Brian Berry

Impact of Concordant and Discordant Bone Marrow Involvement on Outcome in Diffuse Large B-Cell Lymphoma Treated With R-CHOP

PURPOSE In diffuse large B-cell lymphoma (DLBCL), prior studies suggest that concordant bone marrow involvement with DLBCL portends a poorer prognosis, whereas discordant bone marrow involvement with small B-cell lymphoma does not. We examined the significance of bone marrow involvement in patients treated in the current era of therapy including rituximab. PATIENTS AND METHODS We performed a retrospective analysis of the prognostic impact of bone marrow involvement in an unselected population of patients with newly diagnosed DLBCL treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in British Columbia and Auckland, New Zealand, with complete clinical information and evaluable staging bone marrow biopsies. RESULTS In total, 795 patients were identified. Six hundred seventy (84.3%) of 795 had a negative bone marrow, 67 patients (8.4%) had concordant and 58 (7.3%) had discordant involvement. Median follow-up was 41 months (range, 1 to 115). Progression-free survival (PFS) was inferior in those with concordant (P < .001) and discordant (P = .019) involvement while overall survival (OS) was inferior in those with concordant involvement (P < .001) only. In a multivariate analysis controlling for the International Prognostic Index (IPI) score, concordant involvement remained an independent predictor of PFS (P < .001) and OS (P = .007). Discordant involvement was associated with older age, elevated lactate dehydrogenase, advanced stage, and increased number of extranodal sites and was not a negative prognostic factor independent of the IPI score. CONCLUSION The negative prognostic impact of discordant involvement is adequately represented by the IPI score, while the risk with concordant involvement is greater than that encompassed by this predictor. The results emphasize the need for accurate staging assessment of bone marrow involvement in DLBCL.

Organochlorines and risk of non-Hodgkin lymphoma

Organochlorine chemicals and polychlorinated biphenyls (PCBs) have been suspected as possible risk factors for non‐Hodgkin lymphoma (NHL). We investigated PCBs and organochlorine pesticides and risk of NHL in a population‐based case–control study in British Columbia, Canada. Congeners of PCBs (including dioxinlike congeners) and pesticides or pesticide metabolites were measured in plasma of 422 pretreatment cases and 460 control subjects. This is so far the largest study to examine organochlorines in plasma to date. Several dioxin‐like PCB congeners were associated with increased risk of NHL, including dioxin‐like PCB nos. 118 and 156 with odds ratios (OR) for the highest versus lowest quartile between 1.6 and 1.8. Several non‐dioxin‐like congeners also showed significant associations. The PCB congener with the strongest association was no. 180 with an OR for the highest versus the lowest quartile of 1.83 (95% confidence interval = 1.18–2.84). Six pesticide analytes also showed a significant association with NHL; β‐hexachlorocyclohexane, p,p′‐DDE, hexachlorobenzene, mirex, oxychlordane and trans‐nonachlor. The strongest association was found for oxychlordane, a metabolite of the pesticide chlordane (highest vs. lowest quartile OR = 2.68, 95% confidence interval = 1.69–4.24). Our results provide further evidence that organochlorines contribute to NHL risk.

CHOP-R therapy overcomes the adverse prognostic influence of BCL-2 expression in diffuse large B-cell lymphoma

BCL-2 protein expression correlates with shorter survival in patients with diffuse large B cell lymphoma (DLBCL) who are treated with CHOP chemotherapy. We report a retrospective analysis of the prognostic significance of BCL-2 status in patients who received CHOP with the addition of rituximab (CHOP-R) for DLBCL. Patients over 15 years of age with de novo, HIV negative DLBCL, without CNS involvement, and known BCL-2 protein status were identified from the BCCA Lymphoid Cancer Database. BCL-2 tumour positivity was defined as over 50% of tumour cells with BCL-2 protein expression. 140 patients who received CHOP-R were analysed. The majority (59%) of patients were over 60 years of age. Disease stage distribution was limited (22%) and advanced (78%). BCL-2 protein expression was observed in 90 (64%) cases. IPI score was similar in both BCL-2 positive and negative cases. Median follow-up time for living patients is 40 months. BCL-2 status did not predict for either progression-free or overall survival. IPI score was predictive for progression-free survival but not overall survival. The addition of rituximab to CHOP chemotherapy negates the adverse prognostic influence of BCL-2 protein expression on progression free and overall survival in DLBCL.

Red blood cell storage duration and mortality in patients undergoing percutaneous coronary intervention.

