Poor Prognostic Factor For Overall Survival Research Articles

Survival Outcomes and Prognostic Factors of Transcatheter Arterial Chemoembolization for Hepatic Neuroendocrine Metastases

PurposeTo report survival outcomes in patients with neuroendocrine tumor (NET) with hepatic metastasis who were treated by transcatheter arterial chemoembolization and determine prognostic factors that affect clinical outcome. Materials and MethodsPatients with NET with hepatic metastasis who underwent chemoembolization between April 2002 and July 2011 were included in this single-center, retrospective study. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan–Meier method. The influence of possible prognostic factors on survival was analyzed by log-rank method and multivariate Cox proportional-hazards method. ResultsForty-six patients with hepatic metastasis from nonpancreatic NETs (npNETs; n = 24) or pancreatic NETs (pNETs; n = 22) were included. The median PFS and OS times for the entire group were 16.2 and 38.6 months, respectively, and response rate was 58.1%. Patients with npNET had a similar PFS (17.4 mo vs 15.3 mo) and longer OS (55.0 mo vs 27.6 mo) compared with those with pNET, but there were no significant differences in PFS and OS between groups (P = .398 and P = .375, respectively). By univariate analysis, enterobiliary communication, hepatic tumor burden, and extrahepatic metastasis before the first chemoembolization were significant prognostic factors for poor OS (P = .001, P = .010, and P<.0001, respectively). By multivariate analysis, the same prognostic factors were significant and had relative risks of 4.63, 2.71, and 5.09, respectively. ConclusionsTranscatheter arterial chemoembolization is an effective treatment modality for hepatic metastasis from NETs, with a median OS of 38.6 months and response rate of 58%. Enterobiliary communication, large hepatic tumor burden, and extrahepatic metastasis were significant risk factors for poor survival outcome.

Stage IE/IIE extranodal NK/T-cell lymphoma arising in the nasal cavity: Analysis of CT findings and their prognostic value

To investigate the computed tomography (CT) findings in patients with stage IE/IIE extranodal natural killer/T-cell lymphoma (ENKTL) arising in the nasal cavity and to evaluate whether imaging findings revealed by CT have prognostic value. The CT findings of 62 patients diagnosed with IE/IIE ENKTL arising in the nasal cavity were retrospectively reviewed. Imaging findings were investigated, and evaluated imaging findings were analysed for the prognostic value of overall survival (OS) and disease-free survival (DFS). Of the 62 patients, 21 (34%) presented with a superficial infiltrative, 38 (61%) with a mass forming, and three (5%) with a combined pattern. Of all imaging findings, local invasiveness (n = 26, 42%), including bony destruction, erosion, or soft-tissue involvement, was the only independent prognostic factor for OS [p = 0.008; hazard ratio (HR): 3.85; 95% confidence intervals (CI): 1.42-10.44] and DFS (p = 0.001; HR: 4.25; 95% CI: 1.72-10.47). In a subgroup analysis of 36 cases with no local invasiveness, a superficial infiltrative pattern in one nasal cavity was a positive prognostic factor for OS (p = 0.028) and DFS (p = 0.008). Imaging findings at CT provided clinically useful predictions for treatment outcomes. Local invasiveness revealed by CT findings was a strong prognostic factor for poor OS and DFS. In addition, in patients with no local invasiveness, a superficial infiltrative pattern in one nasal cavity predicted favourable OS and DFS.

Radiotherapy and chemotherapy are associated with improved outcomes over surgery and chemotherapy in the management of limited-stage small cell esophageal carcinoma

BackgroundThis retrospective study evaluates the efficacy and safety of surgery and chemotherapy (S +CT) vs. radiotherapy and CT (RT+CT) in patients with limited stage small cell esophageal cancer (LS-SCEC). Patients and methodsPatients included in analysis (from our hospital and the literature) were treated with S+CT or RT+CT between 1989 and 2012. The primary end point was overall survival (OS); secondary end points included tumor response and toxicity. Kaplan–Meier OS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS. ResultsA total of 127 patients were included: 14 from our hospital and 113 from the literature. Fifty-four (43%) and 73 (57%) patients received S+CT or RT+CT, respectively. The median OS of all patients was 21.0months. OS was longer for those who received RT+CT rather than S+CT (33.0 vs. 17.5months, p=0.02), especially those with N1 disease. Uni- and multi-variate analyses showed tumor location (upper 1/3rd of esophagus) and type of treatment (S+CT) were poor prognostic factors of OS. ConclusionLS-SCEC patients treated with RT+CT had an improved OS compared to those treated with S+RT. Thus, RT+CT should be considered as a primary approach for these patients.

