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A response by Alessandro M. Gianni, Pinuccia Valagussa, and Gianni Bonadonna to letters to the editor about their article "High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma" in the May 1, 1997 issue is presented.

Background: We compared a regimen of six chemotherapeutic agents administered sequentially at high doses, followed by myeloablative treatment and bone marrow transplantation, with a regimen of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) as initial or salvage treatment for adults with diffuse large-cell lymphoma. Methods: Ninety-eight eligible patients with diffuse large-cell lymphoma of the B-cell type were randomly assigned to receive either MACOP-B (50 patients) or high-dose sequential therapy (48 patients). If the assigned treatment failed, the study design allowed patients to cross over to the other treatment group. Results: After a median follow-up of 55 months, the patients given high-dose sequential therapy, as compared with those treated with MACOP-B, had significantly higher rates of complete response (96 percent vs. 70 percent, P = 0.001), freedom from disease progression (84 percent vs. 49 percent, P<0.001), freedom from relapse (88 percent vs. 70 percent, P = 0.055), and event-free survival (76 percent vs. 49 percent, P = 0.004). The difference in overall survival at seven years, which also favored the group assigned to high-dose sequential therapy, was marginally significant (81 percent vs. 55 percent, P = 0.09). Conclusions: High-dose sequential therapy is superior to standard-dose MACOP-B for patients with diffuse large-cell lymphoma of the B-cell type. (N Engl J Med 1997;336:1290-7.) [ABSTRACT FROM AUTHOR]

Purpose: We explored the potential overall survival (OS) benefit of bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone (BEACOPP) over doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) in a pooled analysis of four randomized trials. Patients and methods: Primary objective was to evaluate the OS impact of BEACOPP using individual patient data. Secondary objectives were progression‐free survival (PFS), secondary cancers, and use of autologous stem cell transplantation (ASCT). Results: About 1227 patients were included. The 7‐year OS was 84.3% (95% CI 80.8‐87.2) for ABVD vs 87.7% (95% CI 84.5‐90.2) for BEACOPP. Two follow‐up periods were identified based on survival curves and hazard ratio (HR) over time. For the first 18 months, there was no difference. For the second period of ≥18 months, ABVD patients had a higher death risk (HRABVD vs BEACOPP = 1.59; 95% CI 1.09‐2.33). A Cox model stratified by trial and evaluating the effect of treatment and International Prognostic Index (IPI) score as fixed effects showed that both were statistically significant (treatment, P =.0185; IPI score, P =.0107). The 7‐year PFS was 71.1% (95% CI 67.1‐74.6) for ABVD vs 81.1% (95% CI 77.5‐84.2) for BEACOPP (P <.001). After ABVD, 25 secondary cancers (4.0%) were reported with no myelodysplasia (MDS)/acute myeloid leukemia (AML) compared to 36 (6.5%) after BEACOPP, which included 13 patients with MDS/AML. Following ABVD, 86 patients (13.8%) received ASCT vs 39 (6.4%) for BEACOPP. Conclusions: This analysis showed a slight improvement in OS for BEACOPP and confirmed a PFS benefit. Frontline use of BEACOPP instead of ABVD increased secondary leukemia incidence but halved the requirement for ASCT. [ABSTRACT FROM AUTHOR]

Dissecting the pathogenesis of classical Hodgkin lymphoma (cHL), a common cancer in young adults, remains challenging because of the rarity of tumor cells in involved tissues (usually <5%). Here, we analyzed the coding genome of cHL by microdissecting tumor and normal cells from 34 patient biopsies for a total of ~50?000 singly isolated lymphoma cells. We uncovered several recurrently mutated genes, namely, STAT6 (32% of cases), GNA13 (24%), XPO1 (18%), and ITPKB (16%), and document the functional role of mutant STAT6 in sustaining tumor cell viability. Mutations of STAT6 genetically and functionally cooperated with disruption of SOCS1, a JAK-STAT pathway inhibitor, to promote cHL growth. Overall, 87% of cases showed dysregulation of the JAK-STAT pathway by genetic alterations in multiple genes (also including STAT3, STAT5B, JAK1, JAK2, and PTPN1), attesting to the pivotal role of this pathway in cHL pathogenesis and highlighting its potential as a new therapeutic target in this disease. [ABSTRACT FROM AUTHOR]

