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Here we report a rare case of concomitant pulmonary chondroid hamartoma and follicular non Hodgkin lymphoma in a 65-year-old woman with a history of 4-month nonspecific symptoms like fever, sweating and weight loss.

Primary bone lymphoma (PBL) is a rare disease. Little is reported about response evaluation procedures in these patients. Our aim was to evaluate response to therapy according to fluorodeoxyglucose-positron emission tomography (FDG-PET) results, and in particular to test the Deauville 5-point scale as compared to the visual evaluation of FDG-PET scans in PBL. In this single-center study, we diagnosed 31 consecutive patients with PBL, of which 24 were evaluated with end-of-treatment FDG-PET. Patients' ages ranged from 19 to 82 years. Six patients were treated with chemotherapy, 24 with chemotherapy and radiotherapy, and one patient with radiotherapy alone. Six patients were affected by a pathological fracture. Four patients died within the range of 3 to 36 months after diagnosis. The average follow-up of the remaining patients was 70 (24–173) months. Overall survival was 87% at 5 years. The only positive prognostic factor was complete remission after chemotherapy. According to visual criteria, end-of-treatment FDG-PET was evaluated in 24 patients and it was positive in 11 (46%) and negative in 13 patients. We organized a retrospective central-blinded revision of end-of-therapy FDG-PET scans using the 5-point Deauville Score (DS). We reviewed 17 out of 24 patients and obtained the following results: at the end of therapy, 12 patients with DS score 2, three patients with DS score 3, one patient with DS score 4, and none with DS score 5. Considering that all the 24 patients achieved complete remission after treatment, visual interpretation produced 11/24 false-positive results, and DS interpretation produced 1/17 false-positive results, thus significantly reducing the number of false positives. In PBL, the final evaluation at the end of therapy with FDG-PET should be evaluated using Deauville 5-point scale in order to significantly reduce the risk of false-positive scans.

Early-stage follicular lymphoma (FL) can be cured with involved-field radiotherapy (IF-RT); however, many patients relapse in non-irradiated areas. A combined association with chemotherapy could increase treatment efficacy, but toxic effects could be unacceptable. In vitro synergistic effect between rituximab (R) and RT has been observed, but clinical data are limited. We retrospectively analyzed 41 early-stage FL patients receiving R and IF-RT as first-line treatment. We administered R 375mg/m2 weekly for four courses, before or after IF-RT (median dose 24 Gy). Primary outcome was PFS, secondary endpoints were CR rate, OS and safety. All patients achieved CR, after a median follow-up of 46 months only three patients relapsed after 18, 26 and 42 months; estimated 5-year PFS was 90%. We suggest R in association with IF-RT could represent a feasible first-line treatment option for early-stage FL and could increase efficacy without additional toxicity compared to available data about RT alone.

Objective.Hemarthrosis triggers hemophilic arthropathy, involving the target joints. The histopathogenesis of blood-induced joint damage remains unclear. The triad of receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG; RANK-RANKL-OPG) controls bone turnover. Our aim was to evaluate RANK-RANKL-OPG expression in the synovium of hemophilic patients with severe arthropathy.Methods.Synovial biopsies were obtained from 18 patients with hemophilic arthropathy and 16 with osteoarthritis (OA) who were undergoing total knee replacement and synovectomy. The severity of hemophilic arthropathy was evaluated according to ultrasonography score, the World Federation of Hemophilia (WFH) orthopedic joint scale, and the radiographic Pettersson score. RANK-RANKL-OPG expression was examined by immunohistochemistry and Western blotting. Serum levels of soluble RANKL (sRANKL) and OPG from an extended group of 67 patients with hemophilic arthropathy and 30 healthy controls were measured by ELISA.Results.The mean ultrasonography, WFH orthopedic joint scale, and Pettersson scores in patients with hemophilic arthropathy indicated severe arthropathy. A decreased expression of OPG was found in hemophilic arthropathy synovium compared with patients with OA. RANK and RANKL immunopositivity was strong in the lining and sublining layers in hemophilic arthropathy synovial tissue. Western blotting confirmed the immunohistological findings. Serum levels of sRANKL and OPG in patients with hemophilia were lower than in healthy controls.Conclusion.In hemophilic arthropathy, the synovium highly expressed RANK and RANKL, whereas OPG immunopositivity decreased, suggesting an osteoclastic activation. Low tissue expression of OPG paralleled the serum levels of this protein and the severity of hemophilic arthropathy assessed by ultrasonography, Pettersson, and WFH orthopedic joint scale scores.