Lung parenchymal invasion in pulmonary carcinoid tumor: An important histologic feature suggesting the diagnosis of atypical carcinoid and poor prognosis

The majority of previous studies on pulmonary carcinoid tumor have usually focused on clinical behavior or outcome, seldom considering histopathologic features. We retrospectively collected 63 cases of resected pulmonary carcinoid tumors from 1995 to 2011 at Samsung Medical Center, Seoul, Korea. The clinical and pathological features were correlated and survival analyses were performed. Forty cases (63.5%) were classified as typical carcinoid (TC) and 23 cases (36.5%) were classified as atypical carcinoid (AC) according to WHO classification criteria. AC patients showed a higher frequency of current smoking status and a higher stage of the tumor by the American Joint Committee on Cancer than TC patients. The disease was associated with death and recurrence in five and seven patients, respectively, with almost all of the associations found in AC patients. The five-year survival rate of TC and AC were 100% and 83.5%, respectively, with AC showing poorer prognosis than TC in overall survival (OS) and disease free survival (DFS) (p=0.005 and p=0.002). Lung parenchymal invasion was observed more commonly in AC than in TC (39.1% vs 12.5%, p=0.01) and was a poor prognostic factor in OS and DFS. Rosette-like arrangements were found only in six cases of AC, while abundant basophilic cytoplasm mimicking paraganglioma and ossification were found only in TC. Through the comprehensive study of pulmonary carcinoid tumor in Korea, we suggest that lung parenchymal invasion could be a useful histologic feature to suspect the diagnosis of AC in daily practice as well as to predict the prognosis of carcinoid tumor.

Association of diabetes mellitus with increased mortality in patients receiving curative surgery for colon cancer.

399 Background: Diabetes mellitus (DM) is associated with increased risk of colon cancer and has potential impact on its prognosis. This study aimed to investigate the association between DM and the prognosis of patients with early colon cancer who underwent curative surgery. Methods: We established the patient cohort of the study by searching the database of the population-based Taiwan National Cancer Registry. All patients who had newly diagnosed stage I or II colon cancer from 2004 to 2007 and underwent surgical resection with uninvolved surgical margins were enrolled. Information of DM, anti-DM medication, and other comorbidities was retrieved from the database of National Health Insurance, Taiwan. Colon cancer-specific survival (CSS) and overall survival (OS) were compared between patients with and without DM. The Cox proportional hazard model was used to estimate the adjusted hazard ratio (HR) of clinicopathologic variables in multivariate analysis. Results: A total of 5,525 patients were identified; 1,009 of them (18.9%) had DM and 4,325 of them (81.1%) had no DM. Patients with DM had an older median age at diagnosis (69.9 y vs. 66.8 y, p &lt; 0.001), similar initial stage and grade, fewer adjuvant chemotherapy (26.5% vs. 31.2%, p = 0.003). Patients with DM had significantly poorer CSS and OS than patients without DM (Table). In multivariate analysis adjusting for age, gender, stage, adjuvant chemotherapy and comorbidities, DM remained an independent prognostic factor for poorer OS (adjusted HR: 1.45, p &lt; 0.001). Among patients with DM, patients who used insulin had significantly poorer CSS and OS than patients who did not (5-year CSS: 79.5% vs. 85.5%, p = 0.047; 5-year OS: 50.9% vs. 70.4%, p &lt; 0.001). Conclusions: In patients receiving curative surgery for early colon cancer, patients with DM had poorer OS than patients without DM. [Table: see text]

Autologous stem cell transplantation with busulfan, cyclophosphamide, and etoposide as an intensifying frontline treatment in patients with peripheral T cell lymphomas: a multicenter retrospective trial

The effectiveness of high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) as a frontline treatment in peripheral T cell lymphomas (PTCLs) is still unclear. We retrospectively investigated the clinical outcomes of HDT/ASCT as an intensifying frontline treatment in 31 patients with newly diagnosed PTCLs. The conditioning regimen of HDT/ASCT consisted of busulfan, cyclophosphamide, and etoposide (BuCyE). At diagnosis, five (16.1 %) patients were classified as high risk according to the prognostic index for PTCL (PIT). The disease status of the patients before HDT/ASCT consisted of 23 patients (74.2 %) with complete response (CR) and eight patients (25.8 %) with partial response (PR). Six (75 %) out of eight patients with PR at pretransplantation were improved in terms of the response to CR after HDT/ASCT. At a median follow-up of 32.4 months, the 3-year probability of overall survival (OS) and progression-free survival (PFS) was 64.5 ± 8.6 %. Transplant-related mortality occurred in three patients (9.7 %), due to septic shock, hemorrhage, and delayed pneumonia, respectively. Bone marrow involvement of PTCL at diagnosis was a poor prognostic factor for OS. In conclusion, frontline HDT/ASCT with a conditioning regimen of BuCyE may be an effective and tolerable intensifying therapeutic option to improve outcomes in patients with PTCLs.

The prognostic factors for locally advanced cervical cancer patients treated by intensity-modulated radiation therapy with concurrent chemotherapy.

