In an effort to clarify the biochemical pathogenesis of the acute reversible siderblastic anemia of alcoholics, bone marrow delta-aminolevulinic acid (ALA) synthetase activity was measured in anemic alcoholic patients with and without pathological ring sideroblasts in their marrows and compared with the activity of this enzyme in normal subjects and in patients with idiopathic sideroblastic anemia. Mean ALA-synthetase activity measured (following addition of exogenous pyridoxal phosphate in three patients with the ring sideroblast morphologic abnormality) was 502 f 147 (SE) pmoles ALA per lo6 erythroblasts per 30 minutes, as compared with 201 f 69 in the seven alcoholic patients without pathologic sideroblastic marrow abnormalities, 169 f 32 in the six normal subjects, and 52 * 4 pmoles ALA per lo6 erythroblasts per 30 minutes in two patients with idiopathic sideroblastic anemia. Comparison of enzyme activity in the presence and absence of pyridoxal phosphate revealed that addition of this enzyme cofactor accentuated ALA-synthetase activity by an average of only 24% in the alcoholic sideroblastic group, as compared with 42% accentuation in the normal group and 8% accentuation in the idiopathic sideroblastic group. These results suggest that abnormalities in pyridoxal phosphate metabolism in alcoholics may not be of importance in the inhibition of heme biosynthesis at the level of ALA synthetase but, rather, that an enzymatic or metabolic block should be sought at a more distal site in the heme biosynthetic pathway.

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Aim: Men with intermediate-risk prostate cancer represent a heterogeneous group of patients with varying prognoses. Intraductal carcinoma (IDC), cribriform architecture (CA), and high copy number alteration burden are novel pathological and genomic indices that predict aggressive disease and inferior clinical outcomes in patients with localised prostate cancer. We aimed to test the independent prognostic effect of these indices in a cohort of intermediate-risk prostate cancers. Experimental methods: We defined a set of clinical and genomic indices to test for their prognostic significance in a cohort of individuals with NCCN-defined intermediate-risk prostate cancer, who were treated with radical prostatectomy (RadP) or radiotherapy (RT) (N = 173, RadP; N = 358, RT). Clinical indices include primary T-category, pre-treatment PSA level, Gleason's score and pattern, and presence of IDC and/or CA. Pathological features were reviewed centrally by two expert pathologists. Copy number alteration burden was assessed in 215 tumours of the cohort using SNP array profiling (Affymetrix Oncoscan), and reported as percent genome aberration (PGA). Our primary endpoint was to test if a model incorporating IDC/CA and PGA stratifies patients with intermediate-risk disease for risk of biochemical relapse after primary treatment. Results: Biochemical relapse was associated with PGA on univariable and multivariable analysis for the sub-cohort of 215 patients (HR of High vs Low PGA defined by median = 1.61, 95% CI = 1.04-2.49, Wald's p = 0.033). Based on modelling of the clinical indices, presence of IDC/CA was associated with biochemical relapse-free rate (bRFR) on univariable and multivariable analyses (HR = 1.90, 95% CI = 1.34-2.69, p = 0.00034), along with PSA level. Risk stratification considering both IDC/CA and PGA indicated an additive prognostic effect of IDC/CA to PGA for early biochemical relapse, with 18-month bRFR of 83% in High PGA, present IDC/CA vs 94% in Low PGA, absent IDC/CA subgroups (HR = 2.55, 95% CI = 1.49-4.39, p = 0.00069). A comparison of risk stratification models revealed that inclusion of PGA to IDC/CA yielded the strongest model for predicting 18-month bRFR in patients with intermediate-risk prostate cancer following treatment (area under the curve, AUC = 0.580, 95% CI = 0.456-0.675 [T-category, PSA, and IDC/CA] vs 0.649, 95% CI = 0.476-0.776 [T-category, PSA, IDC/CA, and PGA]). Conclusions: We herein demonstrate for the first time a novel risk stratification model integrating pathological (IDC/CA) and genomic (PGA) indices to identify patients with unfavourable intermediate-risk prostate cancer, who may benefit from intensification to conventional definitive treatment. Citation Format: Melvin Lee Kiang Chua, Jure Murgic, Melania Pintilie, Emilie Lalonde, Charlotte Kweldam, Winnie Lo, Alejandro Berlin, Alan Dal Pra, Michele Orain, Valerie Picard, Helene Hovington, Alain Begeron, Yves Fradet, Bernard Tetu, Julie Livingstone, Alice Meng, Jun Yan Zhang, Gaetano Zafarana, Neil Fleshner, Mike Fraser, Paul Boutros, Robert Bristow, Theodorus van der Kwast. Prognostic significance of copy number alteration burden in unfavorable intermediate-risk prostate cancers harboring intraductal carcinoma and cribriform architecture. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4339.