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ObjectiveIn field hockey, injuries are assessed by various recording techniques leading to a heterogenic collection of poorly comparable injury data.MethodsInjury data were prospectively collected at the 2016 Men’s Hockey Junior World Cup using the match injury reports (MIRs), video injury clips provided by the Fédération Internationale de Hockey, and daily medical reports (DMRs). A pilot study comparing injury type, mechanism, location on the field, injured body part and overall injury incidence among the different injury recording techniques was performed.ResultsMIRs and video injury clips were completely available for analysis. DMRs were returned from 11 out of 16 teams (69%). In total, MIRs yielded 28, video analysis 36, and DMRs 56 injuries. Overall injury rate varied between 24.8 and 57.9 injuries per 1000 player match hours. The majority of injuries affected the lower limbs by all three methods (41.7–61.2%) and were mainly caused by having been hit by the ball (20.4–50%) or stick (11.1–28.6%). Reports of concussions during competition were incoherent between MIR (2 cases) and DMR (no cases). The DMR was the only method to record overuse injuries (16.1%), injuries in training (12.5%), and time-loss injuries of one or two days (12.5%) or of three or more days (14.3%).ConclusionInjury data vary substantially between the MIR, DMR and injury video recording technique. Each recording technique revealed specific strengths and limitations. To further advance injury research in field hockey, the strengths of each recording technique should be brought together for a synergistic injury assessment model.

Batik is one of popular arts of Indonesia. The batik industries in Sragen, Central Java, are prepared to compete in global market. In order to realize that objective, batik products should fulfill some qualifications, one of which is “environmental friendliness”. As batik production is usually generating wastewater which pollutes the environment, the technology of wastewater treatment should be developed to solve the problem. This preliminary study has been done to assess the effectiveness of anaerobic baffled reactor (ABR) and rotating biological contactor (RBC) in batik wastewater treatment. In 40 days of treatment period, the ABR performance in reducing pollutants showed an effectiveness up to 75%, whereas RBC effectiveness was in the range of 15-57%. Concerning the quality standard of wastewater, the wastewater treatment system showed a good performance to decrease pH, whereas the COD was still high. Further optimization, then, is needed to improve the quality of effluent.

Although soldering is a common laboratory procedure, the use of soldering alloys may adversely affect metal-ceramic bond strength and potentially decrease the longevity of metal-ceramic restorations.The purpose of this study was to investigate the effect of soldering on metal-ceramic bond strength of a representative Ni-Cr base metal alloy.Twenty-eight rectangular (25 x 3 x 0.5 mm) Ni-based alloy (Wiron 99) specimens were equally divided into soldering (S) and reference (R) groups. Soldering group specimens were covered with a 0.1-mm layer of the appropriate solder (Wiron-Lot) and reduced by 0.1 mm on the opposite side. Five specimens of each group were used for the measurement of surface roughness parameter (R(z)) and hardness, and 3 were used for measurement of the modulus of elasticity. Six specimens of each group were covered with porcelain (Ceramco 3) and subjected to a 3-point bending test for evaluation of the metal-ceramic bond strength according to the ISO 9693 specification. The data from surface roughness, hardness, modulus of elasticity, and metal-ceramic bond strength were analyzed statistically, using independent t tests (alpha=.05).Statistical analysis of the R(z) surface roughness parameter (S: 3.4 +/- 0.3 mum; R: 3.7 +/- 0.7 microm; P=.07) and bond strength (S: 46 +/- 3 MPa; R: 40 +/- 5 MPa; P=.057) failed to reveal any significant difference between the 2 groups. The specimens of the soldering group demonstrated significantly lower values both in hardness (S: 128 +/- 11 VHN; R: 217 +/- 4 VHN; P.001) and in modulus of elasticity (S: 135 +/- 4 GPa; R: 183 +/- 6 GPa; P=.035) than the reference group.Under the conditions of the present study, the addition of solder to the base metal alloy did not affect the metal-ceramic bond strength.

Purpose Bortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma. Patients and Methods We randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance). Results In the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients. Conclusion Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.

We report 6 pregnancies in 5 females with low-risk myelodysplastic syndromes (MDS) (median age at diagnosis 28 years, range 26-29) observed in the last 15 years. In 2 cases pregnancy was concomitant to the diagnosis of MDS, in the remaining 4 cases the intervals from diagnosis were 2, 3, 4 and 9 years, respectively. One patient had a foetal growth retardation corrected with steroid treatment while the remaining 5 pregnancies were uneventful. After a median time from delivery of 104 months (range 18-187) none of the patients developed acute myeloid leukemia (AML) and all are alive in stable disease. In conclusion, selected females with low-risk MDS could not be discouraged to have full term pregnancies.

Plasma cell leukemia (PCL) represents the most advanced stage of multiple myeloma (MM) with the neoplastic cells circulating in the peripheral blood. Its diagnosis requires an absolute peripheral b...

