Poor Prognosis Subgroup Research Articles

A new pathological system for grading DCIS with improved prediction of local recurrence: results from the UKCCCR/ANZ DCIS trial

Background:There is no consensus agreement regarding optimal management of locally excised ductal carcinoma in situ (DCIS) or features of greatest assistance in predicting disease behaviour. Cases in the UKCCCR/ANZ DCIS trial have been histologically reviewed to determine the features of prognostic importance.Method:A total of 72% of 1694 cases entered into the UKCCCR/ANZ DCIS trial had full pathological review. A large number of histological features were assessed, blinded to outcome and compared regarding ability to predict ipsilateral recurrence, as either DCIS or progression to invasive carcinoma.Results:Pathological features associated with ipsilateral recurrence in univariate analysis included high cytonuclear grade, larger lesion size, growth pattern, presence of necrosis or chronic inflammation, incompleteness (or uncertainty of completeness) of excision and smaller margin width. Receipt of post-operative radiotherapy was also a strong prognostic factor.We report a novel sub-division of the large group of high-grade lesions, which enables identification of a very poor prognosis sub-group; namely, DCIS that is of high cytonuclear grade, predominantly (>50%) solid architecture, bearing extensive comedo-type necrosis (>50% of ducts). In addition, we found little difference in ipsilateral recurrence rates between low- and intermediate-grade groups. Hazard ratios for low, intermediate, high and the new, very high, grade were 0.42, 0.33, 0.62 and 1.00, respectively, for ipsilateral in situ or invasive recurrence.Conclusion:We present a novel pathological classification for DCIS with substantially better prognostic discrimination for ipsilateral recurrence than the classical categorisation based on cytonuclear grade alone.

A gene expression signature identifies two prognostic subgroups of basal breast cancer

Prognosis of basal breast cancers is poor but heterogeneous. Medullary breast cancers (MBC) display a basal profile, but a favorable prognosis. We hypothesized that a previously published 368-gene expression signature associated with MBC might serve to define a prognostic classifier in basal cancers. We collected public gene expression and histoclinical data of 2145 invasive early breast adenocarcinomas. We developed a Support Vector Machine (SVM) classifier based on this 368-gene list in a learning set, and tested its predictive performances in an independent validation set. Then, we assessed its prognostic value and that of six prognostic signatures for disease-free survival (DFS) in the remaining 2034 samples. The SVM model accurately classified all MBC samples in the learning and validation sets. A total of 466 cases were basal across other sets. The SVM classifier separated them into two subgroups, subgroup 1 (resembling MBC) and subgroup 2 (not resembling MBC). Subgroup 1 exhibited 71% 5-year DFS, whereas subgroup 2 exhibited 50% (P = 9.93E-05). The classifier outperformed the classical prognostic variables in multivariate analysis, conferring lesser risk for relapse in subgroup 1 (HR = 0.52, P = 3.9E-04). This prognostic value was specific to the basal subtype, in which none of the other prognostic signatures was informative. Ontology analysis revealed effective immune response (IR), enhanced tumor cell apoptosis, elevated levels of metastasis-inhibiting factors and low levels of metastasis-promoting factors in the good-prognosis subgroup, and a more developed cell migration system in the poor-prognosis subgroup. In conclusion, based on this 368-gene SVM model derived from an MBC signature, basal breast cancers were classified in two prognostic subgroups, suggesting that MBC and basal breast cancers share similar molecular alterations associated with aggressiveness. This signature could help define the prognosis, adapt the systemic treatment, and identify new therapeutic targets.

Characterization of Metastatic Breast Cancer Patients with Non-Detectable Circulating Tumor Cells.

Abstract Background: Circulating tumor cells (CTC) are independent predictor of progression free and overall survival in metastatic breast cancer patients, with superior prognosis for patients with CTC <5 per 7.5mL of peripheral blood. However, 30-50% of patients have non-detectable CTC. The aim of this study was to assess the prognostic factors in MBC patients with non-detectable CTC.Methods: This retrospective study included 271 MBC patients evaluated between January 2004 and December 2007. Median age of patients was 56 years (range: 23-82 years). CTCs were enumerated before patients started a new line of treatment using the CellSearchTM. Overall survival (OS) was calculated from the date of CTC measurement, estimated by the Kaplan-Meier product limit method, and compared between groups with the log-rank test.Results: Median CTC count was 2 (range: 0-1780) per 7.5 mL. CTCs were not detected in 99 (36.5%) patients, while 112 (41.3%) patients had CTC ≥ 5. Median OS for patients with 0 CTC; 1-4 CTC and ≥ 5 CTC was 29.3; 26.4; and 19.4 months (p = 0.04), respectively. Patients with brain metastasis have the highest probability of non-detectable CTC (71.4% vs. 33.6%; p = 0.001), while patients with bone metastasis are more likely to have CTC ≥ 1 (48.2% vs. 31.8%; p = 0.01). There was no association between other tumor characteristics (ER, PR, HER2, number and localization of tumor metastasis) and non-detectable CTC status. Patients with CTC = 0 have non-significantly better OS compared to patients with CTC ≥ 1 (29.3 vs. 23.3 months; p = 0.09) and have superior survival in all but one analyzed subgroups; only inflammatory breast cancer (IBC) patients with CTC = 0 have inferior OS compared with patients with CTC ≥ 1 (26 vs. 37 months; p = 0.67). In a subgroup of patients with non-detectable CTC, triple negative MBC has the poorest survival (median OS = 18.8 months), while hormone receptor positive MBC, without visceral metastases and non-inflammatory breast cancer has the best survival (median OS = 36.9 months). In multivariate analysis, hormone receptor status and line of therapy were only independent prognostic factors for OS in patients with non-detectable CTC (Table 1).Conclusion: Patients with non-detectable CTC before start of new line of therapy comprise a heterogeneous group of patients with substantially different prognosis. Triple negative and IBC patients represent poor prognosis subgroups. These data suggest heterogeneity of microscopic disease in advanced cancer and indicate the need to investigate combining additional detection technologies. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3006.

