Extra Nodal Research Articles

Discrepancy of Interim PET/CT Responses Based on Visual and Quantitative SUV-Based Assessments in the Patients with Diffuse Large B-Cell Lymphoma and Extranodal Involvements

Background18 F-FDG PET is currently used in diffuse large B-cell lymphoma (DLBCL) for staging and evaluation of therapeutic efficacy at various time points. Nevertheless, the predictive value of interim PET/CT (iPET/CT) has not been consistent throughout the studies. Since FDG is not a tumor-specific substance, it may accumulate to the point of being detected in a variety of benign conditions or infectious lesions, which may give rise to false positive interpretation. Particularly, iPET/CT assessment in patients with multifocal, non-contiguous involvement at extranodal (EN) sites may result in a false determination of prognosis due to tracer uptake of inflammatory or physiologic anatomic sites, which could contribute to the variability in outcomes and the poor reproducibility. Therefore, the purpose of this study is to investigate the predictive accuracy of iPET/CT response based on visual and quantitative SUV-based assessments in patients with DLBCL and EN involvements.MethodsiPET/CT responses for 163 patients with newly diagnosed DLBCL and EN involvements were investigated retrospectively. iPET/CT responses were based on the visual and quantitative SUV-based assessments. Briefly, the assessment of PET/CT was performed at the time of diagnosis, at the third or fourth cycles and at the completion of R-CHOP. For visual assessment, the five-point scale (5-PS) based on the Deauville criteria was used and graded as negative or positive by comparison with initial PET/CT scan and grade 1-3 were considered as negative and grade 4-5 were considered the residual metabolic response. Second, we classified patients using the quantitative analysis of 18 F-FDG uptake changes based on the percentage of SUVmax reduction (DSUVmax) between initial and interim PET/CT scans. The cutoff points of DSUVmax were 65.7% based on previous reports.ResultsMedian age was 61 years (range 18-83 years) and 88 patients (54.0%) in advanced disease (III/IV). Patients were classified according to the IPI risk with 95 patients (58.3%) being classified as low or low-intermediate and 68 patients (41.7%) as high-intermediate or high risk. Number of extranodal site(s) were 1 site in 102 patients (62.6%), 2 sites in 39 (23.9), 3 sites in 18 (11.0), and 4 sites in 4 (2.5%). iPET/CT responses based on visual analysis were classified into grade 1-3 of 5-PS in 99 patients (60.7%) and grade 4-5 in 64 (39.3%), and based on SUV-based, classified into higher the cutoff of DSUVmax (>65.7%) in 140 patients (85.9%) and lower (<65.7%) in 23 patients (14.1%), respectively. On visual assessment, iPET/CT-positive patients had no difference of relapse rates (28.3±5.4%) compared to those of iPET/CT-negative patients (23.1±4.5%) (p=0.419). Among the patients with 5-PS grade 4-5, 46 patients (71.9%) achieved higher the optimal cutoff of DSUVmax (>67.5%).The 5-year overall survival (OS) rates and progression free survival (PFS) rates were 75.6±3.8% vs 60.6±11.7% (p=0.056), and 77.9±3.7% vs 55.9±12.1% (p=0.007) depending on the cutoff of DSUVmax, respectively. Among the patients with 1 EN involvement, DSUVmax successfully predict the long-term outcomes in terms of 5yr-OS (83.2±4.3% vs 62.1±14.6%, p=0.012) and PFS (86.9±3.9% vs 41.3±16.6%, p<0.001), while for those with more than 1 EN involvements, DSUVmax failed to predict long-term outcomes. In the multivariate analysis, DSUVmax <65.7% (HR=2.675, 95% CI 1.304-5.486, p=0.007), ECOG 2-3 (HR=2.553, 95% CI 1.228-5.309, p=0.012), and the involvement of more than 1 EN sites (HR=2.370, 95% CI 1.247-4.504, p=0.008) were unfavorable factors for PFS. Visual assessments based on Deauville 5-PS score could not predict the disease progression or long-term outcomes regardless of the number of extranodal involvements or IPI risk groups.ConclusionThe quantitative SUV-based assessments in iPET/CT could have significant potential as a prognostic predictor of PFS and OS, especially in the patients with 1 EN site involvement. However, the visual assessments have the limitations to predict long-term outcomes with high false positive rates at EN involvements. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Risk Factors for CNS Relapse Among Patients with DLBCL Treated with EPOCH-R

