A B S T R A C T PurposeMost patients with hepatocellular carcinoma (HCC) have associated chronic liver disease, the severity of which is currently assessed by the Child-Pugh (C-P) grade. In this international collaboration, we identify objective measures of liver function/dysfunction that independently influence survival in patients with HCC and then combine these into a model that could be compared with the conventional C-P grade. Patients and MethodsWe developed a simple model to assess liver function, based on 1,313 patients with HCC of all stages from Japan, that involved only serum bilirubin and albumin levels. We then tested the model using similar cohorts from other geographical regions (n ϭ 5,097) and other clinical situations (patients undergoing resection [n ϭ 525] or sorafenib treatment for advanced HCC [n ϭ 1,132]). The specificity of the model for liver (dys)function was tested in patients with chronic liver disease but without HCC (n ϭ 501). ResultsThe model, the Albumin-Bilirubin (ALBI) grade, performed at least as well as the C-P grade in all geographic regions. The majority of patients with HCC had C-P grade A disease at presentation, and within this C-P grade, ALBI revealed two classes with clearly different prognoses. Its utility in patients with chronic liver disease alone supported the contention that the ALBI grade was indeed an index of liver (dys)function. ConclusionThe ALBI grade offers a simple, evidence-based, objective, and discriminatory method of assessing liver function in HCC that has been extensively tested in an international setting. This new model eliminates the need for subjective variables such as ascites and encephalopathy, a requirement in the conventional C-P grade.

The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (T-PLL), and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. IntroductionThe Ataxia Telangiectasia Mutated (ATM) tumor suppressor gene encodes a principal DNA damage-signaling protein, and cells with ATM dysfunction exhibit increased radiosensitivity, loss of cellcycle checkpoints, and p53 dysfunction. [1][2][3][4][5] In addition to the impaired apoptotic response, the cellular phenotype of these cells can be attributed to subtle but significant defects in both major types of DNA double strand break (DSB) repair: error-prone non-homologous end joining (NHEJ), preferentially employed in the gap 1 (G1) phase of the cell cycle, and error-free homologous recombination (HR) repair, restricted to synthesis/gap 2/mitosis (S/G2/M) phases of the cell cycle. 6-11 After DNA damage, ATM mutant cells consequently exhibit prolonged DNA DSBs and abnormal retention of DNA proteins at the sites of DNA DSB observed as intra-nuclear foci. [6][7][8][9][10][11] Inactivation of ATM is a frequent event in lymphoid malignancies such as B-cell chronic lymphocytic leukemia (CLL), [12][13][14] T-prolymphocytic leukemia (T-PLL) 15,16 and mantle cell leukemia (MCL). 17 CLL is the most common leukemia in western countries. While many patients do not require therapeutic intervention, those with progressive CLL have a poor overall outcome, and survival is greatly impaired by the presence of genetic abnormalities such as 11q deletions/ATM mutations and 17p deletions/TP53 mutations. [18][19][20][21][22][23] The less-frequent malignancies, T-PLL and MCL, also commonly harbor 11q deletions and ATM mutations, 15-17 which may contribute to their dismal clinical responses. Progressive lymphoid malignancies are currently treated with combinations of nucleoside analogues and alkylating agents, which typically exert their effect through the generation of DNA damage and subsequent induction of an ATM/p53-dependent apoptotic pathway. 24 Consistent with this mechanism, ATM mutant CLL cells exhibit resistance to fludarabine-induced apoptosis in vitro. 21 The adverse impact of ATM inactivation on clinical responses of this subtype to current therapies may be evident at several levels: The presence of pathogenic ATM mutations causes rapid clonal expansion of 11qdel subclones 21 and significantly reduces overall survival 21 as well as progression-free survival in patients treated in the United Kingdom CLL4 trial (A.S., V.W., D.O., G.P., A.M.R.T., T.S., manuscript in preparation). Recent developments in front-line regimens by the addition of rituximab to fludarabine and cyclophosphamide (FCR) and second-line alemtuzumab and flavopiridol [22][23][24][25][26][27] has resulted in some clinical benefits for 11q del CLL 24 as well as other progressive lymphomas. 26,27 Despite these improvements, immunosuppression and toxicity ...

CLL with 11q deletion can be divided into two subgroups based on the integrity of the residual ATM allele. Patients with complete loss of ATM function, due to biallelic ATM defects, have defective responses to cytotoxic chemotherapeutics in vitro and a poorer clinical outcome. ATM mutant subclones can develop during an individual's disease course and give rise to additional expansion of the 11q deleted subclone.