To identify the prognostic factors for locally advanced cervical cancer patients treated by intensity-modulated radiotherapy (IMRT) and concurrent cisplatin-based chemotherapy. A total of 125 patients with stage IB2-III cervical carcinoma were treated with IMRT and concurrent cisplatin-based chemotherapy, plus high dose rate (HDR) brachytherapy between January 2004 and November 2010, in our institution. All patients received external irradiation of 45-54 Gy with the IMRT technique and concurrent cisplatin-based chemotherapy monthly or weekly. HDR brachytherapy of 20-30.5 Gy was prescribed to point A, as a local boost. Prognostic factors including age, histology, stage, lymph nodes metastasis, pretreatment hemoglobin level, serum squamous cell carcinoma antigen (serum SCC-Ag), chemotherapy regimens and the cumulative dose of weekly cisplatin, were analyzed. The endpoints were overall survival (OS), local failure-free survival (LFFS) and disease-free survival (DFS). The median follow-up time was 42 months. The 4-year OS, LFFS and DFS were 73.8%, 77.9% and 67.2%, respectively. Four (3.2%) patients developed ≥grade 3 acute gastrointestinal (GI) toxicity and 29 (23.2%) patients developed ≥grade 3 acute hematological toxicity. Five (4.0%) patients developed ≥grade 3 late GI toxicity and seven (5.6%) patients developed ≥grade 3 late genitourinary system toxicity. On univariate analysis, adenocarcinoma was a poor prognostic factor for OS (p = 0.05), LFFS (p = 0.01) and DFS (p = 0.006). Patients with lymph nodes metastasis at diagnosis had worse OS (p = 0.02). The high cumulative dose of cisplatin (>180 mg/m(2)) had better OS (p = 0.03) and tended to have better survival on LFFS (p = 0.13) and DFS (p = 0.10). On multivariate analysis, adenocarcinoma was a significant independent prognostic factor for OS (p = 0.001), LFFS (p = 0.005) and DFS (p < 0.001). Initial lymph nodes metastasis was an independent predictor of OS (p = 0.013). Cumulative dose of weekly cisplatin significantly affected OS (p = 0.041), and high cumulative dose of cisplatin tended to have better LFFS (p = 0.083). Higher pretreatment hemoglobin level had better LFFS (p = 0.034). Adenocarcinoma and lymph nodes metastases were poor prognostic factors for patients with locally advanced cervical cancer. Lower pretreatment hemoglobin level had poorer local control. Chemotherapy with a high cumulative dose of cisplatin tended to result in better survival.

Factors influencing hepatocellular carcinoma prognosis after hepatectomy: a single-center experience

Background/AimsRecurrence after hepatic resection is one of the most important factors impacting the prognosis and survival of patients with hepatocellular carcinoma (HCC). We identified prognostic factors affecting overall survival (OS) and disease-free survival (DFS) in patients with HCC after hepatic resection.MethodsThis study was of a retrospective cohort design, and 126 patients who underwent hepatic resection for HCC at Gachon University Gil Medical Center between January 2005 and December 2010 were enrolled. Various clinical, laboratory, and pathological data were evaluated to determine the prognostic factors affecting OS and DFS.ResultsTwo- and 4-year OS and 2- and 4-year DFS were 78.1% and 65% and 51.1% and 26.6%, respectively. In a multivariate analysis, preoperative α-fetoprotein (> 400 ng/mL), tumor size (≥ 5 cm), multiple tumors (two or more nodules), presence of portal vein invasion, modified Union for International Cancer Control (UICC) stage III/IV, and Barcelona Clinic Liver Cancer (BCLC) stage B/C were independent prognostic factors affecting a shorter OS. In the multivariate analysis, presence of microvascular invasion, modified UICC stage III/IV, and BCLC stage B/C were independent prognostic factors for a shorter DFS.ConclusionsThe presence of vascular invasion was an independent poor prognostic factor for OS and DFS in patients with HCC after hepatic resection. Thus, close postoperative surveillance for early detection of recurrence and additional treatments are urgently needed in patients with vascular invasion after hepatic resection.

Role of surgical resection for multiple hepatocellular carcinomas

To clarify the role of surgical resection for multiple hepatocellular carcinomas (HCCs) compared to transarterial chemoembolization (TACE) and liver transplantation (LT). Among the HCC patients who were managed at Yonsei University Health System between January 2003 and December 2008, 160 patients who met the following criteria were retrospectively enrolled: (1) two or three radiologically diagnosed HCCs; (2) no radiologic vascular invasion; (3) Child-Pugh class A; (4) main tumor smaller than 5 cm in diameter; and (5) platelet count greater than 50 000/mm(3). Long-term outcomes were compared among the following three treatment modalities: surgical resection or combined radiofrequency ablation (RFA) (n = 36), TACE (n = 107), and LT (n = 17). The survival curves were computed using the Kaplan-Meier method and compared with a log-rank test. To identify the patients who gained a survival benefit from surgical resection, we also investigated prognostic factors for survival following surgical resection. Multivariate analyses of the prognostic factors for survival were performed using the Cox proportional hazard model. The overall survival (OS) rate was significantly higher in the surgical resection group than in the TACE group (48.1% vs 28.9% at 5 years, P < 0.005). LT had the best OS rate, which was better than that of the surgical resection group, although the difference was not statistically significant (80.2% vs 48.1% at 5 years, P = 0.447). The disease-free survival rates were also significantly higher in the LT group than in the surgical resection group (88.2% vs 11.2% at 5 years, P < 0.001). Liver cirrhosis was the only significant prognostic factor for poor OS after surgical resection. Clinical liver cirrhosis rates were 55.6% (20/36) in the resection group and 93.5% (100/107) in the TACE group. There were 19 major and 17 minor resections. En bloc resection was performed in 23 patients, multi-site resection was performed in 5 patients, and combined resection with RFA was performed in 8 patients. In the TACE group, only 34 patients (31.8%) were recorded as having complete remission after primary TACE. Seventy-two patients (67.3%) were retreated with repeated TACE combined with other therapies. In patients who underwent surgical resection, the 16 patients who did not have cirrhosis had higher 5-year OS and disease-free survival rates than the 20 patients who had cirrhosis (80.8% vs 25.5% 5-year OS rate, P = 0.006; 22.2% vs 0% 5-year disease-free survival rate, P = 0.048). Surgical resection in the 20 patients who had cirrhosis did not provide any survival benefit when compared with TACE (25.5% vs 24.7% 5-year OS rate, P = 0.225). Twenty-nine of the 36 patients who underwent surgical resection experienced recurrence. Of the patients with cirrhosis, 80% (16/20) were within the Milan criteria at the time of recurrence after resection. Among patients with two or three HCCs, no radiologic vascular invasion, and tumor diameters ≤ 5 cm, surgical resection is recommended only in those without cirrhosis.