Background: Central nervous system (CNS) relapse in pts with aggressive non-Hodgkin lymphoma (NHL) is a generally fatal complication, with median overall survival (OS) of less than six months (Abramson et al., 2010). Several studies have identified features associated with increased risk of CNS relapse, such as extranodal (EN) sites of disease, elevated lactate dehydrogenase (LDH), presence of B symptoms, and bone marrow involvement (Bernstein et al., 2009; van Besien et al., 1998). Moreover, multivariate analyses have suggested that LDH greater than 3x upper limit of normal (ULN) is strongly associated with increased risk of death or progression among patients with aggressive NHL (Zhou et al., 2014). Despite little evidence on its true efficacy, prophylaxis (ppx) intrathecal (IT) chemotherapy, most frequently with methotrexate (MTX), is often used to among pts thought to be at high risk for CNS relapse. Data on efficacy or need for CNS prophylaxis in patients receiving infusional therapy with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (R-EPOCH) is not available. As R-EPOCH, is being increasingly used in pts with lymphoma, we sought to evaluate the role of IT chemotherapy when used with this regimen.Methods: We conducted a retrospective chart review analysis of patients with diffuse large B-cell lymphoma (DLBCL) who received R-EPOCH as frontline therapy, between 2005 and 2014. Use of IT ppx was at the discretion of the treating physician. We excluded patients under the age of 18, those receiving fewer than two cycles of R-EPOCH, those with CNS involvement at time of diagnosis, and those who received high-dose intravenous CNS ppx. Two-tailed Fisher's exact test was used to determine whether any of the following baseline features was associated with risk of CNS relapse: age>60, ECOG PS>1, LDH>normal and/or >3x ULN, presence of B symptoms, two or more EN sites, anatomic location of EN sites, international prognostic index (IPI) score > 1, bone marrow involvement, and HIV infection. In order to determine whether IT ppx was associated with any improvement in CNS and/or systemic control of disease, we compared, using Kaplan-Meier survival curves with log-rank analyses, the patterns of overall survival (OS), progression-free survival (PFS), and freedom from CNS progression (FFCP, in which death is not counted as an event) between patients receiving IT ppx and those not receiving it.Results: We identified 117 patients for analysis. Median age was 53 (range 19-80). 26% had ECOG PS>1; 76% had LDH above upper limit of normal (ULN). 38% had two or more EN sites of disease, and 68% had stage III-IV disease. 62 patients received IT ppx, and 55 did not. Of those receiving IT ppx, 95% received MTX, with the remainder receiving cytarabine. Those receiving IT ppx were more likely to have >1 EN site of disease, and IPI score >1 (Table 1). A total of seven had observed CNS relapse, occurring at a median of 6 months from time of NHL diagnosis (range 2-24 months). At a median follow up of 18 months, the 24-month PFS and OS were 80% and 83%, respectively. Median PFS and OS were not reached. The only factors associated with increased risk of CNS relapse were genitourinary EN disease and LDH >3x ULN (Table 2). There were no significant differences in OS, PFS, or FFCP among patients who did and did not receive CNS prophylaxis (Figure 1, panels A-C).Conclusions: The risk of CNS progression among DLBCL patients receiving R-EPOCH was similar to previous reports with R-CHOP, at 6%. GU location of EN disease and LDH >3xULN were associated with increased risk of CNS relapse. IT ppx was not associated with improved outcomes. Despite the common use of IT PPX in pts treated with R-EPOCH, our data suggest that this practice might not impact CNS progression and/or relapse, though randomized studies would be needed to answer this. Such studies are warranted in order to better determine what factors are associated with CNS progression, and whom, if anyone, may benefit from IT ppx. [Display omitted] [Display omitted] DisclosuresNabhan:Celgene Corporation: Honoraria, Research Funding. Petrich:Seattle Genetics: Consultancy, Honoraria, Research Funding.

Clinical Outcome of 96 Post-Transplant Lymphoproliferative Disease Patients in a Renal Transplant Cohort

Introduction: Post-Transplant Lymphoproliferative Disease (PTLD) is a rarewell-recognized group of lymphoid and or plasmacytic proliferations that occur following both solid organ (SOT) and allogenic hematopoietic stem cell transplantation (HSCT) as a result of immunossupression. A continuum of disease has been described, including early lesions, polymorphic PTLD and monomorphic PTLD. Epstein-bar virus (EBV) is considered the most important causative factor, with EBV positivity observed within up 90% of tumor lymphocytes. Optimal risk stratifications specific to kidney transplantation are still lacking.Patient and Methods: In our series, we retrospectively analyzed 98 consecutively cases of PTLD diagnosed between 2001 and 2014 at Hospital do Rim (HRim), a school hospital from the Federal University of São Paulo, São Paulo, Brazil. HRim is considered the leading renal transplant hospital in the world for the past 15 years. For this study, only PTLD patients with tumors whose histology could be confirmed by hemopathologist review, EBV-association established and whose clinical, epidemiological and laboratorial parameters could be retrieved were included in this study. Response was defined as complete (CR) or less than CR (partial response or refractory disease). Event was defined as treatment related mortality, progression (defined as time for initiation of second-line therapy) or relapse. Patients with conflicted data or loss of follow up were excluded.Results: A total of 98 patients were diagnosed with PTLD from 7665 renal transplants performed in this period, with a incidence of 1,3%. Two patients were excluded from the analysis due to conflicting clinical data. Median age at diagnosis was 41.4 years (range from 4-74), with a 0,6:1 Female:Male ratio. Median time of transplant to PTLD diagnosis was 56 months (range 1-967). Thirty-six patients (37.5%) received anti-thymocyte globulin (ATG), and the most common immunossupressive regimen (IR) consisted of cyclosporine or tacrolimus associated with prednisone and azathioprine (66, 69%). Monomorphic PTLD was observed in 75 (78%) patients, and two patients presented with HL. EBV positivity was seen in 67 patients (70.5%), being more frequent within PTLD cases diagnosed during the first 3 years of transplantation (90%). All patients had their IR reduced after PTLD diagnosis. The incidence of loss of engraftment following IR reduction was 19% (20 patients). Overall responses were: CR in 67% (n=64) and Partial response/Refractory disease in 33% (n=32); 30 patients died due to treatment-related toxicity and/or disease progression. Overall Survival (OS) for the entire group was 63% in 5 years (CI95% 73-83%), with a progression free survival (PFS) of 58% (CI95% 91-97%). EBV positivity was seen in 67 patients (70.5%). Median number of extra nodal sites involved was 1,2. The median overall survival time was 97 months. Patient survival following diagnosis was 77% at 1 year, 63% at 5 years and 38% at 10 years. The most common extra-nodal sites involved were: Gastro-intestinal Tract (43, 45%) followed by Central Nervous System (23, 24%). Extra nodal involvement was correlated with poorer outcome (p 0.014) as was the loss of engraftment (p<0.0001).Conclusions: PTLD is a rare complication of immunossupression, usually related to EBV, specially for PTLD diagnosed within the first 3 years of transplantation. Basically, the initial treatment consists of reduction or withdrawal of the immunossupressive regimen followed by specific imuno-chemotherapy as needed. In our cohort, the incidence of loss of engraftment was low, although it was correlated with inferior outcome, together with extranodal involvement. To date this is the largest cohort of post-renal transplant lymphoproliferative disease ever reported. DisclosuresNo relevant conflicts of interest to declare.