Background High-dose therapy followed by autologous stem-cell transplantation is standard of care for patients with relapsed or primary refractory Hodgkin's lymphoma. Roughly 50% of patients might be cured after autologous stem-cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. We aimed to assess whether brentuximab vedotin improves progression-free survival when given as early consolidation after autologous stem-cell transplantation. Methods We did this randomised, double-blind, placebo-controlled, phase 3 trial at 78 sites in North America and Europe. Patients with unfavourable-risk relapsed or primary refractory classic Hodgkin's lymphoma who had undergone autologous stem-cell transplantation were randomly assigned, by fixed-block randomisation with a computer-generated random number sequence, to receive 16 cycles of 1·8 mg/kg brentuximab vedotin or placebo intravenously every 3 weeks, starting 30–45 days after transplantation. Randomisation was stratified by best clinical response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and primary refractory Hodgkin's lymphoma versus relapsed disease less than 12 months after completion of frontline therapy versus relapse 12 months or more after treatment completion. Patients and study investigators were masked to treatment assignment. The primary endpoint was progression-free survival by independent review, defined as the time from randomisation to the first documentation of tumour progression or death. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01100502. Findings Between April 6, 2010, and Sept 21, 2012, we randomly assigned 329 patients to the brentuximab vedotin group (n=165) or the placebo group (n=164). Progression-free survival by independent review was significantly improved in patients in the brentuximab vedotin group compared with those in the placebo group (hazard ratio [HR] 0·57, 95% CI 0·40–0·81; p=0·0013). Median progression-free survival by independent review was 42·9 months (95% CI 30·4–42·9) for patients in the brentuximab vedotin group compared with 24·1 months (11·5–not estimable) for those in the placebo group. We recorded consistent benefit (HR <1) of brentuximab vedotin consolidation across subgroups. The most frequent adverse events in the brentuximab vedotin group were peripheral sensory neuropathy (94 [56%] of 167 patients vs 25 [16%] of 160 patients in the placebo group) and neutropenia (58 [35%] vs 19 [12%] patients). At time of analysis, 28 (17%) of 167 patients had died in the brentuximab vedotin group compared with 25 (16%) of 160 patients in the placebo group. Interpretation Early consolidation with brentuximab vedotin after autologous stem-cell transplantation improved progression-free survival in patients with Hodgkin's lymphoma with risk factors for relapse or progression after transplantation. This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation. INSET: Panel: Research in context.. [ABSTRACT FROM AUTHOR]

We have shown that human B-cell non-Hodgkin lymphomas (B-NHLs) express heat shock protein (HSP)H1/105 in function of their aggressiveness. Here, we now clarify its role as a functional B-NHL target by testing the hypothesis that it promotes the stabilization of key lymphoma oncoproteins. HSPH1 silencing in 4 models of aggressive B-NHLs was paralleled by Bcl-6 and c-Myc downregulation. In vitro and in vivo analysis of HSPH1- silenced Namalwa cells showed that this effect was associated with a significant growth delay and the loss of tumorigenicity when 104 cells were injected into mice. Interestingly, we found that HSPH1 physically interacts with c-Myc and Bcl-6 in both Namalwa cells and primary aggressive B-NHLs. Accordingly, expression of HSPH1 and either c-Myc or Bcl-6 positively correlated in these diseases. Our study indicates that HSPH1 concurrently favors the expression of 2 key lymphoma oncoproteins, thus confirming its candidacy as a valuable therapeutic target of aggressive B-NHLs. [ABSTRACT FROM AUTHOR]

The anti-lymphoma activity and mechanism(s) of action of the multikinase inhibitor sorafenib were investigated using a panel of lymphoma cell lines, including SU-DHL-4V, Granta-519, HD-MyZ, and KMS-11 cell lines. In vitro, sorafenib significantly decreased cell proliferation and phosphorylation levels of MAPK and PI3K/Akt pathways while increased apoptotic cell death. In vivo, sorafenib treatment resulted in a cytostatic rather than cytotoxic effect on tumor cell growth associated with a limited inhibition of tumor volumes. However, sorafenib induced an average 50% reduction of tumor vessel density and a 2-fold increase of necrotic areas. Upon sorafenib treatment, endothelial and tumor cells from SU-DHL-4V, Granta-519, and KMS-11 nodules showed a potent inhibition of either phospho-ERK or phospho-AKT, whereas a concomitant inhibition of phospho-ERK and phospho-AKT was only observed in HD-MyZ nodules. In conclusion, sorafenib affects the growth of lymphoid cell lines by triggering antiangiogenic mechanism(s) and directly targeting tumor cells. [ABSTRACT FROM AUTHOR]

