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BACKGROUND. Several histological subtypes of lymphoma can occur in the same patient. This event may happen sequentially or simultaneously. We describe a case of sequential diffuse large B-cells lymphoma (DLBCL), occurred shortly after therapy and rapidly fatal, after primary mixed cellularity Hodgkin lymphoma subtype (MCHLs). CASE REPORT. A 24-year-old woman was admitted in March 2006 to our Unit with fever, loss of weight and left sovraclavear lymphoadenopathy. On admission, chest radiography and total body computerized tomography (TB-CT) evidenced bulky mediastinal disease, lung involment, pericardial and pleural effusion. Left sovraclavear limphoadenopaty biopsy was performed and histology revealed MCHLs. Clinical stage was IVB with mediastinal bulky disease (Ann-Arbor Classification). Chemotherapy with doxorubicin-bleomycin-vinblastin- dacarbazine (ABVD) was starded. After 2 cycles TB-CT and PET showed reduced involvement of mediastinum and middle lobe of right lung. We decided to continue with further 4 cycles of ABVD chemotherapy. At restaging, TB-CT was negative; yet TB-PET was again positive with further strong reduction of mediastinal captation and absence of pulmonary involvment. Radiotherapy involved field (RT-IF) on mediastinum was started. Treatment was not well tolerated because infectious episodes occurred. After 3 weeks since the end of radiotherapy the patient showed fever and catarrhal cough. In the suspect of the bronchopneumonia, we performed cultural examination of sputum and hemoculture, turned out negative; broad-spectrum antibiotic and antimicotic therapy was started. TB-CT, performed after a month, showed an oval lesion on right lung, mediastinal ipercaptation, right pleural effusion, sub-diaphragmatic lymphoadenopathies, cystic lesions of kidneys. The patient underwent medistinal biopsy with histologic diagnosis of DLBCL, but she died a week later for heart and respiratory failure. Overall survival was only of 12 months. DISCUSSION. Possibility of development in the same patient of various types of lymphomas has been recognized for some time. To explain this occurrence, the term of multiple histology lymphomas (MHL) has been coined. MHLs may be sequential (different lymphomas at different times) or simultaneus (different lymphomas occurring at same time in the same lymphnode or at different sites). This event is mostly observed in non Hodgkin lymphoma (NHL). (Tucci et al, Haematologica 2005). Eventuality of a NHL after a primitive Hodgkin lymphoma (HL) is very rare (less than 1% of cases), with a variable time of insorgence (incidence is higher in the first 2 years from diagnosis of HL). Simultaneous HLs and NHLs are also very rare. All HL subtypes may evolve in a NHL DLBCL is main histology subtype of NHL from primary HL, with frequent extranodal involvement. Prognosis is poorer than primary NHLs. (Rueffer et al, JCO 2001). Our case shows a quick transformation to DLBCL of a MHLs. This event happened 3 weeks about for the end of therapy. Latent period is very short to consider DLBCL like a secondary neoplasm. Most reliable hypothesis is the common B-cellular derivation of HL and B-NHL, such as it has recently been demonstrated (Fraga M et al, Histol Histopathol 2007). CONCLUSION. The transformation of a HL into a NHL is a very rare event. Since HL is probably a B-cell derived lymphoma, the transformation into an aggressive NHL has to be suspected in presence of dubious images and symptoms and a biopsy has to be performed and standard therapy for NHL quickly started.

BACKGROUND. Several histological subtypes of lymphoma can occur in the same patient. This event may happen sequentially or simultaneously. We describe a case of sequential diffuse large B-cells lymphoma (DLBCL), occurred shortly after therapy and rapidly fatal, after primary mixed cellularity Hodgkin lymphoma subtype (MCHLs).