Tandem Autologous(ASCT)/ Allogeneic Reduced Intensity Conditioning Transplantation (RIC) with Identical Sibling Donor Versus ASCT in Previously Untreated Multiple Myeloma (MM): Long Term Follow up of a Prospective Controlled Trial by the EBMT.

Abstract 52 Introduction:Allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning (RIC) is a controversial treatment in multiple myeloma. There are only few prospective studies and results are contradictory. The EBMT initiated a prospective study in the year 2000 comparing ASCT followed by RIC to ASCT. Patients and Method: 358 myeloma patients from 26 European centres were included in a prospective study comparing ASCT-RIC versus ASCT based on the availability of an HLA identical sibling donor. Patients with an HLA-identical sibling were allocated to the ASCT-RIC-arm (n=107) and patients without a matched sibling donor to the ASCT (n=251). Study inclusion was at the time of conditioning for the first autologous transplant at the achievement of a response status of at least stable disease after VAD ( vincristine, doxorubicine, dexamethasone)-like induction treatment of previously untreated patients. Single or tandem (n=122) autografting was optional in the ASCT arm. Conditioning for ASCT was melphalan 200 mg/m2, and for RIC fludarabine 30 mg/m2 × 3 plus TBI 2 Gy. The accrual period was from February 2001 to February 2005, and median follow-up time is 60 months. The two treatment groups were well matched for the standard prognostic parameters, karyotype (del(13) or not), and response status at ASCT. Results: On an intention to treat basis the cumulative 24 months non-relapse-mortality (NRM) was 13 % in the ASCT-RIC- and 5 % in the ASCT arm (p=0.014) and the CR rate was 43 % (CI:35-54%) and 38% (CI:32-45%) respectively. At 60 months after transplantation Relapse/Progression rate was 49% (CI: 40-60%) and 75% (CI: 69-80%) (significant at 5% level), PFS 35% (CI: 27-45%) and 18% (CI:14-24%) (significant at 5% level) and OS 65% (CI:56-74 %) and 57% (CI:51-64%) (at 84 months 60% and 22%) for the ASCT-RIC- and ASCT -arms, respectively. A comparison between those patients who received a second allo (n=88) versus a second auto (n= 104) the corresponding figures were for CR rate 51 % in the ASCT-RIC-arm and 43 % in the ASCT-arm, Relapse/Progession rate 45% and 77%, PFS 39% and 19% and OS 63% and 60% respectively. Information about the chromosome 13 deletion (del(13q14)) was present in 214 patients. In those with the deletion (n= 92) OS at 60 months was 70% and 53%, and PFS 30% and 11% for the ASCT-RIC- and ASCT-arms, respectively. The corresponding figures for patients without the deletion ( n=122) was for OS 70% vs 61% and PFS 44% vs 19%. Relapse rates were lower in the ASCT-RIC in both subgroups. Conclusion: The risk of myeloma relapse was significantly lower in the ASCT-RIC group as compared to ASCT group, both on an intention to treat analysis and when only those patients that received the correct treatment were analysed. NRM was significantly lower in the ASCT group, but still on an acceptable level in the ASCT-RIC group considering the significantly lower relapse/progression rate, improved PFS and a tendency for better long term OS. An improvement or tendency for improvement were seen in both poor (deletion 13) and good (no deletion 13) prognosis subgroups. Disclosures:Bjorkstrand:Roche: Employment, Karolinska Institutet employee until the closing of the study.

Minimal Disseminated Disease Is An Independent Poor Prognosis Marker Among High Risk Burkitt's Lymphoma Patients .

