Poor Event-free Survival Research Articles

Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3).

Infants with acute lymphoblastic leukemia (ALL) present with aggressive disease and a poor prognosis. Early relapse within 6-9 months of diagnosis is common. Approximately 75% of infants have MLL-rearranged (MLL-R) ALL with event free survival (EFS) ranging from 20% to 30%. Children's Oncology Group (COG) P9407 used shortened (46 weeks), intensified therapy to address early relapse and poor EFS. P9407 therapy was modified three times for induction toxicity resulting in three cohorts of therapy. One hundred forty-seven infants were enrolled in the third cohort. We report an overall 5-year EFS and OS of 42.3 ± 6% and 52.9 ± 6.5% respectively. Poor prognostic factors included age ≤90 days at diagnosis, MLL-R ALL and white cell count ≥50,000/μl. For infants ≤90 days of age, the 5-year EFS was 15.5 ± 10.1% and 48.5 ± 6.7% for those >90 days (P < 0.0001). Among infants >90 days of age, 5-year EFS rates were 43.8 ± 8% for MLL-R versus 69.1 ± 13.6% for MLL-germline ALL (P < 0.0001). Age ≤90 days at diagnosis was the most important prognostic factor. Despite shortened therapy with early intensification, EFS remained less than 50% overall in MLL-R ALL.

24hr Ambulatory Blood Pressure Monitoring (ABPM) Risk Stratifies Hypertensive Kidney Transplant Recipients (KTRs).

Background and Methods: Systolic hypertension has been shown to be associated with adverse clinical outcomes after renal transplantation. In non-transplant patients, 24hr ambulatory blood pressure monitoring (ABPM) has been shown to be a superior predictor of clinical outcomes when compared to clinical blood pressure readings alone. In this study we have prospectively analysed129 kidney transplant recipients (KTR) diagnosed with hypertension based on the clinic blood pressure (CBP) of >130/80mm Hg. All these patients underwent ABPM and groups were stratified based on ABPM systolic (>/<130mm Hg) and diastolic blood pressure (</>80mm Hg) values (SBP & DBP). The primary outcome measure was a composite of graft loss, cardiovascular event or death over a 5year follow-up. Results: Of the 129 KTRs, only 64 had average 24hr SBP>130 mm Hg on ABPM. Overall, CBP significantly overestimated SBP even in the true hypertensive KTRs based on ABPM (CBP, 164± 16 mm Hg, ABPM, 143± 9 mm Hg, P<0.0001). Based on the ABPM readings, 33% of hypertensive KTRs required an increase in their anti-hypertensive therapy (P=0.01). Day time (P=0.002) and 24hr average SBP (P<0.001) were strongly associated with the composite end point in a univariate Kaplan Meier analysis. Whilst the 24hr average DBP (P=0.03) was significantly associated with poor event free survival, nocturnal dipper status was not significant. The influence of 24hr average SBP on event free survival was more significant in KTRs with diabetes (P=0.02), lower eGFR (P=0.001), proteinuria (P=0.007), who are younger (P=0.02) and female (P=0.01). Similar non-significant trends were seen with DBP as well. Despite a significant improvement in CBP in both the groups over 5 years, eGFR and proteinuria remained significantly worse in the true hypertensive group based on the assessment of ABPM during this period.Figure: No Caption available.Conclusions: To conclude, 24hr ABPM helps to risk stratify apparent hypertensive KTRs based on CBP. True hypertensives based on ABPM represent a significantly high risk population with adverse medium term outcomes despite appropriate therapy.

Inflammatory myofibroblastic tumors of the nasal cavity and paranasal sinus: a clinicopathologic study of 25 cases and review of the literature

Inflammatory myofibroblastic tumor (IMT) is rare in nasal cavity and paranasal sinus. The aim of this study was to describe the clinicopathological features of sinonasal IMT and analyze the relationship between the clinicopathological features and the prognosis. A retrospective study of 25 IMT patients between 2001 and 2012 was performed. Data on clinical features, treatment, and follow-up were recorded. The histological characters were observed. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan-Meier method. Clinically, the most common symptoms were nasal obstruction, facial pain, and toothache. Twenty patients received follow-ups 6-120months after initial diagnosis. Fifteen (75%) developed recurrence 1 or more times. One patient had left cervical lymph node metastasis (5%). Five patients died of the tumor (25%). Histologically, the IMTs composed of bland spindle cells admixed with a prominent infiltrate of plasma cells and lymphocytes and showed obvious atypia in recurrent cases. Histology with necrosis, mitosis (≥1/10 HPF), ganglion-like cells, histological pattern I or II and relapse (≥4 times) was significantly associated with poor OS and EFS. IMT of the nasal cavity and paranasal sinuses exhibits relatively bland histologic appearances, but can shows strongly aggressive behavior and relatively poor outcomes. Multiple relapse, necrosis, frequent mitosis, the presence of ganglion-like cells, and histological pattern might be associated with poor clinical outcomes.

