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BACKGROUND We evaluated the role of [18F]FDG PET/CT in tumor response assessment and prognosis of primary extranodal lymphoma (PEL) patients. METHODS We examined retrospectively, 56 PEL patients: 31 with aggressive diffuse large B cell lymphoma (DLBCL) and 25 with indolent lymphoma (20 mucosa-associated lymphoid tissue lymphoma and five follicular lymphoma). All patients had undergone [18F]FDG PET/CT at diagnosis (PET-I) and 50 of them also after therapy (PET-II). Moreover, 52 patients were subjected to a mean follow-up period of 76 months. RESULTS PET-I was positive in 50 (89%) patients (mean SUVmax 10.3±6.7). In the assessment of tumor response, according to Lugano classification, 45 patients showed complete metabolic response (CMR), four patients had partial metabolic response (PMR) and one had progressive metabolic disease (PMD). Based on 66% ΔSUVmax cut-off, among CMR patients, 41 showed a ΔSUVmax>66% whereas among non-responders, four patients showed a ΔSUVmax

Background In this prospective study, the impact of granulocyte colony-stimulating factors (G-2 CSF) administered during induction treatment with bendamustine plus rituximab for indolent non- Hodgkin Llymphoma (NHL) was evaluated by comparing patients who received secondary prophylaxis with filgrastim (control group) versus. patients who received pegfilgrastim as primary prophylaxis (peg-group). The primary endpoint was the incidence rate of febrile neutropenia (FN)- related chemotherapy disruptions (regarding dose-dense and/or dose-intensity of schedule). The Ssecondary endpoint included days of hospitalization due to FN, and G-CSF-related side effects (grade ≥3 WHO toxicity criteria) in each group. Methods One hundred twenty-two: 122 consecutive patients, with untreated indolent NHL, were referred to our outpatient unit for remission induction immuno-chemotherapy with bendamustine-rituximab. During the first period, 61 patients received secondary prophylaxis with filgrastim, given “on demand” if ANC was

Introduction Peri-implant breast seroma is a late clinical presentation of reconstructive surgery or augmentation mammoplasty with breast implants. Pre-operative cytological evaluation of the peri-implant breast seroma is a common clinical approach, showing mainly an inflammatory reaction or more rarely a breast implant-associated anaplastic large cell lymphoma. Herein, we reported the role of cytology in the evaluation of peri-implant breast seroma and its critical pre-operative implications. Methods Eight cases of peri-implant breast seroma from files at Luigi Vanvitelli University were identified between January and December 2017. In all cases, seroma was aspirated; cytospins were performed and stained by Papanicolaou stain; finally, in all cases, a cell block was obtained for immunocytochemical evaluation and, in one case, for FISH to detect ALK1-gene translocation. Results The median age of patients was 48 years and the mean time between the implant placement and the occurrence of peri-implant breast seroma was 18 months. Microscopic examination showed breast implant-associated anaplastic large cell lymphoma in one case, aspecific inflammatory reaction in six cases and silicon-associated reaction in one case. Conclusions Peri-implant breast seroma may be caused by several pathological conditions with different clinical behaviour. A proper cytological approach to peri-implant breast seroma allows a correct differential diagnosis between inflammatory conditions and breast implant-associated anaplastic large cell lymphoma and an appropriate management of the patient.

Hepatitis C virus (HCV) has been recognized to be both a hepato- and lymphotropic virus. HCV lymphotropism represents an essential detail in the pathogenesis of virus-related autoimmune and lymphoproliferative disorders, ranging from clonal expansion of B-cells with organ and non-organ-specific autoantibody production up to overt non-Hodgkin’s lymphoma along a continuous step-by-step model of B-cell lymphomagenesis, where the intermediated mixed cryoglobulinemia could be considered as a stage of suppressible antigen-driven lymphoproliferation. The HCV long-lasting extrahepatic replicative state generates an abnormal systemic immunological response, including rheumatoid factor (RF) and cryo- and non-cryoprecipitable immune complexes, as well as clinical manifestations, comprising dermatitis, polyarthralgias and arthritis, pulmonary disease, aplastic anemia, glomerulonephritis and vasculitis. The mechanism of these extra-hepatic disorders is thought of as linked to immune complex disease, but their pathogenesis is poorly clarified. Immune-suppressive treatment could induce high-level hepatitis C viremia and impair hepatic disease. We report a female patient, whose chronic HCV-related liver cirrhosis with associated explosive, but oligosymptomatic lymphoproliferative immune response, i.e., RF beyond three thousand times the upper of normal range (unr), type II cryoglobulinemia with cryocrit 40% and monoclonal gammopathy IgM-k, has been successfully and safely treated by long-lasting (sixty-six months) combined antiviral therapy (pegylated interferon alfa and ribavirin), at moderate and tapering dose regimen, prolonged for nearly 24 months after the first viral suppression. At the last follow-up (fifty-one months), the patient was showing very-long term antiviral response, progressive decline of secondary immune activation and absence of significant side-effects. Further research is required to fully verify the real impact on therapeutic choice/regimen.

Between November 2012 and July 2014, in accordance with national law 648/96, brentuximab vedotin was available in Italy for patients with relapsed systemic anaplastic large cell lymphoma outside a clinical trial context. A large Italian observational retrospective study was conducted on the use of brentuximab vedotin in everyday clinical practice to check whether clinical trial results are confirmed in a real-life context. The primary endpoint of this study was best response; secondary endpoints were the overall response rate at the end of the treatment, duration of response, survival and safety profile. A total of 40 heavily pretreated patients were enrolled. Best response was observed after a median of four cycles in 77.5%: globally, 47.5% patients obtained a complete response, 64.2% in the elderly subset. The overall response rate was 62.5%. At the latest follow up, 15/18 patients are still in complete remission (3 with consolidation). The progression-free survival rate at 24 months was 39.1% and the disease-free survival rate at the same time was 54% (median not reached). All the long-term responders were aged

BACKGROUND Flow cytometry (FC) is a useful adjunct to fine-needle aspiration cytology (FNC) in evaluating lymphoproliferative disorders. The authors present a critical review of 307 lymph nodal and extra lymph nodal lymphoproliferative disorders that were diagnosed with FNC and FC. METHODS FC was performed over a 4-year period on 185 palpable and 122 impalpable lymph nodal and extra lymph nodal lymphoproliferative processes under ultrasound or computed tomography guidance. FC was performed using the following fluoresceinated antibodies: CD3, CD4/CD8, CD2/CD7/CD3, CD5/CD10/CD19, CD19/κ/λ, FMC7/CD23/CD19, CD38/CD56/CD19, and bcl-2. The series included 15 inadequate, 10 suspicious, and 135 benign reactive hyperplasias (BRHs); 70 primary non-Hodgkin lymphomas (NHLs), and 77 recurrent NHLs (rNHLs). FC/FNC diagnoses of suspicious, NHL, and rNHL were controlled either histologically or clinically or by the interphase fluorescence in situ hybridization demonstration of t(11;14)(q13;q32) in two cases of mantle cell lymphoma. BRHs were controlled by follow-up. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the FC/FNC diagnoses of NHL, rNHL, and BRH were calculated as well as the identification of specific subtypes among the small- and medium-sized cells. RESULTS Statistical analysis showed 93% sensitivity, 100% specificity, 100% PPV, and 91% NPV in NHL, rNHL, and BRH discrimination. The subclassification of small cell and medium-sized NHLs showed 63% sensitivity, 88% specificity, 95% PPV, and 37% NPV. CONCLUSIONS FC applied to FNC enhanced the precision of cytologic diagnosis in lymph nodal and extra lymph nodal lymphoproliferative disorders and allowed further subclassification in more than half of the cases, thus avoiding invasive surgical biopsies in many patients. Cancer (Cancer Cytopathol) 2004;102:55–65. © 2003 American Cancer Society.