Summary: Background: The development of new drugs for patients with refractory urothelial cancer is still an unmet medical need. Preclinical evidence lends support to a rationale for targeting of the VEGF or platelet-derived growth-factor axis. We therefore investigated the activity and safety of pazopanib, a multitarget drug with antiangiogenic activity, in patients with urothelial cancer. Methods: In an open-label, single-group, phase 2 study, patients (aged ≥18 years) with relapsed or refractory urothelial cancer were given pazopanib 800 mg per day, orally. They were treated until disease progression or prohibitive toxicity occurred. The primary endpoint was the proportion of patients who achieved a confirmed objective response, defined as complete or partial response, after independent review, and was analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01031875. Findings: The trial has been completed. 21 (51%) of 41 patients enrolled were given pazopanib as third-line or further-line treatment. 26 (63%) patients had an Eastern Cooperative Oncology Group performance status of 1 or 2. Seven patients had a confirmed objective response (17·1%, 95% CI 7·2–32·1), all of which were partial responses. The most frequent treatment-related grade 3 adverse events were hypertension (three [7%]), fatigue (two [5%]), and gastrointestinal and vaginal fistulisations (two each [5%]). One patient died as a result of duodenal fistulisation that was related to tissue response of bulky tumour masses. Interpretation: Pazopanib has single-agent activity in patients with heavily pretreated metastatic urothelial cancer, and warrants further study in this setting. Particular attention should be paid to patients with bulky tumour masses adjacent to viscera because fistulisation is probably related to the response to pazopanib and is the most frequent serious adverse event. Funding: Fondazione IRCCS Istituto Nazionale dei Tumori provided the grant. GlaxoSmithKline provided the study drug and provided funding for the independent radiological review. [Copyright &y& Elsevier]

The safety and activity of the multikinase inhibitor sorafenib were investigated in patients with relapsed or refractory lymphoproliferative disorders who received sorafenib (400 mg) twice daily until disease progression or appearance of significant clinical toxicity. The primary endpoint was overall response rate ( ORR). Biomarkers of sorafenib activity were analysed at baseline and during treatment. Thirty patients (median age, 61 years; range, 18-74) received a median of 4 months of therapy. Grade 3-4 toxicities included hand/foot skin reactions (20%), infections (12%), neutropenia (20%) and thrombocytopenia (14%). Two patients achieved complete remission ( CR), and two achieved partial remission ( PR) for an ORR of 13%. Stable disease ( SD) and progressive disease ( PD) was observed in 15 (50%) and 11 patients (37%), respectively. The median overall survival ( OS) for all patients was 16 months. For patients who achieved CR, PR and SD, the median time to progression and OS was 5 and 24 months, respectively. Compared with patients with PD, responsive patients had significantly higher baseline levels of extracellular signal-regulated kinase phosphorylation and autophagy and presented a significant reduction of these parameters after 1 month of therapy. Sorafenib was well tolerated and had a clinical activity that warrants development of combination regimens. [ABSTRACT FROM AUTHOR]