Low lymphocyte-to-monocyte ratio predicts unfavorable prognosis in non-germinal center type diffuse large B-cell lymphoma

The peripheral blood lymphocyte to monocyte ratio (LMR) at diagnosis has been used to predict survival in diffuse large B-cell lymphoma (DLBCL) patients, but its prognostic significance with respect to different cell-of-origin (COO) subtypes remains unknown. We retrospectively analyzed 168 de novo DLBCL patients in this study and found that a low LMR (≤2.6) correlates with B symptoms, elevated LDH, advanced Ann Arbor stage and higher international prognostic index (IPI) score (p<0.05). The low LMR is a negative prognostic parameter for overall survival (OS) and event-free survival (EFS) in non-germinal center (GC) type DLBCL patients, as compared with the high LMR, especially in those treated with R-CHOP. However, the LMR has less correlation with the OS and EFS in GC type DLBCL patients (p=0.545 and 0.547, respectively). Multivariate analysis adjusting for IPI revealed that the low LMR indicates a shorter survival retain both OS and EFS in non-GC subtypes (p=0.023 and 0.005, respectively). In the non-GC DLBCL patients treated with R-CHOP a low LMR still showed a trend to predict poor EFS (p=0.052). In conclusion, these data suggest that a low LMR at diagnosis may imply a poor prognosis in non-GC subtype DLBCL patients, especially in those treated with R-CHOP, but not in those GC subtype DLBCL patients.

The risk of traumatic lumbar punctures in children with acute lymphoblastic leukaemia

BackgroundTraumatic lumbar punctures with blasts (TLP+) in children with acute lymphoblastic leukaemia (ALL) obscure central nervous system status and are associated with a poorer event-free survival (EFS). MethodsWe conducted a retrospective cohort study of all lumbar punctures (LPs) for children with ALL diagnosed at our institution from 2005 to 2009. We utilised random-effects and fixed-effects repeated-measures logistic regression analyses to identify risk factors for TLPs. Fixed-effects models use each patient as his or her own control. We used survival analysis to describe outcomes after a TLP+. Results264 children underwent 5267 evaluable lumbar punctures (LPs), of which 944 (17.9%) were traumatic. In the multivariable random-effects model, variables significantly associated with TLPs were age <1year (odds ratio (OR) 3.46, 95% confidence interval (CI) 2.06–5.81) or age ⩾10years (OR 2.00, CI 1.66–2.40); body mass index percentile ⩾95 (OR 1.44, CI 1.19–1.75); platelet count <100×103/μL (OR 1.49, CI 1.08–20.7); fewer days since previous LP (OR 5.13, CI 2.34–11.25 for ⩾16days versus 0–3days); and a preceding TLP (OR 1.43, CI 1.19–1.73). In the fixed-effects model, image-guidance reduced the odds of TLP (OR 0.55, CI 0.32–0.95). The 5-year EFS (±SE) for children with TLP+ (77±8%) was significantly lower than for children with CNS1 status (93±2%; p=0.002). ConclusionsThe frequency of TLP remains high. Consistent with previous studies, a TLP+ at diagnosis was associated with a poorer EFS. These risk factors can allow identifying interventions to reduce TLPs and directing interventions to those at highest risk.