Abstract 2944Poster Board II-920 Introduction:The chromosomal translocation t(8;14)(q24;q32) represents a specific tumor marker in Burkitt's lymphoma (BL). This chromosomal aberration involves the MYC oncogene on chromosome 8 and the immunoglobulin heavy-chain (IgH) locus on chromosome 14. We have previously demonstrated that this genetic abnormality can be used as a marker of Minimal Disseminated Disease (MDD) in BL (Mussolin et al, JCO, 2007). The aim of the study was to assess of the prevalence of MDD in BL at diagnosis in children enrolled in the AIEOP LNH-97 clinical protocol and the evaluation of its impact on prognosis. Patients and Methods:We established a simplified long-distance PCR (LD-PCR) assay which can amplify up to 15-20 Kb DNA sequence making it possible to detect the t(8;14) at the genomic level with the sensitivity of 10-4. The assay was based on 4 separate PCR reactions in which one primer complementary to the first exon of the MYC gene is used with one of four primers for the IgH locus (1 for the JH region and 1 for each of the 3 constant regions). Results:LD-PCR was applied to prospectively study 124 BL biopsies and detected a specific PCR product in 88 of them (71%). Of the 88 positive BL patients we studied both the tumor and the bone marrow (BM) at diagnosis in 76: BM was positive by LD-PCR in 25 patients (33%), whereas only 10 (13%) were positive at the standard morphological and/or immunophenotypical analyses. Most of the MDD positive patients (88%) belonged to the R4 Risk Group according to BFM definition (stage III or stage IV according to St. Jude staging classification and LDH≥1000 U/l). The 3-year progression-free survival (PFS) was 68% (SE 10%) in MDD positive R4 patients compared with 96% (SE 4%) in MDD negative R4 patients (p= 0.02), whereas there was no difference in PFS between children with morphological involvement of BM at diagnosis versus those who had negative BM (PFS=62.5% (SE 17%) vs. PFS= 87% (SE 6%), respectively, p= 0.09). By multivariate analysis (including MDD, gender, LDH, CNS involvement) MDD was predictive of higher risk of failure (Hazard Ratio: 8.4 , p= 0.04). Conclusions:We demonstrated that MDD identifies a poor prognosis subgroup among high risk Burkitt's lymphoma patients. We suggest that a more effective risk-adapted therapy, possibly including anti-CD20 monoclonal antibody, should be considered in these patients. Disclosures:No relevant conflicts of interest to declare.

Amonafide L-Malate (AS1413) in Combination with Cytarabine Is Equally Effective in Older and Younger Patients with Secondary Acute Myeloid Leukemia (AML); Final Data From a Phase II Study.

Abstract 1047Poster Board I-69 Background:A major issue in the treatment of AML is the low response rate achieved with standard remission induction therapy in patients with “poor-risk” prognostic factors. One such poor-risk factor is secondary AML (sAML), AML following myelodysplasia or cytotoxic therapy for other malignancies. sAML is strongly associated with multi-drug resistance (MDR) mechanisms: up to 70% of sAML patients show overexpression of P-glycoprotein (Pgp) or other MDR mechanisms. Amonafide L-malate (amonafide, AS1413) is a unique DNA intercalator that is not a substrate for MDR, unlike anthracyclines commonly used in the treatment of AML. This phase II study evaluated amonafide in combination with cytarabine in patients with sAML. Methods:Patients received amonafide 600 mg/m2/day IV on days 1-5 and cytarabine 200 mg/m2/day IV by continuous infusion on days 1-7. Induction was repeated if leukemia persisted on day 14 marrow examination. Consolidation consisted of hematopoietic stem cell transplant (HSCT; n=10) or intermediate-dose (n=13)/high-dose (n=7) cytarabine, depending on age and HSCT donor availability. Bone marrows were centrally reviewed. The primary endpoint was complete remission with (CR) or without (CRi) hematopoietic recovery; secondary endpoints were duration of remission (DOR), survival and safety. Results:88 patients with a median age of 62.5 years (range 23-87) were treated; Of these, 45 (51%) had received prior leukemogenic therapy (tAML) and 43 (49%) had prior MDS; 1 (1%) had favorable, 36 (41%) had intermediate and 42 (48%) had unfavorable cytogenetics. Overall CR + CRi rate was 42% (CRi 3%); median duration of remission (DOR) was 312 days. CR rates and DOR among age <60 and ≥60, 13/33 (39.4%), 312 days and 24/55 (43.6%), 316 days; among tAML and prior MDS, 18/45 (40%), 512 days and 19/43 (44.2%), 186 days; intermediate and unfavorable cytogenetics, 23/36 (61.1%), 282 days and 10/42 (23.8%), 322 days. Median overall survival for the whole population was 200 days and for responders 435 days. Non-hematologic grade ≥ 3 adverse events included febrile neutropenia (35%), hypotension (16%), pneumonia (14%), respiratory failure (11%), and bacteremia (11%). The death rate within 28 days of induction therapy was 20.5%. Median time to hematopoietic recovery of neutrophil count > 500/cmm and platelets of 20,000/cmm was 29 and 28 days, respectively. Conclusions:Amonafide produced a high complete remission rate and durable responses in both older and younger patients with sAML. Efficacy was maintained across several poor-prognosis subgroups frequently characterized by MDR, for which amonafide is not a substrate. A phase III study (ACCEDE) is evaluating amonafide + cytarabine vs. daunorubicin + cytarabine in patients with sAML. Disclosures:Erba:Genzyme: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria; Pharmion: Honoraria; MGI Pharma: Honoraria; Cephalon: Honoraria, Research Funding; Wyeth: Research Funding; Antisoma: Research Funding; Lilly: Research Funding; Gemin-X: Research Funding; Kanisa: Research Funding. O'Donnell:Genzyme: Consultancy; Eisai: Consultancy; Celgene: Consultancy. Allen:Antisoma: Research Funding. Powell:Antisoma: Research Funding. Stone:Celgene: Consultancy, Speakers Bureau; Merck: Consultancy; Genzyme: Consultancy; Eisai: Consultancy. Bennett:Antisoma: Consultancy. Lundberg:Antisoma: Employment. Capizzi:Antisoma: Consultancy. Rizzieri:Antisoma: Research Funding.

