A B S T R A C T PurposeAdult post-transplantation lymphoproliferative disease (PTLD) has a reported 3-year overall survival (OS) of 35% to 40%. The impact of rituximab on the outcome of PTLD is not well defined. MethodsWe examined the clinical features and outcomes among a large cohort of solid organ transplantation (SOT) -related patients with PTLD who were recently treated at four Chicago institutions (from January 1998 to January 2008). ResultsEighty patients with PTLD were identified who had a median SOT-to-PTLD time of 48 months (range, 1 to 216 months). All patients had reduction of immunosuppression as part of initial therapy, whereas 59 (74%) of 80 patients received concurrent first-line rituximab with or without chemotherapy. During 40-month median follow-up, 3-year progression-free survival (PFS) for all patients was 57%, and the 3-year overall survival (OS) rate was 62%. Patients who received rituximab-based therapy as part of initial treatment had 3-year PFS of 70% and OS 73% compared with 21% (P Ͻ .0001) and 33% (P ϭ .0001), respectively, without rituximab. Notably, of all relapses, only 9% (4 of 34 patients) occurred beyond 12 months from PTLD diagnosis. On multivariate regression analysis, three factors were associated with progression and survival: CNS involvement (PFS, 4.70; P ϭ .01; OS, 3.61; P ϭ .04), bone marrow involvement (PFS, 2.95; P ϭ .03; OS, 3.14; P ϭ .03), and hypoalbuminemia (PFS, 2.96; P ϭ .05; OS, 3.64; P ϭ .04). Furthermore, a survival model by multivariate CART analysis that was based on number of adverse factors present (ie, 0, 1, Ն 2) was formed: 3-year PFS rates were 84%, 66%, 7%, respectively, and 3-year OS rates were 93%, 68%, 11%, respectively (P Ͻ .0001). ConclusionThis large, multicenter, retrospective analysis suggests significantly improved PFS and OS associated with early rituximab-based treatment in PTLD. In addition, clinical factors at diagnosis identified patients with markedly divergent outcomes.

Perioperative chemotherapy is underused in the management of surgically resectable stage III transitional cell carcinoma of the bladder. This finding may reflect a delay in implementing the results of recently reported randomized trials, a low incidence of referrals by urologists for chemotherapy and/or confidence in salvage chemotherapy as an equivalent alternative. Further followup will determine if this treatment pattern changes in the future.

The prevalence of ifosfamide encephalopathy during the study period was 16%. Albumin was significantly lower among those patients who experienced encephalopathy, whereas age, creatinine, and ifosfamide dose were not significantly different between the 2 groups.

Purpose: We investigated the cytotoxicity and mechanisms of cell death of the broadspectrum histone deacetylase (HDAC) inhibitor PCI-24781, alone and combined with bortezomib in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines and primary lymphoproliferative (CLL/SLL) cells. Experimental Design: Apoptosis, mitochondrial membrane potential, cell cycle analysis, and reactive oxygen species (ROS) were measured by flow cytometry, whereas caspase activation was determined by Western blot. Nuclear factor κB (NF-κB)-related mRNAs were quantified by reverse transcription-PCR, NF-κB-related proteins by Western blotting, and NF-κB DNA-binding activity by electromobility shift assay. Finally, gene expression profiling was analyzed. Results: PCI-24781 induced concentration-dependent apoptosis that was associated with prominent G 0 /G 1 arrest, decreased S-phase, increased p21 protein, and increased ROS in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines. Dose-dependent apoptosis with PCI-24781 was also seen among primary CLL/SLL cells. PCI-24781-induced apoptosis was shown to be ROS-and caspase-dependent. Combined PCI-24781/bortezomib treatment resulted in strong synergistic apoptosis in all non-Hodgkin lymphoma lines (combination indices, 0.19-0.6) and was additive in Hodgkin lymphoma and primary CLL/SLL cells. Further, PCI-24781/bortezomib resulted in increased caspase cleavage, mitochondrial depolarization, and histone acetylation compared with either agent alone. Gene expression profiling showed that PCI-24781 alone significantly down-regulated several antioxidant genes, proteasome components, and NF-κB pathway genes, effects that were enhanced further with bortezomib. Reverse transcription-PCR confirmed down-regulation of NF-κB1 (p105), c-Myc, and IκB-kinase subunits, where NF-κB DNA binding activity was decreased. Conclusion: We show that PCI-24781 results in increased ROS and NF-κB inhibition, leading to caspase-dependent apoptosis. We also show that bortezomib is synergistic with PCI-24781. This combination or PCI-24781 alone has potential therapeutic value in lymphoma.

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Purpose: Andrographolide is a diterpenoid lactone isolated from Andrographis paniculata (King of Bitters), an herbal medicine used in Asia. It has been reported to have anti-inflammatory, antihypertensive, antiviral, and immune-stimulant properties. Furthermore, it has been shown to inhibit cancer cell proliferation and induce apoptosis in leukemia and solid tumor cell lines.Experimental Design: We studied the Burkitt p53-mutated Ramos cell line, the mantle cell lymphoma (MCL) line Granta, the follicular lymphoma (FL) cell line HF-1, and the diffuse large B-cell lymphoma (DLBCL) cell line SUDHL4, as well as primary cells from patients with FL, DLBCL, and MCL.Results: We found that andrographolide resulted in dose-and time-dependent cell death as measured by MTT. Andrographolide significantly increased reactive oxygen species (ROS) production in all cell lines. To determine mechanism of cell death, we measured apoptosis by Annexin V/propidium iodide in the presence and absence of the antioxidant N-acetyl-L-cysteine (NAC), the glutathione (GSH)-depleting agent buthionine sulfoxamine (BSO), or caspase inhibitors. We found that apoptosis was greatly enhanced by BSO, blocked by NAC, and accompanied by poly(ADP-ribose) polymerase cleavage and activation of caspase-3, caspase-8, and caspase-9. We measured BAX conformational change and mitochondrial membrane potential, and using mouse embryonic fibroblast (MEF) Bax/Bak double knockouts (MEF

Survival differences by race and gender are partially explained by differences in tumor and demographic characteristics in black males and females, and fully explained by these characteristics in white females. Treatment delays and under treatment due to comorbid conditions, age and other factors may also contribute to these disparities.