MYC and BCL2 protein expression predicts survival in patients with diffuse large B‐cell lymphoma treated with rituximab

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease and "double-hit" DLBCL, with both MYC and BCL2 translocations has a poor prognosis. In this study, we investigated whether MYC and BCL2 protein expression in tissue would predict survival in DLBCL. The study included 106 cases of de novo DLBCL treated with rituximab and cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or CHOP-like regimens. The results were validated on an independent cohort of 205 DLBCL patients. Patients with low expression of BCL2 (≤30%) and MYC (≤50%) had the best prognosis, whereas those with high BCL2 (>30%) and MYC (>50%) had the worst outcome. In multivariate analysis, the combination of the BCL2 and MYC was an independent predictor of overall survival (OS) and event-free survival (EFS) (P = 0·015 and P = 0·005, respectively). The risk of death was nine times greater for patients with high BCL2 and MYC compared to those with low expression. High BCL2 and MYC was a strong predictor of poor OS (P < 0·001) and EFS (P = 0·0017) in patients with the germinal centre B-cell (GCB) type, but not in the non-GCB type. In DLBCL, high co-expression of MYC and BCL2 was an independent predictor of poor survival, and could be used to stratify patients for risk-adapted therapies.

Impact of Myocardial Viability and Left Ventricular Lead Location on Clinical Outcome in Cardiac Resynchronization Therapy Recipients with Ischemic Cardiomyopathy

Cardiac resynchronization therapy (CRT) recipients with ischemic cardiomyopathy (ICM) have scar segments that may limit ventricular resynchronization and clinical response. The impact of myocardial viability at the left ventricular (LV) pacing site on CRT response is poorly elucidated. A retrospective cohort of 160 ICM patients with single photon emission computed tomography-myocardial perfusion imaging before device implantation were included. Coronary venous angiography and chest radiographs helped classify segmental location of LV lead (LVL). The primary outcome was a composite of heart failure (HF) hospitalization and mortality at 3 years, and secondary outcome was change in systolic function at 6 months. The patients were divided into groups based on the myocardial substrate at the site of LVL: LVL on or adjacent to (1) normal myocardium (LVL-N, n = 64), (2) segmental scar (LVL-S, n = 62), and (3) scar and ischemia (LVL-SI, n = 34). Upon follow-up, 75 (47%) patients reached primary endpoint with a higher incidence noted in LVL-S (60%), and LVL-SI (53%), compared to 31% in LVL-N (P = 0.004). Kaplan Meier method demonstrated poor event free survival for primary outcome in LVL-S (P = 0.002), and LVL-SI (P = 0.03). In Cox proportional hazard model, LVL-S (HR: 2.26, P = 0.004), and LVL-SI (1.9, P = 0.047) were independent predictors of primary outcome. In CRT recipients with ICM, scar and reversible ischemia in or adjacent to LV pacing site were independent predictors of HF hospitalization and death.

Prognostic Significance of Pretreatment Serum Cytokines in Classical Hodgkin Lymphoma

Although the International Prognostic Score (IPS) is the gold standard for risk-stratifying patients with classical Hodgkin lymphoma (cHL), these criteria do not accurately predict outcome. As cytokines are critically involved in driving cHL, we tested whether pretreatment serum cytokine levels could provide additional prognostic information. Thirty cytokines were measured in pretreatment serum from 140 patients with cHL and compared with 50 nonlymphoma controls. Patients were followed for event-free survival (EFS) and overall survival (OS), and Cox proportional hazards regression models were used to assess the association of individual cytokines and the cytokine profiles with outcome via unadjusted and IPS-adjusted HR. Twelve cytokines (EGF, bFGF, G-CSF, HGF, IL-6, IL-8, IL-12, IL-2R, IP-10, MIG, TNF-α, and VEGF) were significantly (P < 0.05) higher in patients with cHL than controls; elevated levels of HGF, IL-6, IL-2R, IP-10, and MIG were all associated with poorer EFS. Only interleukin-2 receptor (IL-2R; P = 0.002) and interleukin (IL)-6 (P < 0.001) were independently prognostic. Patients with increased IL-6 and IL-2R had a significantly higher risk of early relapse and death, a finding that remained significant even after IPS-based risk stratification. Although elevated IL-6 and IL-2R correlated with the IPS, soluble CD30 (sCD30), and thymus and activation-related chemokine (TARC) levels, the two-cytokine model remained independently predictive of prognosis. Elevated pretreatment serum cytokines are associated with increased disease relapse and inferior survival in cHL. Thus, the pretreatment cytokine profile, particularly serum levels of IL-6 and IL-2R, may be used to identify patients with cHL at high risk for early-disease relapse.