Soft tissue sarcomas of the trunk wall (STS-TW): a study of 343 patients from the French Sarcoma Group (FSG) database

Background: Soft tissue sarcomas of the trunk wall (STS-TW) are usually studied together with soft tissue sarcomas of other locations. We report a study on STS-TW forming part of the French Sarcoma Group database.Patients and methods: Three hundred and forty-three adults were included. We carried out univariate and multivariate analysis for overall survival (OS), metastasis-free survival (MFS) and local recurrence-free survival (LRFS).Results: Tumor locations were as follows: thoracic wall, 82.5%; abdominal wall, 12.3% and pelvic wall, 5.2%. Median tumor size was 6.0cm. The most frequent tumor types were unclassified sarcoma (27.7%) and myogenic sarcoma (19.2%). A total of 44.6% of cases were grade 3. In all, 21.9% of patients had a previous medical history of radiotherapy (PHR). Median follow-up was 7.6 years. The 5-year OS, MFS and LRFS rates were 60.4%, 68.9% and 58.4%, respectively. Multivariate analysis retained PHR and grade for predicting LRFS and PHR, size and grade as prognostic factors of MFS. Factors influencing OS were age, size, PHR, depth, grade and surgical margins. The predictive factors of incomplete response were PHR, size and T3.Conclusions: Our results suggest similar classical prognostic factors as compared with sarcomas of other locations. However, a separate analysis of STS-TW revealed a significant poor prognosis subgroup of patients with PHR.

MicroRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification

AbstractAberrant expression of microRNAs has been recently associated with chronic lymphocytic leukemia (CLL) outcome. Although disease evolution can be predicted by several prognostic factors, a better outcome individualization in a given patient is still of utmost interest. Here, we showed that miR-29c and miR-223 expression levels decreased significantly with progression from Binet stage A to C were significantly lower in poor prognostic subgroups (defined by several prognostic factors) and could significantly predict treatment-free survival (TFS) and overall survival (OS). Furthermore, we developed a quantitative real-time polymerase chain reaction (qPCR) score combining miR-29c, miR-223, ZAP70, and LPL (from 0 to 4 poor prognostic markers) to stratify treatment and death risk in a cohort of 110 patients with a median follow-up of 72 months (range, 2-312). Patients with a score of 0/4, 1/4, 2/4, 3/4, and 4/4 had a median TFS of greater than 312, of 129, 80, 36, and 19 months, respectively (hazard ratio, HR0/4 < 1/4 < 2/4 < 3/4 < 4/4 = 17.00, P < .001). Patients with a score of 0-1/4, 2-3/4, and 4/4 had a median OS of greater than 312, of 183 and 106 months, respectively (HR0/4 < 1/4 < 2/4 < 3/4 < 4/4 = 13.69, P = .001). This score will help to identify, among the good and poor prognosis subgroups, patients who will need early therapy and thus will require a closer follow-up.

Use of laser capture microdissection to derive poor prognosis gene expression signatures of epithelial abdominal malignant mesothelioma

e22098 Background: Prior work in abdominal malignant mesothelioma (AMM) has established a poor prognosis profile of biphasic AMM when compared to more favorable prognosis epithelial AMM. It is evident, however, that epithelial AMM shows heterogeneity in biologic behavior and prognosis. Given improvements in therapy and survival in AMM, stratification of patients with epithelial AMM into favorable and poor prognosis subgroups is desirable and gene expression profiles may provide poor prognosis signatures to further guide therapy. Methods: Favorable and poor prognosis subgroups were defined as 1000 days of survival time (based on median survival of 90 patients with AMM at Columbia Presbyterian as of Sept 2007). Fourteen frozen epithelial AMM (7 favorable prognosis, 7 poor prognosis) with high quality RNA were laser capture microdissected using a PALM Zeiss microscope and analyzed using Affymetrix U133 Plus 2 microarrays. Unsupervised hierarchical clustering and supervised subgroup analysis were performed using BRB tools version 3.2. Results: Unsupervised hierarchical clustering revealed 2 main clades that contained 6 of 7 poor prognosis and 6 of 7 favorable prognosis tumors, respectively. Supervised class comparison revealed a 39-gene signature that distinguished the 2 classes (permutation values of p &lt; .001). High expression of Nde1, UHRF1, and EZH2 by qPCR on a set of 32 AMM (using an upper quartile cutoff) was associated with poor survival (Log rank statistic p&lt;.01, p&lt;.003 and p&lt;.03 respectively). Immunohistochemistry performed on tissue microarrays of 122 AMM for p16 loss and increased EZH2, Col3A1 and UHRF1 immunoreactivity was associated with poor survival (Log rank statistic p&lt;.0001, p&lt;.009, p&lt;.0001 and p&lt;.012, respectively). Conclusions: Using a training set of laser captured favorable and poor prognosis epithelial AMM, a 39-gene signature was obtained that is associated with prognosis. Validation of several of the candidate genes by qPCR expression and immunohistochemistry was performed, confirming favorable and poor prognosis strata among the epithelial AMM. Identification of poor prognosis epithelial AMM at the time of initial biopsy/tumor cytoreduction could lead to more aggressive primary therapeutic intervention. No significant financial relationships to disclose.