Objective:Pregnant women with systemic sclerosis (SSc; scleroderma) have an increased risk of premature delivery and small full-term infants. During placental development, angiogenesis and vascular remodelling are essential for a successful pregnancy outcome. An analysis was made of the pathological changes and expression of angiogenic factors in SSc placentas.Methods:Placenta biopsies were obtained from three patients with SSc and four healthy uncomplicated pregnancies after delivery at 34–38 weeks of gestation. The sections were stained with Masson’s trichrome and phosphotungstic-acid-haematoxylin and immunostained for connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and receptors VEGFR-1 and VEGFR-2.Results:The pathological findings were signs of decidual vasculopathy, increased syncytiotrophoblast knotting, placental infarcts and villous hypoplasia. Severe and diffuse perivascular and stromal fibrosis of decidua and chorionic villi, and extensive deposition of fibrinoid material around decidual vessels and in intervillous spaces were observed. Strong CTGF expression in the vessel wall, decidual cells and fibroblasts and α-SMA+ myofibroblasts were found. VEGF and VEGFR-2 expression was stronger in SSc than in healthy placentas, while VEGFR-1 expression was similar to controls. PlGF immunopositivity was weaker in SSc.Conclusion:In SSc placentas, severe fibrosis and abnormal vascular remodelling were detected. This may result in reduced blood flow leading to deep sufferance of maternal placenta and possible premature delivery.

Rats transgenic for HLA-B27 and human beta2microglobulin (B27TR) develop a multi-systemic disease resembling inflammatory bowel disease (IBD) and spondyloarthritis. TNFalpha has a crucial role in chronic inflammation. Our objective was to evaluate the effect of anti-TNFalpha treatment on spontaneous IBD in B27TR. Nine-week-old B27TR received monoclonal anti-TNFalpha or an isotypic IgG2a,k up to age of 18 weeks. A second group was monitored up to 18 weeks and then randomly assigned to anti-TNFalpha or IgG2 a,k treatment. Each rat was monitored for clinical IBD manifestations. After sacrifice, the colon was examined for pathological changes. TNFalpha receptors (TNF-R1, TNF-R2), Fas/Fas-L expression and apoptosis were evaluated. IgG2a,k-treated and untreated B27TR presented signs of IBD at 11 weeks, whereas in anti-TNFalpha-treated B27TR no IBD signs were detected. In the late treatment, IBD signs improved after 1 week. Histopathological analysis of IgG2a,k-treated B27TR colon showed inflammatory signs that were widely prevented by early anti-TNFalpha treatment. Late treatment did not significantly reduce inflammation. TNF-R1 was weakly expressed in intestinal epithelial cells of IgG2a,k-treated B27TR, while it was comparable to controls in anti-TNFalpha-treated animals. TNF-R2 immunopositivity was strongly evident in IgG2a,k-treated B27TR, whereas was absent in anti-TNFalpha-treated rats. RT-PCR confirmed these results. IgG2a,k-treated B27TR showed, at 18 weeks, few Fas-positive cells and an increase of Fas-L-positive cells. At 27 weeks, Fas-/Fas-L-positive cell number was significantly low. Anti-TNFalpha treatment increased Fas-L expression, whereas Fas increased only with the early treatment. TNFalpha blockade is effective in preventing inflammation in early phase of IBD, maintaining the homeostatic balance of apoptosis.