Prognostic value of volumetric parameters measured by 18F-FDG PET/CT in patients with head and neck squamous cell carcinoma

The objective of this study was to investigate the value of metabolic tumour volume (MTV) assessed with (18)F-FDG PET/CT in predicting event-free survival (EFS) and overall survival (OS) in patients with head and neck squamous cell carcinoma (HNSCC), and particularly to compare it with more conventional parameters such as maximum standardized uptake value (SUVmax). Patients referred to our department for (18)F-FDG PET/CT for staging of HNSCC were prospectively included between February 2009 and March 2011. Each patient was scanned using a Philips Gemini PET/CT system at 1 h after injection. The MTV was calculated semiautomatically for the primary site using methods based on SUV with various thresholds: 3-D contour around voxels equal to or greater than 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5 and 7.0 times SUV, or more than 30%, 40% and 50% of SUVmax. ROC analysis was used to test the statistical significance of the differences among the calculated MTVs. EFS and OS were determined using the Kaplan-Meier method and compared with MTV in univariate and multivariate analyses, including the usual prognostic factors: age, sex, primary site, treatment, SCC histologic grade, AJCC stage, TNM classification, tumour SUVmax and SUVpeak. The study included 80 consecutive patients (70 men, 10 women; mean age 62.4 ± 9.0 years). ROC analysis revealed that pretreatment MTV using a threshold of 5.0 times SUV (MTV5.0) was the best parameter to predict recurrence and death after treatment. In univariate analysis, MTV5.0 >4.9 ml was predictive of poor EFS (p < 0.0001) and poor OS (p < 0.0001). In multivariate, MTV5.0 persisted as an independent predictive factor for EFS (p = 0.011) and OS (p = 0.010), while SUVmax became nonsignificant (p = 0.277 for EFS, p = 0.975 for OS). Our results suggest that MTV measured by (18)F-FDG PET/CT has independent prognostic value of in patients with HNSCC, stronger than SUVmax.

CD34 expression predicts an adverse outcome in patients with NPM1-positive acute myeloid leukemia

Patients with acute myeloid leukemia (AML) harboring an NPM1 mutation exhibit a heterogeneous clinical outcome. Recent studies have shown that the absence of FLT3 internal tandem duplication (FLT3-ITD) mutation confers a favorable prognosis in NPM1-positive AML. However, the prognostic impact of immunophenotypes in this subgroup remains unclear. In this study, FLT3 mutation status and immunophenotypic profile of 85 NPM1-positive patients with de novo AML were retrospectively analyzed and correlated with their clinical features and survival outcomes. Univariate analysis detected 5 markers with prognostic relevance: older age (≥60 years), high white blood cell (WBC) count (>30 × 10(9)/L), FLT3-ITD, CD7, and CD34 expression. Multivariate analysis showed that high WBC count was the only independent predictor of a lower complete remission rate (P = .019). Older age (P = .035), high WBC count (P = .008), FLT3-ITD (P = .012), and CD34 expression (P = .006) were independent predictors of a shorter event-free survival (EFS). High WBC count (P = .014), FLT3-ITD (P = .005), and CD34 expression (P = .047) were independent predictors of a shorter overall survival (OS). Furthermore, based on FLT3-ITD status in NPM1 mutation-positive patients, we showed that both high WBC and CD34 expression conferred a poor EFS (P = .010 and P = .016, respectively) and OS (P = .032 and P = .001, respectively) in the FLT3-ITD-negative group, whereas high WBC predicted a poor EFS (P = .016) and OS (P = .027) in the FLT3-ITD-positive group. Our results confirm the prognostic value of assessing FLT3-ITD mutations in NPM1-positive AML and identify the adverse prognostic impact of high WBC and CD34 expression in this subgroup of AML.

Superior vena cava syndrome and poor performance status at presentation affect survival in mediastinal T-lymphoblastic lymphoma—a single institute experience from India

Analysis of mediastinal T-lymphoblastic lymphomas (T-LBL) with T-acute lymphoblastic leukemia has precluded identification of prognostic factors. Newly diagnosed T-LBL patients presenting with mediastinal mass and <20% bone marrow involvement were analyzed for clinical features and outcome. In 55 patients with median age 18 years, 39 (71%) had "B" symptoms, 46 (83.6%) had bulky mediastinal mass and two thirds of patients (n = 36) had superior vena cava syndrome/superior mediastinal syndrome (SVCS/SMS). With acute lymphoblastic leukemia (ALL)-like protocols in majority, complete remission was achieved in 58.2% patients. Estimated 5-year overall survival (OS) and event-free survival (EFS) were 59.8 and 51.6% (median follow-up-35 months). On multivariate analysis, poor Eastern Cooperative Oncology Group (ECOG) performance status (PS > 2; n = 14) affected OS (p = 0.007), while Poor ECOG PS and SVCS/SMS affected EFS (p = 0.008 and p = 0.035, respectively). Combination of baseline-poor PS and presence of SVCS/SMS predicted poor EFS in a prognostic model (HR 6.20; p = 0.002). This is the first outcome study from Asia which has been able to predict baseline ECOG PS and presence of SVCS/SMS as prognostic factors affecting EFS.