Pralatrexate, a new hope for aggressive T-cell lymphomas?

Aggressive T-cell lymphomas represent a particularly poor-prognosis subgroup of lymphomas. This is especially true for patients with recurrent or refractory disease who typically have a limited response to salvage therapy and an extremely poor overall survival. There is thus a strong need to develop potentially active drugs for these malignancies. Pralatrexate is a novel antifolate designed to have high affinity for the reduced folate carrier type 1. Preclinical and clinical studies have demonstrated that pralatrexate has significant activity against T-cell lymphomas.The dose-limiting toxicity for pralatrexate is mucositis,which could be abrogated with folic acid and vitamin B12 supplementation. Pralatrexate is now being evaluated in phase II clinical trials for the treatment of peripheral T-cell lymphoma, and in a phase I/II trial in combination with gemcitabine for the treatment of non-Hodgkin's lymphoma. Because of the limited therapies available for aggressive T-cell lymphoma, pralatrexate could secure a niche for the treatment of this condition, provided on going clinical trials and future phase III trials confirm the efficacy of the drug.

Prediction of high-risk patients by genome-wide copy number alterations from remaining cancer after neoadjuvant chemotherapy and surgery

In breast cancer, changes of gene copy number were analyzed by cDNA microarray-based comparative genome hybridization using post-treatment archived tissues. Genomic DNA was extracted from 45 surgical specimens after chemotherapy. Informative genes were selected by t-test and were statistically validated by prediction analysis using support vector machine in R package. Fluorescence in situ hybridization and quantitative PCR were performed for validation. We developed three clinical models: comparing good vs. poor prognosis (I), comparing good vs. poor prognosis among poor responders (II) and among good responders (III). 158 gene set (I) differentiated high and low risk of relapse group with 92% accuracy. 51 gene set (II) differentiated good and poor prognosis subgroups among poor responders with 99.9% accuracy. 32 gene set (III) differentiated good and poor prognosis subgroups among good responders with 96% accuracy. This approach has potential applications in the identification of high risk of recurrence after neoadjuvant chemotherapy and surgery.

MicroRNA-29c and 223 Are Powerful Prognostic Factors for Chronic Lymphocytic Leukemia and Improve Risk Stratification When Combined with ZAP70 and LPL in a qPCR Score.

Background: MicroRNAs (or miR) are a novel class of small noncoding RNA involved in gene regulation. Aberrant microRNA expression has been recently associated with chronic lymphocytic leukemia (CLL) outcome. Currently, the heterogeneous evolution of this disease can be predicted by several prognostic factors. Nevertheless, a better individualization of the outcome in a given patient is still of utmost interest.Methods: In the current study, we investigated the expression of two microRNAs, miR-29c and miR-223, compared them to other biological or clinical markers and proposed a quantitative real-time PCR (qPCR) score to better assess CLL outcome. All cut-offs were calculated by ROC curve analysis maximising the correlation with the immunoglobulin variable heavy chain (IgVH) mutational status; statistical differences were evaluated by Mann Whitney test or Kruskal-Wallis test ; treatment-free (TFS) and overall (OS) survival differences were investigated by log-rank test or Cox proportional hazard ratio (HR).Results: miR-29c and miR-223 expression decreased significantly with progression along Binet Stage A to C (P=0.0010 and P=0.0183, respectively), and were significantly lower in poor prognosis subgroups defined by cytogenetic abnormalities, IgVH mutational status, lymphocyte doubling time, solubleCD23, β2-microglobulin, ζ-associated protein 70 (ZAP70), lipoprotein lipase (LPL) and CD38 expression. Furthermore, miR-29c and miR-223 could predict TFS (n=110, P=0.0015 and P<0.0001, respectively) and OS (n=110, P=0.0234 and P=0.0008, respectively). Regarding all these results, we developed a qPCR score (from 0 to 4 poor prognostic markers) combining miR-29c, miR-223, ZAP70 and LPL in order to stratify treatment and death risk in a 110 patient cohort with a median follow-up of 72 months (range, 2–312). Patients with a score of 0/4, 1/4, 2/4, 3/4, and 4/4 had a median TFS of >312, 129, 80, 36 and 19 months, respectively (HR=17.00, P<0.0001). Patient with a score of 0–1/4, 2–3/4 and 4/4 had a median OS of >312, 183 and 106 months, respectively (HR=13.69, P=0.0001). Interestingly, during the first 50 months after diagnosis, only 10% of patients with a 0/4 score required a treatment, when compared to 100% of the 4/4. Furthermore, during the total follow-up (312 months), patients with a 4/4 score had a 27-fold higher risk to be treated and a 31-fold higher risk to die comparing to patients with a 0/4 score. This score was validated by a 10-fold cross-validation (prediction accuracy of 82%). Finally, in Binet stage A patients (n=77), this score remained relevant and significant for TFS and OS prediction (HR=18.56, P<0.0001 and HR=12.5, P=0.0068, respectively).Conclusions: we showed that (i) miR-29c and miR-223 levels were decreased in poor prognosis patients regarding several well-known prognostic factors; (ii) a low level of these two microRNAs is thus associated to disease aggressiveness, tumor burden and poor clinical evolution; (iii) we also showed that these two microRNAs could predict TFS and OS; (iv) we proposed a qPCR score to better individualize evolution of a particular CLL patient. This score will help to identify patients who will need early therapy and require thus a closer follow-up.