Abstract 805FN2 Background. Achievement of CR is generally associated with improved clinical outcomes for patients (pts) with MM and represents a primary endpoint of current clinical trials. The GIMEMA Italian Myeloma Network designed a phase 3 study to demonstrate that the triplet VTD regimen was superior over a doublet such as thalidomide-dexamethasone (TD) as induction therapy prior to double ASCT for newly diagnosed MM. On an intention-to-treat basis, the rate of complete or near complete response (CR/nCR) was 31% for the 236 pts on VTD induction therapy, while it was 11% (p Methods. For this purpose, in a molecular substudy to the main clinical study we assessed the ability of gene expression profile (GEP) to predict attainment of CR/nCR in 122 pts enrolled in the VTD arm of the study. Their characteristics at baseline, including cytogenetic abnormalities, were comparable with those of the whole population of 236 pts. Highly purified CD138+ plasma cells were obtained at diagnosis from each of these pts and were profiled for gene expression using the Affymetrix U133 Plus2.0 platform. In order to build a low-dimensional signature with optimal performance, genomic data were analyzed with an original algorithm that exploits quadratic discriminant analysis with a bottom-up approach that builds N-gene signatures starting from two-dimensional signatures. Gene models were applied to test datasets to predict achievement of either CR/nCR or less than nCR, and classification performances were validated by a leave-one-out crossvalidation procedure. Results. Thirty four pts out of the 122 (28%) who were included in the present analysis achieved a CR/nCR, while the remaining 88 patients failed this objective. The molecular approach described above allowed to identify several gene signatures among which we choose a 163-gene signature that provided a predictive capability of 79% sensitivity, 87% specificity, 71% positive predictive value (PPV) and 92% negative predictive value (NPV). These expression values were used in an unsupervised hierarchical clustering to stratify the population of 122 profilated pts into 3 well defined subgroups. Seventy nine pts were included in subgroup A, while the remaining 43 pts were included in either subgroup B (n=22) or subgroup C (n=21). Notably, 19 out the 34 CR/nCR pts (56%) clustered in subgroup B, whereas the remaining 15 pts were randomly distributed within subgroup A. Analysis of demographic and disease characteristics of the pts belonging to the 3 major subgroups, revealed that in subgroup B the frequencies of pts carrying del(13q) (78%) or del(17p) (22%) or with an IgA isotype (54%) were significantly higher in comparison with the corresponding values found in subgroup A (47%, 4%, and 10%, respectively) and subgroup C (38%, 10%, and 5%, respectively). In order to obtain a more feasible set of genes predictive of CR/nCR, several smaller signatures originating from the 163-gene signature were further analyzed by means of the same algorithm described above. The best predictive capability was obtained with a 41-gene signature that provided 88% sensitivity, 97% specificity, 91% PPV and 95% NPV. A GeneGo ® network analysis of genes included in the signatures showed that the most relevant network nodes included tumour suppressor genes (FBXW7 and MAD), genes involved in inflammatory response (TREM1 and TLR4) and genes involved in B cell development (IKZF1, IL10 and NFAM1). Genes included in the signatures do not gather in specific chromosomes, thus confirming the absence of bias on selection of signatures genes, potentially due to prevalence of MM typical chromosomal aberrations. Conclusions. GEP analysis of a subgroup of pts who received VTD induction therapy allowed to provide a 41-gene signature that was able to predict attainment of CR/nCR and, conversely, failure to achieve at least nCR in 91% and 95% of cases, respectively. These favorable results might represent a first step towards the possible application of a tailored therapy based on the single patient's genetic background. Supported by: Fondazione Del Monte di Bologna e Ravenna, Ateneo RFO grants (M.C.) BolognAIL. Disclosures: Bringhen: Celgene: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Merck Sharp & Dhome: Membership on an entity's Board of Directors or advisory committees. Offidani:Janssen: Honoraria; Celgene: Honoraria.

Monoclonal gammopathy of undetermined significance (MGUS) has been associated with an increased risk of thrombosis. We carried out a retrospective multicentre cohort study on 1491 patients with MGUS. In 49 patients (3.3%) MGUS was diagnosed after a thrombotic event. Follow-up details for a period of at least 12 months after diagnosis of MGUS were obtained in 1238 patients who had no recent history of thrombosis (2 years) prior to diagnosis, for a total of 7334 years. During the follow-up, 33 of 1238 patients (2.7%) experienced thrombosis, with an incidence of 2.5 arterial events and 1.9 venous events per 1000 patient-years. Multivariate analysis showed increased risks of arterial thrombosis in patients with cardiovascular risk factors [hazard ratio (HR) 4.92, 95%confidence interval (CI) 1.42-17.04], and of venous thrombosis in patients with a serum monoclonal (M)-protein level16 g/l at diagnosis (HR 3.08, 95%CI 1.01-9.36). No thrombosis was recorded in patients who developed multiple myeloma (n = 50) or other neoplastic diseases (n = 21). The incidence of arterial or venous thrombosis in patients with MGUS did not increase relative to that reported in the general population for similarly aged members. Finally, the risk of venous thrombosis did increase when the M-protein concentration exceeded16 g/l.