Bendamustine was introduced in Italy from 2008 and it was used as salvage therapy in patients pretreated, particularly in indolent lymphomas. Before approval as first-line treatment by the National Health System, starting from 2011 and thanks to our regional regulation, was possible to use Bendamustine in first line therapy as ‘off-label’ drug. The aim of this study was to collect all consecutive patients treated in first line with Bendamustine in 7 Tuscany centers. From June 2011 to December 2012, 72 patients were prospectively included in the study. Diagnosis was: Lymphocytic lymphoma in 25 patients (34%), Follicular lymphoma in 18 (25%), Diffuse large B cell lymphoma in 11 (15%), Mantle cell lymphoma in 10 (14%), Lymphoplasmocytic lymphoma in 5 (7%) and MALT in 3 (5%). Thirty-nine patients were treated with Bendamustine 90 mg/m2 for two days, 28 with 70 mg/m2 and 5 with 120 mg/m2. The analyzed population must be considered negatively selected as such was not proposed the standard therapy. Moreover the data coming from literature and the experience in pre-treated patients increased the interest of clinicians for this drug. In 14 patients Bendamustine was used alone, in 56 in combination with Rituximab or other drug. The overall median age was 69 years (range 45-89), in DLBCL was 81 years and 78 years in MCL. Considering the advanced age of this population we applied the geriatric score assessment and 25% of patients were unfit or frail. The median number of cycles performed was 4 (range 2 - 6). All patients but 2 were evaluable for response, 35 obtained a complete remission, 27 a partial remission considering the intention to treat the overall response rate was 86%, stable disease in 2 patients, progressive disease in 6 patients and not evaluable in 2 patients. According to histotype to note that all but two indolent lymphoma obtained a response; in aggressive lymphomas 4/11 DLBCL and 5/9 MCL reached a complete remission but 4 DLBCL and 2 MCL experienced rapid progression of the disease. Treatment was well tolerated, we observed: grade 3-4 neutropenia in 18 patients, no grade 3-4 anemia or thrombocytopenia. According to extrahematological toxicity was reported only grade 3-4 infection in 3 patients no other grade 3-4 toxicities were reported. Skin rush grade 1 was reported in in 5 patients. No toxic deaths were observed. After a median follow-up of 18 months the overall survival was 83%; 10 patients died all due to progressive disease. Progression free survival, after a median observation period of 12 months, was 60%; sixty-two patients are alive, 31 in continuous complete remission, 3 relapsed and 28 with disease under control. In conclusion in this ‘real life’ negatively selected population, the use of Bendamustine showed a very high response rate particularly in indolent lymphomas, promising results, also, are observed in aggressive lymphoma suggesting that this drug can be used with interesting result in elderly patients who can not receive the standard therapy. Disclosures No relevant conflicts of interest to declare.

About 60% of patients with diffuse large B-cell lymphoma (DLBCL) may be cured by primary chemotherapy with an R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen. Most of the rest will die of the disease, mainly due to the occurrence of tumor drug resistance. Many efforts have been made to explain the molecular mechanisms of drug resistance in patients with cancer, including those with DLBCL. This exploratory study was designed to correlate the mRNA expression levels of candidate genes mainly involved in the doxorubicin pathway (ABCB1, GSTP1, TOPO2α, BCL2, PKCβII) with the outcome of 54 patients with DLBCL undergoing a dose-dense R-CHOP regimen. After multivariate analysis, high GSTP1 (p = 0.003) and TOPO2α (p = 0.02) gene expressions were associated with shorter overall survival and progression-free survival, respectively, suggesting that these genes may represent an unfavorable prognostic factor in the case of R-CHOP treatment. These biomarkers may be useful for selecting patients eligible for personalized chemotherapy after validation in an independent set.

Abstract 1615 Background: Diffuse large B cell lymphoma (DLBCL) is one of the most common types of non-Hodgkin's lymphoma. R-CHOP21 (C21) is considered the standard therapy but a large number of studies have tested R-CHOP14 (C14). Aims: The aim of our study was to evaluate retrospectively a cohort of patients (pts) treated with C21 or C14 and to compare the efficacy of the therapy. Methods: All pts with diagnosis of DLBCL or follicular grade IIIb lymphoma, treated with curative intent in 9 Italian Hematological Centers, were accrued. All patients treated with C14 used G-CSF as primary prophilaxis, and only elderly (over 70 years) patients treated with C21 used G-CSF as primary prophilaxis. Results: From january 2002 to june 2011, 950 pts were accrued, 643 pts were treated with C21 and 307 were treated with C14. The median age was 63 (range 19–89). The two cohorts of pts were balanced for all clinical characteristics a part for age (60 years) with more aged pts in C21 arm (p 0.001), bone marrow positivity and more than 3 lymph node stations involved that were higher in C14 arm (p: 0.05 and p: 0.001). After induction therapy 751 pts (79%) obtained a complete remission: 501/643 (78%) after C21 and 250/307 (81%) after C14. The remaining pts obtained partial response in 110 and 48 or no response in 32 and 9 respectively for C21 and C14. After a median period of observation of 38 months 104 pts relapsed (14%), 68 (65%) in the C21 arm and 36 (35%) in the C14 arm. After a median observation period of 3 years, considering the two therapies, C21 vs C14, no differences were reported in OS (Figure 1), PFS (Figure 2) and DFS: 80% vs 84%, 69% vs 71% and 54% vs 56% respectively. In univariate analysis OS was lower in older pts (azard ratio (ar): 2.57), IPI 2 (ar: 2.09), IPI 3 (ar: 4.36), IPI 4–5 (ar: 6.36), bulky disease (ar: 1.70), symptomatic disease (ar: 2.23). In multivariate analysis factors which mantained significantly worst prognosis were older age (ar: 1.35), IPI 2 (ar: 1.95), IPI 3 (ar: 3.76), IPI 4–5 (ar: 5.01) and bulky disease (ar: 1.43). As expected hematological grade III/IV toxicity was more frequent in pts treated with C14. No differences in extra-hematological toxicity were observed. Secondary malignancies were reported: 7 in C21 and 3 in C14. After 3 years of median observation 188 pts are dead: 137 (73%) in C21 and 51 (27%) in C14 (not statistically significant, p:0.08). The large majority of pts are dead for disease progression or relapse. Conclusions: In conclusion our results confirm that C14 do not improve the results of the standard C21 in the whole lymphoma population. Dose dense therapy did not affect OS or PFS also analysing sub group of pts. As expected a higher frequency of neutropenia was observed in C21 arm but did not translate in increasing infection rate. Further prospective randomized studies are needed to verify this preliminary observations. Disclosures: No relevant conflicts of interest to declare.