Analysis of response to neoadjuvant chemotherapy (NCT) with doxorubicin plus cyclophosphamide followed by paclitaxel (AC- T) in triple negative locally advanced breast cancer (LABC) in Brazil

11551 Background: Breast cancer is the commonest and most lethal female cancer in Brazil. Barretos Cancer Hospital is a reference center for cancer prevention and treatment. In 2006, stage III represented 31% of our patients (pts). Combination of highly effective drugs as anthracyclines and taxanes can improve complete response rates, a known marker for better survival. As triple negative LABC is a poor prognosis subtype, this combination could improve treatment benefits. Methods: We reviewed all charts of pts with stage III breast carcinoma, confirmed by biopsy with ER/PR negative and c-erbB2 IHC-score 0 or +/3+, who performed NCT with ACx4 (doxorubicin 60mg/m2 + cyclophosphamide 600mg/m2 q3w) followed by Tx4 (paclitaxel 175mg/m2 q3w) between Jan/2006 and Jan/2007. Primary endpoint: complete pathologic response rate (pCR), defined by absence of invasive carcinoma in both surgical specimen and axillary lymph nodes. Secondary endpoints: complete clinical response (cCR) and partial response (PR) rates, conservative surgery rate, compliance and toxicity. This study was approved by our institutional ethics committee. Results: 24 pts were included, median age: 53y [35–67], median follow-up: 15m [8,9–22,5]. Stages were IIIA-14pts (58,3%), IIIB-9pts (37,5%), and IIIC-1pt (4,2%). Median tumor size (MTS): 60mm [25–130], 20 pts (83,3%) had tumor >50mm. Response rates were pCR-5pts (20%), cCR-8pts (33%), PR-12pts (50%). Stable disease and progression of disease during NCT occurred in 2pts (8,5%) each. MTS reduced to 13mm (3–95). 5 pts (20%) were submitted to conservative surgery. There was no death or grade 4 toxicity. All pts received at least 8 cycles of NCT, but 7pts (30%) had reducing dose, due to toxicity. Grade 3 adverse events included: thrombocytopenia-3pts, neutropenia-1pt, peripheral neuropathy-2pts, anemia-1pt. Conclusions: AC-T is a good option to NCT in this specific poor prognosis subgroup with large tumors and triple negative LABC, with acceptable toxicity, and pCR comparable to the literature. Considering its lower costs it could be a reasonable choice for developing nations. Prospective studies and longer follow-up are needed to confirm this preliminary data. No significant financial relationships to disclose.

Lack of Survival Improvement in Patients with Large Cell Lymphomas of T-Cell Phenotype: A SEER Analysis Comparing Outcomes According to Phenotype and Year of Diagnosis.