The NCCN-IPI Helps to Identify Very High-Risk Patients with DLBCL and Can be Improved By Other Independent Clinical Factors Including Bulky Disease and beta2-Microglobulin

The International Prognostic Index (IPI) has been the basis for predicting the outcome of diffuse large B cell lymphoma (DLBCL). With the improvement in prognosis with immunochemotherapy the predictive power of the IPI has been questioned.Recently, the enhanced NCCN-IPI has been proposed to provide a better discrimination of risk groups. Additionally, other patient- and disease-specific factors not incorporated in the prognostic algorithms and easily assessed at diagnosis have been shown to impact on the clinical course. The prognostic value of the NCCN-IPI together with other clinical characteristics remains to be widely validated.We aimed to assess the power of NCCN-IPI in risk group discrimination and compare it with IPI, as well as to investigate if the Body Mass Index (BMI), gender, diameter of the largest mass and levels of β2-microglobulin have independent prognostic impact when controlling for NCCN-IPI risk.We conducted a retrospective analysis of consecutive R-CHOP treated de novo DLBCL cases diagnosed between January 2002 and December 2013 in a single center.Kaplan-Meier method was used to estimate the overall (OS) and progression-free survival (PFS) distributions for risk groups. Logrank test with p-value adjustment by Hochberg method was used for pairwise comparisons between risk groups within each index. Independent prognostic impact of BMI, gender, bulky disease and β2-microglobulin was assessed by multivariate analysis using Cox model.410 patients were included in the analysis, with a median age of 64 (16-89) years; 51% were male. The distribution according to age, stage, extranodal (EN) sites, performance status, β2-microglobulin, BMI and bulky disease (Table 1) were similar to published data.With a median follow-up of 59 months, 5-yr OS and PFS were 69% and 65%, respectively. The distribution of patients according to IPI and NCCN-IPI risk groups is detailed in Table 1. Both scores adequately stratified patients according to risk of progression and death. In our cohort OS and PFS of low and low-intermediate risk groups using the NCCN-IPI were not significantly different. We documented a migration of patients from low (62%) and high (48%) to intermediate risk groups using the NCCN-IPI compared to the IPI. This score allowed a better discrimination between high-intermediate and high-risk disease (pairwise comparison of OS and PFS within NCCN and IPI risk scores of p=0.0087 vs p=0.044 and p=0.032 vs p=0.096, respectively). Only 12 patients classified as intermediate-risk IPI migrated to high NCCN risk group. Of these, 5 relapsed and 6 died (4 of lymphoma).Multivariate analysis showed that bulky disease and β2-microglobulin are independent prognostic factors for OS and PFS when controlling for NCCN-IPI.Using a large series of unselected R-CHOP treated patients, we pursued the validation of the NCCN-IPI as a better prognostic tool for DLBCL. In contrast to the original series, the NCCN-IPI showed limited discrimination capacity for OS and PFS between low- and low-intermediate risk groups. However, the new prognostic index helps to identify particularly poor prognosis patients that might benefit from alternative therapies. We also identified bulky disease and β2-microglobulin as independent prognostic factors in addition to NCCN-IPI and that could be incorporated in future prognostic scores. Additional studies are needed to evaluate the ability of biomarkers to improve the clinical risk stratification systems. Table 1CharacteristicsValue, n (%)AgeMedian (range), yr64 (16-89)≥60 years241 (59%)Male208 (51%)Performance status (ECOG) ≥2a66 (16%)Stage ≥ III221 (54%)BMIbUnderweight (<18.5)15 (4%)Normal (18.5-24.9)170 (43%)Overweight (25.0-29.9)139 (35%)Obese (>29.9)73 (18%)Bulky disease (>7 cm)c157 (40%)β2 microglobulin >ULNd154 (45%)≥2 EN sites92(23%)BM, CNS, liver/GI or lung involvement136 (33%)IPIe vs NCCN-IPIe (%)Low12 vs 34Low-Int38 vs 26High-Int35 vs 20High18 vs 125-yr OS (%)IPI (low, low-int, high-int, high)87, 70, 59, 50p= 8x10-12NCCN-IPI (low, low-int, high-int, high)88, 82, 59, 47p= 2x10-125-yr PFS (%)IPI (low, low-int, high-int, high)86, 66, 51, 48p= 2x10-11NCCN-IPI (low, low-int, high-int, high)84, 78, 54, 45p= 7x10-10BM: bone marrow, CNS: central nervous system, GI: gastrointestinal, int: intermediate.a: 405 pts, b: 397 pts, c: 391 pts, d: 341 pts, e: 403 pts. DisclosuresNo relevant conflicts of interest to declare.