Somatic Mutations of K-Ras and BRAF in Thai Colorectal Cancer and their Prognostic Value

The study aimed to determine the incidence of K-ras and BRAF mutations in colorectal cancers (CRCs) in Thai patients and evaluate association with clinicopathological parameters including treatment outcomes in terms of event free survival (EFS). Two-hundred colorectal cancer specimens were collected for studies of K-Ras codon 12, 13 and 61, and BRAF codon 600 by polymerase chain reaction and direct nucleotide sequencing. The overall incidence of K-Ras mutations in our patients was 23%. K-ras mutation frequencies in CRC stages (AJCC) I, II, III and IV were 6.7%, 16.1%, 23.3% and 26.6%, respectively (p-value>0.05). The three most common mutation forms were G12D, G12V and G13D. K-Ras mutation status was associated with poorer EFS in stage I-III CRCs (p-value 0.03). The study found a lower mutation frequency of K-Ras and BRAF compared to reports involving other ethnic groups. However, K-Ras mutations did have a negative prognostic value in early-stage CRCs.

Prognostic implications of tumor extent in early-stage diffuse large B-cell lymphoma

Therapeutic strategies for early-stage diffuse large B-cell lymphoma (DLBCL) are often influenced by tumor extent, but the prognostic value of this parameter is rarely defined. Here, a retrospective analysis was performed to define the impact of tumor extent on survival of patients with early-stage DLBCL. Eighty-six patients with stage II DLBCL, diagnosed from 2000-2007, were categorized into localized (n = 55, 64 %) and disseminated groups (n = 31, 36 %) based on tumor extent at time of diagnosis. Treatment modalities, chemotherapy regimen and number of chemotherapy cycles were the same between groups. With a median follow-up of 7.6 years (range 2.1-12.1 years), overall 5-year event-free survival (EFS) and overall survival (OS) were 70.6 and 76.5 %, respectively. EFS (P = 1.00) and OS (P = 0.20) did not differ between the two groups. Older age (>60 years) was significantly associated with poor EFS (P = 0.01) and OS (P = 0.04). High-risk patients as rated by stage-modified international prognostic index (IPI) had inferior EFS (P = 0.04) and OS (P = 0.06) compared with the intermediate-risk group. These results indicate that tumor extent has no prognostic value in patients with early-stage DLBCL. Consistent with previous studies, age and stage-modified IPI were useful prognostic indices for these patients.

NOVEL Recurrent Genetic Aberrations in Pediatric AML: An AIEOP AML-2002 Study Group.