BACKGROUND: In elderly patients with newly diagnosed multiple myeloma (MM), the addition of bortezomib to standard, combined oral melphalan and prednisone (MP) significantly increases the response rate and event-free survival compared with MP alone. METHODS: In this phase 1/2 trial, the authors assessed the dosing, efficacy, and safety of a lower dose-intensity MP schedule plus weekly bortezomib as salvage treatment for elderly patients with MM. To assess the maximum tolerated dose, 19 patients who had relapsed/refractory MM after 1 or 2 lines of treatment entered the first phase of the study. They received melphalan at a dose of 24 mg for 28 days; bortezomib 1.3 mg/m2 on days 1, 8, 15, and 22; and prednisone at a dose of 50 mg every other day of a 28-day cycle for a total of 9 cycles. At the end of the first phase, based on the good efficacy and acceptable toxicity of this combination, an additional 23 patients were enrolled. RESULTS: After a median follow-up of 21 months, of 42 patients who relapsed, 24 (57%) obtained at least a partial response, 4 had stable disease, and 11 had progressive disease. The median time to progression was 18 months, and the median overall survival was 30 months. Grade 3 and 4 toxicity was observed in 16 of 42 patients (38%) and was more frequent during the early cycles. CONCLUSIONS: A weekly infusion of bortezomib associated with lower dose-intensity MP induced a high proportion of responses and was well tolerated in elderly patients with relapsed/refractory MM. Cancer 2013. © 2012 American Cancer Society.

Bisphosphonates (BPs) are used intravenously to treat cancer-related conditions for the prevention of pathological fractures. Osteonecrosis of the jaw (BRONJ) is a rare complication reported in 4-15% of patients. We studied, retrospectively, 55 patients with multiple myeloma or Waldenstrom's macroglobulinemia followed up from different haematological departments who developed BRONJ. All patients were treated with BPs for bone lesions and/or fractures. The most common trigger for BRONJ was dental alveolar surgery. After a median observation of 26 months, no death caused by BRONJ complication was reported. In all, 51 patients were treated with antibiotic therapy, and in 6 patients, this was performed in association with surgical debridement of necrotic bone, in 16 with hyperbaric O(2) therapy/ozonotherapy and curettage and in 12 with sequestrectomy and O(2)/hyperbaric therapy. Complete response was observed in 20 cases, partial response in 21, unchanged in 9 and worsening in 3. The association of surgical treatment with antibiotic therapy seems to be more effective in eradicating the necrotic bone than antibiotic treatment alone. O(2) hyperbaric/ozonotherapy is a very effective treatment. The cumulative dosage of BPs is important for the evolution of BRONJ. Because the most common trigger for BRONJ was dental extractions, all patients, before BP treatment, must achieve an optimal periodontal health.

In a recent phase 3 trial, bortezomib-melphalan-prednisone-thalidomide followed by maintenance treatment with bortezomib-thalidomide demonstrated superior efficacy compared with bortezomib-melphalan-prednisone. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions: 372 patients received once-weekly and 139 twice-weekly bortezomib. In this post-hoc analysis we assessed the impact of the schedule change on clinical outcomes and safety. Long-term outcomes appeared similar: 3-year progression-free survival rate was 50% in the once-weekly and 47% in the twice-weekly group (P > .999), and 3-year overall survival rate was 88% and 89%, respectively (P = .54). The complete response rate was 30% in the once-weekly and 35% in the twice-weekly group (P = .27). Nonhematologic grade 3/4 adverse events were reported in 35% of once-weekly patients and 51% of twice-weekly patients (P = .003). The incidence of grade 3/4 peripheral neuropathy was 8% in the once-weekly and 28% in the twice-weekly group (P < .001); 5% of patients in the once-weekly and 15% in the twice-weekly group discontinued therapy because of peripheral neuropathy (P < .001). This improvement in safety did not appear to affect efficacy. This study is registered at http://www.clinicaltrials.gov as NCT01063179.

High-dose (200 mg/m2, MEL200) and intermediate-dose melphalan (100 mg/m2, MEL100) showed significant activity in myeloma. In a phase 3 study, 298 patients were randomly assigned to receive 2 autologous transplantations after conditioning with MEL200 or MEL100. Ninety-six of 149 (64%) completed MEL200 and 103 of 149 (69%) MEL100. Best response to MEL200 was: complete remission 22 of 149 (15%); partial remission 95 of 149 (64%), for an overall response rate of 79%. Best response to MEL100 was: complete remission 12 of 149 (8%); partial remission 95 of 149 (64%), for an overall response rate of 72%. Overall survival did not differ (P = .13); median progression-free survival (31.4 vs 26.2 months, P = .01), median time to progression (34.4 vs 27.0 months, P = .014) were longer in the MEL200. Treatment-related mortality was 3.1% in the MEL200 and 2.9% in the MEL100 group. Severe neutropenia and infections were marginally superior, whereas severe thrombocytopenia, mucositis, gastrointestinal adverse events, and the overall occurrence of at least 1 nonhematologic grade 3 or 4 adverse event were significantly higher in the MEL200 cohort. We conclude that MEL200 leads to longer remission duration and should be considered the standard conditioning regimen for autologous transplantation. This study was registered at www.clinicaltrials.gov as #NCT00950768.