Background. We describe a case of lymphoplasmocytic lymphoma, refractory to conventional treatments and complicated with bone lesions and acute renal failure, completely regressed after therapy with bortezomib. Case report. Woman, 48 years old, in march 1994 receives diagnosis of lymphoplasmocytic lymphoma, refractory to conventional chemotherapy (chlorambucil, CHOP, fludarabine), immunotherapy (rituximab), radiotherapy. She comes to our attention in november 2005 for disease’s progression, associated to severe renal failure (sieric creatinine=3.65 mg/dl; creatinine clearance = 17.52 ml/min), caused by serious monoclonal proteinuria (21500 mg/24h). We decide to use dexamethazone (20 mg) and bortezomib at a reduced dose (1mg/m2 twice a week on days 1,4,8,11, for eight cycles). At the end of second cycle with bortezomib, there is a conspicuous reduction of proteinuria (350 mg/24h) with partial recovery of renal function (sieric creatinine = 1.7mg/dl; creatinine clearance=23.68ml/min) Because of severe neurologyc toxicity (convulsion, peripheric neuropathy) and appearance of herpetic lesions, we decide to suspend treatment with bortezomib. After eleven months from the end of treatment with bortezomib, PET total-body, shows only a moderate hypercaptation on the anterior segment of lower lobe of right lung. At a follow-up of 20 months renal function results clearly improved (sieric creatinine = 1.4 mg/dl; creatinine clearance=44.57 ml/min) with normalization of proteinuria (104 mg/24h). Discussion. Renal faillure in course of lymphoplasmocytic lymphoma is a not frequent event. It is due to amount of paraprotein on endothelial side of glomerular basal membrane. Generally standard treatments not improves the renal failure. The therapeutic activity of the antiproteosome in myeloma and in different lymphomas is currently well documented (O’Connor et al, JCO2005, 23 (4):676–684; K. Anderson et al, JCO2006 Annual Meeting Proceedings Part I. Vol 24 (18S): 7504). Other authors have demonstrated the renal repair (A. K. Malani et al, Acta Haematologica2006;116 (4):255–258). Conclusion. bortezomib, proteosome inhibitor, can be used to improve not only myeloma and lymphoma course but also to repair renal failure, when caused by paraprotenemia/paraproteinuria.

Background: NHLB is an unusual entity. Primary NHL of the bone comprising approximately 5–12 % of all bone cancer and less than 12% of all extra-nodal lymphomas; surgery resection does not have a therapeutic role and diagnosis is usually established by bone biopsy. Aim of the study: To demonstrate the clinical features of bone lesion in order to optimize diagnostic approaches and to evaluate prognostic factors and treatment. Patients and Methods: Ten pts with NHLB were diagnosed with surgical bone biopsy in the last 5 years. Pain and soft tissue swelling were the commonest symptoms. Two pts showed a unique bone lesion which was classified as primary lymphoma of the bone (PLB). In 8 cases, dissemination of the disease with multiple bone and/or visceral involvement was apparent (dNHL). The characteristics of pts were: median age 58,4 years (range 39–82 yrs), male: 70%; female: 30%; CS I, 20%, and CS IV, 80%, BM+ vs BM− (20% vs 80%); IPI was: low, 0–2, in 50%, vs high, 3–5 in 50%; bulky disease in 20%. All pts had B-phenotype; DLBCL in 8 pts, lymphoplasmocitoid lymphoma in 1 pt and follicular lymphoma, grading 2, in 1 pt, according to REAL-classification. Nine pts received CT with CHOP- like regimens (6 courses) to be repeated every 2 or 3 weeks. Only one pt received HDT with PBSCT. Three pts received CT + local irradiation (30 Gy). Results: CR was achieved in 80% of cases; all these pts were alive and disease free. Only the pt with unique bone lesion and lymphoplasmocitoid features, received only surgery therapy and is alive and disease free. Two pts died for PD at +1 and +6 months at initial sites of disease. Median OS was 19.6 months (range 1–62) and DFS was 20 months (range 2–58). Conclusions: The long-term survival of these pts is favourable but dependent on histology and clinical stage and appears to parallel that of pts with lymphoma of similar histology involving other sites.

Background: NHLB is an unusual entity. Primary NHL of the bone comprising approximately 5–12 % of all bone cancer and less than 12% of all extra-nodal lymphomas; surgery resection does not have a therapeutic role and diagnosis is usually established by bone biopsy.