AbstractAbstract 2494 Introduction.Acute myeloid leukemia (AML) is an heterogeneous disease with known specific recurrent genetic aberrations. The continuous and increasing identification of new genetic mutations has permitted to identify new subgroups with different prognosis. In the present work we evaluated the incidence of rare genetic abnormalities in pediatric AML such as del(4)(q12)FIP1L1-PDGFRA, t(16;21)(p11;q22)FUS-ERG, t(8;16)(p11;p13)MOZ-CBP, t(11;17)(q23;q12–21)MLL-AF17, t(4;11)(q35;q23)MLL-ArgB2, t(5;11)(q35;p15.5)NUP98-NSD1, t(3;5)(q25;q34)NPM1-MLF1, and MLLPTD. Methods.We selected 306 patients with AML other than acute promyelocytic leukemia, negative for known recurrent genetic abnormalities involving MLL, CBF-beta and FLT3 genes. RNA was extracted from fresh bone marrow at diagnosis, and multiplex RT-PCR was employed. Sequencing by Sanger method was applied to all positive cases to characterize breakpoints of fusion. The Kaplan-Meier method was used for estimating the probability of event-free survival (EFS). Results.We identified one patient each positive for t(16;21)(p11;q22)FUS-ERG, t(11;17)(q23;q12–21)MLL-AF17, and t(4;11)(q35;q23)MLL-ArgB2, respectively, this suggesting that these rearrangements are rare in pediatric AML. 2/306 patients had del(4)(q12)FIP1L1/PDGFRA, and 4/306 the t(8;16)(p11;p13)MOZ-CBP; both these anomalies should be investigated in larger cohorts for definining their prognostic value. Interestingly 6/306 (2%) patients had the t(3;5)(q25;q34)NPM1-MLF1, 6/306 (2%) the MLLPTD, and 8/306 (2.6%) were found to carry the t(5;11)(q35;p15.5)NUP98-NSD1. Since the t(5;11) fusion was recently associated to FLT3ITD, we enlarged the screening to 42 de novo AML harbouring FLT3ITD mutation enrolled in the AIEOP-LAM 2002 protocol finding that 6 of them (14%) had the NUP98-NSD1 fusion gene. We documented a poor EFS for patients with t(5;11)NUP98-NDS1 (n=12) as compared to patients negative for molecular lesions and enrolled in the LAM 2002-AIEOP protocol (25% vs 53.1% at 3 years, p<0.01, n=154). We did not find differences in clinical or biological features of the isolated t(5;11) and t(5;11)+FLT3ITD positive patients (Table 1). We then evaluated the prognostic impact of the t(5,11) in the FLT3ITD+ cohort of AML, finding that the NUP98/NSD1 identifies a previously unrecognized subgroup of FLt3ITD patients with worse prognosis (EFS 33.3% vs 42.7 at 8y, p= 0.2). Furthermore, to analyze whether MLLPTD might also have a role in the progression to relapse, we screened 40 AML at relapse; however, we did not find the abnormality in this cohort. By contrast, 4 patients harbored at relapse the same MLLPTD found at diagnosis, suggesting the stability of this mutation. Conclusions.We provide evidence that NUP98-NSD1 may be considered a recurrent translocation in pediatric AML with poor prognosis. Being cryptic to conventional karyotyping, we confirmed the need of using molecular approaches for a proper identification of this anomaly. We also suggest that the NUP98-NSD1 fusion gene be considered for a better evaluation of the FLT3ITD+ patients. Disclosures:No relevant conflicts of interest to declare.

Elevated pretreatment serum levels of interferon‐inducible protein‐10 (CXCL10) predict disease relapse and prognosis in diffuse large B‐cell lymphoma patients

Although standard clinical prognostic factors predict outcome in diffuse large B-cell lymphoma (DLBCL), predicting the outcome of patients might be further refined using biological factors. We tested whether serum cytokines could provide prognostic information in DLBCL patients. Thirty cytokines were measured in pretreatment samples from newly diagnosed DLBCL patients using a multiplex ELISA. Sixty-nine patients treated with R-CHOP plus epratuzumab were used in an initial cohort and 185 patients treated with standard R-CHOP served as a subsequent validation cohort. In the initial cohort, elevated serum interleukin-10 [IL-10; hazard ratio (HR) = 6.6, P = 0.022], granulocyte macrophage colony-stimulating factor (HR = 10.8, P= 0.027) and IP-10 (interferon-inducible protein-10, CXCL10; HR = 3.32, P = 0.015) were associated with event-free survival (EFS). An identical analysis of the subsequent validation cohort confirmed that elevated serum levels of IP-10 were strongly associated with a poor EFS (HR = 2.42, P = 0.0007); and also identified interleukin-8 (IL-8; HR = 3.40, P = 0.00002) and interleukin-2 receptor (IL-2R, CD25; HR = 2.59, P = 0.0012) as significantly associated with prognosis. The prognostic significance of elevated IP-10 remained significant after adjustment for the International Prognostic Index (EFS - HR 1.99, P = 0.009, overall survival-HR 1.93, P = 0.021). Elevated pretreatment serum IP-10 levels are therefore associated with an increased likelihood of disease relapse and an inferior survival in patients with DLBCL.