Abstract 128 Background. In newly diagnosed myeloma patients the combination of bortezomib with melphalan-prednisone (VMP) was superior to MP. In relapsed-refractory patients the 4 drug combination bortezomib-melphalan-prednisone-thalidomide (VMPT) induced a high proportion of complete responses (CR). Aims. This prospective, randomized, phase III trial, compared VMPT with a maintenance regimen including bortezomib and thalidomide with VMP without a maintenance regiment. The primary end point was PFS. Methods. Patients (N=511) older than 65 years were randomly assigned to receive VMPT followed by maintenance with bortezomib and thalidomide (N=254) or VMP (N=257). Initially, patients were treated with nine 6-week cycles of VMPT (induction: bortezomib 1.3 mg/m2 days 1,4,8,11,22,25,29,32 in cycles 1–4 and days 1,8,22,29 in cycles 5–9; melphalan 9 mg/m2 days 1–4; prednisone 60 mg/m2 days 1–4 and thalidomide 50 mg days 1–42; maintenance: bortezomib 1.3 mg/m2 every 15 days and thalidomide 50 mg/day) or VMP (bortezomib, melphalan and prednisone at the same doses and schedules previously described without maintenance). In March 2007, the protocol was amended: both VMPT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m2 days 1,8,15,22 in cycles 1–9). Results. All patients have been evaluated in intention-to-treat. Patient characteristics were similar in both groups, median age was 71 years. The response rates were always superior in the VMPT group: at least PR rate (86% vs 79%, p=0.02), at least VGPR rate (55% vs 47%, p=0.07) and CR rate (34% vs 21% p=0.0008), respectively. Maintenance treatment did not increase the best response achieved during VMPT induction. After a median follow-up of 17.8 months, the 2-year PFS was 70.0% in the VMPT group and 58.2% in the VMP group (HR=0.62, 95% CI 0.44–0.88, p=0.008). The achievement of CR significantly prolonged PFS in both VMPT (p Disclosures: Palumbo: Janssen-Cilag: Honoraria; Celgene: Honoraria. Off Label Use: thalidomide, lenalidomide, bortezomib . Bringhen:Celgene: Honoraria; Janssen Cilag: Honoraria. Patriarca:Janssen Cilag: Honoraria; Celgene: Honoraria. Petrucci:Celgene: Honoraria; Janssen-Cilag: Honoraria. Musto:Janssen Cilag: Honoraria; Celgene: Honoraria. Boccadoro:Celgene: Consultant, advisory committee, Research Funding; Janssen Cilag: Consultant, advisory committee, Research Funding; Pharmion: Consultant, advisory committee, Research Funding.