High Serum CEA and CYFRA21-1 Levels after a Two-Cycle Adjuvant Chemotherapy for NSCLC: Possible Poor Prognostic Factors.

ObjectiveThe aim of this study was to test whether carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA21-1) can be used as a prognostic factor for non-small-cell lung cancer (NSCLC) after two cycles of adjuvant chemotherapy in NSCLC patients.MethodsA total of 169 patients underwent at least two cycles of adjuvant chemotherapy. The serum levels of CEA and CYFRA21-1 were recorded after the second cycle of chemotherapy, and the patient follow-up was conducted. Overall survival (OS) and disease-free survival (DFS) were used as the primary endpoint and the secondary endpoint, respectively.ResultsThe high levels of CEA and CYFRA21-1 after two cycles of adjuvant chemotherapy were poor prognostic factors for OS, with risk ratios (RR) of 2.003 and 1.702, respectively. A high CEA level was a poor prognostic factor (RR 1.152) for DFS. The median survival time (MST) of the high CEA level group was 26 months, whereas that of the normal group was 61 months (P<0.0001). The median DFS time of the high CEA group and the normal group was 34 and 53 months, respectively (P<0.0001). The MST of the high CYFRA21-1 group and the normal group was 43 and 56 months, respectively (P<0.0001).ConclusionsThe high serum levels of CEA or CYFRA21-1 after two cycles of adjuvant chemotherapy are poor prognostic factors for NSCLC patients.

Epithelial cell adhesion molecules and epithelial mesenchymal transition (EMT) markers in Ewing's sarcoma family of tumors (ESFTs). Do they offer any prognostic significance?

Epithelial marker and adhesion molecule expression has been reported in Ewing's sarcoma family of tumors (ESFTs), although the prognostic significance has not been assessed systematically. We performed immunohistochemical analysis of epithelial cell adhesion molecule and epithelial mesenchymal transition markers on 415 genetically confirmed ESFTs. Survival analyses were performed in 217 patients. The atypical histological subtype expressed a high proportion of the epithelial markers compared with conventional and PNET variants. We observed that expression of desmoplakin (p < 0.001) and PI3K (p = 0.003) was higher in disseminated than in localized disease. Multivariate analysis showed that desmoplakin and pGSK3β constitute independent good prognostic factors for progression free survival (PFS), while ZO-1 and Snail represent independent good prognostic factors for overall survival (OS). In contrast, CK8/18 represents an independent poor prognostic factor for OS and the radiotherapy treatment group demonstrated an independent poor prognostic factor for PFS and OS. Although the expression of pan-cytokeratin has been previously highlighted in a significant proportion of ESFT, its expression did not reveal prognostic significance in the present series. Considering the results of prognostic analysis herein reported, we strongly recommend a prospective validation of at least the immunomarkers with prognostic significance (desmoplakin, ZO-1, CK8/18, pGSK3β, and Snail) in prospective series that include localized and disseminated tumors.

Preoperative Cholangitis and Metastatic Lymph Node Have a Negative Impact on Survival After Resection of Extrahepatic Bile Duct Cancer

The significance of the presence of preoperative inflammation for the prognosis of patients with extrahepatic bile duct cancer (BDCA) was evaluated. The clinical data of 84 patients who underwent surgery for BDCA from August 2003 to May 2009 were reviewed, and survival analysis was performed. The patients were classified into two groups according to the presence of preoperative cholangitis: Group A had no cholangitis (n = 59), and group B had cholangitis (n = 25). There were no differences in sex, mean age, TNM stage, biliary drainage, type of resection, or radicality between the two groups (p > 0.05). The 3-year disease-specific survival (DSS) and disease-free survival (DFS) rates for the group B patients (21.5 and 11.9 %, respectively) were significantly lower than those for the group A patients (66.1 and 57.3 %, respectively; p = 0.013 and 0.001, respectively). The multivariate analysis showed that preoperative inflammation and lymph node metastasis were the independent prognostic factors for both overall survival (OS) [p = 0.021, relative risk (RR) = 2.224 and p = 0.015, RR = 2.367, respectively] and DFS (p = 0.014; RR = 2.192 and p = 0.013; RR = 2.240, respectively). The rates of angiolymphatic and perineural invasion were higher for group B than those for group A (p = 0.016 and 0.030, respectively). The presence of preoperative inflammation is an independent poor prognostic factor for OS and DFS for patients with BDCA.

