 4 recurrent tumors. The other proteins were detected in some tumors, but showed no correlation with histological subtype or recurrence of tumor. Conclusion: The results of the current study emphasize the prognostic value of a p53 alteration as an independent prognostic marker. Further, it could be demonstrated for the first time that proteins known for their association with radio- and chemotherapy resistance can be overexpressed in some ACCs suggesting that those molecules could influence the outcome of new therapeutical approaches.

Molecular prognostic factors in rectal cancer treated by radiation and surgery.

The aim of this study was to determine the biologic significance of tumor response and the prognostic value of molecular markers in a group of patients with rectal cancer treated with preoperative radiation therapy and radical surgery. Microsatellite instability, microvessel count, and immunohistochemistry for proliferating cell nuclear antigen, p53, p21, bcl-2, and vascular endothelial growth factor were performed in the preradiation biopsy specimen of 72 patients with rectal cancer treated by preoperative radiation therapy and radical curative surgery. Preoperative tumor stage by endorectal ultrasound was compared with pathology stage of the resected specimen. Mean follow-up was 50 months. Twenty-eight patients (39 percent) responded to radiation therapy. The response was complete in 8 (12 percent) and partial in 20 patients (27 percent). Tumors with positive nodes in the surgical specimen were less likely to have responded to preoperative radiation (P = 0.03). Only p21 expression was individually associated with response to radiation (56 vs. 30 percent; P = 0.03). Tumors that were p53-negative/p21-positive or p21-positive/bcl-2-positive were also more likely to respond to radiation (83 vs. 35 percent; P = 0.03 and 71 vs. 31 percent; P = 0.01, respectively). The tumor relapsed in 21 patients (29 percent): locally in 7 (10 percent) and distally in 14 (19 percent). Recurrence was associated with lack of response to radiation, female gender, distal tumor location, high proliferating cell nuclear antigen labeling index, and low microvessel count. Probability of survival was greater for patients with well or moderately differentiated tumors and tumors that responded completely to radiation. Tumor response to radiation is associated with improved tumor control and overall survival rate, and p21 expression is a marker of tumor radiosensitivity in patients with rectal cancer. Furthermore, a high proliferating cell nuclear antigen labeling index and a low microvessel count in the preradiation biopsy specimen may be prognostic indicators for tumor recurrence.