Abstract 1868 Poster Board I-893 Introduction Bortezomib was initially reported to overcome the poor prognosis related to the presence of del(13q) in patients with advanced refractory/relapsed multiple myeloma (MM). However, more recent evaluations of genomic aberrations in MM provided demonstration that only t(4;14) and del(17p) retained prognostic value for both EFS and OS, thus identifying a subgroup of patients at high risk of progression or death. The combination of bortezomib with melphalan and prednisone, actually licensed as first-line therapy for MM patients who are not eligible for autologous stem-cell transplantation (ASCT), showed comparable activities in terms of time to progression and OS among patients with or without high-risk cytogenetic profiles. However, the number of high-risk patients analyzed was very limited, due to the low frequency of these genomic abnormalities. To more carefully assess the role of bortezomib in patients with high-risk cytogenetics [(e.g. carrying t(4;14) and/or del(17p)], we performed a post-hoc analysis of two phase 3 studies of first-line bortezomib-based regimens for the treatment of a large series of MM patients. Both studies are actually conducted by the Italian Myeloma Network GIMEMA. Patients and methods The activity of three different bortezomib-based regimens in terms of achievement of best high-quality response (immunofixation negative CR) and PFS was analyzed. Regimens evaluated were bortezomib-thalidomide-dexamethasone (VTD), bortezomib-melphalan-prednisone (VMP) and bortezomib-melphalan-prednisone-thalidomide (VMPT). VTD was followed by ASCT. Treatment details are as follows: VTD (Bortezomib, 1.3 mg/m2 twice-weekly, every 21/d cycle; Thalidomide, 200 mg/d; Dexamethasone, 320 mg/cycle); VMP (Bortezomib 1.3 mg/m2 on d 1, 8, 15 and 22, every 35/d cycle; Melphalan, 9 mg/m2 on d 1 through 4, every cycle; Prednisone, 60 mg/m2 on d 1–4 of each cycle); VMPT (VMP, as previously described; Thalidomide, 50 mg/d). A total of 566 patients for whom results of interphase FISH analysis at diagnosis were available for the presence or absence of del(13q) and/or t(4;14) and/or del(17p), were included in the present study. Three cytogenetic subgroups of patients were identified, including those without genomic abnormalities (group 1; n=257), those with del(13q) alone (group 2; n=162) and those who carried t(4;14) and/or del(17p) with or without del(13q) (group 3; n=147). For the purpose of the present analysis, clinical outcomes (e.g. CR rate and PFS) of patients treated with the 3 bortezomib-based regimens were compared according to the presence or absence of different genomic aberrations (e.g. group 1 vs 3 and group 2 vs 3). Results Overall, the frequency of patients belonging to group 1 (no abnormalities), group 2 [del(13q) alone] and group 3 [t(4;14)±del(17p)] was 45%, 29% and 26%, respectively. Comparable rates of genomic aberrations were detected in patients treated with the 3 bortezomib-based regimens [no genetic abnormalities: 46% in VTD vs 48% in VMP vs 42% in VMPT; del(13q) alone: 30% in VTD vs 28% in VMP vs 28% in VMPT; t(4;14)±del(17p): 24% in VTD vs 24% in VMP vs 30% in VMPT]. No statistically significant difference in terms of CR rate was detected by comparing patients in group 3 with those in group 1 (38% vs 31.5%, respectively; P=0.1) and in group 2 (48%, P=0.07). The 2-year projected PFS was 63% for patients with high-risk cytogenetics vs 71% for those with del(13q) alone (P=0.1) vs 75% for patients without cytogenetic abnormalities (P=0.01). The finding that in the high-risk cytogenetic subgroup the VMP regimen comprising once-weekly standard-dose bortezomib effected the lowest rate of CR and PFS may explain, at least in part, the longer PFS for the subgroup without cytogenetic abnormalities. Indeed, after exclusion from the analysis of the VMP regimen, no statistically significant difference in terms of PFS was seen among VTD- and VMPT-treated patients according to the presence of high-risk cytogenetics or the absence of genomic abnormalities (P=0.09). Conclusions These results, based on a post-hoc analysis of patients with different age and treatment exposure, should be cautiously interpreted, although consistencies exist between them and previous reports on the activity of bortezomib in MM with high-risk cytogenetic abnormalities. Further analyses of large series of homogeneously treated patients are needed before firm conclusions can be drawn about the ability of bortezomib-based regimens to overcome the adverse prognosis related to t(4;14) and/or del(17p). Disclosures: Cavo: Ortho Biotech, Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Boccadoro:Ortho Biotech, Janssen-Cilag: Honoraria, Speakers Bureau. Palumbo:Ortho Biotech, Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau.

Smoldering multiple myeloma (SMM) is an asymptomatic plasma-cell disorder with a high risk of progression to a symptomatic multiple myeloma (MM). The time and mechanisms underlying the progression are still unclear. The Bcl-2 family proteins are frequently aberrantly expressed in MM and support proliferation, survival and drug-resistance. The activity of inhibitors of the anti-apoptotic Bcl-2 family members is currently under investigation in MM, while their therapeutic potential has never been explored in SMM. In this study, we investigated the constitutive protein expression profile of anti-apoptotic Bcl-2 family members and the functional effects of their pharmacological modulation by the Bcl-2/Bcl-xL inhibitor ABT-737 (kindly provided by Abbott Laboratories) on primary cells from SMM and symptomatic MM at different stages of the disease. Mononuclear cells isolated from BM aspirates of MM patients were fractionated into purified CD138+ (>80%) and CD138- populations. Protein extracts were prepared and subjected to Western blot analysis for anti-apoptotic Bcl-2 family members. Within the CD138+ malignant plasma cells, SMM samples were characterized by elevated Mcl-1 levels and barely detectable expression of Bcl-xL, while symptomatic MM samples exhibited higher levels of both Mcl-1 and Bcl-xL. No significant differences in Bcl-2 level expression were instead observed between SMM and symptomatic MM samples. We, then, investigated the functional effects of ABT-737 on MM cell line and on CD138+ malignant plasma cells from SMM and symptomatic MM samples. MM cell lines exposed to increasing concentrations of ABT-737 (10–1000 nM) for up 72 hours showed a dose- and time-dependent cell growth inhibition (IC50 200–400 nM at 72 hours) due to the loss of mitochondrial membrane potential, caspase activation and significant increase in the proportion of apoptotic cells. In addition, cell cycle analysis demonstrated a significant G1-phase depletion in KMS18 cells exposed to 1000 nM ABT-737 for 72 hours (26.9%±1.4 vs 54.6%±4.5, p=0.021). Western Blot analysis demonstrated that ABT-737 dramatically reduces Bcl-2 protein levels, with appearance of cleaved forms, while Mcl-1 was down-regulated only at higher doses. No effects were seen on Bcl-xL expression. The ABT-737 activity was then examined on CD138+ purified primary cells from 9 SMM samples cultured with ABT-737 (10–1000 nM) for 72 hours. A remarkable reduction in cell growth and increase in the percentage of apoptotic cells was observed in response to 100 nM ABT-737. In particular, a statistically significant pro-apoptotic activity of 100 nM ABT-737 was demonstrated by the increment of the subG1 peak after 24 hours (25.0%±9.8 vs 60.1%±17.0, p=0.00011, and vs 78.1%±14.0, p=0.0003, in the presence of 100 and 1000 nM ABT 737, respectively). Similar results were obtained in the CD138+ fraction from symptomatic MM (7 newly diagnosed and in 9 relapsed/refractory) with a significant increment of the subG1 peak after 24 hours of ABT-737 exposure (27.9%±15.5 vs 53.4%±16.8, p