BACKGROUND: Because the long-term toxicity of myeloablative radioimmunotherapy remains a matter of concern, the authors evaluated the hematopoietic damage and incidence of secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/AML) in patients who received myeloablative doses of the radiolabeled antibody yttrium-90 (90Y)-ibritumomab tiuxetan. METHODS: The occurrence of sMDS/AML was investigated prospectively in 53 elderly patients with non-Hodgkin lymphoma (NHL) who underwent an autograft after high-dose radioimmunotherapy (HD-RIT) myeloablative conditioning with 90Y-ibritumomab tiuxetan. Bone marrow (BM) hematopoietic progenitors and telomere length (TL) also were investigated. RESULTS: At a median follow-up of 49 months, 4 patients developed sMDS/AML at 6 months, 12 months, 27 months, and 36 months after HD-RIT, and the 5-year cumulative incidence of sMDS/AML was 8.29%. A significant but transient decrease in BM granulocyte-macrophage progenitors was observed; whereas multilineage, erythroid, and fibroblast progenitors were unaffected. A significant and persistent shortening of BM TL also was detected. A matched-pair analysis comparing the study patients with 55 NHL patients who underwent autografts after chemotherapy-based myeloablative conditioning demonstrated a 8.05% 5-year cumulative incidence of sMDS/AML. CONCLUSIONS: HD-RIT for patients with NHL was associated with 1) limited toxicity on hematopoietic progenitors, 2) accelerated TL shortening, and 3) non-negligible incidence of sMDS/AML, which nevertheless was comparable to the incidence observed in a matched group of patients who received chemotherapy-based conditioning. Thus, in the current series of elderly patients with NHL, the development of sMDS/AML was not influenced substantially by HD-RIT. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: BEACOPP, an intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, has been advocated as the new standard of treatment for advanced Hodgkin's lymphoma, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Methods: We randomly assigned 331 patients with previously untreated and unfavorable Hodgkin's lymphoma (stage IIB, III, or IV, or an international prognostic score of ≥3 on a scale of 0 to 7, with higher scores indicating increased risk), to receive either BEACOPP or ABVD, each followed by local radiotherapy when indicated. Patients with residual or progressive disease after the initial therapy were to be treated according to a state-of-the-art high-dose salvage program. The median follow-up period was 61 months. Results: The 7-year rate of freedom from first progression was 85% among patients who had received initial treatment with BEACOPP and 73% among those who had received initial treatment with ABVD (P=0.004), and the 7-year rate of event-free survival was 78% and 71%, respectively (P=0.15). A total of 65 patients (20 in the BEACOPP group, and 45 in the ABVD group) went on to receive the intended high-dose salvage regimen. As of the cutoff date, 3 of the 20 patients in the BEACOPP group and 15 of the 45 in the ABVD group who had had progressive disease or relapse after the initial therapy were alive and free of disease. After completion of the overall planned treatment, including salvage therapy, the 7-year rate of freedom from a second progression was 88% in the BEACOPP group and 82% in the ABVD group (P=0.12), and the 7-year rate of overall survival was 89% and 84%, respectively (P=0.39). Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group. Conclusions: Treatment with BEACOPP, as compared with ABVD, resulted in better initial tumor control, but the long-term clinical outcome did not differ significantly between the two regimens. (Funded by Fondazione Michelangelo; ClinicalTrials.gov number, NCT01251107.) [ABSTRACT FROM PUBLISHER]

The introduction of high-dose (HD) chemotherapy (CT) and autologous stem cell (ASCT) or bone marrow transplant (ABMT) in the last two decades has improved the prognosis of patients with refractory or relapsed Hodgkin lymphoma (HL) over conventional-dose salvage CT. To evaluate the outcome of adult patients with HL treated with HD CT and ASCT or ABMT after failure or relapse from first-line treatment with CT ± radiotherapy, we report the results of a retrospective analysis in 82 consecutive patients given HD CT and autologous transplant as second-line therapy between October 1984 and December 2006. Thirty-two patients were given sequential high-dose cytoreductive therapy while 50 received other conventional induction regimens. Seventy-three patients with chemoresponsive disease underwent the myeloablative phase, while eight patients had progressive disease during cytoreductive CT. After a median follow-up of 73 months, the 10-year progression-free survival (PFS) and overall survival (OS) were 57% and 51%, respectively. According to response to first-line treatment, PFS and OS were, respectively, 54% and 82% for patients with complete remission (CR) lasting 12 months or more; 49% and 51% for patients with CR less than 12 months; and 47% and 50% for patients who never achieved CR or progressed during first-line CT (induction failure). Response to cytoreductive CT significantly influenced outcome, with PFS and OS being, respectively, 56% and 68% vs. 44% and 47% ( p = 0.009) in patients in CR versus patients not in CR after induction therapy. Treatment was well tolerated, and therapy related mortality was only 3.7%. These long-term results confirm that HD CT and ASCT or ABMT was feasible, safe, and very effective. Therefore, this therapeutic strategy may represent an active salvage approach even in the unfavorable group of patients with induction failure. [ABSTRACT FROM AUTHOR]