BACKGROUND Blood transfusion has been associated with an increased mortality in patients undergoing percutaneous coronary intervention (PCI). Although the reasons for this remain unclear, it may be related to the structural and functional changes occurring within red blood cells (RBCs) during storage. We investigated whether RBC storage duration was associated with mortality in patients requiring transfusion after PCI. METHODS We collected data on all RBC transfusions occurring within 10 days of PCI (excluding those related to cardiac surgery) using the British Columbia Cardiac Registry and Central Transfusion Registry. Transfusion details were analyzed according to 30-day survival. RESULTS From a total of 32,580 patients undergoing PCI, 909 (2.8%) patients received RBCs with a mean storage duration of 25 +/- 10 days. In these 909 patients, mean transfusion volumes were lower in survivors (2.8 +/- 2.1 vs 3.8 +/- 2.9 U, P = .002) than those who died within 30 days. In a multivariate analysis to adjust for baseline risk, mean RBC storage age (HR 1.02 [95% CI 1.01-1.04], P = .002) and transfusion volume (HR 1.26 [95% CI 1.18-1.34], P < .001) both predicted 30-day mortality. Transfused patients who received only older blood (RBC min age >28 days) appeared to be at greater risk of death (HR 2.49 [95% CI 1.45-4.25], P = .001). CONCLUSION Red blood cell transfusion is associated with increased 30-day mortality in patients undergoing PCI. Although current transfusion practice permits RBC storage for up to 42 days, the use of older red cells may pose an additional hazard to this patient group.

Genetic variation in cell death genes and risk of non-Hodgkin lymphoma.

Background Non-Hodgkin lymphomas are a heterogeneous group of solid tumours that constitute the 5th highest cause of cancer mortality in the United States and Canada. Poor control of cell death in lymphocytes can lead to autoimmune disease or cancer, making genes involved in programmed cell death of lymphocytes logical candidate genes for lymphoma susceptibility. Materials and Methods We tested for genetic association with NHL and NHL subtypes, of SNPs in lymphocyte cell death genes using an established population-based study. 17 candidate genes were chosen based on biological function, with 123 SNPs tested. These included tagSNPs from HapMap and novel SNPs discovered by re-sequencing 47 cases in genes for which SNP representation was judged to be low. The main analysis, which estimated odds ratios by fitting data to an additive logistic regression model, used European ancestry samples that passed quality control measures (569 cases and 547 controls). A two-tiered approach for multiple testing correction was used: correction for number of tests within each gene by permutation-based methodology, followed by correction for the number of genes tested using the false discovery rate. Results Variant rs928883, near miR-155, showed an association (OR per A-allele: 2.80 [95% CI: 1.63–4.82]; pF = 0.027) with marginal zone lymphoma that is significant after correction for multiple testing. Conclusions This is the first reported association between a germline polymorphism at a miRNA locus and lymphoma.

Enoxaparin for Unstable Angina and Ancrod for Cardiac Surgery following Heparin Allergy

OBJECTIVE: To describe a patient who presented with heparin allergy and required alternate anticoagulation for unstable angina and coronary artery bypass surgery. To review therapeutic alternatives to porcine heparin for patients with hypersensitivity or intolerance to standard heparin anticoagulation. CASE SUMMARY: A 74-year-old man with a 15-year-old coronary artery bypass graft presented to the emergency room with unstable angina and was scheduled for urgent coronary artery revascularization. A bolus dose of porcine heparin was administered followed by a continuous infusion. Shortly afterward the patient developed a type I allergic reaction to the porcine heparin that was confirmed by rechallenge. Three alternatives to porcine heparin were tried, including bovine lung heparin, low-molecular-weight heparin (enoxaparin), and ancrod. The patient was found to be cross-sensitive to bovine lung heparin, but tolerated enoxaparin for unstable angina without cross-sensitivity. Anticoagulation for cardiopulmonary bypass was achieved with an infusion of ancrod that was later reversed with cryoprecipitate. The patient was discharged postoperatively on day 5 without the complication of excessive bleeding. DISCUSSION: Type I allergic reaction to unfractionated heparin is a rare occurrence and could be the result of a variety of factors. Possible causes for the reaction include a porcine protein, a preservative contained in the heparin solution, or a hapten formed between heparin and a plasma protein. We considered four alternatives to heparin anticoagulation: rush desensitization, bovine lung heparin, low-molecular-weight heparin, and ancrod. The patient was cross-sensitive to bovine lung heparin, but was able to tolerate low-molecular-weight heparin (enoxaparin). This was unexpected because enoxaparin is derived from unfractionated porcine heparin. Testing for cross-sensitivity had no value in this case, as two negative subcutaneous test doses were followed by dramatic reactions when the drugs were given intravenously. Although enoxaparin has been used for anticoagulation during bypass surgery, there is more experience with ancrod as an alternative to heparin. Repeat bypass surgery, which normally results in above-average blood loss, was successfully performed with a very low fibrinogen concentration (<0.15 g/L) during ancrod anticoagulation. CONCLUSIONS: We conclude that ancrod was a safe and effective alternative to heparin for coronary artery bypass surgery in this patient in whom a heparin product had caused a hypersensitivity reaction. We discovered on two occasions that a negative subcutaneous test dose for heparin allergy did not predict a severe type I allergic reaction when the heparin was later administered intravenously. Furthermore, we found that a low-molecular-weight heparin administered subcutaneously for a short period of time did not cause cross-sensitivity in a patient with a type I allergy to unfractionated heparin.