Introduction: Standard chemotherapy represented by the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) regimen is successful in about 60% of patients (pts) with diffuse large B-cell lymphoma (DLBCL). Pts who do not benefit from this treatment, due to the development of tumor drug resistance, have a very poor prognosis. Currently, knowledge on reasons of treatment related failures in DLBCL are scanty and predictive biomarker of response are largely unknown. We hypothesized that polymorphisms of gene involved in the pharmacokinetics and pharmacodynamics of drugs included in R-CHOP regimen may play a role in predicting the outcome in DLBCL pts.Thus, we designed a multicentre prospective pharmacogenetic trial aimed at identifying gene polymorphisms potentially predictive of drug efficacy/resistance in DLBCL pts treated with R-CHOP. An interim analysis on the first 80 enrolled ptswas planned and has been performed. Methods: The study included chemonaive DLBCL pts at various stages of disease candidate to an R-CHOP standard treatment. The Ethical Committee of each participating centre approved the pharmacogenetic protocol, and all pts signed a written informed consent. According to the aims of this interim analysis, the impact of single nucleotide polymorphisms (SNPs) on R-CHOP efficacy was evaluated by objective response (OR) rate at the end of treatment. The efficacy of R-CHOP was evaluated according to the Cheson criteria by performing standard hematochemical and instrumental (TC and FDFG-PET) tests and defining complete remission (CR), partial remission (PR), non response or progressive disease (PD). Genomic DNA wasextracted from peripheral blood of 80 pts. Twentysingle nucleotide polymorphisms (SNPs) from18candidate genes (ABCB1, ABCC1, ABCC2, ABCG2, CYBA, CYP2C9, FCGR2A, GSTP1, IL2, MLH1, NCF4, NQO1, NQO2, RAC2, TNF, TOP2A, TP53, TUBB)involved in pharmacokinetics and pharmacodynamics of R-CHOP (www.pharmgkb.org) have been analysed by a genotyping array based on Affimetrix methodology. Univariate analysis was performed to evaluate associations between polymorphisms and clinical/pathological characteristics or OR (Fisher exact test). Multivariate logistic regression analysis was performed to estimate adjusted odds ratios along with the corresponding 95% confidence intervals for the polymorphisms and OR. Results: Median age was 63 years. There were 37 men and 43 women. 47.5 % of pts were in stage I-II,52.5 % of pts in stage III-IV. 27.5% of ptshad bulky disease, 43.8 % of pts had involvement of extranodal site. 47.5% of pts had pathological LDH value. According to the revised IPI, 15 % pts were in the low risk group, 58.7 % in the intermediate risk group, and 26.3 % in the high risk group.Overall, 468 courses of R-CHOP had been administered (mean: 5.85 courses, range: 4-6). 81% of pts had CR to R-CHOP whereas the remaining showed PR (14%) or PD(5%). No statistically significant correlation was found between OR and clinical characteristics of pts.However, stage III-IV pts showed a worst OR than stage I-II pts (77% vs 87% of CR, respectively); pts with bulky disease had worst OR than non-bulky disease pts(73% vs 84.5% of CR, respectively); ptswith R-IPI 3-5 a worst OR than pts with R-IPI 0-2 (71.5% vs 85% of CR, respectively). Univariate and multivariateanalysis identified TOPOII rs13695as a predictor of OR (p=0.042). Pts with CT or TT genotypesshowed worst OR than CC wild-type homozygous pts (odds ratio 3.070, CI95% 1.113-13.457). Also, a statistical trend toward significance was observed for MLH1 rs1800734 polymorphism (p=0.062): ptswith homozygous genotype for the mutant allele showed a better OR than wild-type and heterozygous pt genotypes. Conclusions: No significant relationship between clinical/pathological characteristics and OR was observed. Our preliminary data show that SNPs affecting a gene involved in doxorubicin pharmacodynamics, i.e. the drug target TOPOII, as well asone of the major components of DNA mismatch repair, i.e. MLH1 gene,may predict response in DLBCL pts treated with R-CHOP. These preliminary results from the interim analysis are promising and warrant completion of pt accrual to reach the planned number of cases at the end of our study. Acknowledgments This work was supported by a grant from the Associazione Giacomo Onlus, Castiglioncello (LI), Italy to E.M. and Cassa di Risparmio di Firenze, Firenze, Italy to S.N. Disclosures No relevant conflicts of interest to declare.