Dynamic imaging response following radiation therapy predicts long-term outcomes for diffuse low-grade gliomas

Quantitative imaging assessment of radiation therapy (RT) for diffuse low-grade gliomas (DLGG) by measuring the velocity of diametric expansion (VDE) over time has never been studied. We assessed the VDE changes following RT and determined whether this parameter can serve as a prognostic factor. We reviewed a consecutive series of 33 adults with supratentorial DLGG treated with first-line RT with available imaging follow-up (median follow-up, 103 months). Before RT, all patients presented with a spontaneous tumor volume increase (positive VDE, mean 5.9 mm/year). After RT, all patients demonstrated a tumor volume decrease (negative VDE, mean, -16.7 mm/year) during a mean 49-month duration. In univariate analysis, initial tumor volume (>100 cm(3)), lack of IDH1 expression, p53 expression, high proliferation index, and fast post-RT tumor volume decrease (VDE at -10 mm/year or faster, fast responders) were associated with a significantly shorter overall survival (OS). The median OS was significantly longer (120.8 months) for slow responders (post-RT VDE slower than -10.0 mm/year) than for fast responders (47.9 months). In multivariate analysis, fast responders, larger initial tumor volume, lack of IDH1 expression, and p53 expression were independent poor prognostic factors for OS. A high proliferation index was significantly more frequent in the fast responder subgroup than in the slow responder subgroup. We conclude that the pattern of post-RT VDE changes is an independent prognostic factor for DLGG and offers a quantitative parameter to predict long-term outcomes. We propose to monitor individually the post-RT VDE changes using MRI follow-up, with particular attention to fast responders.

VEGFA and VEGFR2 genetic polymorphisms and survival in patients with diffuse large B cell lymphoma

We evaluated the impact of functional polymorphisms in the vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor 2 (VEGFR2) genes on the survival of patients with diffuse large B cell lymphoma (DLBCL). Five potentially functional polymorphisms in the VEGFA (rs699947, rs2010963 and rs3025039) and VEGFR2 (rs1870377 and rs2305948) genes were assessed in 494 DLBCL patients treated with rituximab plus CHOP chemotherapy. The associations of genotype and haplotype with overall survival (OS) and progression-free survival (PFS) were analyzed. Of the five polymorphisms, VEGFR2 rs1870377T>A was significantly associated with both OS and PFS; in the dominant model, patients with the AA + TA genotypes had significantly better OS (P = 0.002) and PFS (P = 0.004) than those with the TT genotype. The association between significantly better OS and the AA + TA genotypes was observed separately in patients with low (0-2; P = 0.035) and high (3-5; P = 0.043) International Prognostic Index scores. Multivariate analysis showed that, relative to the AA + TA genotypes, the TT genotype was an independent prognostic factor for poor OS (HR, 1.71; 95% CI, 1.21-2.43; P = 0.002) and PFS (HR, 1.57; 1.13-2.17; P = 0.004). Other independent significant predictors of survival in patients with DLBCL were International Prognostic Index score, age > 60 years, lactate dehydrogenase concentration >normal, extranodal disease >1 and presence of B symptoms. The VEGFR2 rs1870377 polymorphism might affect survival in patients with DLBCL, suggesting that angiogenesis might be related to poor survival in these patients.

Multiplication of Chromosome 17 Centromere Is Associated with Prognosis in Patients with Invasive Breast Cancers Exhibiting NormalHER2andTOP2AStatus

PurposeThis study aimed to investigate the clinical significance of chromosome 17 centromere (CEP17) multiplication (increased copy number of CEP17) related to human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) status in patients with invasive breast cancer.MethodsWe constructed tissue microarrays using 594 invasive breast cancer samples and performed single-color silver-enhanced in situ hybridization (SISH) assay for HER2, TOP2A, and CEP17 to assess for copy number aberrations. The association of CEP17 multiplication with patient survival was analyzed according to HER2 and TOP2A status.ResultsAmong 567 informative cases, HER2 amplification was noted in 22.8%, TOP2A amplification in 8.3% and TOP2A deletion in 11.1%. CEP17 multiplication was identified in 33.2% and was significantly associated with worse overall survival (OS) (p=0.02) and disease-free survival (DFS) (p=0.02). CEP17 multiplication correlated with patient survival in patients with normal TOP2A or non-amplified HER2 status, but the prognostic significance was lost in those with altered TOP2A or amplified HER2. On multivariate analyses, CEP17 multiplication was an independent prognostic factor for poorer OS (p=0.02) and DFS (p=0.01) in patients with normal TOP2A and non-amplified HER2.ConclusionCEP17 multiplication was identified as a promising prognostic marker in patients with invasive breast cancer exhibiting either non-amplified HER2 or normal TOP2A status.

Value of the Metastatic Lymph Node Ratio for Predicting the Prognosis of Non‐Small‐Cell Lung Cancer Patients

The aim of this study was to investigate the relation between the metastatic lymph node ratio (LNR) and the prognosis of non-small-cell lung cancer (NSCLC). A total of 301 patients with N1 or N2 NSCLC who underwent complete pulmonary resection were analyzed retrospectively. The correlations between the LNR and clinical and pathologic data were analyzed using χ(2) test analysis. The prognostic value of the LNR was calculated by univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazard model analysis. The risk groups were classified by a combination of the LNR and pN stage. The LNR was correlated with age, smoking status, pathologic type, subcarinal lymph node, clinical staging, N stage (P < 0.05), and the number of positive lymph nodes and positive lymph node stations (P < 0.0001). In the univariate analysis, the LNR played an important role in predicting overall survival (OS) (P < 0.0001) and disease-free survival (P < 0.0001) by Kaplan-Meier survival analysis. In the multivariate analysis, high LNR (>18%) was an independent poor prognostic factor for OS [hazard ratio (HR) 2.5034, 95% confidence interval (CI) 1.6096-3.8933, P < 0.0001] and DFS (HR 1.9023, 95% CI 1.2465-2.9031, P = 0.0031). Stratification into high-, medium-, and low-risk groups-based on high-risk factors (LNR > 18%, N2) intermediate-risk factors (LNR > 18%, N1 or LNR < 18%, N2), and low-risk factors (LNR < 18%, N1)-could efficiently predicted outcomes (P < 0.0001) of patients with lymph node-positive NSCLC. The combination of the LNR and pN status provides a valuable help with prognosis. However, these results must be evaluated further in a large prospective randomized clinical trial.