Objective: Follicular lymphoma (FL) is the second most frequent type of non-Hodgkin’s lymphoma (NHL) representing 20–25% of all lymphomas worldwide. FDG-PET is currently adopted for staging and monitoring of patients (pts) with Hodgkin’s disease and aggressive NHL. Furthermore, the intensity of FDG uptake, as evaluated by standardized uptake value (SUV), has been recently shown to differentiate indolent from aggressive NHL and to correlate with tumor aggressiveness (Schöder H, et al. J Clin Oncol23: 1–9, 2005). In contrast, no data are yet available as to the prognostic significance of SUV in FL. Materials and methods: We investigated 62 consecutive patients (pts), median age 55 years (range 27–82 yrs), with newly diagnosed FL (WHO criteria) who underwent pre-treatment FDG-PET scanning at our institution. FDG-PET was performed before bone marrow biopsy and evaluators were blinded to the results of other diagnostic procedures. In all PET positive cases, areas of abnormal FDG uptakes were identified and the highest SUV per patient was calculated as previously described (Schöder H, et al. 2005). Study of SUV correlations with known prognostic factors in FL was performed by means of the SPSS (v11.01) statistical package using Chi-square, linear regression and receiver operating characteristic (ROC) curve analyses. Results: Overall, FDG-avid disease was demonstrated in 52 out of 62 pts (83.8%). The rate FDG-PET positivity did not correlate with histologic grading (G1, 76.9%; G2, 90.9 %; G3b, 85.7%; p=0.4), tumor cell proliferation rate (Ki-67 staining), extranodal involvement, bone marrow infiltration, B symptoms and bulky disease. Conversely, the rate of PET positivity appeared to progressively increase among pts with higher FL International Prognostic Index (FLIPI) score (low, 66.6%; intermediate, 93.7%, high, 95.4%; p=0.016), even though a direct correlation with single IPI components (age, stage, hemoglobin, LDH) was not statistically significant (p=0.49), except for the presence of > 4 involved nodal areas (p=0.04). The mean SUV of the entire pts population was 6.34 (r 1.2–24.5) and no significant differences were evidenced in relation to histologic grading (SUV: G1, 6.42; G2, 5.76; G3, 7.08). Even though a stepwise increase in mean SUV was evident among FLIPI risk subsets: low, 5.2(r 1.6–15), intermediate, 6.6 (r 1.3–24), high, 6.7 (r 1.2–16.2), statistical significance was not reached. In contrast, by stratifying pts according to 4 different groups with increasing SUV (i.e. <4, 4–8, 8–12, >12) statistically significant associations were found with tumor cell proliferation rate (Ki-67; p=0.02), B symptoms (p=0.03) and bulky disease (p=0.0003). Finally, analysis of the ROC curve against prognostic factors confirmed that a SUV <11.7 is strongly associated (97.7%; p< 0.00001) with the absence of bulky disease. Conclusions: The intensity of FDG uptake in FL is independent from histologic grading but appears to correlate with some biologic features reflecting either tumor aggressiveness (i.e. proliferation rate) or host-tumor interplay (i.e. B symptoms) or high tumor load (i.e. bulky disease). While the rate of FDG-PET positivity is overall correlated with FLIPI risk, this appears mostly linked with nodal dissemination (> 4 sites) which may increase the probability of FDG uptake. These data suggest that serial FDG-PET evaluations are warrented in pts with FL.

Objective: Follicular lymphoma (FL) is the second most frequent type of non-Hodgkin's lymphoma (NHL) representing 20–25% of all lymphomas worldwide. FDG-PET is currently adopted for staging and monitoring of patients (pts) with Hodgkin's disease and aggressive NHL. Furthermore, the intensity of FDG uptake, as evaluated by standardized uptake value (SUV), has been recently shown to differentiate indolent from aggressive NHL and to correlate with tumor aggressiveness (Schöder H, et al. J Clin Oncol 23: 1–9, 2005). In contrast, no data are yet available as to the prognostic significance of SUV in FL.

Several studies showed that the response rate to standard dose of recombinant Human Erythropoietin (rHuEPO) in MDS patients is generally low, with only few cases presenting a significant increase of haemoglobin (Hb) levels. So, currently, the interest has focused on the use of high dose rHuEPO. The rationale for using high dose rHuEPO was elucidated: residual normal stem cells and/or abnormal clone of MDS stem cells, unresponsive to low levels of endogenous EPO, might respond to high doses of rHuEPO. The aim of this study was to assess the efficacy and safety of high dose rHuEPO treatment. EPO alfa 40.000 IU was given subcutaneously twice weekly for 4 weeks. Twenty-five patients with low-risk MDS (17 RA and 8 RARS) and Hb levels ≤ 10 g/dL were included in this study; sixteen patients were female and 9 male; mean age of enrolled patients was 74 years (range 66 – 85). Twenty-two of 25 patients completed the scheduled treatment and were evaluated for response. At 4 weeks eighteen of 22 patients (81%) showed a Hb mayor response (Hb increase ≥ 2 g/dL); Hb mean value at baseline was 8,15 g/dL (range 7 – 10), at 4 weeks was 13,15 g/dL (range 10 – 14,6). In 4 of 22 patients (19%) the high dose rHuEPO did not induce an increase of Hb levels after 4 weeks of treatment; in addition, these patients needed of RBC transfusions to maintain Hb levels ≥ 8 g/dL. The failure of treatment with rHuEPO occurred in patients with diagnosis of RARS. In our study there were no statistically significant differences between the group of patients with erythroid hyperplasia and the group of patients with normal percent of bone marrow erythroid cells (P = 0,4); no significant difference was noted in response rates between patients with RBC pre-treatment transfusion need and those with stable anaemia without prior transfusion (P = 0,09). In our study, Hb mayor response occurred also in one patient with marked marrow fibrosis. In this study all patients presented defective endogenous EPO production related to their degree of anaemia, with serum EPO levels ≤ 100 mU/ml (mean value 43,5; range 6 – 98). The responder patients need continuous maintenance treatment to maintain their response; EPO alfa 40.000 IU was given subcutaneously once a week; at 12 weeks overall response rate was 77%: 13/18 patients maintained their mayor response, 4/18 patients showed decreased Hb levels in comparison to initial response (Hb decrease > 1 < 2 g/dL), 1 patient progressed on RAEB. Hb mean value at 12 weeks was 11,8 g/dL (range 9,2 – 13,5). The median duration of maintenance of the erythroid response was 7,5 months (range 2 – 24 months). Treatment with high dose of rHuEPO is well tolerated; only one adverse event of arterial hypertension of moderate severity was reported as possible episode related to treatment. In conclusion, our study shows that, in low-risk MDS patients with defective endogenous EPO production, EPO alfa 40.000 IU, given subcutaneous twice weekly for 4 weeks, induces rapid, significant and persistent increase of Hb, without important adverse events; continuous maintenance treatment with 40.000 IU/w is necessary for the majority of the responding patients to maintain their response.