Organ failure secondary to fibrosis is the main cause of morbidity and death in patients with systemic sclerosis. Gastrointestinal tract dysmotility is a major visceral manifestation, clinically ranging from an asymptomatic form to severe paresis. Although the oesophagus is the most frequently affected part of the gastrointestinal tract, all other segments can be involved. The present study was undertaken to evaluate the histopathological changes of the gastric wall in a series of full-thickness biopsies from systemic sclerosis patients who underwent gastric surgery due to severe gastroesophageal involvement. Gastric biopsies were processed for light microscopy and transmission electron microscopy. The histological and ultrastructural observations revealed a generalized fibrosis affecting all the gastric wall layers. The most severe changes were observed in the muscularis mucosae and muscle layers. Wide areas of marked focal fibrosis with dense collagen bundles and elastic fibre deposition surrounding smooth muscle cells were found. Myofilaments and thickened dense bodies were severely disarranged or absent in most smooth muscle cells. Nerve fibres showed ultrastructural alterations, such as oedematous axoplasm and scarce cytoskeletal elements. Abundant elastic and collagen fibres enveloped nerve fibres, nerve endings and interstitial cells of Cajal, thereby separating them from smooth muscle cells and blood microvessels. This study provides evidence for a prominent fibrosis and severe ultrastructural alterations of smooth muscle cells and nerve fibres as the main histopathological hallmarks in the gastric wall of systemic sclerosis patients.

Transgenic rats with high expression of HLA-B27 and human β2-microglobulin (B27TR) develop a multisystem inflammatory disease resembling human inflammatory bowel disease (IBD) and spondyloarthropaties (SpA). Tumour necrosis factor α (TNF-α) has a crucial role in sustaining chronic inflammation in the gut and joints. The aim of this work was to evaluate whether TNF-α blockade could prevent or reduce the inflammation of peripheral joints in B27TR. A first group of 9-week-old B27TR received an anti-TNF-α monoclonal antibody (mAb) or an isotypic IgG2a,k up to the age of 18 weeks. An untreated group was monitored up to the age of 18 weeks and then randomly assigned to a 9-week treatment with anti-TNF-α mAb or IgG2a,k. Each rat was monitored for clinical IBD and peripheral joint manifestations. After sacrifice the colon and hind paws were examined for macroscopical and microscopical pathological changes. Early TNF-α blockade prevented, and late treatment improved IBD signs in B27TR. Erythema, oedema, inflammatory infiltrate close to the tendons and enthesis, proliferating chondrocyte-like cells, signs of new endochondral bone ossification and bone erosion were observed in peripheral joints of four out of six IgG2a,k-treated B27TR, both at 18 and 27 weeks. Immunopositivity for phosphorylated Smad1/5/8 indicated that the process of joint remodelling was activated in B27TR. Some entheses showed chondroid nodules. Anti-TNF-α treatment reduced inflammation and preserved the enthesis organization in most animals. Occasional and transient erythema and oedema were still present in three of six of the late anti-TNF-α-treated animals. Smad1/5/8 signalling was not inhibited by late anti-TNF-α treatment. In B27TR, articular involvement follows IBD onset and develops at entheses. Early TNF-α blockade prevents the onset of IBD and consequently the development of enthesitis in peripheral joints in the B27TR model of human SpA.