Intravascular lymphomatosis (IVL) is a rare large-cell lymphoproliferative disorder characterized by a widespread lymphoma proliferation within the lumen of medium and small vessels, frequently presenting with skin and/or central nervous system (CNS) manifestations. The tumor is of B-cell origin in most cases. Prognosis is poor with a reported median survival of 5-7 months. We describe here two cases of IVL. The first was that of a 55-year-old woman with a large B-cell lymphoma of the leg, successfully treated with conventional chemotherapy (CHT) followed by autologous peripheral stem cell transplantation. At 3 months from the autograft she relapsed with a picture of hemophagocytic syndrome (HPS) and CNS symptoms. She died before any specific treatment, and post-mortem examination revealed the intravascular proliferation of lymphoma B-cells in the brain and bone marrow. The second case was that of a 60-year-old male with CNS involvement at diagnosis. He responded poorly to CHOP-like CHT, and died 2 months after diagnosis and 6 months after onset of symptoms. Failure of CHT at least in some IVL patients may be related to a delay in the initiation of therapy due to non-specific neurological symptoms. Therefore, early diagnosis based upon aggressive attempts immediately followed by adequate therapy may prove beneficial to these patients. In the present report, we performed an extended medline-based review of the published series of patients with IVL.

Ocular adnexa B-cell lymphomas are a relatively rare group of extranodal lymphomas, marginal-zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas) being the most frequent type at this location. As with other nongastrointestinal MALT lymphomas, ocular adnexa MALT lymphomas have distinct characteristics from those of the gastric MALT model, implying specific pathogenic events, which could be of interest in the prediction of clinical behavior and the choice between therapeutic options. In a series of 39 cases of ocular adnexa MALT lymphomas, studied using a tissue microarray, we observed that the most frequent alteration was related to apoptosis regulation. Thus, caspase 3 activity was completely abolished, and phosphorylated IkappaBalpha, a marker of NF-kappaB activation, showed increased expression, while cases with an increased number of large cells displayed increased expression of survivin and other cell-cycle-related proteins, such as cyclin A, cyclin E and Ki67, and p16 expression was reduced. There were no occurrences of t(11;18)(q21,q21), while 5/37 cases exhibited t(14;18)(q32;q21). Aberrant nuclear expression of bcl10 was observed in 11 cases, independently of the presence of translocations, and was significantly associated with phosphorylated IkappaBalpha expression and a reduced TdT-mediated biotin-dUTP nicked-end labeling apoptotic index. Moreover, patients with tumoral bcl10 nuclear expression showed shorter failure-free survival.

Objective: To evaluate the diagnostic efficiency of fine needle aspiration cytology/flow cytometry (FNAC/FC) in the diagnosis and classification of non-Hodgkin lymphoma (NHL) in a series of 446 cases and to compare the results with those of previous experiences to evaluate whether there had been an improvement in FNAC/FC diagnostic accuracy. Methods: FNAC/FC was used to analyse 446 cases of benign reactive hyperplasia (BRH), NHL and NHL relapse (rNHL) in 362 lymph nodes and 84 extranodal lesions. When a diagnosis of NHL was reached, a classification was attempted combining FC data and cytological features. Sensitivity, specificity and positive and negative predictive values (PPV and NPV) of FNAC/FC in the diagnosis and classification of NHL were calculated and compared with those available in the literature. Results: FNAC/FC provided a diagnosis of NHL and rNHL in 245 cases and of BRH in 188 cases. In nine cases, the diagnosis was 'suggestive of NHL' (sNHL) and in four cases was inadequate. Histology and clinical follow-up confirmed 102 cases of NHL and detected one false positive. In 18 cases of BRH diagnosed by FNAC/FC, histological examination revealed 14 BRH and four NHL (false negatives). All nine cases diagnosed as sNHL were confirmed by histology. Including sNHL cases as false negatives, statistical analysis showed 94.9% sensitivity, 99.4% specificity, 99.6% PPV and 93.4% NPV in the diagnosis of NHL. A specific subtype was diagnosed in 125 cases and confirmed in 67 of 70 cases that had histological biopsies. Statistical analysis did not demonstrate significant improvements between the present series and previous studies either in diagnosis or in classification of NHL. Conclusions: FNAC/FC is a fundamental tool in the diagnosis and classification of NHL but the exiguity of diagnostic material and other technical and clinical limitations will probably continue to limit further improvement of the technique.

Background: Occult HBV infection (OBI) is defined by the persistence of HBV in the liver without serum HBsAg and HBVDNA. It represents a life-threatening event during immunosuppressive chemotherapies. An OBI occurs in approximately 18% of HBcAb + patients. International guidelines suggest surveillance for HBV markers in immunosuppressed patients. In Non-Hodgkin Lymphoma (NHL), the prevalence of OBI reactivation remains to be established. Methods: In order to determine the prevalence of occult HBV reactivation in a large cohort of patients during chemotherapy for NHL, we analysed 498 NHL patients in a centre of Southern Italy. We evaluated HBV markers, NHL type, treatment type and occurrence of HBV reactivation. Results: Forty % of patients were treated with monoclonal antibodies and 60.3% without. Ninety-six patients were HBcAb+, HBsAg-. HBV reactivation occurred in ten subjects of this subgroup. All of them were successfully treated with Lamivudine. None of the patients experienced liver-related death. The prevalence of OBI reactivation was of 10.42% in HBcAb + HBsAb-patients. This event occurred in 50% of patients treated with mild immunosuppressive therapies. Each reactivation was treated with Lamivudine. Discussion: This report suggests that a strict surveillance is important and cost-effective in HBcAb + HBsAg- NHL patients treated with mild immunosuppressive therapies, in order to detect an occult HBV reactivation.

Purpose The sensitivity of lymph node excisional biopsy requires validation. Power Doppler ultrasound (US) helps predict the malignant status of lymphadenopathies. We used power Doppler US to select for biopsy the lymph node most suspected of malignancy. Patients and Methods One hundred fifty-two patients having lymphadenopathies with clinical suspicion of lymphoma were divided into two well-matched groups and randomly assigned to undergo either standard or power Doppler US-directed lymph node excisional biopsy. Results Histology showed a malignancy in 64% of patients in the standard group (lymphoma, 49 patients; carcinoma, two patients) and in 87% of patients in the US-assisted group (lymphoma, 62 patients; carcinoma, one patient). There were significantly fewer biopsy-related complications in the assisted group than in the standard group. During the follow-up of the patients with lymph nodes reported as being reactive, 14 of 29 patients in the standard group were rebiopsied and were found to have lymphoma (13 patients) or carcinoma at the subsequent lymph node histology, whereas none of the patients in the assisted group (nine patients) required a second biopsy. Thus, biopsy provided false-negative results for malignancy in 21% of patients affected by lymphoma in the standard group and never in the assisted group (P < .01). Conclusion Power Doppler US is an accurate tool for screening lymphadenopathies to be removed by excisional biopsy in patients with suspected lymphoma.

PurposePromising new therapeutic options for follicular lymphoma (FL) include fludarabine plus mitoxantrone (FM) and the mouse/human anti-CD20 antibody, rituximab. We performed a randomized comparative trial of FM with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) front-line chemotherapy with and without sequential rituximab.Patients and MethodsAll previously untreated CD20+FL patients presenting in 15 Italian cooperative institutions from October 1999 were randomly allocated to FM or CHOP. Following clinical or molecular restaging, patients in complete remission (CR) with bcl-2/IgH negativity (CR−) received no further treatment; those in CR with bcl-2/IgH positivity (CR+) received rituximab, as did those in partial remission (PR) with bcl-2/IgH negativity (PR−) or positivity (PR+); nonresponders (NR subgroup) were off study.ResultsAfter chemotherapy, the FM arm achieved higher rates of CR (68% [49 of 72 patients] v 42% [29 of 68 patients]; P = .003) and CR−(39% [28 of 72 patients] v 13 of 68 patients [19%]; P = .001). Rituximab elicited CR−in 55 of 95 treated patients (58%). The final CR−rate was higher in the FM arm (71% [51 of 72 patients] v 51% [35 of 68 patients]; P = .01). However, with a median follow-up of 19 months (range, 9 to 37 months), no statistically significant difference was found among the various study arms in terms of both progression-free (PFS) and overall survival (OS).ConclusionThese results indicate that FM is superior to CHOP for front-line treatment of FL and that rituximab is an effective sequential treatment option. However, they also confirm that this superiority is unlikely to translate into either better PFS or OS.

