scholarly journals Effect of Pesticide Exposure on Non-Hodgkin Lymphoma Incidence and Survival in California

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 5006-5006
Author(s):  
Christina Poh ◽  
John D. McPherson ◽  
Joseph Tuscano ◽  
Qian Li ◽  
Arti Parikh-Patel ◽  
...  

Abstract Introduction: While previous studies propose pesticide exposure to be a risk factor for non-Hodgkin lymphoma (NHL) development, results are inconclusive. In addition, the impact of pesticide exposure on NHL survival is not well-established. Therefore, we identified NHL patients from the California Cancer Registry and linked these patients with the statewide pesticide use reporting database to determine the impact of pesticide exposure on NHL-related incidence and outcomes. Methods: Using the California Cancer Registry, we identified patients with a first primary diagnosis of NHL from 2010-2016 and linked these patients with CalEnviroScreen 3.0 to obtain production agriculture pesticide exposure to 70 chemicals from the state mandated Pesticide Use Reporting (PUR) by census tract from 2012-2014. In addition, data from PUR was integrated into a geographic information system that employs land use data to estimate cumulative exposure to specific pesticides previously associated with NHL (glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4-dimethylamine salt) between 10 years prior up to 1 year after NHL diagnosis. SEER*Stat software was used to calculate NHL subtype incidence rates by census tract pesticide use level. Multivariable cox proportional hazards regression models were used to evaluate the impact of total pesticide exposure from CalEnviroScreen 3.0 and individual pesticide exposure from geographic land use data on lymphoma-specific and overall survival. Results: Among 35,808 NHL patients identified, 44.2% were exposed to pesticide in their census tract of residence. Pesticide exposure was higher in Hispanic/Latino (46.5%) and non-Hispanic white (45.6%) then Asian/Pacific Islander (37.2%) and African American (34.9%) patients with NHL. Glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4-dimethylamine salt exposure was reported in 34.1%, 26.0%, 10.6%, 14.0% and 12.8% of NHL patients, respectively. Pesticide exposure was not associated with increased NHL incidence by NHL subtype or subgroups defined by sociodemographic factors. Total pesticide exposure at time of diagnosis was not associated with lymphoma-specific or overall survival. In addition, no association was consistently found between glyphosate, organophosphorus, carbamate, phenoxyherbicide and 2,4 dimethylamine salt exposure and lymphoma-specific or overall survival. Conclusion: In this large population-based study of neighborhood agricultural pesticide exposure, pesticide exposure was noted to be prevalent among patients diagnosed with NHL, with high pesticide exposure particularly observed in Hispanics/Latinos and non-Hispanic whites. However, pesticide exposure was not consistently associated with increased NHL incidence or worse NHL lymphoma-specific or overall survival. Disclosures Poh: Acrotech: Honoraria; Incyte: Research Funding; Morphosys: Consultancy. Tuscano: BMS: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Acrotech: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2710-2710
Author(s):  
Catherine Bulka ◽  
Loretta Nastoupil ◽  
William McClellan ◽  
Alex Ambinder ◽  
Adrienne A. Phillips ◽  
...  