BackgroundEarly endothelial cell (EC) activation/damage and profibrotic Th2-associated cytokines play a pivotal role in systemic sclerosis (SSc). Interleukin 33 (IL33) is a novel member of the IL1 family that promotes Th2 responses and inflammation through the ST2 receptor. IL33 is also a chromatin-associated transcriptional regulator in ECs.ObjectiveTo investigate the role of the IL33/ST2 axis in SSc.MethodsSkin biopsies were obtained from 30 patients with SSc (15 early/15 late stage) and 10 healthy subjects. Lung, kidney, heart, oesophagus, stomach, placenta biopsies and bronchoalveolar lavage cells from patients with SSc and controls were also analysed. IL33/ST2 expression was investigated by immunohistology, confocal immunofluorescence microscopy, western blotting and RT-PCR.ResultsIn skin biopsies from control subjects, constitutive nuclear IL33 protein expression was found in dermal ECs and keratinocytes, while ST2 was weakly expressed in ECs and fibroblasts. In skin biopsies from patients with early SSc, IL33 protein was downregulated or absent in ECs and epidermis while IL33 mRNA was normally expressed or even upregulated. Moreover, ECs, perivascular infiltrating mast cells, CD68-positive macrophages, CD3-positive T cells, CD20-positive B cells and activated fibroblasts/myofibroblasts exhibited strong ST2 expression. In skin biopsies from patients with late SSc, IL33 was constitutively found in most ECs while ST2 immunostaining was weaker. In early SSc, the loss of endothelial IL33 protein and the overexpression of ST2 involved all affected organs. Dermal and pulmonary fibroblasts showed IL33 expression in SSc.ConclusionIL33 and ST2 are abnormally expressed in SSc. In early SSc, upon EC activation/damage IL33 may be mobilised from ECs to signal through ST2 in key profibrotic players such as inflammatory/immune cells and fibroblasts/myofibroblasts.

The HLA-B27 gene is strongly associated with the spondyloarthropathies (SpA), a group of chronic inflammatory diseases affecting the bowel, the joints, and the axial skeleton. Yet the basis for this association remains unknown, despite extensive study in the past years. The HLA-B27 transgenic rat spontaneously develops a disease that strikingly resembles human SpA. The purpose of this article is to review the contribution of studies on the HLA-B27 transgenic rat model aimed to elucidate the intimate relationship between gut and joint involvement in SpA.

Introduction Standard therapy of MALT lymphomas is not defined apart from H Pylori eradication for gastric localization. Aim This study was designed to evaluate the use of Rituximab (R) alone or in combination with Chlorambucil (RC) in the treatment of patients with diagnosis of MALT. Patients and methods All patients with histologically confirmed diagnosis of MALT lymphoma were selected from our data base. Only patients treated with R or RC were analysed and evaluated. The scheme: rituximab 375 mg/sqm weekly for 4 doses, then monthly for 4 infusions alone or in combination with chlorambucil at the dosage of 0,1 mg/Kg/die for 45 days, then on days 1 to 15 monthly for 4 months. Results From January 2000 to December 2012, 136 patients were diagnosed and treated in our Institution, 76 were selected because of uniformly treated with R or RC. The median age at diagnosis was 68 years (range 32-85). In 20 patients the disease was localized in conjunctiva; 17 in the stomach; 14 in the lung; 13 in salivary glands; 3 intestine; 2 respectively in lacrimal gland, liver, skin; 1 in breast, cheek and tongue. Stage was IA in 63 patients (83%), IB in 1, IIA in 5 patients and IIB in 1, IIIA in 1 patient, IVA in 4 patients and IVB in 1. Bone marrow biopsy was negative in 59 patients, positive in 5 and not performed in 12 patients. The proliferative index was evaluated in 50 patients with Mib1 monoclonal antibody: 42 patients showed less than 30% of positivity and 8 had more than 30% of positivity. The diagnosis of MALT in 4 patients was associated with Sjogren Syndrome, in 4 patients with a positive HCV and in 1 with scleroderma. According to treatment 61 patients were treated with the combination of Rituximab and Chlorambucil and 15 were treated with Rituximab alone. At the end of treatment 69 patients (91%) obtained a complete remission and 7 (9%) a partial remission with an overall response rate of 100%. With a median observation period of 54 months (range 1-160) the overall survival was 89%. Eight patients died 5 for progression of disease (2 after a relapse) and 3 for causes not related to the lymphoma. Ten patients (14%) relapsed, 8 of these patients were retreated with Rituximab and obtained a new complete remission. Conclusions After a long follow-up the combination of Rituximab and Chlorambucil or Rituximab alone proved to be low toxic, feasible and effective therapy for MALT lymphomas. Disclosures: No relevant conflicts of interest to declare.