Assessment of 285 cases of chronic lymphocytic leukemia seen at single large tertiary center in Northern India

Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the West accounting for about 30% of leukemias, but about 2–4% in India. There is no large series reported from India, and hence we decided to undertake this study. We assessed the clinicohematological profiles and treatment outcomes in 285 patients seen over 11 years at our center (median age 59 years, 209 males). Sixty-three patients (22%) were asymptomatic and diagnosed incidentally. The median total leukocyte count at presentation was 50 × 109/L. Rai stage distribution was: stage 0, 10%; stage I, 16%; stage II, 33%; stage III, 20%; and stage IV, 21%. Fifty percent of patients required treatment at presentation. Ninety-six patients received chlorambucil-based (overall response rate [ORR] 69%, complete remission [CR] 3%) and 27 patients received fludarabine-based (ORR 89%, CR 44%) chemotherapy. With a median follow-up of 2.9 years, the median overall survival (OS) and event-free survival (EFS) were 5.1 and 4.6 years, respectively. Fludarabine was more toxic, as half of the patients developed febrile neutropenia and various infections. The majority of patients presented with advanced stage disease. Fludarabine was less commonly used as first-line therapy. Advanced clinical stage (Rai III and IV) was associated with poor OS (hazard ratio [HR] 2.46, 95% confidence interval [CI] 1.19–5.11, p = 0.001) and EFS.

HIF‐1α up‐regulation is associated with adverse clinicopathological and biological factors in neuroblastomas

To study the expression of hypoxia-inducible factor 1α (HIF-1α) in clinical neuroblastoma (NB) samples and its association with the clinicopathological features, biological features and survival of NB patients. Immunohistochemistry indicated that elevated HIF-1α expression was present in 30 of 90 (33%) NBs. This expression was correlated significantly and positively with higher clinical stage (P = 0.002), ≥18 months of age at presentation (P = 0.020), high-risk group (P = 0.005), unfavourable pathology (P = 0.002), MYCN amplification (P < 0.001), 1p deletion (P = 0.004) and 17q gain (P = 0.002). Enzyme-linked immunosorbent assays showed that total HIF-1α protein was significantly higher in NBs of patients with all examined adverse prognostic factors except for age. Univariate survival analysis revealed that higher-than-median HIF-1α total protein levels were associated significantly with a decrease in event-free survival (EFS) (P = 0.017), but not in overall survival (OS) (P = 0.12). HIF-1α immunoexpression by ≥10% of tumour cells was associated significantly with decreased OS and EFS (P = 0.002 and P = 0.004, respectively), but not in multivariate analysis after adjusting for the high-risk group (P = 0.16 and P = 0.19, respectively). HIF-1α was increased significantly in patients with NB associated with unfavourable characteristics. HIF-1α is a prognostic indicator of poor OS and EFS and defines subgroups of NBs with aggressive clinical behaviour.

Predictive V16alue of Thymidylate Synthase Expression in Gastric Cancer: A Systematic Review with Meta-analysis

The relationship between thymidylate synthase (TS) expression and outcomes in gastric cancer (GC) patients remains controversial, although most studies reported poor survival and reduced response to fluoropyrimidine were related to high TS in tumors. We carried out a systematic review of the literature with meta-analysis to estimate the predictive value of TS expression from published studies. We identified 24 studies analysing the outcome data in gastric cancer stratified by TS expression. Effect measures of outcome were hazard ratios (HRs) for overall survival (OS) and event-free survival (EFS), or the odds ratio (OR) for overall response rate (ORR). HRs and ORs from these eligible studies were pooled using random-effects meta- analysis. Fifteen studies investigated outcomes in a total of 844 patients with advanced GC, and nine studies investigated outcomes in a total of 1,235 patients with localized GC undergoing adjuvant therapy. Meta- analysis of estimates showed high TS expression was significantly associated with poor OS in the advanced setting (HR: 1.43, 95%CI: 1.08 - 1.90), and poor EFS in the adjuvant setting (HR: 1.53, 95%CI: 1.01 - 2.32). Subgroup analysis demonstrated TS expression to have even greater value in predicting OS, EFS and ORR in advanced GC patients treated with fluoropyrimidine monotherapy (HR for OS: 2.32, 95%CI: 1.53 - 3.50; HR for EFS: 1.76, 95%CI: 1.19 - 2.60; OR for ORR: 0.32, 95%CI: 0.11 - 0.95). High levels of TS expression were associated with a poorer OS for advanced GC patients compared with low levels. In the adjuvant setting, high TS expression was also associated with a worse EFS. Additional studies with consistent methodology are needed to define the precise predictive value of TS.