Non-Hodgkin Lymphoma Risk and Variants in Genes Controlling Lymphocyte Development

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of solid tumours of lymphoid cell origin. Three important aspects of lymphocyte development include immunity and inflammation, DNA repair, and programmed cell death. We have used a previously established case-control study of NHL to ask whether genetic variation in genes involved in these three important processes influences risk of this cancer. 118 genes in these three categories were tagged with single nucleotide polymorphisms (SNPs), which were tested for association with NHL and its subtypes. The main analysis used logistic regression (additive model) to estimate odds ratios in European-ancestry cases and controls. 599 SNPs and 1116 samples (569 cases and 547 controls) passed quality control measures and were included in analyses. Following multiple-testing correction, one SNP in MSH3, a mismatch repair gene, showed an association with diffuse large B-cell lymphoma (OR: 1.91; 95% CI: 1.41–2.59; uncorrected p = 0.00003; corrected p = 0.010). This association was not replicated in an independent European-ancestry sample set of 251 diffuse large B-cell lymphoma cases and 737 controls, indicating this result was likely a false positive. It is likely that moderate sample size, inter-subtype and other genetic heterogeneity, and small true effect sizes account for the lack of replicable findings.

Non-red blood cell transfusion as a risk factor for mortality following percutaneous coronary intervention

BACKGROUND Bleeding following percutaneous coronary intervention (PCI) is common and may lead to transfusion and death. Although previous work has examined the effect of red blood cell (RBC) transfusion in patients with coronary disease, no study had investigated whether transfusion of non-RBC components was associated with mortality following PCI. METHODS All subjects transfused in the 10 days following PCI were identified using the British Columbia Cardiac and Central Transfusion Registries. Patients undergoing cardiac surgery following PCI were excluded as transfusion was assumed to be due to surgical related bleeding. Transfusion products were categorised as RBC and non-RBC comprising platelets, plasma and cryoprecipitate. Blood product use was compared according to thirty day mortality using multivariate regression and propensity adjustment for confounding variables. RESULTS From a total of 32,580 patients who underwent PCI, 952 patients received at least 1 blood product within 10 days of PCI. Non-RBC transfusion occurred more commonly in the cohort of transfused patients dying within 30 days (p<0.001). After adjustment for baseline risk, transfusion of plasma/cryoprecipitate (HR 5.17; 95% C.I. 2.87-9.32, p<0.001) and platelets (HR 2.13; 95% C.I. 1.10-4.13, p=0.03) was associated with increased 30 day mortality. In a propensity risk adjusted model, transfusion of plasma/cryoprecipitate and RBC transfusion volume remained as significant predictors of 30-day mortality (p<0.001). CONCLUSIONS Transfusion following PCI appears to be associated with an increased risk of death within 30 days. We now report that transfusion with plasma rich non-RBC products may confer an additional mortality risk to patients undergoing PCI.

Detection of a TRAF1-ALK fusion in an anaplastic large cell lymphoma patient with chemotherapy and ALK inhibitor-resistant disease

BackgroundThe anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase, which was first identified as the fusion partner of the nucleophosmin (NPM1) gene in the recurrent t(2;5)(p23;q35) found in a subset of anaplastic large cell lymphoma (ALCL). Several distinct, non-NPM1, ALK fusions have subsequently been described in lymphomas and other tumor types. All of these fusions result in the constitutive expression and activation of ALK and ALK signaling pathways, ultimately leading to the malignant phenotype.Case reportA non-NPM1 fusion partner of ALK was identified in a 32-year-old Caucasian male ALCL patient whose disease was refractory to standard chemotherapy and autologous stem cell transplantation, and exhibited a poor response to a first-generation ALK inhibitor. Non-allele-specific ALK RT-qPCR revealed ALK overexpression and 5′ RACE PCR revealed that the patient’s lymphoma expressed a TRAF1-ALK fusion.ConclusionsWe report the case of an ALCL patient whose tumor harbored the newly recognized TRAF1-ALK fusion and describe the clinical outcome after treatment with an ALK inhibitor. The short survival of our patient may reflect a propensity toward aggressive behavior in lymphomas that express this ALK fusion.

Successful treatment of non-Hodgkin lymphoma associated immune thrombocytopenia with involved field radiotherapy

Immune thrombocytopenia complicates the course and impacts the outcome of non‐Hodgkin lymphoma (NHL‐ITP, non‐Hodgkin lymphoma–immune thrombocytopenic purpura). The response to corticosteroids and/or intravenous immune globulins is usually short lasting, but NHL‐ITP usually responds to anti‐lymphoma chemotherapy. It is not clear if this success is due to the elimination of the lymphomatous tissue or to the immunosuppressor/immunomodulator effect of chemotherapy. Myelosuppressive anti‐lymphoma chemotherapy carries the risk of severe thrombocytopenia that may not respond adequately to platelet transfusion support. We report on a patient with recurrent diffuse large B‐cell lymphoma that coincided with immune thrombocytopenia. Both diseases completely responded to involved field radiation therapy. This supports the hypothesis that at least in some cases of NHL‐ITP, the lymphomatous clone secretes the anti‐platelet antibodies. This supports the therapeutic decision making for these patients. Copyright