Blood-Brain Barrier Disruption (BBBD)-Based Immunochemotherapy for Primary Central Nervous System Lymphoma (PCNSL), Early Results of a Phase II Study.

Primary central nervous system lymphoma is a rare but aggressive brain malignancy. It is associated with poor prognosis even with the current standard of care. The aim of this study was to evaluate the effect and tolerability of blood-brain barrier disruption treatment combined with high-dose treatment with autologous stem cell transplantation as consolidation on primary central nervous system lymphoma patients. We performed a prospective phase II study for 25 patients with previously untreated primary central nervous system lymphoma. The blood-brain barrier disruption treatment was initiated 3-4 weeks after the MATRix regimen using the previously optimized therapy protocol. Briefly, each chemotherapy cycle included two subsequent intra-arterial blood-brain barrier disruption treatments on days 1 and 2 via either one of the internal carotid arteries or vertebral arteries. Patients received the therapy in 3-week intervals. The treatment was continued for two more courses after achieving a maximal radiological response to the maximum of six courses. The complete treatment response was observed in 88.0% of the patients. At the median follow-up time of 30 months, median progression-free and overall survivals were not reached. The 2-year overall and progression-free survival rates were 67.1% and 70.3%, respectively. Blood-brain barrier disruption treatment is a promising option for primary central nervous system lymphoma with an acceptable toxicity profile.

Chronic Cutaneous Disorders Are Associated with a More Favorable Disease Presentation and Outcome in Patients with Hodgkin Lymphoma.

INTRODUCTION: In epidemiological studies, chronic inflammation or previous major infection have revealed to be associated with an increased risk of developing Hodgkin lymphoma (HL). The association of chronic inflammation with the disease outcome is poorly defined. In this retrospective study based on 92 consecutive HL patients, we explored the incidence of previous inflammatory processes or previous major infection in newly diagnosed HL patients and their association with treatment outcome. METHODS: Medical history before lymphoma diagnosis including previous infection; dental inflammation; cutaneous problems; and inflammatory respiratory, gastrointestinal, or musculoskeletal diseases was collected from the patient records. Also clinical HL presentation, given treatments, and the disease outcome were recorded. RESULTS: Forty-six percent of HL patients had some of the studied inflammatory factor at the time of diagnosis. Chronic dermatological diseases were present in 16.3% of patients, and they were associated with an improved relapse-free survival (p = 0.028). Dermatological issues were also associated with early-stage disease and the absence of B-symptoms. Other studied inflammatory factors were not associated with any clinical variables or treatment outcome. CONCLUSION: Our results demonstrated that among patients with HL, preexisting cutaneous symptoms are associated with a limited-stage disease, the absence of B-symptoms, and favorable prognosis.

Strong Prolyl Hydroxylase Domain 1 Expression Predicts Poor Outcome in Radiotherapy-treated Patients with Classical Hodgkin's Lymphoma.

BACKGROUND: Hypoxia-inducible factors (HIFs) and prolyl hydroxylase domain (PHD) proteins control cellular oxygen homeostasis and a wide range of other processes. MATERIALS AND METHODS: We immunohistochemically assessed the expression of HIF1α, HIF2α, PHD1, PHD2 and PHD3 in 115 cases of classical Hodgkin's lymphoma, all treated in the first line with doxorubicin, bleomycin, vinblastine and darcabazine (ABVD) chemotherapy. RESULTS: In advanced-stage patients treated with involved-field radiotherapy (IFRT), nuclear HIF1α expression in reactive cellular infiltrate predicted prolonged relapse-free survival (RFS) (p=0.026). Strong cytoplasmic PHD1 expression in Reed-Sternberg cells was associated with poor RFS among patients treated with IFRT and advanced-stage patients treated with ABVD and IFRT (p=0.0028 and p=0.0058, respectively). In Cox regression analysis, PHD1 was a more significant predictor of relapse (risk ratio=18.383; 95% confidence interval(CI)=1.521-222.246; p=0.022) than the International Prognostic Score. CONCLUSION: HIF and PHD expression appear to be novel prognostic biomarkers in classical Hodgkin's lymphoma.

Low Rap1-interacting factor 1 and sirtuin 6 expression predict poor outcome in radiotherapy-treated Hodgkin lymphoma patients.