Outcome for adolescent and young adult patients with osteosarcoma

There are conflicting data regarding age as a prognostic factor in osteosarcoma. The authors conducted a study evaluating the impact of age on prognosis in children and young adults with osteosarcoma enrolled on North American cooperative group trials. Patients with high-grade osteosarcoma of any site enrolled on North American cooperative group trials CCG-7943, POG-9754, INT-0133, and AOST0121 were included in this study. Primary tumor site, age, sex, ethnicity, histologic response, and presence of metastatic disease at diagnosis were evaluated for their impact on overall survival (OS) and event-free survival (EFS). A total of 1054 patients were eligible and had complete data available for the study. Age was not significantly associated with any other presenting covariate analyzed except sex. Age 18 or older was associated with a statistically significant poorer EFS (P = .019) and OS (P = .043). The 10-year EFS and OS in patients <10, 10 to 17, and ≥18 years old were 55%, 55%, 37% and 68%, 60%, 41%, respectively. The poorer EFS in patients ≥18 years old was because of an increased rate of relapse. Presence of metastatic disease at diagnosis, poor histologic response, and pelvic tumor site were also associated with a poorer prognosis. In multivariate analysis, age continued to be associated with poorer EFS (P = .019) and OS (P = .049). In osteosarcoma, age 18 to 30 years is associated with a statistically significant poorer outcome because of an increased rate of relapse. Poorer outcome in adolescent and young adult patients is not explained by tumor location, histologic response, or metastatic disease at presentation.

P5-14-23: Clinical Outcomes of Different Subtypes Detected by Immunohistochemistry of Early Invasive Breast Cancers in a Monoinstitutional Series.

Abstract Background Early invasive breast cancer (EIBC) is an heterogeneous disease. Immunohistochemical (IHC) markers can be used to classify tumors in different biological subtypes with different clinical behavior. Purpose: The aim of our study was to evaluate survival outcomes for patients (pts) with different subtypes of EIBC as classified using four ICH markers (ER, PR, HER2 and Ki67). Methods: We evaluated data from 3403 consecutive cases of EIBC treated from 1995 to 2008 and classified as: luminal A (positive ER and PR, negative HER2 and Ki67&amp;lt; 14%), luminal B (positive ER and/or PR, negative HER2 and Ki67&amp;gt;14%), luminal C (positive ER and/or PR, positive HER2, any Ki67), HER2+ (negative ER and PR, positive HER2, any ki67), triple negative (negative ER and PR, negative HER2, any ki67). Log-rank test and Kaplan-Meyer estimator were performed to evaluate the impact of ICH subtypes on overall survival (OS), Event Free Survival (EFS) and their correlation with other known prognostic factors such as N, G, Size, Age. Results: We identified 917 luminal A (26.9%), 1731 luminal B (50.9%), 279 (8.2%) luminal C, 183 HER2 + (5.4%) and 293 triple negative (8.6%). Median age was 61 years. Luminal A was more frequently (p&amp;lt;0.001) associated with older age, smaller size, negative axilla involvement, low grading. Observed events (relapses, contralateral and second tumors) were: 54 in luminal A (6%), 215 in luminal B (16%), 40 in luminal C (14%), 42 in HER2+ (23%) and 59 in triple negative (20%). Disease free interval (DFI) was shorter in luminal C, HER2 and TN (median DFI: 30, 26 and 19 months) than in Luminal A and B (median DFI: 51 and 41 month). Luminal A and B presented more bony and less visceral recurrences than luminal C, HER2 and triple negative tumors. At median follow up of 51 months EFS was 94.1% in luminal A, 87.5% in luminal B, 85.5% in luminal C, 76.8% in HER2+ and 79.7% in triple negative. Corresponding OS was 95.3% in luminal A, 89% in luminal B, 89.2% in luminal C, 80.9% in HER2+, 81.9% in triple negative. Different subtypes EFS according to nodal status, grading, tumor size and age, was reported in table 1. Considering only Luminal subtypes, Luminal B and C were significantly associated with poor EFS vs Luminal A EIBCs in both N0 (p=0.046) and N+ pts (p&amp;lt;0.001), in T1 (p=0.013) and T2 (p=0.03) pts, in pts older than 40 years (p=0.002). Conclusions: Luminal A showed better prognosis in term of EFS and OS than other subtypes regardless other prognostic factors as clinical features (age) and tumor extent (T and N). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-23.