Abstract: We explored the influence of morphology on geographic differences in 5-year survival for non-Hodgkin lymphoma (NHL) diagnosed in 1990–1994 and followed for 5years: 16,955 cases from 27 EUROCARE-3 cancer registries, and 22,713 cases from 9 US SEER registries. Overall 5-year relative survival was 56.1% in EUROCARE west, 47.1% in EUROCARE east and 56.3% in SEER. Relative excess risk (RER) of death was 1.05 (95% confidence interval (CI) 1.01–1.10) in EUROCARE west, 1.52 (95% CI 1.44–1.60) in EUROCARE east (SEER reference). Excess risk of death was significantly above reference (diffuse B lymphoma) for Burkitt’s and NOS lymphoma; not different for lymphoblastic and other T-cell; significantly below reference (in the order of decreasing relative excess risk) for NHL NOS, mantle cell/centrocytic, lymphoplasmacytic, follicular, small lymphocytic/chronic lymphocytic leukaemia, other specified NHL and cutaneous morphologies. Interpretation of marked variation in survival with morphology is complicated by classification inconsistencies. The completeness and standardisation of cancer registry morphology data needs to be improved. [Copyright &y& Elsevier]

Objective: To optimize transduction efficiency of mobilized CD34+ cells with serotype-5 adenoviruses (Ad5s), we investigated the activity of the chemical cocktail BoosterExpress Reagent in enhancing Ad5-mediated gene transfer into CD34+ cells. Methods: Enriched CD34+ cells were transduced with three different Ad5s at increasing multiplicity of infections (MOIs) in the presence and absence of BoosterExpress Reagent. Percentages of transduced cells and levels of transgene expression were quantified by flow cytometry. Propidium iodide staining and colony growth were used to assess the toxicity of the transduction protocol. Expression of adenovirus receptors was investigated by flow cytometry. Results: Irrespective of the Ad5 used, transduction with BoosterExpress Reagent using an MOI of 500 resulted in an average six- to seven-fold increase of transduction efficiencies and 1.5- to 2-fold increase of the levels of transgene expression, which could be detected up to 7 days post-transduction. Although BoosterExpress Reagent alone did not affect the plating efficiency of CD34+ cells, adenovector transduction plus BoosterExpress Reagent significantly reduced the plating efficiency due to the marked increase of transduced cells. However, adenoviral transduction in the presence of BoosterExpress Reagent failed to significantly reduce the recovery of CD34+ cells as compared with transduction in the absence of the compound. Coxsackievirus and adenovirus receptor as well as αvβ3, αvβ5, α5, and β1 integrins were upregulated by BoosterExpress Reagent. Conclusions: BoosterExpress Reagent allows high-levels of durable transgene expression, thus making CD34+ cells a suitable target for Ad5-mediated gene transfer. [Copyright &y& Elsevier]

Abstract: Molecular remission (MR) is associated with improved outcome in mantle cell lymphoma (MCL). If MR is not achieved, patients are at high risk of relapse. We retrospectively describe the molecular and clinical follow-ups of 4 patients with molecular relapses (M-rels) who were treated with rituximab. The 4 patients received rituximab-supplemented, high-dose sequential chemotherapy and autologous stem cell transplantation as induction treatment and achieved clinical remission and MR. M-rel was defined as polymerase chain reaction (PCR) positivity in 2 consecutive samples in the absence of clinical relapse. M-rels occurred at 3, 6, 39, and 52 months and were always confirmed by direct sequencing of the clonal rearrangement. Minimal residual disease was monitored by qualitative and real-time quantitative PCR. All patients received 4 courses of rituximab, with 2 additional infusions if PCR positivity remained. After 4-6 courses of rituximab, all patients re-entered MR. No clinical relapses were recorded at 3, 6, 18, and 62 months from treatment, although 1 patient had a second M-rel that was sensitive to rituximab. Our results indicate that rituximab is active against residual MCL cells and suggest that molecularly tailored maintenance therapy needs to be investigated in clinical trials. [Copyright &y& Elsevier]