Abstract Abstract 2710 Background: Increased risk of Non Hodgkin Lymphoma (NHL) has been observed in persons occupationally exposed to benzene, but the risk among persons living near benzene release sites has been less studied. Methods: In order to investigate the spatial patterns of NHL incidence and the association between NHL incidence and distance to benzene release sites, we linked cancer incidence data for the period 1999–2008 from the Georgia Comprehensive Cancer Registry (a CDC-supported a statewide population-based cancer registry collecting all cancer cases diagnosed among Georgia residents since 1995) with population data from the U.S. Census, and with Environmental Protection Agency's Toxics Release Inventory data on the locations of benzene release sites in Georgia between 1988–1998. NHL cases were aggregated by census tract. Descriptive spatial analysis was performed using ArcGIS. Choropleth maps were created to depict the standardized incidence ratios (SIRs) by census tract for NHL and NHL subtypes, and locations of benzene release sites were overlayed upon SIR maps. Spatial Empirical Bayes smoothing was performed on the SIR values using GeoDa 1.01. To assess spatial correlation in SIRs, we conducted global, local, and focal spatial analyses. The global Moran's I and a local Moran's I (also termed Local Indicators of Spatial Autocorrelation [LISA]) were calculated for SIR patterns of NHL and NHL subtypes. The Lawson-Waller Score test was used to individually assess each of the 19 benzene release sites for focal clustering of NHL with Bonferroni correction for the 19 comparisons. We performed Poisson regression on NHL incidence rates, using the mean distance between the tracts centroids and release sites as a marker of exposure. Results: 12,716 incident NHL cases occurred among adults residing in Georgia during this period. There was a positive spatial autocorrelation for cases of NHL, B-cell NHL, T-cell NHL and for diffuse large B-cell lymphoma indicating that cases NHL in Georgia were geographically clustered (all global Moran's p-values < 0.05). LISA cluster maps of SEB-smoothed SIRs (Figure) show the locations of “hot-spots” (high-high clusters) and “cold-spots” (low-low clusters). High SIRs were clustered in the metro-Atlanta area for NHL and NHL subtypes, while low SIRs were mostly in the southern region of the state. The Lawson-Waller test scored each census tract for the difference between the observed and expected NHL incidence, weighted by inverse distance to the sites. Results were statistically significant at the á= 0.0026 level (Bonferroni correction) for 15 of the 19 benzene release sites. All sites located within the metro-Atlanta area had significant focal clustering, with greater incidence rates observed in the tracts near these sites than expected. Mean distance from benzene release site had a protective effect with a 0.4% decrease in the incidence rate of NHL for every mile the mean distance increased. Conclusions: Clusters of NHL were significantly spatially associated with benzene release sites located in the metropolitan Atlanta area, but not with release sites in other areas of the state. Populations living in a census tract ≥100 miles away from all benzene release sites in Georgia have approximately a 40% decrease in the expected incidence of NHL when compared to populations living in a census tract adjacent to a benzene release site. While the overall incidence of NHL in Georgia is low (17.4/100,000 individuals in the population/year), this represents a significant change in incidence pattern. Additional studies are needed to identify factors that modify this risk. Disclosures: Flowers: Genentech/Roche (unpaid): Consultancy; Millennium (unpaid): Consultancy; Celgene: Consultancy; Celgene: Research Funding; Spectrum: Research Funding; Millennium: Research Funding; Gilead: Research Funding; Janssen: Research Funding.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5100-5100
Author(s):  
Nicholas J. Ollberding ◽  
Andrew M. Evens ◽  
Briseis Aschebrook-Kilfoy ◽  
Donne Bennett D. Caces ◽  
Dennis D Weisenburger ◽  
...  

Abstract Abstract 5100 Introduction: Smoking has been suggested as a potential risk factor for the development of non-Hodgkin lymphoma (NHL). However, the prognostic impact of smoking in patients with NHL has not been well studied and may have important implications regarding outcome. Methods: In a population-based cohort of 308 NHL patients diagnosed between 1999 and 2002, we examined the association between cigarette smoking habits prior to NHL diagnosis and overall survival (OS). Multivariable Cox proportional hazards models adjusted for age, gender, and education were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for all NHL, and for follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Measurements of smoking included categories for smoking status, pack-years of smoking, years of smoking, daily number of cigarettes smoked, and years since quitting smoking. Continuous exposures for cigarette smoking were also examined with potential non-linear relations tested using restricted cubic splines. We conducted subgroup analyses adjusting for established clinical and prognostic variables. Results: In the patient cohort, a total of 96 deaths occurred over a median follow-up period of 8. 2 years. For all NHL cases, current smokers had worse survival (HR=1. 8 [1. 0–3. 1], ptrend=0. 07, for risk of all-cause mortality) when compared to never smokers. The inferior survival was also associated with pack-years of smoking (HR=1. 5 [0. 9–2. 4], ptrend=0. 12, for >30 pack-years) and smoking duration (HR=1. 5 [0. 9–2. 3], ptrend=0. 13, for >30 years). Smoking remained an independent predictor of OS after adjustment for initial treatment, stage at diagnosis and the presence of B symptoms: HR=2. 6 [1. 1–6. 3], ptrend=0. 03, for current smokers; HR=2. 4 [1. 1–5. 6], ptrend=0. 03, for patients with >30 pack-years of cigarette smoking; and HR=2. 5 [1. 2–5. 5], ptrend=0. 02, for patients smoking longer than 30 years. Among former smokers, a shorter interval from quitting to diagnosis was associated with worse survival (per 5 years of quitting cigarette smoking, HR=0. 9 [0. 8–1. 0], ptrend=0. 06). The associations with cigarette smoking and OS were stronger for FL than for DLBCL. In analyses stratified by age at diagnosis, the associations for current smokers (HR=3. 7 [1. 5–9. 2], ptrend=0. 01), daily number of cigarettes smoked (HR=2. 8 [1. 0–7. 5], ptrend=0. 04), and years of cigarette smoking (HR=3. 0 [1. 1–8. 3], ptrend=0. 04) were stronger for patients diagnosed at <60 years of age. The risk estimates for smoking with OS did not depart from unity among those diagnosed at ≥ 60 years of age. The associations between cigarette smoking and OS were similar for men and women. Conclusion: Our data suggest that cigarette smoking prior to diagnosis is associated with inferior OS in NHL patients. The reduction in survival is most prominent for patients diagnosed at <60 years of age and for those with FL. Among former smokers, greater time from cessation of smoking to diagnosis may improve OS. Further research examining the impact of smoking cession on OS among NHL patients is warranted. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14 ◽  
Author(s):  
Tae Min Kim ◽  
Nehal Lakhani ◽  
Justin Gainor ◽  
Manali Kamdar ◽  
Philip Fanning ◽  
...  

Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host's immune response. The high affinity CD47 blocker fusion protein, ALX148, is linked to an inactive immunoglobulin Fc region to minimize toxicity. ALX148 is half the size of an antibody, has been well tolerated, and enhances the innate and adaptive immune response against cancer in combination with anticancer therapeutics across solid and hematologic tumors (ASCO 2020 #3056, EHA 2020 #EP1247). Characterization of ALX148's tolerability profile and antitumor activity in combination with rituximab are reported in patients (pts) with non-Hodgkin Lymphoma (NHL). Methods: Patients with relapsed or refractory CD20-positive B-cell NHL for which no curative therapy was available received ALX148 (10 mg/kg QW or 15 mg/kg QW) in combination with rituximab (375 mg/m2 weekly for 4 doses followed by once monthly for 8 doses). The primary endpoint for the safety population was dose limiting toxicity (DLT). Tumor response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed in all pts. Data are reported as of 30Jun2020 in these fully enrolled cohorts with final data to be updated at the time of presentation. Results: A total of 33 patients with NHL were administered ALX148 in combination with rituximab. Twenty-two pts with median age of 66 years (range 32-80) were administered ALX148, 10 mg/kg QW (ALX10), in combination with rituximab [DLBCL, n=11; mantle cell lymphoma (MCL), n=4; follicular lymphoma (FL), n=5; and marginal zone lymphoma (MZL), n=2]. Eleven pts with median age of 64 years (range 53-78) were administered ALX148, 15 mg/kg QW (ALX15), in combination with rituximab (DLBCL, n=6; MCL, n=1; FL, n=3; and MZL, n=1). There have been no DLTs reported in the fully enrolled safety cohorts, and the MTD of ALX148 in combination with rituximab has not been reached. The maximum ALX148 administered dose is 15 mg/kg QW. Twenty-eight pts experienced any AE, while 16 pts reported mostly low grade treatment-related adverse events (TRAE). The most common TRAEs were rash (21%, n=7), fatigue (9%, n=3), anemia, nausea, neutropenia, and pruritus (6%, n=2 each). With a median follow up of 14 months, objective responses were observed across all histologies in response-evaluable ALX10 pts: 40.9% ORR (4CR,5PR, 6SD, n=22 total) and with a median follow up of 9 months in ALX15 pts: 63.6% ORR (3CR, 4PR, 1SD, n=11 total). Preliminary results indicate favorable ALX148 PK and near complete CD47 receptor occupancy across the dosing interval. Final results will be updated at time of presentation. Conclusions: ALX148 demonstrates excellent tolerability with durable responses in combination with rituximab in patients with relapsed/refractory NHL. The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity and favorable PK/PD characteristics in combination with rituximab were observed at all dose levels with greater objective response rates reported at the MAD of 15 mg/kg QW. Disclosures Kim: Boryung: Consultancy; Voronoi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Takeda: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding; AstraZeneca: Consultancy. Lakhani:incyte: Research Funding; merck: Research Funding; mersana: Research Funding; northern biologics: Research Funding; odonate: Research Funding; pfizer: Research Funding; ikena: Research Funding; symphogen: Research Funding; taiRx: Research Funding; tesaro: Research Funding; livzon: Research Funding; loxo: Research Funding; macrogenics: Research Funding; inhibRx: Research Funding; cytomx: Research Funding; formation biologics: Research Funding; forty seven inc: Research Funding; alexion Pharmaceuticals: Research Funding; Alpine Biosciences: Research Funding; ALX Oncology Inc.: Research Funding; Apexian: Research Funding; asana biosciences: Research Funding; ascentage pharma: Research Funding; beigene: Research Funding; celgene: Research Funding; cerulean pharma: Research Funding; constellation pharma: Research Funding; coordination therapeutics: Research Funding; regeneron: Research Funding; sapience therapeutics: Research Funding; shattuck labs: Research Funding; innovent bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; jounce therapeutics: Research Funding. Gainor:theravance: Consultancy; adaptimmune: Research Funding; ariad: Research Funding; astrazeneka: Research Funding; blueprint medicines: Research Funding; lily: Consultancy; gilead sciences: Consultancy; merck: Consultancy, Research Funding; moderna therapeutics: Consultancy, Research Funding; tesaro: Research Funding; blueprint medicines: Consultancy; novartis: Research Funding; oncorus: Consultancy; regeneron: Consultancy; bristol-myers Squibb: Consultancy, Research Funding; amgen: Consultancy; array biopharma: Consultancy, Research Funding; agios: Consultancy; ironwood pharmaceuticals: Consultancy; takeda: Consultancy; genentech: Consultancy, Research Funding; jounce therapeutics: Consultancy, Research Funding. Kamdar:Roche: Research Funding. Fanning:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Squifflet:ALX Oncology Inc.: Consultancy; IDDI: Current Employment. Jin:ALX Oncology Inc.: Current Employment. Forgie:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company; Pfizer Inc.: Ended employment in the past 24 months. Wan:Tallac Therapeutics: Current Employment, Current equity holder in private company; ALX Oncology Inc.: Consultancy, Current equity holder in publicly-traded company. Pons:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Randolph:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Kim:F. Hoffmann-La Roche: Research Funding; Pfizer: Research Funding; JJ: Research Funding; Celltrion: Research Funding; Kyowa Kirn: Research Funding; Donga: Research Funding; Mundipharma: Research Funding.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5326-5326
Author(s):  
Solomon A. Graf ◽  
Ryan C. Lynch ◽  
David G. Coffey ◽  
Mazyar Shadman ◽  
Sandra Kanan ◽  
...  