Metabolic Tumor Volume Influences Response to Brentuximab-Vedotin in Relapsed Refractory Hodgkin Lymphoma

Purpose: The total metabolic tumor volume at baseline (T-MTV0) computed on PET has been proposed as a prognostic factor at staging in Hodgkin lymphoma (HL) and diffused large B cell lymphoma (DLBCL). It has also been described to play a role in non-HL treatment by monoclonal antibodies since it could influence antibody exposure and efficacy in a murine model (Dayde D, et al. Blood 2009) that has been confirmed in DLBCL patients study (Casasnovas O, et al. Abstract Lugano 2015). We hypothesized the metabolic tumor burden could influence the efficacy of a monoclonal antibody-drug conjugated (ADC) such as monotherapy based anti-CD30 ADC brentuximab-vedotin (BV). In the present study, we assessed the pre-treatment baseline total metabolic tumor volume based on PET evaluation in the response to BV treatment as a single agent in patients with RR-HL, as well as its prognostic value.Methods: A retrospective multi-center study was built from January 2011 to June 2015. Forty-one consecutive heavily pre-treated patients with a diagnosis of relapsed refractory HL (RR-HL) were included. PET was performed at baseline (PET0) and after 4-6 cycles of BV defining two groups of responders, good responder group achieving a complete metabolic response (CMR group, 23 patients), and non-responder group (no-CMR group, 18 patients), using the revised Lugano classification with the 5-point scale visual analysis PET/CT. T-MTV0 was measured with a semiautomatic method using a 41%-SUVmax-threshold. SUVmax at PET0 (SUVmaxPET0) was measured in each patient and represented the hottest lesion independently from the site. To assess the influence of the T-MTV0 on BV efficacy, we compared the baseline metabolic tumor volume between the two groups. The ROC curve was established to determine the optimal cut-off of T-MTV0 to predict treatment failure.Results: T-MTV0 ranged from 14 cm3 to 213 cm3 in the 41 patients (median 62 cm3; 25th - 75th percentiles 25 - 94 cm3) and SUVmaxPET0 ranged from 4,1 to 19,3 (median 10,4; 25th-75th percentiles 7,8 - 13,7). T-MTV0 was significantly higher in the no-CMR group as compared with the CMR group (median 96 and 30 cm3; 25th-75th percentiles 90 - 139 cm3 and 18 - 38 cm3, respectively; p< 0.01). Considering metabolic sites, the nodal metabolic tumor volume (N-MTV0) represented the main component of T-MTV0 and was significantly higher than the extra nodal metabolic tumor volume (EN-MTV0) in the CMR group (p = 0.025). However, the EN-MTV0 dominated in the no-CMR group and was significantly higher than the N-MTV0 (p = 0.01). SUVmaxPET0 as well as clinical characteristics were not significantly different in the two groups. Furthermore the TMTV0 cut-off value was 62 ml and predictive of treatment failure.Conclusion: In the present study, we demonstrated that tumor metabolic burden and nodal or extra-nodal localizations influence response to BV as a single agent in RR-HL patients, offering some future research directions in the development of new schedules of antibodies administration in anticancer therapy such as the concept of the individual adjustment of treatment dose to tumor burden. This may guide clinicians in their choice of therapeutic strategy. DisclosuresThieblemont:St. Louis Hospital, Paris, France: Employment. Cartron:Sanofi: Honoraria; Gilead: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria; Celgene: Honoraria.

Obesity Is a Prognostic Factor in Elderly Female Patients with Aggressive B-Cell Lymphomas Treated with R- CHOP

Background: Obesity occurs in more than 20% of patients (pts) above 65 years. In solid tumors e.g. breast or colorectal cancer, outcome of obese patients is inferior when compared to normal weight patients. In lymphoma patients data so far are controversial, while recently published data showed that obesity in lymphoma patients was not associated with inferior outcome.Methods: 576 patients with aggressive B-cell lymphomas included in the RICOVER60 study ( 6 or 8 cycles CHOP-14 + 8 doses of Rituximab) were analysed as training set. 151 patients from the RICOVER-noRTh study were used as validation set. We analysed EFS, PFS and OS with regard to body mass index (BMI ≥ 30 vs. < 30) and gender. No significant changes in body weight/BMI occurred during treatment, therefore BMI at cycle 1 was used for analysis. In Cox regression models BMI was adjusted for known prognostic factors.Results: All pts. were > 60 years of age (36% > 70 years), 46% female., 1% pts. low weight (BMI <18.5), 38% normal weight (18.5≤BMI<25), 42% overweight (25≤BMI<30) and 19% pts. obese (BMI≥30). Clinical characteristics were well balanced between training and validation set and between obese (BMI≥30) and non-obese patients (BMI<30). 71% of patients (73% male pts., 70% female pts.) completed therapy per protocol. Pts. with BMI ≥ 30 received less frequently complete treatment (61%) than patients with BMI < 30 (74%; no gender differences). There was no difference between obese/non-obese patients regarding hematotoxicity or infection during cycles. EFS, PFS and OS according to BMI (BMI ≥ 30 vs. BMI < 30) showed no significant difference for all and for male pts., but in female pts. EFS (p=0.041), PFS (p=0.038) and OS (p= 0.031) was significant better for non-obese pts. (figure 1). In a multivariate analysis adjusting for IPI risk factors (LDH>N, ECOG>1; stage III/IV, extra nodal involvement >1) these results were confirmed with the following hazard ratios (HR) for obesity (BMI≥ 30) for EFS/PFS/OS: all patients - 1.4/1.4/1.4; male patients - 1.2/1.2/1.0; female patients - 1.7/1.9/2.0 (table 1). These results were consistent also after additional adjustment for age > 70 years, radiotherapy (yes/no) and relative dose. The findings could be validated in an independent validation set of 151 patients from the RICOVER-noRTh study. The HR for EFS/PFS/OS are: all patients - 1.4/1.4/1.7; male patients - 0.7/0.9/1.5; female patients - 2.6/2.0/1.8. Due to small sample size only the HR for female patients for the EFS is significant (p=0.031).Conclusion: Obesity is a risk factor in elderly female pts. with aggressive B-cell lymphoma treated with R-CHOP with regard to EFS, PFS and OS, adjusted for IPI factors. Sex and weight independently affects rituximab clearance. Females are reported to have slower rituximab clearance with better outcome in the elderly and the rituximab clearance increases with body weight. Therefore worse outcome for obese female patients might be the result of faster rituximab clearance in obese females.Table 1: Multivariate analysis adjusting for IPI risk factors: HR for Obesity (BMI ≥ 30)All pts. male pts. female pts.EFS HR 1.4 [95%CI 1.0-1.9; p= 0.067] HR 1.2 [95%CI 0.7-2.0; p=0.473] HR 1.7 [95%CI 1.0-2.7; p=0.032]PSF HR 1.4 [95%CI 1.0-2.0; p= 0.080] HR 1.2 [95%CI 0.7-2.1; p=0.558] HR 1.9 [95%CI 1.1-3.2; p=0.022]OS HR 1.4 [95%CI 0.9-2.1; p= 0.114] HR 1.0 [95%CI 0.5-2.0; p=0.956] HR 2.0 [95%CI 1.1-3.4; p=0.017] DisclosuresHohloch:Spectrum: Research Funding; Spectrum, Roche: Other: Advisory board. Pfreundschuh:Roche: Honoraria; Boehringer Ingelheim, Celegene, Roche, Spectrum: Other: Advisory board; Amgen, Roche, Spectrum: Research Funding. Schmitz:Roche, Takeda, Gillead, Riemser und ctilifesciences: Other: Advisory board, Speakers Bureau. Truemper:Sandoz, Celgene, AMGEN, Nordic Nanovector: Other: Advisory board; Amgen, roche, Mundipharma: Research Funding.