Objectives: To evaluate the prognostic role of pretreatment serum levels of soluble CD30 (sCD30) in patients with advanced stage classical Hodgkin's lymphoma (cHL) treated with adriamycin, bleomycin, vinblastine, and dacarbazine or equivalent regimens. Methods: We identified 321 previously untreated patients with cHL who presented to the participating centers between 1985 and 2002, and had serum samples available for the determination of sCD30 levels. Results: With a median follow-up of 72 months, the actuarial 5-year overall survival was 82%, and failure-free survival (FFS) was 71%. The median serum level of sCD30 was 65 U/mL (range: 1–2230), and was significantly higher ( P < 0.0001) when compared with a group of 113 healthy controls (4 U/mL, range: 0–20). Increasing level of sCD30 was associated with a continuous worsening of FFS and OS, and patients with sCD30 ≥200 U/mL had a 5-year FFS of 39%. With multivariate analysis, sCD30, Ann Arbor stage, and lactic acid dehydrogenase were significant independent factors in terms of FFS. The association of the above-mentioned three independent prognostic variables could discriminate 22% of patients with 5-year FFS of 40%. Conclusions: Our data confirm the independent prognostic role of sCD30 in identifying the patients with high risk of treatment failure, and show that its association with other variables can recognize patients with FFS considerably lower than 50%. [ABSTRACT FROM AUTHOR]

Objective: To explore new treatments specifically targeting malignant plasma cells (PCs), we examined CD52 antigen expression on primary PCs as well as multiple myeloma (MM) cell lines, and investigated in vivo the antimyeloma activity of alemtuzumab. Materials and Methods: PCs were enriched from the marrow of MM patients (n = 39) according to CD138 expression and then analyzed by 3-color flow cytometry and quantitative PCR. The in vivo activity of alemtuzumab was evaluated in a xenotransplant model of MM in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Results: CD52 expression revealed a substantial heterogeneity in terms of both percentage of positive cells and fluorescence intensity, with 25/39 (64%) MM patients showing ≥30% CD138+ PCs expressing the CD52 antigen (mean = 79%; range, 33–100%). Similarly to primary cells, cell lines showed heterogeneous CD52 expression. Expression of CD52 mRNA by quantitative PCR analysis strongly correlated with CD52 antigen detection by flow cytometry. In vivo, alemtuzumab treatment significantly increased the median survival of animals with an early- (64 vs 77 days, p ≤ 0.0005) or advanced-stage (66 vs 75 days, p ≤ 0.02) disease. Conclusion: We conclude that: 1) CD52 is expressed on PCs of a significant proportion of MM patients; 2) alemtuzumab used as a single agent exerts a good antitumor activity in NOD/SCID mice bearing an early-stage disease; and 3) alemtuzumab might have therapeutic potential in a subset of MM patients. [Copyright &y& Elsevier]

Abstract: The aim of this study was to assess the long-term therapeutic outcome and risk of treatment-related complications in Hodgkin’s disease. From May 1973 to September 1990, four randomised studies have been activated at the Milan Cancer Institute using nitrogen mustard, vincristine, procarbazine and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) regimens, with or without irradiation, involving a total of 811 patients with intermediate and advanced Hodgkin’s disease. Overall, ABVD contributed to significantly reduce the relative risk of lymphoma progression and death compared with the MOPP regimen. With a prolonged follow-up, a total of 106 patients (75 of whom were in continuous complete remission after first-line chemotherapy) developed a variety of cancers, resulting in a total risk of 22.2%. Our 25 years of experience re-emphasises that ABVD can cure a high fraction of patients with Hodgkin’s disease. However, patients in continuous complete remission, are at a high risk of developing second cancers, especially when the treatment strategy includes extensive irradiation. The main focus of future trials should be on reducing treatment sequelae to improve the quality of life of long-term survivors. [Copyright &y& Elsevier]

A very short, intensive paediatric chemotherapy programme was tested in a consecutive monoinstitutional group of 22 adult Burkitt's lymphoma (BL) patients. After a 5-week induction phase of weekly infusions consisting of vincristine, cyclophosphamide, doxorubicin, high-dose (HD) methotrexate (MTX) plus leukovorin rescue, and intrathecal MTX or cytarabine (ARA-C), a consolidation phase including HD ARA-C plus cisplatin was given. Responding patients achieving less than complete response (CR) after completion of the initial induction phase, were promptly shifted to a high-dose, stem cell supported sequential chemotherapy schema (R-HDS). Patient characteristics: median age, 35·5 (range 18–76) years; Ann Arbor stage I–II/III–IV, 11/11; bulky disease, 15 patients; LDH ≥ 460 U/l, 11 patients. The median duration of the chemotherapy programme was 62 d (range, 43–94 d). Seventeen patients achieved a CR (77%), one patient died of progressive disease and four partial responders following induction were converted to CR following R-HDS. Of 17 patients in CR, one died of infectious toxicity while in CR, and one relapsed at 30 months and died of progressive disease. After a median follow-up of 28·7 months (range, 6–158 months), 16 patients (73%) were in continued CR. Overall survival and progression-free survival were 77% [95% confidence interval (CI), 52–99%] and 68% (95% CI, 43–99%) respectively. Confirmation of these excellent efficacy and feasibility results by larger, multicentre and prospective studies is warranted. [ABSTRACT FROM AUTHOR]