Purpose To evaluate the efficacy of rituximab maintenance in 60- to 75-year-old patients with advanced follicular lymphoma responding to brief first-line chemoimmunotherapy followed by rituximab consolidation. Patients and Methods A total of 234 treatment-naive 60- to 75-year-old patients began chemoimmunotherapy with four monthly courses of rituximab, fludarabine, mitoxantrone, and dexamethasone (R-FND) followed by four weekly cycles of rituximab consolidation. Of these, 210 patients completed the planned treatment, and 202 responders were randomly assigned to rituximab maintenance (arm A) for 8 months, once every 2 months for a total of four doses, or to observation (arm B). Results Median ages in arms A and B were 66 and 65 years, respectively. After induction and consolidation therapy, the overall response rate was 86%, with 69% complete remissions (CR). After a 42-month median follow-up from diagnosis, 3-year progression-free survival (PFS; the primary end point) and overall survival (OS) were 66% (95% CI, 59% to 72%) and 89% (95% CI, 85% to 93%), respectively. After randomization, 2-year PFS was 81% for rituximab maintenance versus 69% for observation, with a hazard ratio of 0.74 (95% CI, 0.45 to 1.21; P = .226), although this was not statistically significant. No differences between the two arms were detected for OS. Overall, the regimen was well-tolerated. The most frequent grade 3 to 4 toxicity was neutropenia (25% of treatment courses), with 13 infections. Two toxic deaths (0.8%) occurred during induction treatment. Conclusion A brief R-FND induction plus rituximab consolidation achieved excellent results with high CR and PFS rates, supporting the feasibility of this regimen in patients older than 60 years. A short rituximab maintenance did not achieve a statistically significant PFS improvement over observation.

Primary hepatic lymphoma is an extremely rare malignancy accounting for 0.016% of all cases of non-Hodgkin lymphomas. Approximately 1-4% of histologies described show a follicular pattern. We report a case of primary hepatic non-Hodgkin lymphoma that developed in a middle-aged woman three years after radical treatment (neoadjuvant chemoradiotherapy and surgery) for a rectal adenocarcinoma. Abdomen ultrasound showed a single nodule in the liver, which raised the issue of differential diagnosis with a metastasis from rectal cancer. After surgical removal of the nodule, histology revealed a primary B cell, stage IE follicular non-Hodgkin lymphoma, confined to the liver; indeed, no foci of lymphoma were found elsewhere in the body.

In a previous study, we showed the ability of technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) scan to identify active disease in patients with multiple myeloma (Eur J Nucl Med 1998; 25: 714–720). In particular, a semiquantitative score of the extension and in- tensity of bone marrow uptake was derived and correlated with both the clinical status of the disease and plasma cell bone marrow infiltration. In order to estimate quantitatively 99mTc-MIBI bone marrow uptake and to verify the intracellular localization of the tracer, bone marrow samples obtained from 24 multiple myeloma patients, three patients with monoclonal gammopathy of undetermined significance (MGUS) and two healthy donors were studied for in vitro uptake. After centrifugation over Ficoll-Hypaque gradient, cell suspensions were in- cubated with 99mTc-MIBI and the uptake was expressed as the percentage of radioactivity specifically retained within the cells. The cellular localization of the tracer was assessed by micro-autoradiography. Twenty-two out of 27 patients underwent 99mTc-MIBI scan within a week of bone marrow sampling. Whole-body images were ob- tained 10 min after intravenous injection of 555 MBq of the tracer; the extension and intensity of 99mTc-MIBI uptake were graded using the semiquantitative score. A statistically significant correlation was found between in vitro uptake of 99mTc-MIBI and both plasma cell infil- tration (Pearson's coefficient of correlation r=0.69, P

Technetium-99m 2-methoxyisobutylisonitrile (99mTc-MIBI or setamibi) has recently been proposed for use in the evaluation of multiple myeloma (MM). The aims of this study were to investigate its potential predictive value in patients with MM and its possible role in the follow-up. Thirty patients with MM who had undergone two 99mTc-MIBI scintigraphic studies at least 2 months apart constituted the study group; 22 of them received chemotherapy in the interval between the two scans. The scans were classified as showing pattern N when only physiological uptake was present, pattern D when diffuse bone marrow uptake was observed, pattern F when areas of focal uptake of the tracer were evident, and pattern F + D when both D and F patterns were observed. Comparative 99mTc-MIBI scintigraphy was considered indicative of disease progression when there was a worsening of the pattern (i.e. from N to D, or from N or D to F or to F + D) or an increase in the pattern D semiquantitative score. It was considered indicative of disease improvement when the opposite trend was observed; otherwise, it was considered to document a stable condition. A significant association was observed between the baseline scintigraphic pattern and clinical status at follow-up in the group of patients evaluated after chemotherapy (chi 2 = 16.7, P0.05). A negative baseline 99mTc-MIBI scintigram showed a high predictive accuracy (100%) for remission, while the presence of pattern F or F + D was often associated with a less favourable outcome. A multivariate analysis showed that 99mTc-MIBI uptake pattern has an added value in relation to known prognostic variables such as C-reactive protein. 99mTc-MIBI scintigraphy patterns at follow-up were significantly associated with the clinical status evaluated after chemotherapy (chi 2 = 32.6, P0.0001). Considering pattern N as indicating remission, pattern D stable condition, and pattern F or F + D progressive disease, a high concordance between scintigraphic findings and clinical status was found in the 22 patients undergoing chemotherapy (91%). Variation in 99mTc-MIBI findings comparing baseline and follow-up evaluations was significantly associated with clinical status both in patients undergoing chemotherapy (chi 2 = 26.5, P0.0005) and in those not undergoing chemotherapy (chi 2 = 8.0, P0.005). In conclusion, the results of this study suggest a prognostic value of 99mTc-MIBI scintigraphy in patients with MM and a potential role during the follow-up.

Purpose: To evaluate the role of early intensification with high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) as front-line chemotherapy for patients with high-risk, histologically aggressive non-Hodgkin’s lymphoma (NHL). Patients and Methods: We planned a multicenter, randomized trial to compare a conventional chemotherapy regimen of methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B; arm A) with an abbreviated regimen of MACOP-B (8 weeks) followed by HDT and ASCT (arm B) for intermediate-high-risk/high-risk patients (according to the age-adjusted International Prognostic Index). From September 1994 to April 1998, 150 patients with aggressive lymphoma were enrolled onto the trial. Seventy-five patients were randomly assigned to arm A and 75 patients were randomly assigned to arm B. In both arms, involved-field radiation therapy (36 Gy) was delivered to the site of bulky disease. Results: The rate of complete response was 68% in arm A and 76% in arm B (P = not significant [NS]). Three toxic deaths (4%) occurred in arm B and one (1%) occurred in arm A (P = NS). In arm B, 30 patients (40%) did not undergo HDT and ASCT. According to the intention-to-treat analysis at a median follow-up of 24 months, 5-year overall survival probability in arms A and B was 65% and 64% (P = .95), 5-year progression-free survival was 49% and 61% (P = .21), and 5-year relapse-free survival was 65% and 77% (P = .22), respectively. Conclusion: Abbreviated chemotherapy followed by intensification with HDT-ASCT is not superior to conventional chemotherapy in patients with high-risk, aggressive NHL. Additional randomized trials will clarify whether HDT-ASCT as front-line therapy after a complete course of conventional chemotherapy improves survival in this group of patients.