The Raf/MEK/ERK pathway and the Bcl-2 family proteins are commonly overexpressed in hematologic malignancies, where they promote proliferation and survival of the neoplastic cells. We have previously demonstrated that selective MEK inhibitors (MEK-I) exert potent growth-inhibitory effects in preclinical models of both acute myeloid leukemia (AML) and multiple myeloma (MM) (Blood2006, 108:254). More recently, we have obtained evidence that ABT-737, a Bcl-2/Bcl-xL (BH3 mimetic) inhibitor (kindly provided by Abbott Laboratories), shows potent in vitro growth-inhibitory and pro-apoptotic activity on MM cell lines and primary CD138+ bone marrow cells from MM patients, regardless of the disease status (Libotte F, ASH 2008). Moreover, in AML models, we and others have reported a highly synergistic pro-apoptotic interaction between inhibitors of the Raf/MEK/ERK pathway and of the Bcl-2 family (Blood 2002, Cancer Cell 2006, Ricciardi ASH 2008). Here, we analyzed the impact of the simultaneous inhibition of these two pathways on cell proliferation and apoptosis in MM cell lines. To this purpose, we exposed different MM cell lines to increasing concentrations of MEK-I and ABT-737, alone and in combination. While single compounds dose-dependently inhibited cell growth, as assessed by trypan blue exclusion counting, we observed that their combination synergistically enhanced this effect with combination indexes (CI), as measured by isobologram analysis (Chou–Talalay method), of 0.28 and 0.12 for KMS18 and KMS27 cells, respectively. We next analyzed the effects of combined MEK and Bcl-2/Bcl-xL inhibition on apoptosis induction. Both MEK-I and ABT-737 induced apoptosis in MM cells at high concentrations, as determined by sub-G1 DNA peak and Annexin V staining. When used at concentrations that induced minimal apoptosis as single agents (7.55% and 6.8% net apoptosis induction in KMS18 cells after 72 hours of exposure to MEK-I and ABT-737, respectively), the combination of MEK-I and ABT-737 was able to induce substantial apoptosis (more than 50% net apoptosis induction after 72 hours in both KMS18 and KMS27 cell lines). Such pro-apoptotic interaction was highly synergistic in nature, with CI, as defined using isobologram analysis, of 0.2 and 0.17 for KMS18 and KMS27 cells, respectively. Mitochondrial membrane depolarization was similarly enhanced by the combination of MEK-I and ABT-737. Conversely, in the MEK-I resistant MM cell line ARH-77, ABT-737 was still able to induce apoptosis (up to 40% of the cells) but its effect was not significantly potentiated by MEK inhibition. Preliminary results on primary CD138+ MM cells exposed to both inhibitors confirmed the higher cell growth inhibition induced by combining MEK-I and Bcl-2/Bcl-xL inhibition. In conclusion, we demonstrated a striking synergistic pro-apoptotic activity with combined inhibition of Raf/MEK/ERK and Bcl-2 signaling in MM cell lines. Simultaneous disruption of these two pathways warrants further investigation as novel therapeutic strategy for this disease.

Over the last few years, Thalidomide-Dexamethsone (TD) has been one of the most commonly used induction regimens for the treatment of newly diagnosed multiple myeloma (MM). In a phase III study conducted by the Italian Myeloma Network GIMEMA, TD was compared with Velcade-Thalidomide-Dexamethasone (VTD) as induction therapy in preparation for, and as consolidation after, melphalan (200 mg/m2)-based double autologous stem-cell transplantation (ASCT) in pts aged ≤65 years with symptomatic MM. Up-front VTD comprised Velcade, 1.3 mg/m2 on d 1, 4, 8, and 11; Dexamethasone, 40 mg on each day of and after Velcade administration; Thalidomide, 200 mg/d through d 1 to 63. Pts randomized to TD received Thalidomide as in VTD and Dexamethasone, 40 mg/d on d 1–4 and 9–12 of every cycle. Primary study end point was the rate of complete response (CR)/near CR (nCR) following three 21-d cycles of induction therapy. The study was started in May 2006 and was closed to accrual in April 2008, after a total of 480 pts were enrolled. Of these, 399 pts (199 randomized to VTD and 200 to TD) could be evaluated for primary study end point and toxicity of induction regimens (secondary end point). All analyses were intent to treat. In comparison with TD, VTD effected significantly higher rates of response (≥partial response: 78.5% vs 92%, P

Philadelphia positive (Ph+) chronic myeloid leukaemia (CML) presenting synchronously or following non-Hodgkin lymphoma (NHL) has only rarely been reported. Herein, we refer on a case of Ph+ CML occurring after a breast cancer and a NHL with multiple relapses. After obtaining complete cytogenetic remission with imatinib, the patient presented a new NHL relapse, that was treated with rituximab concomitantly to imatinib. Therapy was well tolerated and the patient is presently alive in complete remission of either NHL and CML. We also reviewed the literature relating the uncommon association of these two unrelated diseases.