Dynamic Prognostic Model to Identify Patients with Primary or Post-Polycythemia Vera/Essential Thrombocythemia Myelofibrosis (Mf) At the Highest Risk of Death and Transformation to Acute Myeloid Leukemia

Abstract▪2821▪This icon denotes a clinically relevant abstract BACKGROUND:While patients (pts) with primary or post-polycythemia vera (PV)/post-essential thrombocythemia (ET) myelofibrosis (MF) have a median overall survival of 5–6 years, the survival of particular subsets of pts with MF is highly variable. Pts transforming to acute myeloid leukemia (AML) represent a large proportion of those with the poorest prognosis. Prognostic tools capable of identifying pts at the highest risk of death and transformation may provide an opportunity for tailored early therapeutic intervention (e.g. allogeneic stem cell transplantation [allo-SCT]). OBJECTIVES:To identify risk factors that predict for short survival and for high risk to transformation to AML in a large cohort of pts with MF diagnosed at MD Anderson Cancer Center. PATIENTS AND METHODS:649 pts with MF referred from Feb-1966 to Jun-2010 were assessable for survival analysis, including 177 (27%) with post-PV or post-ET MF. The median follow-up was 19 months (range, 1–180). We first evaluated an extensive list of baseline risk factors for overall survival (OS) by univariate analysis (UVA): age, sex, prior exposure to alkylating agents, hydroxyurea, immunomodulatory drugs (i.e. thalidomide derivatives), and others, MF duration, performance status, splenomegaly, hepatomegaly, hemoglobin, white blood cell count (WBC), platelets, monocytes, peripheral blood (PB) or bone marrow (BM) blast percentage (continuous variable), chromosomal abnormalities, JAK2V617F mutation (yes vs no, and as a continuous variable), total bilirubin, LDH, creatinine level. Multivariate analysis (MVA) identified age ≥60 (p=0.004;HR=1.63), baseline platelets <100×109/L (p<0.001;HR=1.62), BM blast >10% (p=0.002;HR=2.18), worst karyotype (del17p, −5, −7, complex; p<0.001;HR=2.44), transfusion dependency (≥2 red cell transfusions; p<0.001;HR=2.64), PS ≥1 (p=0.003;HR=1.47), LDH >2000 U/L (p<0.001;HR=1.62), prior hydroxyurea (p<0.001;HR=1.69), and male gender (p=0.005;HR=1.41) as independent poor prognostic factors for OS. Using the corresponding hazard ratios, a dynamic risk model for survival in MF was derived based on weighted scores of 0–1, 2–3, 4–5, ≥6. The number of pts and median OS for the 4 risk groups were: Low: 84 (13%), median OS not reached; Intermediate-1: 191 (29%), 74 months; Intermediate-2: 208 (32%), 29 months; High :166 (26%), 11 months. We then examined the same baseline variables used in the OS analysis to identify independent risk factors for AML transformation. MVA identified WBC<3×109/L (p=0.02), PB blasts ≥5% (p=0.01), BM blasts ≥5% (p=0.02), and unfavorable karyotype (p=0.04). The presence at baseline of BM blasts ≥10% and worst karyotype were identified as independent poor prognostic factors for both OS and AML-transformation. Pts with one or both of these two risk factors (n=80, 12% of the population) defined a subgroup of pts with a median OS of only 10 months. This subgroup was considered to have MF at significantly higher risk (compared to pts without any of these 2 adverse factors) for transformation to AML (1-year transformation-free survival 82% vs 98%, p<0.001). Ten of 80 (13%) of pts with any of these two factors progressed to AML within 12 months whereas only 10 of 568 (2%) pts without those two factors progressed to AML within 12 months. The yearly rates of transformation for the whole study group during the first, second, and third year of follow-up were 3%, 2%, and 3%, respectively. CONCLUSION:Analysis of a large population of pts with either primary or post-PV or post-ET MF identified risk factors that at any time during the course of MF predict for short OS and for high risk for AML transformation AML. Pts with such factors may be candidates for more aggressive therapeutic approaches such as allo-SCT. Disclosures:No relevant conflicts of interest to declare.

