Tommasina Perrone

Poor mobilization is an independent prognostic factor in patients with malignant lymphomas treated by peripheral blood stem cell transplantation.

Haemopoietic stem cell therapy is an increasingly adopted procedure in the treatment of patients with malignant lymphoma. In this retrospective analysis, we evaluated 262 patients, 57 (22%) with Hodgkins and 205 (78%) with non-Hodgkins lymphomas (NHL), and 665 harvesting procedures in order to assess the impact of poor mobilization on survival and to determine the factors that may be predictive of CD34+ poor mobilization. The mobilization chemotherapy regimens consisted of high-dose cyclophosphamide in 92 patients (35.1%) and a high-dose cytarabine-containing regimen (DHAP in 87 patients –(33.2%), MAD in 83 (31.7%)). The incidence of poor mobilizers (<2 × 106 CD34+ cells/kg) was 17.9% overall, with a 10% of very poor mobilizers (⩽1 × 106/kg). Refractory disease status and chemotherapeutic load (>3 regimens) before mobilization played a negative role and were associated with poor mobilization. Survival analysis of all harvested patients showed an overall survival at 3 years of 71% in good mobilizers vs 33% in poor mobilizers (P=0.002). The event-free survival at 3 years was 23% in poor mobilizers and 58% in good mobilizers (P=0.04). We conclude that in NHL patients, poor mobilization status is predictive of survival.

Mobilization of peripheral blood stem cells with high-dose cyclophosphamide or the DHAP regimen plus G-CSF in non-Hodgkin's lymphoma.

Our study analyzes the mobilization of hematopoietic stem cells after two chemotherapeutic regimens in non-Hodgkins lymphoma (NHL) patients. The study included 72 patients with NHL (42 follicular and 30 large cells). The mean age was 37 years (range 17–60). Sixty-four patients (88.9%) had stage III–IV disease. Forty-eight patients (66.7%) had bone marrow involvement. Systemic B symptoms were present in 42 patients (58.3%). Mobilization chemotherapy regimens were randomly assigned as DHAP in 38 patients (52.7%) or cyclophosphamide (CPM) (5 g/m2) in 34 (47.2%) and the results of 132 procedures were analyzed. At the time of PBSC mobilization, 46 patients (63.9%) were considered to be responsive (complete remission, partial remission or sensitive relapse) and 26 (36.1%) not responsive (refractory relapse or refractory to therapy). Pre-apheresis CD34+ blood cell count and number of previous chemotherapy treatments were used to predict the total number of CD34+ cells in the apheresis product. The mobilizing regimens (CPM or DHAP) were similar in achieving the threshold CD34+ cell yield, for optimal engraftment. Since DHAP was very effective as salvage treatment, we suggest using DHAP as a mobilizing regimen in patients with active residual lymphoma at the time of stem cell collection.Bone Marrow Transplantation (2002) 29, 285–290. doi:10.1038/sj.bmt.1703364

High Ki67 Index and Bulky Disease Remain Significant Adverse Prognostic Factors in Patients with Diffuse Large B Cell Lymphoma before and after the Introduction of Rituximab

The aim of this study was to evaluate the impact of clinical variables and biologic features on response rate (RR), overall survival (OS) and progression-free survival (PFS) in 111 patients with de novo diffuse large B cell lymphoma (DLBCL). Fifty-three patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) and 58 patients were treated with R-CHOP (rituximab + CHOP). The variables predictive of RR in the CHOP group were B symptoms, age, clinical stage, bone marrow involvement, bulky disease, International Prognostic Index (IPI) and Bcl-2; in the R-CHOP group, these variables were bulky disease, bone marrow involvement, IPI and Ki67 expression >80%. Multivariate analysis showed that in patients treated with CHOP, the independent prognostic factors associated with PFS were age, bulky disease, IPI and Bcl-2 and those associated with OS were performance status, clinical stage, IPI and bone marrow involvement. In contrast, in patients treated with R-CHOP, the variable shown by multivariate analysis to be an independent prognostic factor associated with PFS was bulky disease, whereas Ki67 expression >80% was associated with OS and PFS. Our data show that a high Ki67 expression and bulky disease could represent possible predictive factors of poor prognosis, which would help to identify a high-risk subgroup of newly diagnosed DLBCL.

Fotemustine plus etoposide, cytarabine and melphalan (FEAM) as a new conditioning regimen for lymphoma patients undergoing auto-SCT: a multicenter feasibility study.