Purpose: To prospectively compare the assessment of metabolic response to yttrium 90 ( 90 Y)-ibritumomab tiuxetan radioimmunotherapy (RIT) by using fl uorine 18 ( 18 F) fl uorodeoxyglucose (FDG) combined positron emission tomographic- computed tomographic (PET/CT) imaging at 2 and 6 months to determine the most appropriate time to detect therapeutic response in refractory non-Hodgkin lymphoma (NHL) patients treated with RIT. Materials and Methods: The ethical committee of the university approved the protocol and all patients signed informed consent. Twentythree consecutive patients (10 women, 13 men; mean age, 51.8 years 6 7.3 [standard deviation ]) treated by using RIT for relapsed or refractory follicular NHL were enrolled. For all patients, 18 F FDG PET/CT scanning was performed at baseline and at 2 and 6 months after RIT. Response was assessed by using the International Workshop Criteria (IWC) and revised criteria (IWC + PET) as well as the criteria of the European Organization for Research and Treatment of Cancer. One-way analysis of variance for repeated measures, receiver operator curve analysis, and Kaplan-Meier curves were used for statistical analysis. Results: PET/CT performed at 2 months revealed complete ( n = 12) or partial ( n = 4) metabolic response in 16 of 23 patients with complete or partial clinical response. These fi ndings were all confi rmed at 6-month scanning. PET/CT indicated refractory or persistent disease at 2 and 6 months in the remaining seven patients. Better overall survival was observed for patients with a reduction in the maximum standard uptake value of 49% or higher (both at 2 and 6 months after RIT) when compared with those with a decrease of less than 49% ( P , .05). Conclusion: Early assessment of response to RIT by using PET/CT might be useful in the identifi cation of patients needing additional therapeutic strategies.

Objective To assess the influence of hepatitis C virus (HCV) infection on disease appearance and outcome of ocular adnexal non-Hodgkin lymphoma (ONHL). Design Retrospective comparative study (from January 1, 1992, through December 31, 2006). Methods The medical records of 129 patients with ONHL were retrospectively reviewed. All the patients were tested serologically for the presence of HCV infection. Patients were divided into 2 groups according to the presence or absence of HCV infection. Main Outcome Measures Prevalence of HCV infection, staging to evaluate the extent of disease at the onset, and clinical outcome data on overall and disease-free survival. Results The prevalence of HCV infection among the patients with ONHL was 17.8%. Seropositivity for HCV infection was significantly associated with extraorbital lymphoma at the onset ( P = .006). High prevalence of mucosa-associated lymphoid tissue disease (79.8%) was registered. Protocol therapy included radiotherapy and chemotherapy, depending on the stage of the disease. Complete remission was achieved in 99 patients (76.7%). A total of 23.6% of patients with HCV-seronegative status and 21.7% of those with HCV-seropositive status experienced relapse of the lymphomatous disease. No significant differences in the 5-year overall survival and disease-free survival between the 2 groups were observed. Conclusions Prevalence of HCV infection in patients with ONHL is a relevant issue, accounting for 17.8% of the examined patients. Infection with HCV may influence the initial appearance of ONHL because it is associated with more widespread disease at the onset. However, the overall and disease-free survival of the infected patients are not statistically different than that of patients who are not infected.

Background Among the third-generation chemotherapy regimens specifically adapted in the last decade for elderly aggressive non-Hodgkin’s lymphoma (NHL) patients, we designed an 8-week cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin and prednisone (VNCOP-B) plus granulocyte colony-stimulating factor (G-CSF) regimen which, in a national multicenter trial, induced good complete response (CR) and relapse-free survival rates with only moderate toxic effects. Here we report a prospective, multicenter, randomized trial comparing the efficacy and toxicity of 8- and 12-week regimens of VNCOP-B plus G-CSF. Patients and methods From February 1996 to June 2001, 306 consecutive previously untreated stage II–IV aggressive NHL patients ≥60 years of age were enrolled from 12 Italian cooperative institutions. Of the 297 evaluable patients, 149 and 148 received 8- and 12-week regimens, respectively, of VNCOP-B. Results The CR rates were 63% and 56% in the 8- and 12-week groups; at a median of 32 months (range 3–62 months), relapse-free survival rates were 59% and 55%, respectively. Hematological and non-hematological toxicities were similar in both treatment groups. Conclusions Our data show that extending induction treatment with the VNCOP-B plus G-CSF regimen from 8 to 12 weeks does not raise the CR rate or provide a more durable remission.

BACKGROUND. The development of gene expression profiling and tissue microarray techniques have provided more information about the heterogeneity of diffuse large B-cell lymphoma (DLBCL), enabling categorization of DLBCL patients into 3 prognostic groups according to cell origin (but independently from the International Prognostic Index [IPI] score): germinal center (GCB), activated B-cell (ABC), and not classified (NC) diffuse large B-cell lymphoma. This study investigated the role of immunohistochemical discrimination between GCB and ABC&NC-DLBCL subtypes in identifying those high-risk patients who may benefit from a more aggressive first-line therapeutic approach. METHODS. From February 2003 to August 2006, 45 newly diagnosed DLBCL patients, with IPI≥2, were considered eligible for this study: 13 had a GCB, 8 an ABC, and 24 a NC-DLBCL. GCB patients received 6 courses of rituximab, cyclophophosphamide, doxorubicin, vinicristine, and prednisone (R-CHOP) chemotherapy, with a subsequent, autologous stem cell transplantation in case of partial response. All ABC and NC-DLBCL patients received 6 R-CHOP cycles and autologous stem cell transplantation. RESULTS. Complete response rate for each treatment arm was 84.6% for GCB and 89.7% for ABC&NC-DLBCL (P = .50), with a continuous complete response rate of 81.8% and 84.6%, respectively (P = .59). Projected 4-year overall survival is 100% for GCB and 82% for ABC&NC patients (P = .12). Progression-free survival is 77% and 79% (P = .7), respectively. CONCLUSIONS. The autologous stem cell transplantation consolidation in the ABC&NC-DLBCL subtypes induced the same rate of complete response (and similar progression-free survival rate) compared with GCB-DLBCL. In ABC&NC-DLBCL patients the authors observed a complete response rate of 89.7% vs. 84.6% in the GCB-DLBCL subset, without any significant difference in progression-free survival rate. Cancer 2010. © 2010 American Cancer Society.

Young patients (aged 18-60 years) with good-prognosis diffuse large B-cell lymphoma (DLBCL) [0 and 1 risk factor according to age-adjusted international prognostic index (aa-IPI)] are distinguished from patients with poor-prognosis. Six cycles of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) in combination with rituximab achieved best results in young patients with low-risk DLBCL. We retrospectively analyzed the data of 82 patients (18-60 years) with untreated aa-IPI 0-1 DLBCL, from six Italian institutions, who underwent, between January 2002 and January 2007, rituximab-cyclophosphamide, doxorubicin, vincristine, methotrexate, bleomicin and prednisone (R-MACOP-B) therapy followed, in patients with bulky presentation, by 30-36 Gy involved-field radiation therapy (34 patients). An overall response rate was noted in 77 out of 82 (94%) patients (75 patients had a complete response (91%), 2 patients had a partial response). With a median follow-up of 46 months, 7-year progression-free and overall survival were estimated to be 91% and 94%, respectively. R-MACOP-B regimen followed by involved-field radiation on bulky presentation is safe and very effective in the treatment of young patients with low-risk DLBCL.