Several studies showed that the response rate to standard dose of recombinant Human Erythropoietin (rHuEPO) in MDS patients is generally low, with only few cases presenting a significant increase of haemoglobin (Hb) levels. So, currently, the interest has focused on the use of high dose rHuEPO. The rationale for using high dose rHuEPO was elucidated: residual normal stem cells and/or abnormal clone of MDS stem cells, unresponsive to low levels of endogenous EPO, might respond to high doses of rHuEPO. The aim of this study was to assess the efficacy and safety of high dose rHuEPO treatment. EPO alfa 40.000 IU was given subcutaneously twice weekly for 4 weeks. Twenty-five patients with low-risk MDS (17 RA and 8 RARS) and Hb levels ≤ 10 g/dL were included in this study; sixteen patients were female and 9 male; mean age of enrolled patients was 74 years (range 66 – 85). Twenty-two of 25 patients completed the scheduled treatment and were evaluated for response. At 4 weeks eighteen of 22 patients (81%) showed a Hb mayor response (Hb increase ≥ 2 g/dL); Hb mean value at baseline was 8,15 g/dL (range 7 – 10), at 4 weeks was 13,15 g/dL (range 10 – 14,6). In 4 of 22 patients (19%) the high dose rHuEPO did not induce an increase of Hb levels after 4 weeks of treatment; in addition, these patients needed of RBC transfusions to maintain Hb levels ≥ 8 g/dL. The failure of treatment with rHuEPO occurred in patients with diagnosis of RARS. In our study there were no statistically significant differences between the group of patients with erythroid hyperplasia and the group of patients with normal percent of bone marrow erythroid cells (P= 0,4); no significant difference was noted in response rates between patients with RBC pre-treatment transfusion need and those with stable anaemia without prior transfusion (P= 0,09). In our study, Hb mayor response occurred also in one patient with marked marrow fibrosis. In this study all patients presented defective endogenous EPO production related to their degree of anaemia, with serum EPO levels ≤ 100 mU/ml (mean value 43,5; range 6 – 98). The responder patients need continuous maintenance treatment to maintain their response; EPO alfa 40.000 IU was given subcutaneously once a week; at 12 weeks overall response rate was 77%: 13/18 patients maintained their mayor response, 4/18 patients showed decreased Hb levels in comparison to initial response (Hb decrease > 1 < 2 g/dL), 1 patient progressed on RAEB. Hb mean value at 12 weeks was 11,8 g/dL (range 9,2 – 13,5). The median duration of maintenance of the erythroid response was 7,5 months (range 2 – 24 months). Treatment with high dose of rHuEPO is well tolerated; only one adverse event of arterial hypertension of moderate severity was reported as possible episode related to treatment. In conclusion, our study shows that, in low-risk MDS patients with defective endogenous EPO production, EPO alfa 40.000 IU, given subcutaneous twice weekly for 4 weeks, induces rapid, significant and persistent increase of Hb, without important adverse events; continuous maintenance treatment with 40.000 IU/w is necessary for the majority of the responding patients to maintain their response.