Abstract Background: Frontline treatment of indolent B-cell non-Hodgkin lymphoma (iB-NHL) typically involves intravenously administered anti-CD20 monoclonal antibodies with or without cytotoxic chemotherapy. Effective and low-toxicity therapies with improved convenience of administration are sought. We hypothesized that ixazomib (Ix) could safely and conveniently induce remissions in patients with untreated iB-NHL. Here we present the first data on frontline use of Ix in untreated iB-NHL. Methods: This single-arm, open-label phase II "window" trial for patients with untreated iB-NHL (NCT02339922) opened to enrollment in May 2016. Eligibility included histopathologically confirmed iB-NHL, measurable disease, a clinical indication for treatment based on NCCN guidelines, and no prior systemic treatment. Ix was administered at 4 mg orally once a week on consecutive 28-day cycles until disease progression or unacceptable toxicity and four doses of weekly rituximab (R) were added during the 7th cycle, after the initial window period. The primary endpoint was investigator-assessed response rate after independent radiology review. Response assessment occurred at every 2 cycles and using standard (Lugano) criteria. Tumor tissue was collected for gene expression profiling and immunohistochemical evaluation of molecular pathways associated with proteasome inhibition. Results: As of July 1, 2018, 15 patients were treated. The median age was 64 years (range, 47 to 81) and 53% were men. Disease histologies included follicular lymphoma (FL, n = 10), mantle cell lymphoma (MCL, n = 2), marginal zone lymphoma (MZL, n = 2), and small lymphocytic lymphoma (SLL, n = 1). At the start of therapy, all had stage III/IV disease and B-symptoms were present in 40%. For patients with FL, 80% had poor risk by FLIPI. Overall, the indication for treatment included symptoms due to disease (40%), steady progression of disease (33%), and cytopenia due to disease (27%). To date, 14 patients were evaluable for response and 13 experienced tumor burden reduction during the Ix-only window (Figure 1). Of patients with FL, 6 completed the Ix-only window phase and, of these, 5 achieved PR. An additional 4 patients with FL have not completed all 6 cycles of Ix monotherapy. Of these, 1 patient achieved a PR after 4 cycles and continues on treatment, 1 patient came off study with stable disease after 4 cycles, and 2 patients have experienced tumor reduction without meeting formal response criteria and continue on treatment (after 2 and 4 cycles, respectively). Of those patients with FL that received R, all achieved formal remission (3 CR, 3 PR). Median progression free survival has not been reached with a median follow up of 7.4 months. No patient with non-FL histology had yet achieved a PR during the Ix-only window or had undergone response assessment after receiving R at the time of the data cut. The most common adverse events (AEs) for all pts were grade 1-2 and included nausea (53%), diarrhea (53%), rash (40%), and fatigue (33%). Peripheral neuropathy occurred in 20% patients (grade 2 in 7%). A single grade ≥ 3 AE occurred (syncope, grade 3). Conclusions: Data from this interim analysis suggest that Ix monotherapy is well tolerated and highly active in the frontline treatment of FL with all patients demonstrating tumor reduction to date and augmented responses following the addition of R. Non-FL histologies of B-NHL appear less responsive to Ix, but numbers are small. Accrual on study continues. Correlative analyses are underway to determine if Ix or Ix-R may represent a viable frontline option for some patients with iB-NHL. Figure 1. Waterfall plot of response. Number of cycles of treatment received to date indicated for each subject. Four weekly doses of rituximab are added, per protocol, with the 7th cycle of ixazomib. Asterisk indicates treatment on study ongoing. Disclosures Graf: Acerta: Research Funding; TG Therapeutics: Research Funding; Beigene: Research Funding. Lynch:T.G. Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Shadman:Genentech: Consultancy; Genentech: Research Funding; Verastem: Consultancy; AbbVie: Consultancy; Gilead Sciences: Research Funding; Beigene: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; AstraZeneca: Consultancy; TG Therapeutics: Research Funding; Mustang Biopharma: Research Funding; Pharmacyclics: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding. Gopal:Pfizer: Research Funding; Aptevo: Consultancy; BMS: Research Funding; Brim: Consultancy; Asana: Consultancy; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Takeda: Research Funding; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Incyte: Consultancy; Teva: Research Funding.