Secondary Malignancies in Mantle Cell Lymphoma

Background: Mantle cell lymphoma is a B cell lymphoma (CD5 +) which represents 5-10 % of Non-Hodgkin's lymphoma. Most patients have advanced disease at presentation and thus carry a poor prognosis. This type of uncommon malignant lymphoma has a distinct and recurring cytogenetic abnormality involving t(11, 14) q(13, 32). Although extra nodal involvement is common, not many cases of MCL having concomitant other malignancies are reported. We hypothesized that patients with MCL have chronic immunosuppression, comparable to chronic lymphocytic leukemia patients, and therefore are at risk for developing secondary malignancies similar to CLL patients. The aim of our study is to report the retrospective analysis of patients diagnosed with MCL and the associated secondary malignancies before or after the diagnosis of MCL.Patients and methods: The records of 41 patients who presented with MCL to "The David Lee Cancer Center" at CAMC, WVU with MCL from 2000 - 2015 were retrospectively reviewed. The number of other malignancies presenting before or after the diagnosis of MCL were analyzed.Results: The population with MCL was represented by 41, all Caucasian patients, which were 75.6% male (n = 31) and had an average age of 68.6 ± 11.3 years. Mean follow up for all patients was 23.9 ± 32.43 months. A total of 14.6% (n=6), 83.3% males, experienced a second primary. Within the second primaries 50.0% were GI cancers which included pancreatic cancer and cholangiocarcinoma while 16.7% were prostate cancer, diffuse large B-cell lymphoma or adenocarcinoma of lungs. The time to second primaries varied with 50% of the cases being diagnosed simultaneously with MCL, while 33.3% were diagnosed prior to MCL at an average time of 34.5 months, and 16.7% were diagnosed post MCL diagnosis at an average time of 18 months.Conclusion:Patients with MCL are typically CD5 positive, CD10 negative, and CD23 negative which make it different from other lymphomas like small cell lymphoma, B-cell CLL that are CD 23 positive. Rare cases of MCL may be CD5 negative or CD23 Positive. We hypothesized that MCL patients have an increased risk for developing secondary cancers due to their disease biology and from underlying chronic immunosuppression. Patients with MCL have twice the risk of developing secondary malignancies and an increased frequency of certain types of cancers such as cholangiocarcinoma & pancreatic cancer. DisclosuresNo relevant conflicts of interest to declare.

Clinical Characteristics and Outcome of 104 Patients with Gastric Diffuse B-Cell Non-Hodgkin Lymphoma (DLBCL) a Multicenter Study