Background: The majority of studies suggest that among patients with aggressive non-Hodgkin lymphomas (NHL), T-cell phenotype (TCP) confers a poor prognosis. The worse outcomes in TCP may have become more accentuated since the introduction of rituximab, which has been associated with improved survival in patients with diffuse large B-cell lymphoma (DLBCL). The purpose of our study was to evaluate changes in NHL-survival (NHLS) according to immunophenotype and diagnostic era in a large sample of tumor registry cases.Methods: We analyzed SEER-reported cases aged 19 or older, diagnosed with NHL during the period from 1992 to 2003, and with available information on covariates including gender, race, site of disease, and stage at presentation. Lymphomas with ICD-0-3 codes 9675, 9680, or 684 and B-cell immunophenotype were classified as DLBCL, while TCP cases were identified by codes 9675, 9680, 9684, or 9702 and T-cell immunophenotype. NHLS was analyzed separately for cases diagnosed in 1992–1997 (era 1), and 1998–2003 (era 2), using SAS v9.1. We report 5-year Kaplan-Meier estimates and log rank comparisons, by cell type and era, adjusted for age and SEER summary stage. Since SEER data does not include IPI, we also analyzed two subgroups: patients under age 60 with Ann Arbor stage I/II disease (very good prognosis), and patients with age 60 and older with stage IV (poor prognosis).Results: Based on 7,359 study cases (6,526 DLBCL; 833 TCP) from era 1 and 18,099 (16,858 DLBCL; 1,241 TCP) from era 2, NHLS was significantly better in patients with B-cell v T-cell phenotype (p<0.001 both eras). Five-year rates were 54.4% v 42.9% in era 1, and 61.3% v 42.2% in era 2. Improvement for DLBCL in era 2 compared with era 1 was also significant (p<0.001), while there was no change for TCP (p=0.708). For the subgroup with very good prognosis, outcomes were comparable for DLBCL and TCP in era 1 but significantly different in era 2 (p=0.531 and p<0.001). The outcome for DLBCL patients with good prognosis improved over time (p<0.001) whereas similar benefit was not seen in TCP patients (p=0.273). Five-year NHLS rates were 75.2% v 73.8% in era 1, and 84.7% v 66.6% in era 2. In the poor prognosis subgroup, TCP was associated with worse outcome in both eras (p=0.011 and p=0.001). For these patient population, improvement in NHLS over time was not statistically significant for either DLBCL (p=0.076) or TCP (p=0.858). Five-year rates for DLBCL versus TCP were 30.6% v 22.2% in era 1, and 35.5% v 25.3% in era 2.Conclusions: The survival difference between DLBCL and TCP increased significantly after 1997 and is most likely attributable to widespread use of rituximab for B-cell lymphomas during the period 1998–2003. In DLBCL, the improved outcome was seen mainly in patients with good prognosis. In contrast, there were no significant advances in the treatment of T-cell lymphomas. Novel therapies are urgently needed in patients with TCP.

GLI1 Transcription Factor: A Potential Therapeutic Target in B-CLL.

B-cell Chronic Lymphocytic Leukemia (B-CLL) is characterized by accumulation of clonal lymphocytes resistant to apoptosis. Therefore, identification of molecules responsible for the increased resistance to apoptosis is warranted. The identified molecules could be further targeted to develop effective therapy. Emerging evidence on the mechanism of resistant to apoptosis in several cancers suggests that GLI1 transcription factor, target of hedgehog signaling, may have a potential role in the increased resistance to apoptosis in B-CLL. However such studies have not been reported for B-CLL. Therefore, we investigated the role of sonic hedgehog (Shh)-GLI signaling in the pathogenesis B-CLL using 38 different patient samples and different parameters. The results were analyzed based on good and poor clinical outcome B-CLL subgroups identified on the basis of cytogenetic abnormality and/or CD38 expression levels. Microarray and RT-PCR analyses demonstrated active Shh-GLI signaling molecules in B-CLL cells including GLI1. Our results demonstrate that GLI1 transcripts were significantly (p = 0.003) over-expressed in B-CLL cells of poor clinical outcome patient subgroups (17pdel, 11qdel, trisomy12; N = 20) compared to good clinical outcome (13qdel, normal karyotype; N = 18) as observed in microarray analysis and confirmation by real time PCR. In addition, similar observation was also made with poor prognosis (high CD38 expression) versus good prognosis (low CD38 expression) B-CLL subgroups. Furthermore, higher expression of GLI1 was associated with significantly (p = 0.02) shorter time to treatment compared to lower GLI1 expressing B-CLL patients as determined by Kaplan-Meier survival analysis using log rank test, suggesting the increased expression of GLI1 and its association with the disease progression in poor clinical outcome B-CLL patient sub-groups. Addition of exogenous Shh on the significantly (p<0.01) increased cell survival and up-regulation of GLI1 transcripts, and decreased cell survival and downregulation of GLI1 transcripts in the presence of cyclopamine, known inhibitor of signaling, as determined by MTT assay and RT-PCR in vitro, suggesting the role of GLI1 in the survival of B-CLL. Downregulation of GLI1 expression in B-CLL cells using antisense oligonucleotides resulted in the significantly (p<0.01) increased susceptibility of the B-CLL cells to fludarabine mediated cytotoxicity compare to fludarabine alone or antisense alone or B-CLL cells treated with irrelevant oligonucleotides as determined by MTT assay and Annexin V method for identifying apoptotic cells. There was a significant decrease in BCL2 expression in GLI1-downregulated B-CLL cells suggesting that GLI1 may regulates BCL2 and thereby regulate cell survival/apoptosis in B-CLL. Together, these results demonstrate a role for GLI1 transcription factor for the increased resistance to apoptosis and thereby disease progression in B-CLL, and hence may be a potential therapeutic target to further improve treatment for B-CLL.

Thilliampalam Paramananthan

Three cases of congenital cranial hemihypertrophy are described. CT or ultrasound scans showed unilateral cerebral enlargement with dilatation of the ipsilateral ventricle. Seizures occurred in two patients and the neurodevelopmental...