Abstract 2478 Diffuse large B cell lymphoma (DLBCL) is one of the most common types of non-Hodgkin's lymphoma. Approximately half of patients will be cured of their disease by primary therapy, including the R-CHOP regimen (rituximab, doxorubicin, cyclophosphamide, vincristine, desamethasone). The remaining die of the disease, mainly because of the occurrence of tumor drug resistance. Many efforts have been made to explain the biochemical and molecular mechanisms involved in resistance to the drugs used in the treatment of cancer patients, including those with DLBCL. A dose-intense therapy regimen (e.g. R-CHOP14) may help to improve the treatment outcome of DLBCL patients. We have carried out a retrospective study aimed at correlating the mRNA expression levels of genes involved in metabolism, mechanisms of action and resistance to doxorubicin (i.e. MDR1, GSTP1, TOPO-2a, Bcl-2, PKC-b2) that represents the backbone of the R-CHOP regimen with treatment outcome data of 54 patients at various stages of disease. The expression of the 5 above mentioned genes was determined in formalin-fixed paraffin-embedded samples from DLBCL using real time RT-PCR. A threshold analysis to identify a cut-off distinguishing recurrent or non-recurrent disease was used. The correlations between gene expression data and clinical/pathological characteristics as well as survival parameters have been evaluated by standard statistical tests. The case series included 32 males and 22 females; 6 patients had follicular lymphoma grade IIIb and 48 diffuse large B cell lymphoma; 19 presented symptoms at diagnosis. Thirty patients showed abnormal LDH values, the IPI was intermediate-high risk or high risk in 14 patients. Forty-six patients (85.2%) obtained a complete remission and 8 (14.8%) a partial response. The median overall survival (OS) as well as the median progression free survival (PFS) have not yet been reached after a median follow-up of 43.6 months. The mRNA expression levels of TOPO-2a and GSTP1 were detectable in all samples, that of PKC-b2 in 52 samples, that of MDR1 and bcl-2 in 34 and 29 samples, respectively. A high degree of interpatient variation in relative tumor expression of the study gene was observed: from 0.008 for TOPO-2a to >100.000 for PKCbII. Threshold analysis indicated significant inverse relationships between PKC-b2 and PFS (p=0.046): higher gene expression was associated with shorter PFS. Conversely, higher expression of ABCB1 was associated with prolonged PFS (p=0.039). This kind of analysis also showed associations between OS and TOPO-2a, GSTP1and PKC-b2: higher gene expression was associated with shorter OS. Overall, our results confirm that the high expression of some genes such as TopoIIa, GSTP1 and PKCβII may represent a prognostic factor in case of an intensified anthracycline-based chemotherapy with immunotherapy. Moreover, our results suggest that intensified immunochemotherapy could affect the role of bcl2, ABCB1, GSTP1 and TopoIIa in predicting tumor response. These results and others from related studies may help to identify gene profiles useful for selecting patients eligible for more intensified or personalized chemotherapy. Prospective larger studies are warranted. Supported by a grant from Associazione Giacomo Onlus, Castiglioncello (LI). Disclosures: No relevant conflicts of interest to declare.

Haemophilia is characterised by spontaneous bleeding, mainly in the larger joints. Repeated bleeding episodes lead to synovitis and then to haemophilic arthropathy (HA) with synovial changes, cartilage damage and bone remodelling which result in disability. The pathogenesis of this blood-induced cartilage damage is very little known, but it has been suggested that the recurrent presence of blood induces synoviocyte hypertrophy and hyperplasia with intense neovascularisation and inflammation of the synovial membrane. This results in the production of catabolic enzymes and cytokines by inflammatory cells which induce and exacerbate the pathological process. To …