A 40-year-old female, HIV positive, stage C, since 4 years, complained of a right cervical lymph node swelling. Two years before, the patient had been diagnosed with follicular B-cell non-Hodgkin lymphoma (FL); she had been treated with four cycles of multiagent chemotherapy plus rituximab, the last cycle being administered 10 months before coming to our attention. An ultrasound (US) guided fine-needle cytology (FNC) showed an atypical lymphoid cell proliferation. The phenotype evidenced by flow cytometry (FC) analysis was D5: 10%, CD19: 49%, CD23: 10%, FMC7: 0%, CD10: 40%, CD10/19: 40%, lambda light chain 40%, kappa light chain 0%. FDG-positron emission tomography (PET/CT) scan showed positivity in the corresponding cervical area. Since low LDH values and a reduced lymph node size were observed, the lymph node was therefore excised; the histology revealed a reactive hyperplastic lymph node with florid follicular pattern. A subsequent PCR analysis, performed on DNA extracted from a whole histological section, did not evidence IgH rearrangement. The patient is currently undergoing strict clinical and instrumental follow-up, including PET every 3 months; after 13 months, she is alive without recurrence of lymphoma. Clonal B-cell populations in non-lymphomatous processes have been described in mucosa-associated lymphoid cell populations and reactive lymph nodes, and are considered non-malignant, antigen driven, proliferations of B-lymphocytes determined by an abnormal response to bacterial or viral antigen stimulation. The present case occurred in an HIV patient and was clinically complex because of the patient’s history of FL. This experience suggests much attention in the evaluation of radiological, cytological, and FC data and in clinical correlation in patients suffering from autoimmune or immunodeficiency syndromes. Diagn. Cytopathol. 2009;00:000– 000. ' 2009 Wiley-Liss, Inc.

Summary Background Follicular lymphoma is the most common form of lymphoma in Europe and the USA. In this prospective, single-arm, open-labelled, multicentre non-randomised phase II trial (FLUMIZ [FLUdarabine, MItoxantrone, Zevalin] trial) we aimed to assess the efficacy and safety of fludarabine and mitoxantrone plus radioimmunotherapy in untreated patients with follicular non-Hodgkin lymphoma (NHL). Methods Patients with stage III or IV untreated indolent follicular NHL were enrolled between June 1, 2004, and April 15, 2006, at 13 Italian institutions, and were treated with oral fludarabine (40 mg/m 2 on days 1 to 3) and intravenous mitoxantrone (10 mg/m 2 on day 1) every 28 days for six cycles. Patients who had at least a partial response (PR) with normal platelet counts (>100×10 9 /L) and granulocyte counts (1·5×10 9 /L), and bone-marrow infiltration less than 25% 4–6 weeks after completion of the sixth cycle of chemotherapy were deemed eligible for consolidation treatment 6–10 weeks after the sixth cycle with one course of yttrium-90 ( 90 Y)-labelled ibritumomab tiuxetan (Zevalin), which consisted of an initial infusion of intravenous rituximab (250 mg/m 2 ) on day 1 followed by a second 250 mg/m 2 infusion on day 7, 8, or 9. The second infusion was followed by a weight-based dose of 90 Y-ibritumomab tiuxetan, administered as a slow intravenous push over 10 min. Primary endpoints were complete response (CR) and haematological toxic effects and secondary endpoints were overall survival and progression-free survival. Responses were classified according to the International Workshop for Response Criteria for non-Hodgkin's lymphomas. Analysis was per protocol. This trial is registered as a European Standard Controlled Trial on the EudraCT website http://oss-sper-clin.agenziafarmaco.it, number 2004-002211-92. Findings 61 patients were enrolled in the trial and received six cycles of fludarabine and mitoxantrone, after which an overall response was noted in 98% (60 of 61) of patients (43 of 61 patients had CR and 17 of 61 patients had PR). 57 patients (43 with CR and 14 with PR) were deemed eligible for subsequent 90 Y-ibritumomab tiuxetan. Of the 14 patients who had PR after the initial treatment, 12 obtained CR after 90 Y-ibritumomab tiuxetan. By the end of the entire treatment regimen 55 of 57 patients achieved CR. With a median follow-up of 30 months (range 21–48), 3-year progression-free survival was estimated to be 76% (95% CI 72·3–82·4) and 3-year overall survival 100%. 36 of 57 patients had grade 3 or 4 haematological toxic effects, and blood transfusions were given to 21 of 57 patients. Interpretation This trial has provided evidence for the feasibility, tolerability, and efficacy of fludarabine and mitoxantrone plus 90 Y-ibritumomab tiuxetan in untreated patients with follicular NHL. Funding Italian Association for Leukaemias, Lymphomas, and Myeloma, Bologna, Italy.

BACKGROUND/AIMS:Prevalence of HCV infection in non-Hodgkin's lymphoma is high. The impact of antiviral therapy on the natural history of this subgroup of lymphomas after a successful chemotherapy regimen is still an argument of debate. METHODS:We retrospectively examined 343 chemotherapy-treated patients referred to our centre for five consecutive years. Clinical and histological characteristics, disease free-survival (DFS) and overall-survival (OS) were compared in HCV-positive (69/343) and HCV-negative (274/343) patients. Twenty-five HCV-positive patients received antiviral treatment following chemotherapy discontinuation. Uni- and multivariate analyses were performed. RESULTS: 20% of lymphomas were HCV-positive. Indolent histology was prevalent in the HCV-positive group (p

Some case reports and a Japanese series suggest benefit from the use of rituximab in patients with intravascular large B-cell lymphoma (IVL). Rituximab efficacy was evaluated in Western patients with IVL, comparing outcome of 10 patients treated with rituximab + chemotherapy (R-CT) and of 20 patients treated with chemotherapy alone (CT). There were no significant differences in patients' characteristics between the two subgroups. The addition of rituximab was associated with improved complete remission rate (90% vs. 50%; P = 0.04), event-free survival (3-year: 89% vs. 35%; P = 0.003) and overall survival (3-year: 89% vs. 38%; P = 0.01). In conclusion, rituximab may substantially change the dismal prognosis of IVL.

Technetium-99m 2-methoxyisobutylisonitrile (99mTc-MIBI) has been proposed as a potential tracer in patients with multiple myeloma (MM). The aims of this study were to evaluate the incidence of various patterns of diffuse 99mTc-MIBI uptake in patients with MM, to assess their relationship with clinical status and stage of disease, and to try to clarify the meaning of the diffuse bone marrow uptake of 99mTc-MIBI. Thirty-nine consecutive patients with MM were studied. Twenty-nine of these patients had active disease (13 in stage I, ten in stage II, and six in stage III) and ten were in remission after chemotherapy. Anterior and posterior whole-body scans were obtained 10 min after i.v. injection of 555 MBq of 99mTc-MIBI. The scans were classified as showing: pattern N, when only physiological uptake was present; pattern D, when diffuse bone marrow uptake was observed; pattern F, when areas of focal uptake of the radiotracer were evident; or pattern D+F, when both D and F patterns were observed. Diffuse bone marrow uptake was scored according to extension and intensity. Seven of the 39 patients (18%) showed pattern N, 18 (46%) pattern D, 2 (5%) pattern F, and 12 (31%) pattern D+F. Of the 32 patients with a positive 99mTc-MIBI scan (i.e. showing pattern D, F or D+F), 29 (91%) had active disease. Only three patients in remission showed pattern D, but with a very low bone marrow uptake score. Both extension and intensity of diffuse bone marrow uptake correlated with the amount of the monoclonal component and the percentage of bone marrow plasma cells. The distribution of the 99mTc-MIBI uptake patterns differed among patients in different stages of disease. Using as criteria for advanced stage the presence of either focal uptake (pattern F or D+F) or pattern D with a high score, high (90%) diagnostic accuracy was obtained. In conclusion, the patterns of 99mTc-MIBI uptake in patients with MM are related to both the clinical status and the stage of disease. The presence of focal uptake or of intense diffuse bone marrow uptake suggests that the patient has active and advanced stage disease, while a negative scan in a patient with MM clearly indicates remission.