Summary. We have previously reported on the efficacy of a modified International Prognostic Index (MIPI) in predicting the outcome of patients with primary gastric lymphoma. This prompted the retrospective analysis of a large series of patients with primary intestinal lymphoma (PIL) of both diffuse large B-cell (DLCL) and low-grade (extranodal marginal zone B-cell lymphoma, MZL) histology. Clinical records of 122 patients with localized primary intestinal lymphoma of MZL (n =35) and DLCL (n =87) histology, confirmed by an ad hoc expert panel of pathologists, were reviewed. Forty-nine patients were treated with single therapy, while 72 received combined-modality treatment, which included surgery followed by a short-term chemotherapy. MIPI was included in a multivariate prognostic analysis for overall survival (OS) and event-free survival (EFS). Sixty-five patients (75%) with DLCL and 22 with MZL(65%) achieved complete remission. After a median follow-up of 42 months (range 6–163 months), 5-year estimates of OS and EFS were 68% and 50% for DLCL and 65% and 26% for MZL. OS varied according to MIPI, from, respectively, 86% and 87% for DLCL and MZL patients with 0–1 risk factor to 50% and 32% for patients with > 1 risk factor (P =0·01 and P =0·02). Similar results were obtained for EFS. Cox regression analysis showed an unfavourable MIPI to be the only independent predictor of shorter EFS. This retrospective study shows that stage-MIPI can be a reliable prognostic indicator for PIL of both low-grade MZL and diffuse large B-cell histology, enabling the early identification of patients at higher risk of failure. [ABSTRACT FROM AUTHOR]

Hematological and gene mapping studies of two Southern Italian children doubly heterozygous for δ0-thalassemia and δ0β0-thalassemia have been carried out. No HbA2 was detectable by electrophoresis of total hemoglobin in these patients. Restriction enzyme analysis of the globin gene cluster with δ, γ, ∊ and RIH cloned probes showed all the expected normal bands, in addition to the abnormal fragments related to a previously described type of δ0β0-thalassemic deletion, demonstrating an apparently intact globin gene cluster on the thalassemic chromosome. The relevance of this finding to models for coordinated expression of non α globin genes is discussed. [ABSTRACT FROM AUTHOR]

32P-labelled derived 40-S ribosomal subunits and 80-S monoribosomes entered the polyribosome fraction of a rabbit-reticulocyte lysate active in protein synthesis by a process that was dependent on time, energy and temperature. Both 40-S and 60-S subparticles from the labelled monoribosome entered the polyribosomes at the same rate. The addition of excess unlabelled 40-S subparticles to the cell-free system containing labelled monoribosomes increased the ratio of 60-S to 40-S-subparticle radioactivity in the polyribosome fraction. This indicated a competition between added unlabelled and monoribosome-derived 40-S subparticles for envy into polyribosomes. From the evaluation of the translation time of mRNA, of the rate of monoribosomepolyribosome exchange, and of the equilibrium distribution of the cycling labelled monoribosomes and unlabelled subparticles with polyribosomes it is concluded that the dissociation of single ribosomes into subunits is an obligatory step for their entry into the polyribosomal fraction and that this process is coupled with initiation of mRNA translation. [ABSTRACT FROM AUTHOR]

Abstract: This study describes a patient with a relapsed, diffuse, large B cell lymphoma (DLBCL) treated with radioimmunotherapy (RIT) with yttrium-90 (90Y)-ibritumomab tiuxetan (Zevalin®) who 5 months later developed acute myeloid leukemia (AML) with inversion of chromosome 16. Our data indicate that molecular biological techniques should be used in selected cases to integrate data obtained with standard cytogenetics: using RT-PCR we showed that inversion of chromosome 16 was already present before RIT, in striking contrast to the normal karyotype found with conventional cytogenetics. This approach will allow investigators to avoid misleading data and provide support for conclusions regarding the side effects of treatment. [Copyright &y& Elsevier]