DNMT3A Mutations in Acute Myeloid Leukemia-Stability During Disease Evolution and the Clinical Implication

Abstract 409▪▪This icon denotes a clinically relevant abstract Background:DNMT3A mutations are associated with poor prognosis in acute myeloid leukemia (AML), but the stability of this mutation during the clinical course remains unclear. Materials and Methods:Mutation analysis of DNMT3A exons 2–23 was performed by polymerase chain reaction and direct sequencing in 506 de novo AML patients. Their interaction with clinical parameters, chromosomal abnormalities and genetic mutations were analysed. Results:DNMT3A mutations were identified in 14% of total patients and 22.9% of patients with normal karyotype (CN-AML). 30 different kinds of DNMT3A mutations were identified in 70 patients. Twelve were missense mutations, eight were nonsense mutations, nine were frame-shift mutations and one, in-frame mutation. The most common mutation was R882H (26 patients), followed by R882C (15 patients), R882S (3 patients), R736H (3 patients) and R320X (2 patients). DNMT3A mutations were closely associated with older age, higher white blood cell (WBC) and platelet counts at diagnosis, FAB M4/M5 subtype, intermediate-risk and normal cytogenetics.Among the 70 patients with DNMT3A mutations, 68 (97.1%) showed additional molecular abnormalities at diagnosis. The most common associated molecular event was NPM1 mutation (38 cases), followed by FLT3-ITD (30 cases), IDH2 mutation (16 cases) and FLT3-TKD (9 cases). Patients with DNMT3A mutations had significantly higher incidences of NPM1 mutation, FLT3-ITD, IDH2 and PTPN11 mutations than those with DNMT3A-wild type (54.3% vs. 15.3%, P<0.0001; 42.9% vs. 19.3%, P<0.0001; 22.9% vs. 9.1%, P=0.0016; and 10% vs. 3.5%; P=0.007, respectively). On the contrary, CEBPA was rarely seen in patients with DNMT3A mutations (4.3% vs. 14.7%, P=0.0134). Totally, 40 patients (58.8%) had concurrent both Class I and Class II or NPM1 mutations at diagnosis.With a median follow-up of 55 months (ranges, 1.0 to 160), patients with DNMT3A mutation had significantly poorer overall survival (OS) and relapse-free survival (RFS) than those without DNMT3A mutation (median, 14.5 months vs. 38 months, P =0.013, and medium, 7.5 months vs. 15 months, P=0.012, respectively). In the subgroup of 130 younger patients (less than 60 years) with CN-AML, the differences between patients with and without DNMT3A mutation in OS (median, 15.5 months vs. not reached, P= 0.018) and RFS (median, 6 months vs. 21 months, P=0.004) were still significant. Multivariate analysis demonstrated that DNMT3A mutation was an independent poor prognostic factor for OS and RFS among total patients (HR 2.218, 95% CI 1.333–3.692, P=0.002 and HR 2.898, 95% CI 1.673–5.022, P<0.001, respectively) and CN-AML group (HR 2.303, 95% CI 1.088–4.876, P=0.029 and HR 3.496, 95% CI 1.773–6.896, P<0.001, respectively). Further, a scoring system incorporating DNMT3A mutation and eight other prognostic factors, including age, WBC count, cytogenetics, and gene mutations (NPM1/FLT3-ITD, CEBPA, AML1/RUNX1, WT1, and IDH2 mutations), into survival analysis was proved to be very useful to stratify AML patients into different prognostic groups (P<0.001).DNMT3A mutations were serially studied in 316 samples from 138 patients, including 35 patients with distinct DNMT3A mutations and 103 patients without mutation at diagnosis. Among the 34 patients with DNMT3A mutations who had ever obtained a CR and had available samples for study, 29 lost the original mutation at remission status, but five retained it; all these five patients relapsed finally within a median of 3.5 months and died of disease progression, suggesting presence of leukemic cells. In the 13 patients who had available samples for serial study at relapse, all patients regained the original mutations, including mutant clone was found by TA cloning in one patient. Among the 103 patients who had no DNMT3A mutation at diagnosis, none acquired DNMT3A mutation at relapse, while karyotypic evolution was noted at relapse in 39% of them. Conclusion:DNMT3A mutations are associated with distinct clinical and biological features and poor prognosis in de novo AML patients. Furthermore, the mutation may be a potential biomarker for monitoring of minimal residual disease. Disclosures:No relevant conflicts of interest to declare.

Dual Translocation Is An Independent Poor Prognostic Factor in Diffuse Large B-Cell Lymphoma,

Abstract 3683 Background:Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of diseases, that are associated with variable survival outcomes depending on the presence of certain genetic and molecular features. Of particular interest is a subset known as the “double-hit” (DH) lymphoma. DH lymphoma (dual translocation) is defined by the presence of a chromosomal breakpoint affecting the MYC/8q24 locus with a second oncogene translocation, most commonly a BCL2 rearrangement, and less commonly involving BCL6 or CCND1 rearrangements. However, the incidence of DH lymphoma remains to be determined. These patients typically have poor prognostic factors, with a dismal outcome when treated with rituximab-CHOP (RCHOP) chemotherapy. The aim of this study was to identify any clinical defining characteristics in patients with DH lymphoma, and to compare their outcomes with that of DLBCL patients without dual translocation. Methods:202 newly diagnosed DLBCL patients, of whom 90% received rituximab based chemotherapy, were investigated using immunohistochemistry and fluorescence in situ hybridization (FISH), using breakapart FISH probes targeting BCL2, BCL6, MYC, CCND1 and IgH genes. The clinical characteristics and survival outcomes of patients who were identified with DH lymphoma were compared to those without the dual translocation. Results:Out of the 202 patients with DLBCL, we identified 10 cases (5%) with two or more concurrent translocations involving MYC and BCL2, or MYC and BCL6. Among the 10 patients with DH lymphoma, there were 6 patients with concurrent BCL2 and MYC translocations, 1 patient with BCL6 and MYC translocations and 3 patients with all 3 abnormalities. 7 of the 10 patients were male, with a median age of 68 years (42 – 84). Patients with DH lymphoma also presented with a significantly higher incidence of high-risk clinical features, including advanced stage disease, bulky disease, extranodal disease, bone marrow involvement and a high IPI score. Interestingly, the majority of patients with DH lymphoma expressed a germinal center (GC) phenotype (8 out of 9 patients) based on the Han’s criteria. These patients also demonstrated a significantly poorer overall survival (OS) when compared to patients without dual translocation (2 yr OS 33% vs 84%, p = < 0.001). On multivariate analysis, the presence of a dual translocation was found to be an independent poor prognostic factor for OS (hazard ratio 8.84, 95% CI 3.54 to 22.08). Other factors predictive of an inferior OS included age, stage, bone marrow involvement and patients treated without rituximab. Conclusions:Our findings showed that the presence of dual translocation is an independent poor prognostic factor in DLBCL. It was present in 5% of our cohort and was associated with more advanced disease. Patients with dual translocation also had a significantly poorer survival following treatment with standard chemotherapy such as RCHOP, even though most patients exhibited the GC phenotype. Therefore, the use of novel agents in combination with chemotherapy is an area that deserves further exploration in this type of lymphoma. Disclosures:No relevant conflicts of interest to declare.