Overexpression of P-glycoprotein (Pgp) is one of the primary mechanisms of multidrug resistance (MDR) in several diseases, including multiple myeloma. The aim of this study was to investigate whether the washout of 99mTc-MIBI, a transport substrate of Pgp, is enhanced in the bone marrow of patients with multiple myeloma overexpressing Pgp. Seventeen (17) patients were i.v. injected with 555 MBq of 99mTc-MIBI, and whole-body scans were performed at 10 and 60 minutes. A region of interest (ROI) was drawn over the thoracic spine of each scan, and the washout of 99mTc-MIBI was calculated, after decay correction, as: (10-minute counts/pixel minus 60-minute counts/pixel) divided by 10-minute counts/pixel. Pgp expression was determined in 17 bone marrow samples obtained from the same patients immediately before the 99mTc-MIBI scan. Following centrifugation over the Ficoll-Hypaque gradient, cytospins were obtained and immunostained with C219 monoclonal antibody. The immunostaining of Pgp was graded as 1, 2, or 3 when a faint, moderate, or intense reaction, respectively, was observed in infiltrating plasma cells. Washout of 99mTc-MIBI ranged between 5% and 26%. A statistically significant direct correlation was found between the washout of the tracer and Pgp expression (Spearman rank correlation coefficient r = 0.74, p0.001). A partial overlap of washout values was observed in different classes of Pgp expression, thus preventing the discrimination of individual patients. Washout of 99mTc-MIBI, expressed as the percentage of radioactivity cleared from the bone marrow over a 1-hour period, may be used as a noninvasive tool for in vivo whole-body imaging of Pgp expression and function in multiple myeloma patients.

A prospective, single-arm, open-label, multicenter, nonrandomised phase II trial to evaluate efficacy and safety of short fludarabine, mitoxantrone, and rituximab (FMR) induction followed by radioimmunotherapy, in untreated, intermediate/high-risk follicular non-Hodgkin's lymphoma (NHL) patients.Fifty-five patients were treated using a sequential treatment schedule of four induction cycles of FMR chemoimmunotherapy, and a subsequent consolidating single administration of (90)Y-ibritumomab tiuxetan ((90)Y-IT), 8-14 weeks later. Patients were eligible for radioimmunotherapy if at least in partial response (PR) after induction, with normal platelet and granulocyte counts and a bone marrow infiltration ≤ 25%. Primary study end points were response rate and hematologic toxic effects; secondary end points were overall survival (OS) and progression-free survival (PFS).All the 55 patients received four induction cycles with an overall response rate of 96% (38 complete responses [CR] and 15 PR). Fifty-one patients (38 in CR and 13 in PR) received (90)Y-IT. By the end of the treatment, 49/55 patients achieved a CR. With a median follow-up of 21 months, the estimated 3-year PFS was 81% and the 3-year OS 100%.This study has established feasibility, tolerability, and efficacy of a regimen composed by short FMR induction with (90)Y-IT consolidation in untreated intermediate/high-risk follicular NHL patients.

Low levels of vitamin B12 cause decreased activity of the methinine synthase and methylation cycle impairment, resulting in bnormalities of DNA biosynthesis and cell division. The methyation cycle dysfunction leads to a reduction of various methylated roducts, such as myelin basic protein. Vitamin B12 deficiency may cause anaemia and neurological isorders, including subacute combined degeneration of the spinal ord, peripheral neuropathy, optic atrophy, dementia, and psychitric diseases. Carnivores, including humans, derive vitamin B12 equirement by consumption of meats and food of animal origin, ilk, butter, cheese and eggs. Vitamin B12 absorption needs an dequate HCl concentration in the stomach and the presence of ntrinsic factor, a glycoprotein produced by parietal cells necessary o absorb vitamin B12. The most frequent causes of vitamin B12 deficiency are perniious anaemia, an autoimmune disease caused by autoantibodies gainst parietal cells, achlorhydria, affecting one-quarter of elderly ubjects, and reduced intake with food (e.g. vegetarianism). The itrous oxide exposure during anaesthesia is a rare cause of acute itamin B12 inactivation [1].

BACKGROUND AND OBJECTIVE: To examine the long-term clinical course and prognostic factors of patients with advanced aggressive non-Hodgkin's lymphoma (NHL) treated with third-generation regimens as front-line chemotherapy. DESIGN AND METHODS: A total of 348 patients aged

Starting from the observation that a number of consecutive patients with non-Hodgkin's lymphoma (NHL) resulted positive for hepatitis C virus (HCV) antibodies on routine testing, we set up a survey for HCV contact prevalence in all patients with lymphoproliferative disorders (LPD) followed in our institution. We searched for HCV antibodies by a third-generation ELISA technique, followed by a confirmation test (RIBA III); serum viral RNA and HCV genotype were investigated by a RT-PCR technique. We screened a total of 315 patients suffering from B-NHL (91), multiple myeloma (56), MGUS (48), chronic lymphocytic leukemia (57), Waldentrom's macroglobulinemia (13), Hodgkin's disease (HD)(43), and T-NHL (9). While only 1 of 52 patients with a non-B-LPD (HD or T-NHL) had signs of HCV contact (i.e., 1.9%, which is in the range of the normal population in the South of Italy), 59 of 263 patients with a B-LPD (22.4%) had HCV antibodies or RNA, or both, with no major differences among the various types of disorders, except for WM, in which the rate was higher (61.5%). The same prevalence was found for patients tested at diagnosis or during the follow-up, and in transfused or never-transfused patients. Only a few patients were aware of having a liver disease; one-half of HCV-positive patients never had transaminase increase. A review of data from Central and Northern Italy is included, showing similar findings; a report from Japan has confirmed such an association, while limited surveys in England have not revealed any correlation. These findings may have important biological and clinical implications.

Occult hepatitis B virus (HBV) infection can be defined as the long lasting persistence of viral genome in the liver tissue of patients without HBV surface antigen (HBsAG), with or without antibodies to hepatitis B core antigen (anti-HBc) or hepatitis B surface antigen (anti-HBs).1 The clinical relevance of occult B infection is well documented.2–6 Immunosuppressive therapy can promote viral replication and disease progression. Discontinuation of immunosuppressive drugs may lead to the reconstitution of the immune response to the virus and hence to immune mediated destruction of infected hepatocytes. This is a well recognised occurrence in patients with hepatitis B infection or non-Hodgkin lymphoma (NHL).7,8 We studied the prevalence of occult HBV infection in 58 consecutive NHL patients, six of whom were HBsAG positive and 52 were …

This study aimed at evaluating the role of consolidation radiation in a setting of Hodgkin's lymphoma (HL) patients, using event-free survival (EFS) as end point. Among 260 patients treated with induction chemotherapy for bulky HL, 160 patients achieved negative residual masses at 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scans. They were randomly divided into two well-matched groups to receive either 32 Gy radiotherapy to bulky area or no further therapy. At a median follow-up of 40 months, histology showed a malignancy in 14% of patients in the chemotherapy-only group (HL, 11 patients) and in 4% of patients in the chemotherapy + radiotherapy group (HL, 2 patients; carcinoma in previously irradiated area, 1 patient) (P = 0.03). All the relapses in the chemotherapy-only group involved the bulky site and the contiguous nodal regions. Thus, the overall diagnostic accuracy of FDG-PET to exclude future relapses in the patients nonprotected by radiotherapy was 86% with a false-negative rate of 14%. Our study suggests that the addition of irradiation helps improve EFS in HL patients with post-chemotherapy FDG-PET-negative residual masses.

