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As mortality in breast cancer patients has improved, morbidity of treatment has become increasingly important. Cognitive dysfunction has been considered as a morbid condition that may possibly result from aromatase inhibitor therapy, the standard treatment in postmenopausal, estrogen/progesterone receptor-positive breast cancer patients. Chemotherapy has been associated with cognitive dysfunction through neuropsychological testing and neurological functional imaging, but the relationship between estrogen and cognition remains largely unexplained. In focusing on aromatase inhibitor therapy, most of the studies yielding mixed results have been limited by confounders and small numbers of populations studied. This article briefly summarizes the major studies evaluating aromatase inhibitor therapy and cognitive dysfunction while considering new directions in future study design.

Bortezomib , the first proteasome inhibitor (PI) to be evaluated in humans, is approved in the USA and Europe for the treatment of patients with multiple myeloma, and in the USA for patients with relapsed mantle cell lymphoma (MCL).This review examines the role of bortezomib in the therapy of non-Hodgkin's lymphoma (NHL). Bortezomib may be particularly effective against the NF-κB-dependent activated B-cell subtype of diffuse large B-cell lymphoma. The combination of bortezomib with rituximab and dexamethasone represents a standard approach for the treatment of Waldenström's macroglobulinemia, and that with bendamustine and rituximab has demonstrated excellent efficacy in follicular lymphoma. Combinations with other novel agents, such as inhibitors of cyclin-dependent kinases or histone deacetylases, also hold substantial promise in NHL. Unmet needs in NHL, competitor compounds, chemistry, pharmacokinetics, pharmacodynamics and safety and tolerability of bortezomib are also discussed.The success of bortezomib in MCL has validated the proteasome as a therapeutic target in NHL. Rational combinations, for example, with Bruton's tyrosine kinase inhibitors or BH3-mimetics, may hold the key to optimizing the therapeutic potential of PIs in NHL. Future trials are likely to involve newer agents with improved pharmacodynamic (e.g., carfilzomib, marizomib) or pharmacokinetic (e.g., ixazomib, oprozomib) properties.

Donor T cell mediated graft vs. host effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the HLA in each donor-recipient pair (DRP) undergoing stem cell transplantation (SCT). Whole exome sequencing has demonstrated extensive nucleotide sequence variation in HLA-matched DRP. Non-synonymous single nucleotide polymorphisms (nsSNPs) in the GVH direction (polymorphisms present in recipient and absent in donor) were identified in 4 HLA-matched related and 5 unrelated DRP. The nucleotide sequence flanking each SNP was obtained utilizing the ANNOVAR software package. All possible nonameric-peptides encoded by the non-synonymous SNP were then interrogated in-silico for their likelihood to be presented by the HLA class I molecules in individual DRP, using the Immune-Epitope Database (IEDB) SMM algorithm. The IEDB-SMM algorithm predicted a median 18,396 peptides/DRP which bound HLA with an IC50 of, 235, Words: 6422, Figures: 7, Tables: 3, Supplementary figures: 2, Supplementary tables: 2

Although approved for over a decade, the clinical utility of proteasome inhibitors (PIs) remains largely restricted to the treatment of patients with multiple myeloma (MM) and mantle cell lymphoma (MCL). This has fueled interest in understanding mechanisms of resistance to their antineoplastic actions, leading to the development of new and improved PIs (e.g., carfilzomib, ixazomib, marizomib) and rational combinations with other novel classes of targeted agents. With respect to the latter, histone deacetylase inhibitors (HDACIs) represent one of the most extensively studied classes of agents. PIs and HDACIs interact at multiple levels to trigger synergistic cell killing in a variety of tumor types through multiple mechanisms, including induction of oxidative stress and DNA damage, PI-mediated inhibition of the cytoprotective NF-κB pathway activated by HDACIs, and promotion of proteotoxic stress through simultaneous proteasome inhibition and disruption of aggresome formation and chaperone proteins, leading to the accumulation of misfolded proteins. Clinically, this combination may be closest to regulatory approval in MM, but represents a promising avenue of investigation in MCL, a relatively uncommon but challenging disease that has been the focus of much recent attention given Food and Drug Administration approvals in 2013 for the immunomodulatory drug lenalidomide and the first-in-class Bruton’s tyrosine kinase inhibitor, ibrutinib. In this chapter, we discuss the mechanisms of action of and interactions between PIs and HDACIs with an MCL focus and review the relevant preclinical and clinical data.