perhaps through the activity of executioner caspase proteases. Interestingly, time-dependent downregulation of Mcl-1 paralleled caspase-3 activation described previously, and when ALCL cells were exposed to bortezomib for 24 h, Mcl-1 was completely degraded unless the cells were pre-treated with the broad-range caspase-inhibitor z-VAD-fmk ( Figure S4B, SR786 and FE-PD). Consistently, Mcl-1 associated to Bak in the mitochondria of untreated ALCL cells, but this complex was disrupted when the cells were cultivated in the presence of bortezomib, unless z-VAD-fmk caspase inhibitor was added before bortezomib ( Figure S4C, FE-PD). These data support the hypothesis that late Mcl-1 downregulation observed in ALCL cell lines occurs downstream of caspase activation, and the inability of the proteasome inhibitor bortezomib to affect steady state and function of Mcl-1 in SUDHL1 or KARPAS299 cells would depend on the level of activated caspases. In conclusion, this study underlines for the first time the effectiveness of bortezomib to induce, at clinically achievable concentrations, growth inhibition and apoptosis in ALCL cells in vitro, regardless of the expression and activity of NPM-ALK protein, and suggests that targeting 26S proteasome may represent a novel therapeutic strategy for ALCLs, especially for those that do not express ALK and are associated with worse prognosis.

Cytogenetic study of a day-old infant showed a terminal del(7q): 46,XX,del(7)(pter leads to q32:). This infant had cebocephaly with holoprosencephaly. These clinical findings are atypical for the 7q - syndrome, in which patients usually have growth and mental retardation with few facial abnormalities.

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AAs have the highest incidence of MM among all racial groups. The impact of race on disease presentation and outcome is the focus of this retrospective study. We analyzed 118 patients of 200 AA patients evaluated at our center from 1998 to 2006. The median age was 54 yrs (range: 28–75); 12 (10%) were younger than 40 yrs. Main presenting symptoms included pain (n= 60, 51%), spinal cord compression (n=9, 8%) and fatigue (n=26, 22%). Eleven patients (9%) were diagnosed following routine blood work and 8 (7%) progressed from prior MGUS. Four patients, all < 41 yrs, had plasma cell leukemia plus MM. MM subtype included IgG (n=77, 66%), IgA (n=19, 16%), light chain only (n=16, 14%) and non–secretory (n=4, 3%). Lytic bone disease was present in 67% of the patients; 19% had hypercalcemia. Patients presented with hemoglobin < 8 g/dl (n=33, 28%), creatinine > 2 mg/dl (n=32, 28%), albumin < 3.4 g/dL (n=71, 63%) and B2M > 5.5 g/mL (n=32, 28%) and > 3.5–5.5 (n=19, 17%). Ten patients required Hemodialysis, including 3 at initial presentation. Eighty-eight percent had Durie/Salmon stage III. Cytogenetics samples were available for 100 patients; the median number of samples was 4 per patient (range: 1–15). Abnormal karyotype was detected in 29% of the first sample and in 27% of the patients on follow samples. Hyperdiploid karyotype was seen in 16% of the patients and hypodiploid in 6%. Complex abnormalities of chromosomes 1, 3, 8, 9, 11, 13, 14 and 17 were detected in 17, 10, 5, 6, 6, 14, 6, 7 of the patients, respectively. Induction therapy included dexamethasone (n=21, 18%), dexa/thalidomide (n=29, 25%) and various chemotherapy regimens including MP, VAD, DT-PACE, bortezomib (n=65, 55%). Eight-eight patients (75%) received high dose chemotherapy (transplant) at a median of 0.7 yrs (range: 0.1, 9.2 yrs) after diagnosis; however, only 45% were transplanted within 12 months of diagnosis. After transplant 22% of the patients received consolidation chemotherapy and 40% received thalidomide maintenance; 10% had tandem transplants. A complete, near complete or partial response was achieved by 9 %, 1% and 66% of the patients before transplant and by 26%, 22% and 45% after transplant, respectively. Median event free survival after transplant was 1.9 yrs (CI: 1.5–2.7). Median survival from transplant was 4.6 yrs (CI: 3.9–7.6) and 6.7 yrs (CI: 5–8.6) from diagnosis. Median survival after relapse was 2 yrs (CI: 1.1–3) for transplanted patients. The median follow up for entire group (n=118) was 4 yrs and the median survival from diagnosis was 7.4 yrs (95% CI: 5–8.6 yrs); median survival has not been reached yet for non-transplanted nor MGUS patients. A Cox regression model revealed that B2M and abnormalities of chromosome 13 were predictive of survival (p=0.0001, 0.0017, respectively). These data were compared to the landmark analysis of newly diagnosed MM patients by Kyle et al. (2003). AA patients presented at a younger median age 54 yrs with 10 % < 40 yrs compared with 67 yrs and 2% for Caucasians. AA patients had more severe anemia and renal failure compared to Caucasians (28 vs 7% and 28 vs 18%, respectively). In conclusion, MM present at a younger age in AA. There is delay in diagnosis as reflected by the advanced stage at diagnosis. The median survival was > 7 yrs., a significant improvement in the last 5 years compared to the 3 yr survival reported for MM (AA and Caucasians) patients in the last 3 decades.

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