2020 ◽  
Vol 30 (10) ◽  
pp. 3761-3767
Author(s):  
Wenjing Tao ◽  
Giola Santoni ◽  
My von Euler-Chelpin ◽  
Rickard Ljung ◽  
Elsebeth Lynge ◽  
...  

Abstract Purpose Obesity increases the risk of several cancers, but the influence of bariatric surgery on the risk of individual obesity-related cancers is unclear. This study aimed to assess the impact of bariatric surgery on cancer risk in a multi-national setting. Materials and Methods This cohort study included all adults with an obesity diagnosis identified from national patient registries in all Nordic countries (Denmark, Finland, Iceland, Norway and Sweden) from 1980 to 2012. Cancer risk in bariatric surgery patients was compared with non-operated patients with obesity. Multivariable Cox regression provided adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Age, sex, calendar year, country, length of follow-up, diabetes, chronic obstructive pulmonary disease and alcohol-related diseases were evaluated as confounders. Results Among 482,572 participants with obesity, 49,096 underwent bariatric surgery. Bariatric surgery was followed by a decreased overall cancer risk in women (HR 0.86, 95% CI 0.80–0.92), but not in men (HR 0.98, 95% CI 0.95–1.01). The risk reduction was observed only within the first five post-operative years. Among specific tumours, HRs decreased for breast cancer (HR 0.81, 95% CI 0.69–0.95), endometrial cancer (HR 0.69, 95% CI 0.56–0.84) and non-Hodgkin lymphoma (HR 0.64, 95% CI 0.42–0.97) in female bariatric surgery patients, while the risk of kidney cancer increased in both sexes (HR 1.44, 95% CI 1.13–1.84). Conclusion Bariatric surgery may decrease overall cancer risk in women within the first five years after surgery. This decrease may be explained by a decreased risk of breast and endometrial cancer and non-Hodgkin lymphoma in women.


2017 ◽  
Vol 24 (10) ◽  
pp. 885-894 ◽  
Author(s):  
C.-E. Huang ◽  
Y.-H. Yang ◽  
Y.-Y. Chen ◽  
J.-J. Chang ◽  
K.-J. Chen ◽  
...  