Sirtuins (SIRTs) are a family of histone deacetylases, which widely regulate cellular metabolism and are also involved in DNA repair. Rap1-interacting factor 1 (Rif1) and O6-alkylguanine DNA alkyltransferase (MGMT) are DNA-repair enzymes, which may potentially be involved in resistance to treatment of classical Hodgkin lymphoma (HL). We assessed the expression levels of (previously unstudied) SIRT1, SIRT4, SIRT6, Rif1, and MGMT immunohistochemically in 85 patients with untreated classical HL. Aberrant distributions of SIRT1, SIRT4, and SIRT6 were detected in Hodgkin neoplastic Reed-Sternberg (RS) cells compared with reactive elements. Low-level expression of both Rif1 and SIRT6 predicted dismal relapse-free survival in radiotherapy-treated patients (multivariate analysis; HR 8.521; 95% CI 1.714-42.358; p = .0088). Expression levels of SIRT1, 4, and 6 were abnormally distributed in RS cells, suggesting a putative role of aberrant acetylation in classical HL carcinogenesis. Rif1 and SIRT6 may also have substantial prognostic and even predictive roles in classical HL.

Strong KDM4B and KDM4D Expression Associates with Radioresistance and Aggressive Phenotype in Classical Hodgkin Lymphoma.

BACKGROUND: Epigenetic regulators, including Jumonji domain 2 (JMJD2/KDM4) proteins are involved in post-translational modification of histone demethylation and have a major role in carcinogenesis of many solid tumors. MATERIALS AND METHODS: We assessed immunohistochemically the expression of lysine (K)-specific demethylase 4 (KDM4)A, KDM4B and KDM4D in tumors from 91 patients of adriamycin, bleomycin, vinblastine, darcabazine (ABVD)-treated classical Hodgkin lymphoma. RESULTS: Strong cytoplasmic KDM4B expression in the reactive cellular infiltrate and also in Reed-Sternberg (RS) cells predicted poor relapse-free survival (RFS) (p=0.020 and p=0.022, respectively) in patients with limited-stage disease. Strong KDM4B expression in RS cells was also related to B-symptoms (p=0.007) and advanced stage (p=0.024). Strong KDM4D expression in the cytoplasm of RS cells was also associated with poor RFS in limited-stage patients RFS (p=0.043) and, most significantly, in patients receiving involved-field radiotherapy (p=0.007). CONCLUSION: KDM4B and KDM4D expression may associate with an aggressive subtype of classical Hodgkin lymphoma and be linked with radioresistance.

Oxidative stress markers and mitochondrial antioxidant enzyme expression are increased in aggressive Hodgkin lymphomas.

AIMS: Hodgkin lymphoma treatments are largely based on the generation of reactive oxygen species, but increased expression of antioxidant enzymes may contribute to chemoresistance. The aims of this study were: to define the extent and prognostic value of oxidative stress marker and antioxidant enzyme expression in Hodgkin lymphomas; and to investigate a potential association between antioxidant enzymes and chemoresistance. METHODS AND RESULTS: We immunohistochemically assessed expression of peroxiredoxin (Prx) II, Prx III, Prx V, Prx VI, manganese superoxide dismutase (MnSOD), 8-hydroxydeoxyguanosine (8-OHdG) and nitrotyrosine in 99 cases of uniformly treated Hodgkin lymphoma. Localization of 8-OHdG was assessed using transmission electron microscopy, which demonstrated expression in the cytosol and mitochondria. 8-OHdG expression in Reed-Sternberg (RS) cells was associated with advanced stage (P = 0.006) and a lower International Prognostic Score (P = 0.004). Prx III expression in reactive cellular infiltrate was associated with advanced stage (P = 0.002) and B-symptoms (P = 0.0006). Strong cytoplasmic Prx V immunostaining was associated with a low rate of complete response to chemotherapy (P = 0.043). MnSOD immunostaining in RS cells was related to advanced stage (P = 0.031) and to poorer relapse-free survival (RFS) (P = 0.033). Low 8-OHdG expression in the nuclei of RS cells was a predictor of poorer RFS (P = 0.038). Both 8-OHdG and MnSOD were also significant RFS predictors in multivariate analysis. CONCLUSIONS: Our results suggest that significant oxidative stress exists in Hodgkin lymphomas, both in RS cells and in reactive cellular infiltrates. Mitochondrial antioxidant enzymes are induced in the most aggressive forms of the disease, and they may play some part in chemoresistance.