Number and Size of Lymph Nodes Recovered From Dukes B Rectal Cancers: Correlation with Prognosis and Histologic Antitumor Immune Response

In rectal cancer variation in lymph node recovery influences the detection of nodal metastases and prognosis among Dukes B (Stage II) cases. However, the possible prognostic importance of node size and inherent patient/tumor characteristics in determining node recovery has not been studied. We examined 269 Dukes B (Stage II) rectal tumors, with a mean of 12 nodes per case. Primary tumor characteristics were correlated with the number and size of recovered nodes. Clinical follow-up permitted determination of long-term survival. The five-year survival of 94 Dukes B cases with nine or fewer nodes was 69.4 percent vs. 87.6 percent in 175 cases with ten or more nodes (P = 0.001). Lymph nodes were smaller in patients dying of recurrence; among 130 Dukes B patients whose mean node diameter was <4 mm, survival was 73.3 vs. 88 percent when mean nodal diameter was > or =4 mm. The number and size of recovered nodes was related to patient age, histologic antitumor immune response, and tumor growth pattern. By combining the number and size of nodes, a poor prognosis subgroup of 98 Dukes B patients with relatively few large nodes (no more than 5 measuring > or =4 mm) was identified with a five-year survival of 65.6 percent compared with 89.6 percent for the remaining 158 Dukes B cases (P < 0.0001). In Dukes B rectal tumors, the number and size of lymph nodes are related to inherent patient and tumor characteristics and permit the identification of Dukes B cases at increased risk of recurrence. A valid comparison of nodal sampling efficiency between centers necessitates measuring and counting harvested lymph nodes.

Prognostic significance of cytogenetically detected chromosome 21 anomalies in childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study

Chromosome anomalies have been shown to have prognostic significance in children with acute lymphoblastic leukemia (ALL). Chromosome 21 was evaluated for its ability to predict outcome when found in either a single copy (the Mono21 group) or when involved in a structural aberration (the Misc21 group). Both anomalies were associated with an increased risk of failure for patients with standard-risk ALL, rather than higher-risk ALL. Event-free survival was 50.0% at 5 years and 48.4% at 8 years for standard-risk patients with Mono21+Misc21, compared with 77.8 and 75.5%, respectively, for standard-risk patients without these anomalies of chromosome 21. There was no significant difference in outcome between the Mono21 and the Misc21 group ( P = 0.10). Mono21 and Misc21 were determined to be independently prognostic whether or not the primary leukemic clone had fewer than 45 chromosomes. The frequency of an adverse outcome was comparable to other poor prognosis subgroups such as hypodiploidy (<45 chromosomes), t(9;22), or t(4;11), all of which have been targeted for aggressive therapy even if the case is otherwise standard risk.

Gene Expression Signatures Separate B-Cell Chronic Lymphocytic Leukemia Prognostic Subgroups Defined by ZAP-70 and CD38 Expression Status.

B-cell chronic lymphocytic leukemia (B-CLL) is a heterogenous disease with a highly variable clinical course and analysis of ZAP-70 and CD38 expression on B-CLL cells allowed for identification of patients with good (ZAP-70−CD38−) and poor (ZAP-70+CD38+) prognosis. DNA microarray technology was employed to compare eight ZAP-70+CD38+ with eight ZAP-70−CD38− B-CLL cases. The expression of 358 genes differed significantly between the two subgroups including genes involved in B cell receptor signaling, angiogenesis and lymphomagenesis. Three of these genes, i.e. IRTA4/FcRH2, angiopoietin 2 and Pim2 were selected for further validating studies in a cohort of 94 B-CLL patients. IRTA4/FcRH2 expression as detected by flow cytometry was significantly lower in the poor prognosis subgroup as compared to ZAP-70−CD38− B-CLL cells. In healthy individuals IRTA4/FcRH2 protein expression was associated with a CD19+CD27+ memory cell phenotype. Angiopoietin 2 plasma concentrations were two-fold higher in the poor prognosis subgroup (p<0.05). Pim2 was significantly overexpressed in poor prognosis cases and Binet stage C. Disease progression may be related to proangiogenic processes and strong Pim2 expression.

Pralatrexate: an emerging new agent with activity in T-cell lymphomas

T-cell lymphomas (TCL) represent a particularly poor prognosis subgroup of lymphomas. The goal of this review is to provide emerging information on one agent demonstrating activity in these challenging diseases. Pralatrexate is a novel antifolate designed to have high affinity for the reduced folate carrier type 1 (RFC-1). Preclinical and clinical studies have demonstrated that pralatrexate has significant activity against TCL. The high affinity of pralatrexate for RFC-1 significantly improves its internalization into cells. Preclinical studies in models of B-cell lymphomas and TCL have demonstrated that pralatrexate demonstrates activity superior to traditional antifolates. Phase I studies have shown the dose-limiting toxicity to be stomatitis, which can be abrogated with folic acid and vitamin B12 supplementation. Early phase studies have shown marked activity across a diverse panoply of TCL. Pralatrexate is an antifolate designed to be internalized more rapidly than other traditional antifolates. Preclinical studies have demonstrated its superiority to methotrexate, and early phase I and II studies have shown marked activity across many poor-risk subtypes of TCL. Future studies are directed towards understanding the pharmacokinetic features of the drug, and expanding the population of patients with TCL and B-cell lymphomas.