Background: Gastric lymphoma is the most common extra nodal B cell Non Hodgkin Lymphoma and DLBCL accounts for 70% of cases in the stomach. The clinical course is heterogeneous and clinical symptoms, laboratorial abnormalities and Helicobacter pylori and hepatitis B and C infections, in addition to classical IPI factors, have been related to prognosis. Different clinical behaviors may reflect distinct pathogenic mechanisms. In order to improve outcomes, a better characterization of prognostic factors is required.Aim: We aimed to identify factors with a potential prognosis impact in a consecutive series of gastric DLBCL patients diagnosed and treated in three referee Centers in Brazil, Portugual and Italy, by analyzing demographic and clinical characteristics, response to treatment and outcome (overall survival). The clinical picture of European and Brazilian populations was also compared.Patients and Methods: Between January 2010 and May 2015, 104 DLBCL were enrolled in this study. In order to establishing correlations between the clinical features and response to treatment the following parameters were analyzed: clinical symptoms, serum albumin, serum lactate dehydrogenize (LDH),b 2microglobulin, tumor bulky stage of disease, age-adjusted international prognostic index (aaIPI), and response to treatment. Statistical analysis using SPSS software included descriptive analyses, Kaplan-Meyer estimates for overall survival and Cox regression;p values <0.05 were considered significant. The final analyses were adjusted to Brazilian and European patients due to different clinical data at diagnosis.Results: 104 patients, median age 69 (28-88) years, were enrolled in this study, with a female: male ratio of 1.2:1. Their ECOG performance status was 0 in 48.5%; 1 and 2 in 42.6% and ≥3 in 8.9% cases, whereas aaIPI risk distribution was 12 (12.6%) high risk, 20 (21.1.%) high-intermediate risk and 63 (66.3%) low/low-intermediate high in 57/80 patients (71.2%). The test for identification of Helicobacter Pillory (HP) was performed in 45 patients and was positive in 13 (28.9%); also Hepatitis B serology, available in 97 cases, 46.4% positive. The most common symptoms included abdominal pain (63/74) and weight loss (57/73), dysphalgia (37/72) and nausea, vomiting (37/72). Bulky wasfound in 24%, plus anemia (33/76) and bleeding (22/72). Endoscopic examination was realized in 95%, however, only 10% was submitted to surgery. Brazilian patients were younger and more frequently symptomatic at diagnosis, although aaIPI was similar among the two populations. Almost all patients received chemotherapy (96% RCHOP-like).The median follow-up time was 14 (1-77) months, with 1- and 5-year survival rates of 79 and 76%, respectively. 5-year survival rates were significantly influenced by anemia (p= 0.007), LDH at the diagnosis (p< 0.0001), B symptoms (p<0.0001), clinical stage (p= 0.003), aaIPI 2 and 3 (p<0.0001), nausea (p=0.04) and bulky disease (p=0.02). Other variables, including gender (p= 0.17), presence of dysphagia (p= 0.08), weigh loss (p= 0.11), pain (p= 0.14) and bleeding (p= 0.06) and elevated β2microglobulin at diagnosis (p= 0.09) didn't influence the outcome.Furthermore, multivariate analysis applying Cox Regression and adjusted by Brazilian and European patients confirmed that overall survival was only influenced by aaIPI 2 and 3 (HR 9.16, CI95%: 2.16-16.8; p< 0.0001) and female gender (HR 2.71, CI95%: 1.03-7.13; p= 0.004).In conclusionIn this series of European and Brazilian gastric DLBCL patients were confirmed the impact of aaIPI on survival and identified female gender as poor prognosis factor. Differences in clinical presentation among countries may relate to heterogeneous disease biology and deserve further investigations. DisclosuresLuminari:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees.

The Ki-67 index in non-Hodgkin's Lymphoma: Role and Prognostic Significance

Background: Ki67 is a nuclear and nuclear protein antigen present in all proliferating cells during the active part of the cell cycle: G1, S, G2, and mitosis. The aim of study is to evaluate survival based on Ki67 index in NHL patients in the west of Iran for the first time. Patients and Methods: Between of 2002 to 2014, fifty-six patients with NHL referred to Our Clinic. We checked age, sex, type of NHL, Ki67 index and survival for them. We divided Ki67 index to two groups: low Ki67 (Ki67<65%) and high Ki67 (Ki67≥65%). Results: The mean age at diagnosis for patients was 47.33±166.50 years (range, 13-77 years) that 27 patients (48.2%) had age≤ 50 years and 33 patients (58.9%) were male. Thirty-eight patients (67.9%) had Ki67<60% and 18 patients (32.1%) had Ki67≥65%. The mean Ki67 for Nodal patients was 48.1% and for extra nodal was 54.5%, but there was no significant correlation between them (P=0.360). Conclusion: Ki67 in future studies should be divided based on a fix percent until we can have a better result about the role of Ki67 in NHL patients. Also, Ki67 alone can not be a risk factor in NHL patients and other factors such as age, sex and type of NHL can be affective, too.

Head and neck extra nodal NHL (HNENL)--Treatment Outcome and Pattern of failure--A Single Institution Experience.

Extra nodal lymphoma (ENL) constitutes about 33 % of all non-Hodgkin's lymphoma. 18-28% develops in the head and neck region. A multimodality treatment with multi-agent chemotherapy (CT) and radiotherapy (RT) is considered optimum. We retrieved the treatment charts of patients of HNENL treated in our institute from 2001-2012. The charts were reviewed and the demographic, treatment details and outcome of HNENL patients were retrieved using predesigned pro-forma. We retrieved data of 75 consecutive patients HNENL. Median age was 47 years (Range: 8-76 years). Of the 75 patients 51 were male and 24 were female. 55 patients were evaluable. The patient and tumor characteristics are summarized in Table 1. All patients were staged comprehensively with contrast enhanced computed tomography of head, neck, thorax, abdomen, pelvis and bone marrow aspiration and biopsy 66 patients received a combination multi-agent CT with CHOP being the commonest regimen. 42 patients received 4 or lesser number of cycles of chemotherapy whereas 24 received more than 4 cycles chemotherapy. Post radiotherapy, 41 out of 42 patients had a complete response at 3 months. Only 21 patients had a complete response after chemotherapy. All patients received radiation (mostly involved field radiation) as a part of the treatment. The median radiation dose was 45 Gray (Range: 36 Gray-50 Gray). The radiation was planned by 2D fluoro simulation based technique in 37 cases and by 3 Dimensional conformal radiation therapy (3DCRT) in 36 cases. Two patients were planned by the intensity modulated radiation therapy (IMRT) technique. IMRT was planned for one thyroid and one nasal cavity primary. 5 patients experienced relapse after a median follow up of 19 months. The median survival was not reached. The estimated two and three year survival were 92.9% (95%CI-68.6-95.35) and 88% (95%CI-60.82-92.66) respectively. Univariate analysis revealed higher stage and poorer baseline performance status to be significantly associated with worse progression free survival. 5 patients progressed (relapse or primary disease progression) after treatment. Of the 5 patients, two patients were primary orbital NHL, two patients had NHL nasal cavity and one was NHL thyroid. Combined modality treatment in HNENL confers excellent disease control with acceptable side effects.