Favorable Outcome of Reduced-Intensity Stem Cell Transplantation for Adult T-Cell Leukemia

Abstract 4480 Introduction:Adult T-cell leukemia (ATL) endemic in southwestern Japan is an HTLV-I-induced mature T-cell neoplasm. It has a dismal prognosis when treated with conventional chemotherapy, mainly because ATL cells overexpress multidrug-resistance genes. Allogeneic hematopoietic stem cell transplantation (allo-SCT) has been reported to improve the prognosis. However, it is also known that allo-SCT shows high treatment-related mortality (TRM) because of disease characteristics of severely deteriorated cellular immunity. Therefore, we evaluated the outcome of reduced-intensity stem cell transplantation (RIST), compared to conventional stem cell transplantation (CST) for ATL patients (pts). Patients and methods:We retrospectively analyzed consecutive 20 pts with aggressive ATL (acute type, 16; lymphoma type, 4) who underwent allo-SCT between 2000 and 2010 in our institute. The age of pts who received RIST was significantly older than that of CST (P = <.001). The other parameters were balanced between the two groups (Table 1). [Display omitted] All pts received induction chemotherapy with Japan Clinical Oncology Group (VCAP-AMP-VECP) regimen or biweekly CHOP prior to SCT. Nine pts received a conventional myeloablative conditioning with CY/TBI-based (n=8) or BU/CY-based (n=1) regimens and 11 pts received a reduced-intensity regimen with fludarabine(Flu)/melphalan(Mel)±TBI (Flu 25 mg/m2 on days -6 to -2 + Mel 40 mg/m2 on days -4 and -3 ± TBI 4 Gy on day -1). Graft-versus-host-disease (GVHD) prophylaxis consisted of cyclosporine plus short-term methotrexate (sMTX) for HLA-matched sibling donor recipients and tacrolimus plus sMTX for the others. Cyclosporine or tacrolimus was promptly tapered when complete chimerism was achieved. Results and discussion:The estimated 3-year overall survival (OS) and 3-year progression-free survival (PFS) rates for all pts were 59% and 55%, respectively (Fig. 1). At the median follow-up duration of 25 months (1–67), 12 pts were alive and 8 pts dead. Causes of death were disease progression (n=4) and treatment-related complications including acute GVHD and infection (n=4). The cumulative incidences of disease-associated mortality and TRM at 3 years were 21% and 20%, respectively. Importantly, after 1 year post-transplantation, the curve of PFS reached plateau phase. Therefore, allo-SCT could be a curable therapeutic option for aggressive ATL. [Display omitted] It is notable that RIST showed excellent 3-year OS. Although not significant, 3-year OS for RIST and CST were 70% and 44% (P =.25), respectively (Fig. 2). TRM of RIST trended to be low compared with that of CST (18% vs 22%, P =.87). In addition, chronic GVHD was observed in 91% of the evaluable 11 pts (limited type, 6; extensive type, 5). It is suggested that both improvement of TRM and the induction of graft-versus-leukemia effects may contribute to the favorable outcome in RIST for ATL. Furthermore, it should be stressed that older pts who preferentially received RIST rather than CST achieved favorable survival comparable to younger pts (≥ 50 years: 58% vs < 50 years: 60%, P =.94). We would suggest that RIST should be applied to all ATL pts eligible for allo-SCT, regardless of the age. [Display omitted] Univariate analysis for all pts revealed that only male sexuality was a significant poor prognostic factor for OS (male: 25% vs female: 82%, P =.006). Regarding disease status at SCT, CR or non-CR did not significantly affect OS (CR: 67% vs non-CR: 58%, P =.98). However, PD was an adverse impact on 3-year OS (PD: 33% vs non-PD: 64%, P =.11). It is recommended that ATL pts receive allo-SCT in early phase before the disease becomes chemo-resistant, even if they do not achieve CR. Conclusion:Allo-SCT for ATL remarkably improved the poor prognosis. Especially, RIST is a promising procedure for excellent outcome. Disclosures:No relevant conflicts of interest to declare.