The differential diagnosis between multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) is generally well defined. Consistent with a diagnosis of MM is the presence of a non-IgM monoclonal gammopathy associated to multiple osteolytic lesions and plasma cell infiltration of the bone marrow. Characteristic of WM is the presence of an IgM monoclonal gammopathy associated to lymphoadenopathy, hepatosplenomegaly, anemia and hyperviscosity syndrome in the presence of a monoclonal lymphoplasmacytoid proliferation in the bone marrow. Nonetheless, few cases of IgM myeloma have been reported that display clinico-pathologic features intermediate between MM and WM. Here, this study describes four of 317 (1.2%) patients with an IgM monoclonal gammopathy in whom the morphologic and clinical features were consistent with a diagnosis of IgM myeloma.

One of the major changes suggested by the World Health Organization (WHO) classification with respect to the French-American-British (FAB) proposal for myelodysplastic syndromes (MDS) was to lower the bone marrow (BM) blast count from 30 to 20%, thus eliminating the refractory anaemia with excess of blasts in transformation (RAEB-t) category. However, a general consensus has not been reached, and several authors still retain RAEB-t as an MDS sub-entity. We re-evaluated our series of 74 patients classified as RAEB-t according to the FAB criteria by stratifying them into two subsets: patients with at least 5% peripheral blast (PB) cells but with BM blasts 5% PBs, should be included in the RAEB-II category according to the WHO criteria, with a group of 98 patients who were diagnosed as RAEB-II according to the WHO criteria. The findings showed that the aggregation of these two subsets appeared inappropriate, because patients of the two groups showed different clinical features and rates of acute transformation. In conclusion, the RAEB-t entity according to the FAB criteria, although including heterogeneous clinical patient subsets, should more likely be considered as an advanced stage of MDS, rather than a true acute myeloid leukaemia.

BACKGROUND Current treatment regimens for Waldenstrom macroglobulinemia (WM) are based on the use of oral alkylating agents. Recently, however, other more costly agents have been proposed for the treatment of WM. In the current study, the authors report on results obtained using oral melphalan, cyclophosphamide, and prednisone (MCP) to treat 72 patients with WM, and they compare these results (and the associated costs) with those observed using more aggressive protocols. METHODS Between July 1973 and April 2002, the authors documented overexpression of the immunoglobulin M paraprotein in 317 consecutive patients. Of these, 100 had newly diagnosed WM, and the 72 who were symptomatic were treated using the MCP protocol. Response rate, overall survival (OS), response duration, freedom from progression (FFP), event-free survival (EFS) duration, toxicity, and cost per course in Euro and U.S. dollars were evaluated for patients receiving this regimen. RESULTS Seventy-one of 72 patients (99%) were evaluable. Of these patients, 55 (77%) achieved a response; 7 others (10%) experienced disease stabilization, and the remaining 9 (13%) experienced disease progression. After a median follow-up of 72 months (range, 3–195 months), the median durations of EFS, FFP, response, and OS were 47, 55, 64, and 66 months, respectively. No World Health Organization Grade III or IV toxicities were observed, and side effects were limited to transient nausea, emesis, and mild neutropenia. The cost per course of the MCP regimen was $16, similar to that of standard protocols involving chlorambucil and much less than that of more aggressive protocols (price range, $91–11091) proposed for the treatment of WM. CONCLUSIONS Like chlorambucil-based protocols, the MCP regimen is a cost-effective and safe option for the treatment of patients with WM. Furthermore, the results obtained do not appear to be inferior to those yielded by more expensive, aggressive, and toxic intravenous protocols. Cancer 2005. © 2004 American Cancer Society.

Susceptibility to apoptosis varies in different forms of myelodysplastic syndromes (MDS). Our in vitro study aimed at better defining the cell kinetic profile by investigating whether G-CSF and interferon-alpha (IFNalpha) were capable of controling apoptotic/proliferative mechanisms in RAEB as well as in RAEB-t forms. Apoptosis and cell-cycle distribution were measured in mononuclear and in CD34+ cells from bone marrow samples of 27 MDS patients with RAEB (n = 15) and RAEB-t (n = 12). In selected samples, the in vitro influence of G-CSF and lymphoblastoid (Ly)-IFNalpha on the apoptotic susceptibility and on the cell kinetics of the above MDS populations was evaluated. RAEB samples showed a significantly greater apoptosis than RAEB-t ones, both in mononuclear cells (14.76%+/-8.73 vs. 5.95%+/-3.88, P= 0.0058) and in CD34+ cells (24.66%+/-16.08 vs. 3.96%+/-2.57, P = 0.0007). Short-term cell culture in the presence of G-CSF reduced apoptosis in CD34+ cells in all 4 RAEB samples tested (39.1%+/-40.7 vs. 21.0%+/-23.5, P = n.s.); the percentage of cells in S-phase significantly increased in 3/4 samples (19.90%+/-4.40 vs. 32.40%+/-7.85, P = 0.03). Ly-IFNalpha protected CD34+ cells from apoptosis in 3/4 RAEB samples (25.7%+/-8.06 vs. 10.9%+/-8.8, P = n.s.), but did not modulate cell-cycle distribution. G-CSF and Ly-IFNalpha failed to affect apoptosis and proliferation in RAEB-t. These observations indicate that in RAEB forms increased apoptosis can be efficiently counteracted in most of the samples by both G-CSF and Ly-IFNalpha, suggesting that only in these forms a retained regulatory mechanism on the apoptotic/ proliferative balance may allow therapeutic intervention with apoptotic regulators.