Background/Aims In this study, we determined the genotypic and allelic frequencies of the Interleukin (IL)-10 −1082G/A IL-10 −592A/C , and IL-10 −819C/T polymorphisms, and their association with the risk to develop B cell Non Hodgkin Lymphoma (NHL) in hepatitis virus C (HCV) carriers. Results Genetic polymorphisms in the IL-10 gene promoter were studied in 250 consecutive patients with B-cell NHL with no clinical and/or laboratory findings of cryoglobulinemia, 142 NHL/HCV− and 108 NHL/HCV+ with chronic hepatitis (CH), 120 consecutive subjects with HCV-related CH, and 110 age, sex-matched healthy blood donors. The frequency of the IL-10 −1082GG genotype vs remaining genotypes (IL-10 −1082GA/AA ) was higher in NHL/HCV+ patients than HCV-related CH patients ( P =0.0002, OR=2.89, CI: 1.62–5.15) and in NHL/HCV+ than NHL/HCV− patients ( P =0.0001, OR=2.99, CI: 1.72–5.19). Moreover, the IL-10 −1082GG genotype was more prevalent in indolent NHL/HCV+ cases than aggressive NHL/HCV+ ( P =0.0004, OR=4.97, CI: 2.10–11.79). Finally, we confirmed that IL-10 −1082GG genotype is associated with higher IL-10 production compared to AA homozygous ( P =0.037). Conclusions The high IL-10 production, due to IL-10 −1082GG genotype, influences the clinical expression of the HCV infection by increasing susceptibility to develop NHL and might contribute to the indolent form of the disease.

CONTEXT: Celiac disease is one of the most common lifelong disorders. Non-Hodgkin lymphoma is a possible complication of celiac disease and may lead to a large portion of lymphoma cases. OBJECTIVE: To quantify the risk for developing non-Hodgkin lymphoma of any primary site associated with celiac disease. DESIGN AND SETTING: Multicenter, case-control study conducted between January 1996 and December 1999 throughout Italy. PATIENTS: Cases were older than 20 years (median, 57; range, 20-92 years) with non-Hodgkin lymphoma of any primary site and histological type and were recruited at the time of the diagnosis. Controls were healthy adults (2739 men and 2981 women) from the general population. MAIN OUTCOME MEASURE: Positive test result for class A serum antiendomysial antibody. RESULTS: Celiac disease was diagnosed in 6 (0.92%) of 653 patients with lymphoma. Of the 6 cases, 3 were of B-cell and 3 were of T-cell origin. Four of 6 cases had lymphoma primarily located in the gut. In the control group, 24 (0.42%) had celiac disease. The odds ratio (adjusted for age and sex) for non-Hodgkin lymphoma of any primary site associated with celiac disease was 3.1 (95% confidence interval [CI], 1.3-7.6), 16.9 (95% CI, 7.4-38.7) for gut lymphoma, and 19.2 (95% CI, 7.9-46.6) for T-cell lymphoma, respectively. The risk for non-Hodgkin lymphoma for the overall population, which was adjusted for age and sex, was 0.63% (95% CI, - 0.12% to 1.37%). CONCLUSION: Celiac disease is associated with an increased risk for non-Hodgkin lymphoma, especially of T-cell type and primarily localized in the gut. However, the association does not represent a great enough risk to justify early mass screening for celiac disease

Reticulocyte hemoglobin content (CHr) is considered an index of iron status, helpful in the differential diagnosis of microcytoses. Its potential can be enhanced by comparing CHr dynamic reference values (CHr-e: expected CHr), which are proportional to the MCVr variations occurring in micro- or macrocytosis, with measured CHr values. We demonstrate that the difference between measured CHr and CHr-e (DeltaCHr) is helpful to differentiate the anemic syndromes and, in particular, beta-thalassemia vs. presumable sideropenia. DeltaCHr can also indicate when to interrupt iron supplementation. DeltaCHr allows an insight into the erythropoiesis of thalassemic and sideropenic subjects, pointing out the reduced hemoglobin production and ineffective erythroid activity in these conditions.

Background: Optimal therapeutic management of intravascular lymphoma (IVL) lacks precise guidelines. Patients and methods: The clinico-pathological features of 38 HIV-negative patients with IVL were reviewed to define efficacy of chemotherapy in these malignancies. Clinical characteristics of 22 patients treated with chemotherapy and of 16 untreated patients were compared in order to understand better the impact and causes of potential patient selection. Results: Median age was 70 years (range 34-90), with a male/female ratio of 0.9; 23 (61%) patients had Eastern Cooperative Oncology Group performance status (ECOG-PS) >1; 21 (55%) had systemic symptoms. Cutaneous lesions and anemia were significantly more common among patients treated with chemotherapy; central nervous system (CNS) and renal involvement were significantly more common among untreated patients. Chemotherapy was associated with a response rate of 59% and a 3-year overall survival of 33 ± 11%. Five of six patients with CNS involvement received chemotherapy: four of them died early; only one patient, treated with adriamycin, cyclophosphamide, vincristine, methotrexate, bleomycin and prednisolone (MACOP-B) followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT), was alive at 19 months. High-dose chemotherapy supported by ASCT was indicated at diagnosis in another patient (43 years of age, stage I), who was alive at 71 months, and at relapse after cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) in two patients who died early after transplantation. PS ≤1, disease limited to the skin, stage I, and use of chemotherapy were independently associated with better outcome. Conclusions: Anthracycline-based chemotherapy is the standard treatment for IVL. However, survival is disappointing, with a relevant impact of diagnostic delay and lethal complications. More intensive combinations, containing drugs with higher CNS bioavailability, are needed in cases with brain involvement, and the role of high-dose chemotherapy supported by ASCT should be further investigated in younger patients with unfavorable features. © 2004 European Society for Medical Oncology.

A 49-year-old woman with a four year history of therapy resistant essential thrombocythemia, progressed to acute leukemia that also proved refractory to chemotherapy. Blast cell features including immunophenotype, cytogenetics and in vitro cell cultures, suggested megakaryoblastic leukemia. In serum-free culture, blasts released GM-CSF and IL-6 which sustained autocrine growth and promoted normal myeloid and megakaryocytic colony formation.

Chemotherapy can cause hepatitis flare-up through viral reactivation in patients who have had contact with hepatitis viruses. Few data are available on the genotype of the reactivated viruses.In 40 consecutive adult patients with indolent non-Hodgkin's lymphoma (NHL) receiving fludarabine-based front-line chemotherapy, we performed a prospective study on viral hepatitis reactivation and analyzed the genotype of the reactivated viruses. Before chemotherapy, 4 patients were healthy carriers of hepatitis B surface antigen (HBsAg), 2 had HB core antigen antibodies (anti-HBc), 6 anti-HBs and 6 anti-HCV; 22 were seronegative.Hepatitis flare-up occurred in the 4 HBsAg-positive patients and in 1 anti-HBc-positive patient at a median of 1 month (range 1-4) after chemotherapy, when the CD4/CD8 ratio was still inverted. HBV reactivation was documented in all 5 instances (HBV-DNA 2-8 x 10(6) copies/mL). Two of the 5 patients responded to lamivudine, whereas 1 died of acute liver failure and 2 had persistent severe hepatitis. HBV genome sequencing at hepatitis flare-up showed that deviation from the closest related published sequences was 1.0% and 1.1% in the 2 lamivudine-responsive patients, and 1.5%, 1.8% and 1.7% in the 3 lamivudine-resistant patients. The polymerase open reading frame (ORF) and the HBs ORF of lamivudine-resistant strains contained several novel amino acid substitutions.These results suggest that fludarabine treatment of HBV-infected patients is frequently associated with acute hepatitis due to viral reactivation, and that lamivudine may be less effective in this situation than in other settings of immunocompromised hosts because of the emergence of resistant mutant strains.

