Cues associated with drug taking can trigger relapse, drug seeking, and craving in addicted individuals. Behavioral studies suggest that drug availability and withdrawal can affect the individual response to drug cues. Moreover, the importance of subjective craving in cue-induced relapse has been questioned and an alternative model put forward according to which drug cues trigger habitual drug-seeking behaviors independently of craving. We used functional magnetic resonance imaging to compare the brain response to smoking and control videotapes in 20 healthy smokers, while varying their expectancy to smoke and abstinence levels. The neural response to cigarette cues was strongly modulated by expectancy and, to a lesser extent, abstinence. In people expecting to smoke immediately after the scan, smoking cues activated brain areas implicated in arousal, attention, and cognitive control. However, when subjects knew they would not be allowed to smoke for 4 h, there was almost no brain activation in response to smoking cues, despite equivalent reported levels of craving. In the dorsolateral prefrontal cortex, the neural response was a function of both craving and expectancy. Thalamo-cingulate connectivity, thought to be an index of arousal, was greater during expectancy than nonexpectancy. Our findings confirm the importance of expectancy in the neural response to drug cues, and lend support to the theory that these cues act on brain areas involved in arousal and attention.

Purpose Chronic lymphocytic leukemia (CLL) with 17p deletion typically progresses quickly and is refractory to most conventional therapies. However, some del(17p) patients do not progress for years, suggesting that del(17p) is not the only driving event in CLL progression. We hypothesize that other concomitant genetic abnormalities underlie the clinical heterogeneity of del(17p) CLL. Experimental Design We profiled the somatic mutations and copy number alterations (CNA) in a large group of del(17p) CLL as well as wild type CLL and analyzed the genetic basis of their clinical heterogeneity. Results We found that increased somatic mutation number associates with poor overall survival independent of 17p deletion (p=0.003). TP53 mutation was present in 81% of del(17p) CLL, mostly clonal (82%), and clonal mutations with del17p exhibit shorter overall survival than subclonal mutations with del17p (p= 0.019). Del(17p) CLL has a unique driver mutation profile, including NOTCH1 (15%), RPS15 (12%), DDX3X (8%) and GPS2 (6%). We found that about half of del(17p) CLL cases have recurrent deletions at 3p, 4p, or 9p and that any of these deletions significantly predicts shorter overall survival. In addition, the number of CNAs, but not somatic mutations, predicts shorter time to treatment among patients untreated at sampling. Indolent del(17p) CLLs were characterized by absent or subclonal TP53 mutation and few CNAs, with no difference in somatic mutation number. Conclusions We conclude that del(17p) has a unique genomic profile and that clonal TP53 mutations, 3p, 4p or 9p deletions, and genomic complexity are associated with shorter overall survival.

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The B-cell receptor (BCR) pathway plays an important role in the survival, proliferation and trafficking of cancer cells in a variety of B-cell malignancies. Recently, a number of agents have been developed to target various components of the BCR pathway. One such target is Bruton's tyrosine kinase (BTK), a Tec family kinase member found near the cell membrane that is involved in upstream BCR signaling. The biological function of BTK in several B-cell lymphoid malignancies has led to the development of the oral BTK inhibitor ibrutinib. In chronic lymphocytic leukemia (CLL), ibrutinib has demonstrated durable clinical responses in relapsed/refractory (R/R) patients, including those with the high-risk del(17p) cytogenetic abnormality. These findings have paved the way for trials evaluating ibrutinib in previously untreated CLL patients, and also in combination with chemoimmunotherapy or other novel agents. Durable clinical responses have also been demonstrated in mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia (WM) patients treated with ibrutinib. Ibrutinib is generally well tolerated, although current follow-up remains short and patients of advanced age are more likely to discontinue treatment for toxicity. Treatment-specific side effects such as bleeding and atrial fibrillation may, at least partly, be related to off-target inhibition of non-BTK kinases. Studies evaluating other potential indications for BTK inhibition are ongoing, including in post-allogeneic hematopoietic stem cell transplant patients for whom ibrutinib may be effective in modulating graft-versus-host disease. Combination trials of ibrutinib with venetoclax, a Bcl-2 inhibitor, are underway and are supported by sound preclinical rationale. Several next-generation BTK inhibitors are under development with the goal of decreasing treatment-related toxicity and resistance.