BEAM is a widely used conditioning regimen for relapsed/refractory lymphoma patients undergoing auto-SCT. We conducted a multicenter study with an alternative regimen (fotemustine plus etoposide, cytarabine and melphalan (FEAM)) in which BCNU was substituted by the chloroethylnitrosourea fotemustine (FTM). Eighty-four patients with relapsed/refractory Hodgkins (n=20) and non-Hodgkins lymphoma (n=64) were conditioned with a FEAM regimen (FTM 150 mg/m2 on days –7, –6, etoposide 200 mg/m2 and cytarabine 400 mg/m2 on days –5, –4, –3, –2 and melphalan 140 mg/m2 on day –1). Patients were evaluated for toxicity and engraftment parameters. Median times to neutrophil (>500 × 109/l) and plt (>20 000 × 109/l) engraftment were 11 and 13 days, respectively. Grade 3 mucositis occurred in 19 patients (23%), while G3 nausea/vomiting and G3 diarrhea were observed in 13 (15%) and 6 (7%) patients, respectively. No severe hepatic, renal or pulmonary toxicity was detected. Seven patients (7%) experienced G4 mucositis, while no other G4 toxicities or unexpected adverse events of any grade were recorded. Transplant-related mortality was 2.4%. We conclude that a FEAM regimen is feasible and safe. Although toxicity and engraftment times compared favorably with BEAM, longer follow-up is needed to evaluate fully its efficacy and long-term safety.

Microvascular density, CD68 and tryptase expression in human Diffuse Large B-Cell Lymphoma

Diffuse Large B-cell Lymphoma (DLBCL) is the most common form of Non-Hodgkin lymphoma characterized by clinical and biological heterogeneity attributable both to the tumor cells and the complex tumor-microenvironment surrounding them. Tumor-associated macrophages (TAMs) and mast cells are two major components of the tumor inflammatory infiltrate with a definite role in enhancing tumor angiogenesis. In this study, we have investigated CD68 and tryptase expression and their relationship with microvascular density (MVD) in chemo-resistant and chemosensitive patients affected by DLBCL. CD68 and tryptase expression as well as MVD were increased in chemo-resistant patients when compared with chemosensitive patients. Tryptase expression showed a positive correlation with MVD, supporting a role for mast cell in DLBCL tumor angiogenesis, while CD68 correlation with MVD was not significant, indicating a different role for TAMs than angiogenesis in DLBCL.

Subsets of CD34+ and early engraftment kinetics in allogeneic peripheral SCT for AML

This study aimed to identify which graft product subset of CD34+ cells might be the most predictive of early hematopoietic recovery following allogeneic peripheral SCT (allo-PBSCT). The relationship between the number of ‘mature’ subsets of CD34+ cells (CD34+/CD33+, CD34+/CD38+, CD34+/DR+ and CD34+/CD133−) and ‘immature’ subsets of CD34+ cells (CD34+/CD33−, CD34+/CD38−, CD34+/DR− and CD34+/CD133+) and early neutrophil and platelet engraftment were studied in a homogeneous series (for disease, pre transplant chemotherapy, conditioning regimen and GVHD prophylaxis) of 30 AML patients after allo-PBSCT from HLA-identical siblings. In our experience, the total CD34+/CD133+ cell number was inversely correlated with the days required for the recovery of 0.5 × 109/l neutrophils (r=−0.82, P=0.02) and platelets of 20 × 109/l (r=−0.60, P=0.06); this correlation was better than the total CD34+ cell dose and neutrophil (r=−0.70, P=0.04) and platelet engraftment (r=−0.56, P=0.07). We suggest that a high number of CD34+/CD133+ PBSC may be associated with faster neutrophil and platelet recovery; these findings may help to predict the repopulating capacity of PBSC in patients after allo-PBSCT, especially when a relatively low number of CD34+ cells is infused.

Primary intracranial dural B cell small lymphocytic lymphoma

Primary central nervous system non-Hodgkin lymphomas (PCNSNHL) are extranodal lymphomas arising within and confined to the central nervous system (CNS). A frequency of 1 – 3% of all nonHodgkin lymphomas and 2 – 4% of all brain neoplasms has been reported, with a particularly high incidence in the AIDS population, in transplant recipients and immunocompromised patients [1 – 3]. Meningeal involvement by malignant lymphomas is most often a manifestation of diffuse aggressive lymphomas [1 – 3] while primary dural lymphomas with no associated cerebral parenchyma lesions are rare diseases [4 – 22]. We describe a case of primary B cell small lymphocytic lymphoma (SLL) involving the dura of the frontoparietal and temporal regions, and include a review of the literature, performing a Medline search for cases of primary intracranial dural lymphoma [4 – 22]. A 44-year-old immunocompetent woman referred a 2-week history of headache, diplopia, blurring of vision, loss of concentration, and right eye exophthalmos. Cranial magnetic resonance imaging (MRI) disclosed a large right dural thickening frontal mass, which was hyperintense in T1 weighted images and hypointense in T2 sequences. The administration of Gadolinium diethylenetriamine pentaacetic acid (Gd DTPA) revealed a wide contrast enhanced area involving the meninges and initial invasion of the underlying brain on the right frontoparietal and sphenoidal regions [Figure 1(A)]. Ophthalmic examination confirmed right eye exophthalmos and diplopia; fundoscopic evaluation showed mild pupil pallor, but no evidence of edema. Lumbar puncture was performed: cerebrospinal fluid (CFS) did not show malignant cells; CSF biochemical evaluations were within normal range with a glucose level of 65 mg/dl (n.v. 40 – 70 mg/dl) and protein level of 40 mg/dl (n.v. 15 – 45 mg/dl); polymerase chain reaction studies on CSF samples for Varicella Zoster, Herpes Simplex, Epstein-Barr viruses were negative. The patient underwent a right frontoparietal craniotomy. Intraoperatively, a diffuse plaque-like mass firmly adherent to the dura and infiltrating the pia mater and arachnoid membrane was encountered. The lesion could not be excised, and biopsies were performed. Histological examination revealed a monomorphic population of small lymphocytes diffusely infiltrating the dura [Figure 2(A)]. Immunohistochemical analysis demonstrated CD20 [Figure 2(B)], CD5 [Figure 2(C)], and CD23 [Figure 2(D)] positivity, bcl2 protein expression, and lambda light chain restriction, suggesting a typical pattern of SLL. CT scans of the neck, chest, abdomen, and pelvis showed no evidence of disease. Routine laboratory tests were within normal range, including serum lactate dehydrogenase 92 U/l (n.v. 100 – 190 U/l) and b2 microglobulin 1 mg/ml (n.v. 0.8 – 2.0 mg/ml). Cytological and immunophenotypical analysis did not show bone marrow and peripheral blood involvement. Serum HIV, EBV, CMV tests were negative. The patient was treated according to the IELSG 20 protocol and treatment consisted of four cycles of high dose i.v. methotrexate

