The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High-resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24, and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes. Mutations in genes promoting the tonic B-cell receptor (BCR)→PI3K pathway ( and ) did not differ by age, whereas effectors of chronic BCR→NF-κB signaling were associated with adult-mBL. A subset of adult-mBL had translocation and mutation and elevated mRNA and protein expression, but had a mutation profile similar to mBL. These double-hit lymphomas may have arisen from a tumor precursor that acquired both and translocations and/or () mutation. Gain/amplification of and its paralogue loci was observed in 50% of adult-mBL. In vitro studies suggested's role in constitutive activation of BCR signaling and sensitivity to ibrutinib. Overall integrative analysis identified an interrelated gene network affected by copy number and mutation, leading to disruption of the p53 pathway and the BCR→PI3K or NF-κB activation, which can be further exploited in vivo by small-molecule inhibitors for effective therapy in adult-mBL.

Central nervous system (CNS) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS relapse after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. In a three-center retrospective analysis, we reviewed the data for 457 adult patients with ALL who received a first allogeneic HSCT in first or second complete remission (CR). All patients received CNS prophylaxis as part of their upfront therapy for ALL, but post transplant CNS prophylaxis practice varied by institution, and was administered to 48% of the patients. Eighteen patients (4%) developed CNS relapse after HSCT (isolated CNS relapse, n=8; combined bone marrow and CNS relapse, n=10). Patients with a prior history of CNS involvement with leukemia had a significantly higher rate for CNS relapse (P=0.002), and pre transplant CNS involvement was the only risk factor for post transplant CNS relapse found in this study. We failed to find a significant effect of post-transplant CNS prophylaxis to prevent relapse after transplant. Furthermore, no benefit for post-transplant CNS prophylaxis could be detected when a sub-group analysis of patients with (p=0.10) and without prior CNS involvement (p=0.52) was performed. Finally, we couldn’t find any significant impact for intensity of the transplant conditioning regimen on CNS relapse after HSCT. In conclusion, CNS relapse is an uncommon event following HSCT for ALL in CR1 or CR2, but with higher risk among patients with CNS involvement pre transplant. Furthermore, neither the use of post-HSCT CNS prophylaxis nor the intensity of the HSCT conditioning regimen made a significant difference in the rate of post-HSCT CNS relapse.

Introduction Central nervous system (CNS) recurrence after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS recurrence after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. Our goal was to investigate the post-HSCT outcome of ALL patients and identify patient groups who may benefit from post-HSCT CNS prophylaxis. Methods In this two-center retrospective study, we studied all adult (age≥18) ALL patients who underwent HSCT at MD Anderson Cancer Center or Fred Hutchinson Cancer Research Center between 1997 and 2011. We included all adult ALL patients who were transplanted in the first or second complete remission (CR) and who received any prophylactic or therapeutic CNS therapy before HSCT. We assessed the cumulative incidence of systemic and CNS relapses in a competing risks framework with a competing risk of non-relapse death. Since data from second and subsequent relapses were not available, patients whose first relapse did not include CNS involvement were censored at the time of relapse. To analyze the association between post-HSCT CNS prophylactic therapy and CNS relapse, we used a landmark analysis, including only patients who had not relapsed or died by 3 months post HSCT. Results We included 415 adult ALL patients (239 in CR1 and 176 in CR2) who were transplanted with a myeloablative total body irradiation based (MA-TBI, n=252), myeloablative non-TBI based (MA-nonTBI, n= 130), or reduced intensity conditioning regimen (RIC, n=33). Median age at HSCT was 37 years (range 18-70; 59% male). Sixty seven patients (16%) had a history of pre-HSCT CNS involvement either at diagnosis or at time of first relapse, while 339 patients (81%) had no CNS disease at any time before HSCT. Overall 175 patients (42%) received CNS prophylaxis after HSCT. CNS prophylaxis included intrathecal methotrexate, cytarabine, or both agents. Two patients received prophylactic cerebrospinal radiotherapy. The median follow-up for the 189 surviving patients was 4.2 years. Sixteen patients (3.8% of all patients, 13.2% of all relapses) developed CNS relapse (11 isolated and 5 combined with marrow relapse) at a median of 231 days (range 38-1397) after HSCT. Seven of these patients had pre-HSCT CNS disease. The 4-year cumulative incidence of relapse after HSCT among all patients was 31.7% and 28.2% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.51). The 4-year cumulative incidence of CNS relapse was 6% and 2.6% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.16) (Figure 1). When the analysis was limited to the patients without prior CNS involvement, there was still no benefit to post-HSCT CNS prophylaxis (P=0.63). Patients with a prior history of CNS involvement with leukemia had a significantly higher rate for CNS relapse, 11.6% vs. 2.7% (P=0.003) (Figure 2). The 4-year rate of CNS relapse was not impacted by intensity of the HSCT conditioning regimen and was 3%, 4%, and 6.5% for RIC, MA-TBI, and MA-nonTBI, respectively. Conclusion CNS relapse is an uncommon event following HSCT for ALL in CR1 or CR2. Furthermore, neither the intensity of the HSCT conditioning regimen nor the routine use of post-HSCT CNS prophylaxis made a significant difference in the rate of post-HSCT CNS relapse in patients who had received CNS prophylaxis prior to HSCT. Not surprisingly, patients with a pre-HSCT history of CNS involvement had a significantly higher risk of CNS relapse after HSCT. Disclosures: No relevant conflicts of interest to declare.