The present study was undertaken to determine the feasibility of using primary stability as a predictor of implant success in patients whose implants were immediately loaded.The study included 40 patients, in whom a total of 190 implants were placed, 102 in maxillary sites and 88 in mandibular sites. All were loaded within 72 hours of placement. Sixteen patients were completely edentulous in the mandible and/or the maxilla. The remaining 24, who were partially edentulous, received fixed partial dentures or single-implant restorations. All of the definitive implant restorations were screw retained. The criterion for loading was clinical judgment of primary stability, verified by a "screw test." Impressions were made after implant placement to facilitate the fabrication of a laboratory-made heat-processed provisional restoration from acrylic resin. Following a 4-month period for osseointegration and soft tissue healing, definitive fixed prostheses were fabricated.There were no surgical complications. After 1 to 2 years, all 190 implants had survived and were considered 100% successful, as determined by independent testing of mobility and radiographic evidence of osseointegration. In 4 patients, fracture of the provisional restoration occurred during the healing period.Clinical research has shown that immediate loading is a viable treatment modality. The favorable success rate reported in this study for rough-surfaced implants suggests that adherence to a protocol, an important parameter of which is primary stability above 32 Ncm, can lead to osseointegration.The results of this limited investigation suggest that patients who are partially or completely edentulous may be immediately restored with implants and fixed provisional restorations, provided that the dental implants are adequately stable immediately after their surgical placement. This alternative therapeutic approach did not appear to affect the up-to-2-year survival of the implants in this patient population.

A importância do estudo das características resilientes dos solos e das misturas estabilizadas quimicamente justifica-se pela necessidade de conhecer o seu comportamento mecânico, sob a ação de cargas repetidas e transientes, quando constituintes do pavimento de estradas florestais. O método tradicional de determinação do módulo de resiliência, em laboratório, requer o emprego de um equipamento triaxial de cargas repetidas, que é relativamente complexo e caro, o que leva à necessidade de se desenvolver métodos mais simples para determinação do módulo de resiliência. Assim, buscou-se com este trabalho determinar o módulo de resiliência de um solo argiloso comum na região de Viçosa-MG em seu estado natural e quando estabilizado com cimento e alcatrão, como também propor correlações empíricas entre este e outros parâmetros geotécnicos de fácil obtenção em laboratório. The study of the resilient response of soils and chemically stabilized mixtures is justified by the need to know the behavior of these soils under the action of repeated and transient loads. The traditional method for determining the resilient modulus of soils in laboratory requires complex and expensive repeated-loading triaxial equipment. Therefore, simpler methods should be developed. This work was carried out to identify the geotechnical and resilient properties of a clayey soil from Viçosa-MG in its natural state and after stabilization with cement and tar, and to propose empirical correlations between the resilient modulus of these materials and other geotechnical parameters, easily determined under laboratory conditions.

Dental implants are accepted as a successful alternative to conventional fixed and removable prostheses for the treatment of partial or complete edentulism. However, there have been few studies of the success of implants from the patients' perspective. The purpose of this study was to assess patient overall satisfaction with the outcome of treatment with maxillary anterior implants.A self-administered mailed questionnaire, which was developed for this project, and a data abstraction form, which was designed based on information available from the corresponding dental records of 123 eligible subjects, were utilized to survey implant patients.Seventy-eight of 123 eligible subjects responded to the mailed, self-administered, structured questionnaire. Twelve of the 24 questionnaire variables demonstrated statistically significant bivariate associations with the dependent variable "overall patient satisfaction." Five variables--implant position, definitive restoration shape, appearance, effect on speech, and chewing capacity--were strongly associated with overall satisfaction. No demographic or treatment-related, dental record-abstracted variable, of the 25 that were examined, was statistically significant.The practitioner who provides implant restorations should be aware of the multidimensional aspects of patient satisfaction with implant treatment. This study suggests that patient satisfaction with key elements influences the overall acceptance of maxillary anterior implant prostheses, which are esthetically critical. Communication between dentist and patient is important to achieve optimal results that will be satisfactory to both. Discussion of treatment limitations may also help patients to develop realistic expectations of the final result.In this limited investigation, patient satisfaction with implant position, restoration shape, overall appearance, effect on speech, and chewing capacity were critical for patient overall acceptance of the dental implant treatment.