Abstract 17: Xiap over-expression is a poor prognostic marker in breast cancer and can be targeted to induce efficient apoptosis

Abstract Breast cancer is the most common cancer in females and is ranked only second to lung cancer in cancer-related deaths all over the world in women. Despite improvement in diagnosis and management of breast cancer, the survival rate of this disease for stage 4 disease is still only 22%. X-linked Inhibitor of Apoptosis (XIAP) is a member of the inhibitor of apoptosis family of proteins that has been shown to be over-expressed in a variety of cancers including breast cancer leading to an overall poor survival. However, the role of XIAP in breast cancer from Middle Eastern region has not been fully explored. We therefore examined the expression of XIAP in a cohort of 964 breast cancer cases by immunohistochemistry and found that XIAP was over-expressed in 29.5% (284/964) of the cases and was found to be directly associated with clinical parameters such as tumor size (p = 0.0044), extra nodal extension (p = 0.0041) and poorly differentiated breast cancer (p&amp;lt;0.0001). In addition, XIAP over-expression was also significantly associated with activated AKT (p&amp;lt;0.0001), Ki-67 (p&amp;lt;0.0001) and PARP (p&amp;lt;0.0001). Finally, XIAP over-expression in our cohort of breast cancer was an independent poor prognostic marker in multivariate analysis. Next, we investigated inhibition of XIAP using a specific inhibitor; Embelin on a panel of breast cancer cell lines and found that Embelin treatment led to inhibition of cell viability and induction of apoptosis in breast cancer cells. In order to identify the exact pathway involved in XIAP inhibition, we treated breast cancer cells with different doses of Embelin and found that there was down-regulation of XIAP leading to activation of caspases-9, -3 and PARP. We also found that Embelin treatment caused cleavage of caspase-8 and truncation of Bid leading to activation of the mitochondrial apoptotic pathway and efficient apoptosis. Finally, as our clinical data demonstrated a significant association between XIAP over-expression and activation of AKT in breast cancer samples, we synergistically induced apoptosis in breast cancer cells using sub-optimal doses of Embelin and PI3-kinase inhibitor; LY294002. These data suggest that XIAP may be playing an important role in the pathogenesis of breast cancer and XIAP can be therapeutically targeted either alone or in combination with PI3-kinase inhibition to induce efficient apoptosis in breast cancer cells. Citation Format: Azhar R. Hussain, Maqbool Ahmed, Rong Bu, Shaham Beg, Alanood M. Alrashed, Roxanne Melosantos, Dahish S. Ajarim, Shahab Uddin, Khawla S. AlKuraya. Xiap over-expression is a poor prognostic marker in breast cancer and can be targeted to induce efficient apoptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 17. doi:10.1158/1538-7445.AM2015-17

Primary Hepatic Burkitt Lymphoma: A Bizarre Site and Triumph Tale

Primary hepatic Burkitt lymphoma (PHBL) is an extremely rare form extra nodal lymphoma and till now only 11 case reports have been found in the literature. We are reporting an adult female with primary hepatic Burkitt's lymphoma, who achieved complete remission after 5 months of combination chemotherapy containing vincristine, cyclophosphamide, doxorubicin, methotrexate, prednisolone and intrathecal chemotherapy. She is under regular follow up at our institute.

Adult non Hodgkin's lymphoma patients: experience from a tertiary care cancer centre in north east India.

There is paucity of data on non Hodgkin's lymphoma (NHL) from our population in North-East India. In this retrospective study, patients were consecutively followed-up to see the clinic-pathological pattern of NHL, various responses, and pattern of relapses to first line treatment with chemotherapy. All patients in the present study received standard regimen of cyclophosphamde, doxorubicin, vincristine, prednisolone (CHOP) with or without rituximab (R-CHOP) as per our institutional protocol as first line therapy. Our study has shown that, in our adult population, the majority of NHL cases present with stage II and stage III disease and extra nodal involvement, B-cell lymphomas and diffuse large cell lymphomas being the most common subtypes. International prognostic index was a significant factor for varied responses to treatment. The majority of relapses after complete remission occurred in the first year.

The Jaw Tumor: A Surgical and Oncologic perspective

The Jaw tumor is now a very well-known entity in the field of medicine and Called Burkitt Lymphoma Syndrome or Burkitt’s lymphoma (BL). It is a highly aggressive non-Hodgkin’s lymphoma and is the fastest growing tumors in children especially in East Africa. This is the first malignant extra nodal lymphoma in which Epstein-Barr virus has been detected specially in the tumors of East African origin. The discovery of EBV is the Burk kit’s tumor is another progress that has been MADE THE MEDICAL COMMUNITY to understand the disease process. EBV virus may be playing a role as an oncogene for this disease by retranslocating or translocation the c-MYC gene. Early days when such tumor is introduced by Dennis Burkitt before the medical community there was no real pathological classification, immumohistochemical or biological study. Subsequently it was felt that a chromosal translocation that activates an oncogene called e-MYC is the etiology of such tumor. But current molecular study shows that there are other oncogenes that are involved in the development of this deadly ailment especially in western countries. Our knowledge of BL was inadequate in early years of discovery of BL and so as well our diagnosis and treatment. In early stage of discovery of BL there were very limited option of treatment from local radical surgery, local radiation( which was not available in Uganda during that time) to only two chemotherapies and 5 years of survival rate was only 10%.But with our current knowledge of molecular biology of this malignancy there are multiple options of treatment such as combination of various chemotherapies, monoclonal antibodies either alone and or in combination and with either complete removal of tumor or debunking procedure specially abdominal neoplasm, the current 5 years survival rate is about 90%.This very brief review article describes the background, clinical feature, histology ,molecular study as it relates to prognosis and current treatment of both Burkitt’s tumor and extra nodal abdominal tumor both based on experience of our group in late seventies of treating few cases of devastating abdominal BL and review of few scholarly article on BL. DOI: http://dx.doi.org/10.3329/jbs.v21i0.22513 J. bio-sci. 21: 01-19, 2013