Along with other etiological factors like genetics, family history, age, etc. there is growing scientific evidence that exposure to chemicals, including pesticides is associated with increased incidence of breast cancer among women. Various animal studies have demonstrated the carcinogenic effect of pesticides byacting as Xenoestrogen, interacting and disrupting estrogen receptors or by damaging breast tissue DNA inducing malignancy/catalyzing existing DNA mutation in susceptible individuals. Pesticide's role as a contributing etiological factor in growing incidence of breast cancer is of particular concern as pesticides is one of the chemicals to which humans get exposed every day in significant concentration. In this review we describe various kinds of pesticides and their respective associations to breast cancer.

Introduction During initial diagnosis and therapy, patients with ALL can develop life-threatening complications such as sepsis, leukostasis, hemorrhage, and tumor lysis syndrome. Dedicated multidisciplinary leukemia teams may be needed to provide optimal management of such complications and selection of optimal therapeutic strategy. AH are more likely to have such expertise, adequate resources, standard operating policies and clinical trials, which may influence early mortality and OS. Such trends have been noted for other malignancies, such as lung cancer (Samson, Am Thorac Surg 2015 and Luchtenborg JCO 2013). In acute myeloid leukemia, OS may be better if patients are treated in a high-volume hospital (Giri Blood 2015). Whether OS of ALL differs based on the facility type remains unclear. Methods Using the NCDB Participant User File, we extracted patient-level data of patients with ALL reported between 1998 to 2012. Hospital facilities were classified as either AH (academic/research program) or NAH (community cancer program, comprehensive community cancer program, and other, as per NCDB classification). Patients, who received all of their first course treatment or a decision not to treat made at the reporting facility, were included. Subjects with complete and known data for the variables sex, age, race, education, income, distance traveled for health care, hospital type, facility location, urban/rural location, insurance, Charlson co-morbidity score, chemotherapy use, time from diagnosis to treatment initiation, use of hematopoietic stem cell transplant, 30-day mortality, last contact, and vital status were included. These variables were analyzed in a univariate analysis. Kaplan Meier curves were drawn and compared using log rank test. Multivariate analysis was performed using logistic regression for 30-day mortality and cox regression with backward elimination approach for OS. Statistical analysis was done using PC SAS version 9.4. Results Of 9863 patients with ALL, 5710 (57.9%) were treated in AH. Patients treated at AH versus NAH were more likely to be African-Americans, uninsured and Medicaid insured, travel long distance to receive health care and receive transplant as a part of their treatment. The median OS (23 vs. 17 months) and 1-year OS (67% vs. 59%) were better in AH as compared to NAH (Figure 1). In a multivariate analysis, the 30-day mortality was significantly worse in NAH as compared to AH (odds ratio, OR 1.206; 95% confidence interval, CI 1.011-1.44; p <0.0374) (Table 1). Similarly, Cox regression showed that the OS was significantly worse in NAH as compared to AH (hazard ratio, HR 1.14; 95% CI 1.08-1.19; p <0.001) after adjusting for other covariates. Conclusion OS of patients with ALL may be improved, if patients receive initial therapy in AH. Possible explanations may include increased provider experience, enhanced multidisciplinary care, and access to clinical trials, among others. Improved understanding of such factors may provide opportunity to improve OS of patients treated at NAH. Table 1. Multivariate logistic regression of 30-day mortality Variable Odds ratio 95% confidence interval P value Academic (ref) Non-Academic 1 1.206 1.01-1.44 0.0374 Age - <60 years (ref)- > 60 years 1 2.907 2.28-3.71 <0.001 Charlson comorbidity score -0 (ref) -1- 2 or more 1 1.47 2.13 1.18-1.82 1.57-2.88 0.0005 <0.0001 Chemotherapy - Yes (ref) - No 1 2.93 1.82-4.72 <0.0001 Days until first treatment 0.927 0.91-0.94 <0.0001 High school education - 29% or more (ref) - 20%-28.9% - 14%-19.9% - Less than 14% 1 0.82 0.88 0.63 0.63-1.06 0.69-1.14 0.49-0.81 0.13 0.34 0.0004 Insurance Status - Private insurance/managed care (ref)- Not insured - Medicaid - Medicare - Other government 1 1.46 0.80 1.61 0.45 1.04-2.05 0.57-1.12 1.26-2.06 0.11-1.84 0.03 0.20 0.0002 0.26 Figure 1. Kaplan Meier curve showing cumulative survival among ALL patients treated at AH versus NAH (p value of log rank test <0.001) Figure 1. Kaplan Meier curve showing cumulative survival among ALL patients treated at AH versus NAH (p value of log rank test <0.001) Disclosures No relevant conflicts of interest to declare.