Outcome of Very Late Relapse in Patients with Hodgkin's Lymphomas

Recurrences of Hodgkins Lymphoma (HL) 5 years after the initial therapy are rare. The aim of this study is to report a single centre experience of the clinical characteristics, outcome, and toxicity of pts who experienced very late relapses, defined as relapses that occurred 5 or more years after the achievement of first complete remission. Of 532 consecutive pts with classical HL treated at our Institute from 1985 to 1999, 452 pts (85%) achieved a complete remission. Relapse occurred in 151 pts: 135 (29.8%) within 5 years and 16 over 5 years (3.5%, very late relapses). Very late relapses occurred after a median disease-free interval of 7 years (range: 5–18). Salvage treatment induced complete remission in 14 pts (87.5%). At a median of 4 years after therapy for very late relapse, 10 pts (63%) are still alive and free of disease and 6 (37%) died (1 from progressive HL, 1 from cardiac disease, 1 from thromboembolic disease, 1 from HCV reactivation, and 2 from bacterial infection). The probability of failure-free survival at 5 years was 75%. The majority of deaths are due to treatment-related complications. Therapy regimens for very late relapse HL are warranted to minimize complications.

Assessment of DNA damages in lymphocytes of agricultural workers exposed to pesticides by comet assay in a cross-sectional study

Abstract Purpose: To assess the predictive power of the comet assay in the context of occupational exposure to pesticides. Materials and methods: The recruited subjects completed a structured questionnaire and gave a blood sample. Exposure to pesticides was measured by means of an algorithm based on Dosemeci’s work (Agricultural Health Study). Approximately 50 images were analyzed for each sample via fluorescence microscopy. The extent of DNA damage was estimated by tail moment (TM) and is the product of tail DNA (%) and tail Length. Results: Crude significant risks (odds ratios, ORs) for values higher than the 75th percentile of TM were observed among the exposed subjects (score > 1). The frequency of some confounding factors (sex, age and smoking) was significantly higher among the exposed workers. A significant dose–effect relationship was observed between TM and exposure score. Significant high-risk estimates (ORs), adjusted by the studied confounding factors, among exposure to pesticides and TM, % tail DNA and tail length were confirmed using unconditional logistic regression models. Conclusions: The adjusted associations (ORs) between the comet parameters and exposure to pesticides were significant. The sensitivity of the comet test was low (41%), the specificity (89%) and the predictive positive value (0.77) were found acceptable.

Risk of lymphoma subtypes by occupational exposure in Southern Italy

BackgroundOccupational exposure is known to play a role in the aetiology of lymphomas. The aim of the present work was to explore the occupational risk of the major B-cell lymphoma subtypes using a case–control study design.MethodsFrom 2009 to 2014, we recruited 158 lymphoma cases and 76 controls in the provinces of Bari and Taranto (Apulia, Southern Italy). A retrospective assessment of occupational exposure based on complete work histories and the Carcinogen Exposure (CAREX) job-exposure matrix was performed.ResultsAfter adjusting for major confounding factors, farmers showed an increased risk of diffuse large B-cell lymphoma (DLBCL) [odds ratio (OR) = 10.9 (2.3–51.6)] and multiple myeloma (MM) [OR = 16.5 (1.4–195.7)]; exposure to the fungicide Captafol was significantly associated with risk of non-Hodgkin lymphoma (NHL) [OR = 2.6 (1.1–8.2)], particularly with the risk of DLBCL [OR = 5.3 (1.6–17.3)].ConclusionsAgricultural activity seems to be a risk factor for developing lymphoma subtypes, particularly DLBCL, in the provinces of Bari and Taranto (Apulia Region, Southern Italy). Exposure to the pesticides Captafol, Paraquat and Radon might be implicated.Trial registrationProtocol number UNIBA 2207WEJLZB_004 registered 22/09/2008.