Prognostic significance of the number and type of extra nodal localizations of DLBCL in the rituximab era

IntroductionThe aim of the study was to assess the prognostic significance of the number and type of extra nodal localizations of DLBCL as well as other factors included in IPI in the rituximab era. Materials and methodsWe conducted a retrospective analysis of medical documentation of 178 patients with DLBCL treated in two oncology centers between 2006 and 2011. We distinguished 3 subgroups of patients: with only nodal localization of DLBCL (A, n=80), with 1 extra nodal site (B, n=66) and with ≥2 extra nodal sites (C, n=32). ResultsThe presence and the number of extra nodal lesions did not have a prognostic impact both on the response and survival. Probabilities for OS were 79.4%±6, 85.5%±5 and 78.5%±8 for groups A, B and C respectively. Most common extra nodal localizations of DLBCL were: digestive duct, bones and skin. The site of involvement also did not have a prognostic significance. In a multivariate analysis negative prognostic factors for OS probability were: elevated LDH level (HR: 3.12 [95% CI: 1.3–7.47], p=0.01) and disease stage ≥III (HR: 4.61 [95% CI: 1.32–16.1], p=0.02). ConclusionsNeither the number of extra nodal lesions nor their localization affects prognosis in patients with DLBCL in the rituximab era.

A Rare Cause of Cavitary Lesion in the Lung: Richter's Transformation.

Richter's transformation (RT) refers to the development of aggressive lymphoma during the course of CLL. Clinically, patients with RT present with an aggressive disease course with rapidly enlarging lymph nodes, hepatosplenomegaly, and elevated serum lactate dehydrogenase levels. But rarely it presents with extra nodal organ involvement at the beginning. Common sites of extra nodal involvement are the gastrointestinal tract, eye, central nervous system, lung, and kidney. We are reporting this case that was presented with RT in the lung involvement diagnosed while researching cavitary lesion etiology.

Plasmablastic lymphoma of the testis in a human immunodeficienecy virus patient - report of a rare entity

Testicular lymphoma is the second most common extra nodal lymphomas. It is a highly lethal disease with a median survival of 1-2 years. In human immunodeficiency virus (HIV) patients, primary testicular lymphomas are estimated to comprise > 6% of testicular tumors, and they tend to occur in younger patients. Testicular lymphoma can occasionally be the initial manifestation of the disease in HIV patients.Plasmablastic lymphoma (PBL), which is considered as a variant of diffuse large B-cell lymphoma is a highly aggressive tumor with poor prognosis. PBL has a well-established association with HIV infection and occurs most commonly in the oral cavity. The presentation at extra nodal sites and absence of usual hematolymphoid markers makes its diagnosis more difficult. PBL of the testis as the primary lesion in HIV patients has not been reported so far. We report a case of PBL presenting as a primary testicular lesion in a HIV patient with a grave prognosis.

An uncommon presentation of Burkitt′s lymphoma as a primary gastrointestinal tumor causing intussusception: A case report with review of literature

Burkitts's lymphoma is the commonest subtype of B-cell non-Hodgkins lymphoma in childhood. Though gastrointestinal tract is the commonest extra nodal site, intussusception secondary to Burkitt's lymphoma is an uncommon presentation. We report a case of an 8-year-old female child who presented with acute abdomen. A tumor arising from ileocaecal valve was the lead point causing intussusception that was reduced, and a limited right hemi colectomy was performed. A final diagnosis of Burkitt's lymphoma was made based on immunohistochemistry.

Unusual case of Hodgkin lymphoma presenting as soft tissue mass with intracranial metastasis and review of literature

Hodgkin lymphoma (HL) primarily presents as nodal disease and may involve extranodal sites during the progression of the disease. Extra nodal involvement of lung, gastrointestinal tract, testis and thyroid etc., is well-recognized in non-HL but clinically detectable soft tissue involvement is rare and quite exceptional with HL. We report here an unusual case of a young adult male, who presented with a frontal soft tissue mass associated with cervical lymph node. Histopathology supplemented with immunohistochemistry revealed classical HL. Patient did not respond to treatment adequately, and he developed intracranial metastasis during the course of treatment.

Diffuse large B-cell lymphoma of the thyroid: Seven cases with review of the literature from India

Background: Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of nonHodgkin's lymphoma globally with frequent extra nodal involvement. There is sporadic data available on thyroid DLBCL in Indian population and hence we undertook this retrospective observational study at Kidwai Memorial Institute of Oncology, a tertiary care oncology center in India to analyze the clinico biological features of this disease. Methodology: A total of 7 consecutive cases diagnosed as DLBCL by appropriate lymph node biopsy with evidence of thyroid involvement on fine-needle aspiration cytology of thyroid or thyroid histopathology (following thyroidectomy) were confirmed by immunohistochemistry (WHO classification) between January 2008 and September 2013 were included in this study. Results: A total of 7 patients were included in the study. Median age was 65-years (range: 50-72 years), and all were females. Six out of seven were in stage IIAE and one was in stage IVAE. The distribution according to the international prognostic index was as follows: 3 were in low risk, 1 in low-intermediate, 2 in high-intermediate and 1 in high risk group. Regarding treatment, 5 received CHOP, 1 received COP and 1 received no treatment. 5 patients received radiotherapy. 2 patients underwent subtotal thyroidectomy. Of the 6 patients who received chemotherapy ΁ radiotherapy, 4 had complete response 1 was lost to follow-up at 3 months and 1 alive with no disease at 32 months), 2 had partial response. The median survival was 15 months (3-32 months). Conclusions: Extranodal thyroid DLBCL presents common in elderly age group and in females. A multimodality treatment approach is used to treat this entity and may improve survival compared with unimodality approach.