The existence of an association between infection with hepatitis C virus (HCV) and B-cell non-Hodgkin lymphoma (B-NHL) remains controversial, largely because previous studies were based on prevalent case series or comparisons with less than optimal control groups. This hospital-based case-control study was conducted from January 1998 through February 2001 to evaluate the association between HCV infection and B-NHL of different types. Cases were consecutive patients with a new diagnosis of B-NHL; controls were patients from other departments of the same hospitals. Both groups were interviewed using a standardized questionnaire. The prevalence of HCV infection was calculated by histologic type of B-NHL and clinical behavior (indolent or aggressive). Adjusted odds ratio (OR) and HCV-attributable risk (AR) were estimated. HCV prevalence was 17.5% among the 400 lymphoma patients and 5.6% among the 396 controls. The OR of B-NHL (patients vs controls), adjusted by age, sex, level of education, and place of birth, was 3.1 (95% confidence interval [CI], 1.8-5.2); an OR indicative of positive association was found for indolent and aggressive B-NHL. The estimated AR was 4.6%. This study confirms an association between HCV and B-NHL. In Italy, 1 of 20 instances of B-NHL may be attributable to HCV infection and may, thus, benefit from antiviral treatment.

To evaluate retrospectively the efficacy of rituximab plus chemotherapy in gastric diffuse large B cell lymphoma (DLBCL).Sixty patients (median age: 58 years) with histologically confirmed gastric DLBCL treated at four Italian institutions between 2000 and 2007, were included in this analysis. Patients were selected by stage (I-IV, Lugano staging system), European Cooperative Oncology Group performance status (0-2) and treatment strategies. Treatment strategies were chemotherapy alone (group A, n = 30) [scheduled as cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and CHOP-like], and chemotherapy combined with rituximab (group B, n = 30). The primary end point of the study was complete response (CR) rate; the secondary end points were disease-free survival (DFS) at 5 years and overall survival (OS).Median follow-up was 62 mo (range: 31-102 mo). We observed a significant difference between the two groups (A vs B) in terms of CR [76.6% (23/30) vs 100%, P = 0.04) and DFS at 5 years [73.3% (22/30) vs 100%, P = 0.03). To date, 19 group A (63.3%) patients are alive and 11 have died, while all group B patients are alive. No significant differences in toxicity were observed between the two groups.Rituximab in combination with chemotherapy improves CR rate, DFS and OS. Further prospective trials are needed to confirm our results.

During the last decade an epidemiological association between hepatitis C virus (HCV) and B-cell lymphoproliferative disorders (B-LPD) has been reported; the same association has not been observed for Hodgkin's disease (HD). Hepatitis G virus (HGV) shares genetic and biological features with HCV, thus it might also be involved in lymphomagenesis.The aim of this study was to compare the prevalence of HCV and HGV infection in patients at diagnosis of B-LPD or HD.We tested 227 consecutive untransfused patients (127 with B-LPD and 100 with HD) and 110 healthy controls. The prevalence of HCV infection was significantly higher in B-LPD patients than in controls (17.3% vs. 1.8%, p0.002 ), whereas it was the same in HD patients as in controls. In contrast, the prevalence of HGV was significantly higher in patients, both those with B-LPD (7.8% vs. 0.9%, p0.03) and those with HD (13% vs. 0.9%, p0.002), than in controls. Among the various B-LPD tested, HGV infection was more frequent in B-NHL (11.5%).Our data support the hypothesis that HGV infection may play a role in lymphomagenesis and that this role is different and separate from that of HCV.

Primary mediastinal large B-cell lymphoma (PMLBCL) with sclerosis has recently been recognized as a specific clinical and pathologic entity for which the best therapeutic approach seems to be a combination of chemotherapy and radiotherapy.Between 1989 and 1998, 89 previously untreated patients with PMLBCL with sclerosis were treated with a combination of a third-generation chemotherapy regimen (MACOP-B) and mediastinal radiation therapy. The response evaluations were examined after chemotherapy and at the end of radiotherapy.Twenty-three (26%) patients achieved a complete response (CR) and 59 (66%) obtained a partial response (PR) after the MACOP-B regimen. After radiation therapy, 55/59 (93%) of the patients in PR achieved CR. The CR rate at the end of the treatment was 88% (78/89). Only 7 (8%) patients were non-responders. Among the 78 patients who obtained a CR there were 7 (9%) relapses in a median follow-up of 5 months (all relapses occurred within 9 months); the other 71 patients are currently in continuous CR with a median follow-upof 45 months (range, 4-110 months). Projected overall survival was 86% at 9 years; the relapse-free survival curve of the 78 patients who achieved CR was 91% at 9 years.In patients with PMLBCL with sclerosis, combined modality treatment using the MACOP-B chemotherapy regimen and radiation therapy induces a good remission rate with the patients having a greater than 90% chance of surviving disease-free at 9 years. Radiotherapy often plays a pivotal role in obtaining CR status.

A prospective study to evaluate the role of fludarabine alone or in combination with idarubicin in untreated patients with mantle cell lymphoma (MCL).Twenty-nine untreated patients with mantle cell lymphoma were stochastically treated with intravenous fludarabine at a dose of 25 mg/m(2)/day for 5 days (11 patients) or with a combination of fludarabine and idarubicin (FLU-ID) (fludarabine 25 mg/m(2) i.v. on days 1 to 3 and idarubicin 12 mg/m(2) i.v. on day 1 (18 patients). For both regimens, cycles were given at three-week intervals for a total of six courses. According to the International Prognostic Index, the most part of high-intermediate and high risk factor patients were in the FLU-ID subset: 7 (39%) patients vs. 2 (18%) in the fludarabine alone subset.Of the 29 patients, 8 (28%) obtained a complete response and 10 (35%) a partial response, with an overall response rate of 63%. The remaining 11 (37%) patients did not respond to the therapy. The overall response rates were 64% (7 patients) in the fludarabine group and 61% (11 patients) in the FLU-ID group. The complete response rate was 27% (3 patients) for fludarabine and 28% (5 patients) for FLU-ID. The toxicity was mild in terms of neutropenia and infections, and no fatalities occurred due to drug-induced side effects.These results suggest the efficacy of fludarabine alone or in combination with idarubicin in MCL patients. It will be important to increase this experience and to assess other fludarabine-containing regimens, in particular with cyclophosphamide plus idarubicin and with mitoxantrone and or cyclophosphamide, to test the true role of this approach in MCL.

A case of chorea-acanthocytosis (CA) syndrome is described. The presence of acanthocytes has usually been considered an important diagnostic marker of CA. However, it is not specific and other neurological diseases have to be considered. In the present report we rule out other diagnostic possibilities and show that the acanthocytes in the peripheral blood smears can appear even later during the course of the disease.

We report a patient who developed acute promyelocytic leukemia (APL) concomitantly with a second relapse of non-Hodgkin's lymphoma (NHL), intermediate grade, WF type E. At diagnosis and at first NHL relapse, the patient had received the same chemotherapy regimen, which included drugs targeting DNA topoisomerase II, i.e., etoposide (total dose 5,760 mg) and idarubicin (total dose 180 mg). Thirty-eight months after initial treatment, the patient showed pancytopenia associated with lymphoma recurrence. Bone marrow examination revealed the presence of atypical promyelocytes with Auer rods; cytogenetics showed t(15;17), and molecular analysis detected promyelocytic leukemia-retinoic acid receptor alpha rearrangement. APL reached complete remission after all trans retinoic acid therapy, whereas NHL did not respond to further chemotherapy. In the literature, five other patients developed APL after treatment for lymphoma, from a total of 59 patients developing sAPL after treatment for any type of neoplasia.