2019 ◽  
Vol 9 (2) ◽  
pp. 11
Author(s):  
Nahed Ahmed Soliman ◽  
Lamia M Abdalkader ◽  
Doaa Shams

Background: The pathogenesis of non-Hodgkin lymphoma is a complex process that involves several molecular changes. Alterations in polycomb group proteins as well as Survivin have been described but details are still lacking particularly in T/NK-cell lymphomas. Polycomb proteins have a big role in cell cycle and differentiation. Survivin is another recently recognized player in non-Hodgkin lymphoma.Objective: To study the pattern of Bmi-1 and Survivin in different categories of B- and T/NK- cell non-Hodgkin lymphomas, their association with the clinicopathological parameters, and their impact on the prognosis of non-Hodgkin lymphomas.Material& methods: Immunohistochemical staining was used to study paraffin samples of 267 patients’ biopsies. We used tonsils and reactive lymph node as normal control.Results: Both Bmi-1 and Survivin showed significant upregulation in several subtypes B- (P = .000-.02 for Bmi-1 and .00- .03 forSurvivin) and T/NK cell lymphomas (P= .009-.03 for Bmi-1 and 0.008- 0.009 for Survivin) compared to normal tissue. Significantpositive correlation between Bmi-1 and Survivin was detected in both B- (Co= 0.539**, P = .00) and T - cell lymphomas (Co= 0.560**, P = .000). A statistically significant difference between overall survival and expression of both BMI-1 and Survivin was detected (P = .00 for BMI-1and survivin).Conclusion: Bmi-1 and Survivin show significant upregulation as well correlation with clinicopathological parameters and overall survival of non-Hodgkin lymphomas.


2016 ◽  
Vol 25 (3) ◽  
pp. 739-748 ◽  
Author(s):  
Shah-Jalal Sarker ◽  
Sophia K. Smith ◽  
Kashfia Chowdhury ◽  
Patricia A. Ganz ◽  
Sheryl Zimmerman ◽  
...  

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1374-1374
Author(s):  
Richard J. Jones ◽  
Dajun Yang ◽  
Nathalie Bruey-Sedano ◽  
Robert Z. Orlowski

Abstract Background: The ubiquitin-proteasome pathway has been validated as a target for non-Hodgkin lymphoma (NHL) with the recent approval of bortezomib for mantle cell lymphoma (MCL). In addition to anti-tumor activity, however, proteasome inhibitors have pleiotropic effects, including activation of an anti-apoptotic heat shock protein response, and their use clinically is complicated by toxicities such as peripheral neuropathy. By targeting E3 ubiquitin ligases, which are involved in ubiquitination of only a small subset of cellular proteins, it may be possible to achieve more specific anti-tumor effects with a better therapeutic index. One such attractive target is HDM-2, which is responsible for ubiquitination of the p53 tumor suppressor. Methods: To evaluate the therapeutic potential of agents targeting HDM-2, we studied the impact of the small molecule MI-63, an inhibitor of the HDM-2-p53 interaction, in both p53 wild-type and -mutant cell line models. Results: Treatment of wild-type p53 MCL, NHL, and acute lymphocytic leukemia (ALL) cell lines with MI-63 induced a dose- and time-dependent inhibition of proliferation, with an IC50 in the 1.0–5.0 μM range. This was associated with G1/S cell cycle arrest, and apoptosis mediated by caspases-3, 8 and 9. MI-63 induced accumulation and phosphorylation of p53 at serine 15 and 37, and also enhanced HDM-2 levels. Multiple p53 target genes were induced, including p21Cip1 and p53-upregulated modulator of apoptosis (PUMA), resulting in cleavage of poly-ADP-ribose-polymerase (PARP). MI-63 also decreased the levels of the ribonucleotide reductase subunit R2, and caused a corresponding increase in the R2p53 subunit. MI-63 also decreased the levels of E2F. Cell lines expressing certain p53 mutants were sensitive to the effects of MI-63, resulting in apoptosis. Cells without p53 expression were less sensitive to MI-63, but at higher drug concentrations proliferation was still inhibited, indicating a possible impact on HDM-2-mediated but p53-independent cell death pathways. Primary human umbilical cord vein endothelial cell growth was also inhibited and cells failed to recover after extended exposure to MI-63, whereas primary PBMC’s were unaffected by MI-63. Combinations of MI-63 with the molecularly targeted chemotherapy agents bortezomib and rapamycin were synergistic, with mean CI values of 0.88 and 0.6 respectively. The conventional chemotherapy agents doxorubicin and cisplatin were less effective at inducing synergism, with mean CI values of 1.06 and 0.9 respectively. Pretreatment of cells with MI-63 followed by chemotherapy was antagonistic with all agents used, while treatment with a chemotherapeutic first followed by MI-63 was additive to synergistic, indicating a sequence-dependent interaction. Conclusions: Inhibition of the HDM-2-p53 interaction is a promising approach both by itself, and in combination with currently used chemotherapeutics, against lymphoid malignancies, providing a rationale for translation of such agents into the clinic.


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