Citations

Purpose To update the recommendations for the use of bisphosphonates in the prevention and treatment of bone disease in multiple myeloma. The Update Committee expanded the guideline to include a discussion of osteonecrosis of the jaw (ONJ). Methods For the 2007 update, an Update Committee composed of members from the full panel completed a review and analysis of data published since 2002. Searches of Medline and the Cochrane Collaboration Library databases were performed. Recommendations For multiple myeloma patients who have, on plain radiograph(s) or imaging studies, lytic destruction of bone or spine compression fracture from osteopenia, intravenous pamidronate 90 mg delivered over at least 2 hours or zoledronic acid 4 mg delivered over at least 15 minutes every 3 to 4 weeks is recommended. Clodronate is an alternative bisphosphonate approved worldwide, except in the United States, for oral or intravenous administration. New dosing guidelines for patients with pre-existing renal impairment were added to the zoledronic acid package insert. Although no similar dosing guidelines are available for pamidronate, the Update Committee recommends that clinicians consider reducing the initial pamidronate dose in patients with pre-existing renal impairment. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended in this setting. The Update Committee suggests that bisphosphonate treatment continue for a period of 2 years. At 2 years, physicians should seriously consider discontinuing bisphosphonates in patients with responsive or stable disease, but further use is at the discretion of the treating physician. The Update Committee also discusses measures regarding ONJ.

Abstract To better understand the molecular changes that occur in Waldenstrom macroglobulinemia (WM), we employed antibody-based protein microarrays to compare patterns of protein expression between untreated WM and normal bone marrow controls. Protein expression was defined as a >2-fold or 1.3-fold change in at least 67% of the tumor samples. Proteins up-regulated by >2-fold included Ras family proteins, such as Rab-4 and p62DOK, and Rho family proteins, such as CDC42GAP and ROKα. Other proteins up-regulated by >1.3-fold included cyclin-dependent kinases, apoptosis regulators, and histone deacetylases (HDAC). We then compared the samples of patients with symptomatic and asymptomatic WM and showed similar protein expression signatures, indicating that the dysregulation of signaling pathways occurs early in the disease course. Three proteins were different by >2-fold in symptomatic versus asymptomatic, including the heat shock protein HSP90. Elevated protein expression was confirmed by immunohistochemistry and immunoblotting. Functional significance was validated by the induction of apoptosis and inhibition of proliferation using specific HDAC and HSP90 inhibitors. This study, therefore, identifies, for the first time, multiple novel proteins that are dysregulated in WM, which both enhance our understanding of disease pathogenesis and represent targets of novel therapeutics. [Cancer Res 2007;67(8):3777–8]

Using the Minnesota Multiphasic Personality Inventory (MMPI), this study investigated preoperative and postoperative emotional and personality adjustment of temporal lobectomy patients from two major epilepsy surgery centers. Temporal lobectomy patients were included only if they were without evidence of lesional pathology on magnetic resonance imaging (MRI; other than evidence of mesial temporal sclerosis), were left-hemisphere language-dominant, and had Wide Range Achievement Test-Revised (WRAT-R) reading achievement standard scores of 70 or higher. The MMPI was completed by 175 patients before and after a temporal lobectomy. There were no significant preoperative differences on any MMPI scale between right temporal (n = 79) and left temporal (n = 96) lobectomy patients. Analysis of MMPI data from one of the surgical centers revealed significant effects for postoperative seizure control. Minimal effects of laterality of seizure onset on preoperative or postoperative psychological adjustment were found. Adequacy of preoperative psychological adjustment and postoperative seizure control have a greater impact on preoperative to postoperative psychological adjustment than side of seizure onset.

Highly informative yet simple protocols to assess insulin secretion and action would considerably enhance the quality of epidemiological and large-scale clinical trials. In an effort to develop such protocols, a 5-h, 11-sample oral glucose tolerance test (OGTT) was performed in 100 individuals and a 7-h, 21-sample meal in another 100. Plasma glucose, insulin, and C-peptide concentrations were measured. We show that virtually the same minimal model assessment of β-cell responsivity (dynamic [Φd] and static [Φs]), insulin sensitivity (Si), and disposition index (DI) can be obtained with a reduced seven-sample 2-h protocol: Φd, reduced versus full: 871.50 vs. 873.32, r = 0.98 in OGTT and 494.88 vs. 477.99 10−9, r = 0.91 in meal; Φs: 42.36 vs. 44.35, r = 0.88 in OGTT and 35.31 vs. 35.37 10−9 min−1, r = 0.90 in meal; Si: 24.33 vs. 22.77 10−5 dl · kg−1 · min−1 per pmol/l, r = 0.89 in OGTT and 19.03 vs. 19.77 10−5 dl · kg−1 · min−1 per pmol/l, r = 0.85 in meal; and DI: 1,282.26 vs. 1,273.23, r = 0.84 in OGTT and 726.92 vs. 776.97 10−14 dl · kg−1 · min−2 per pmol/l, r = 0.84 in meal. This reduced protocol will facilitate the study of insulin secretion and action under physiological conditions in nondiabetic humans.

Abstract Gastric emptying of solids and liquids was measured in 12 dogs with and without corporal or antral gastrojejunostomy. Both types of stoma hastened the onset but did not alter the time from onset to complete emptying of 40 small plastic spheres. Corporal gastrojejunostomy slowed the emptying of 400 ml. of 154 mM NaCl but not of 500 mM glucose, whereas antral gastrojejunostomy slowed the emptying of both.

Objective: The five-factor model of personality was used to describe the correlates of smoking abstinence. Methods: Following treatment in the Mayo Clinic Nicotine Dependence Center, the six month abstinence status was determined by self-report. Sixteen months to 2.4 years following the initial treatment evaluation, and 10 months to 1.9 years after the abstinence status was determined, 475 patients were mailed a Neuroticism, Extraversion, Openness, Five-Factor Inventory questionnaire. Ninety-nine abstinent and 151 smoking patients returned a completed questionnaire. Results: Multivariate analysis showed that low scores on neuroticism and openness were associated with tobacco abstinence. In addition, high scores on neuroticism and low scores on agreeableness and conscientiousness were associated with predictors of poor outcome including greater number of cigarettes smoked per day, initiation of smoking prior to age 18, and a Fagerström Test for Nicotine Dependence score of ≥ 6. Conclusions: Personality characteristics as predictors of smoking abstinence following treatment warrant further investigation in prospective clinical trails. Treatment matching using personality profiling as a guide may be a valuable tool for improving abstinence rates following treatment for nicotine dependence.

AbstractWaldenström macroglobulinemia (WM) is an incurable lymphoplasmacytic lymphoma with limited options of therapy. Protein kinase Cβ (PKCβ) regulates cell survival and growth in many B-cell malignancies. In this study, we demonstrate up-regulation of PKCβ protein in WM using protein array techniques and immunohistochemistry. Enzastaurin, a PKCβ inhibitor, blocked PKCβ activity and induced a significant decrease of proliferation at 48 hours in WM cell lines (IC50, 2.5-10 μM). Similar effects were demonstrated in primary CD19+ WM cells, without cytotoxicity on peripheral blood mononuclear cells. In addition, enzastaurin overcame tumor cell growth induced by coculture of WM cells with bone marrow stromal cells. Enzastaurin induced dose-dependent apoptosis at 48 hours mediated via induction of caspase-3, caspase-8, caspase-9, and PARP cleavage. Enzastaurin inhibited Akt phosphorylation and Akt kinase activity, as well as downstream p-MARCKS and ribosomal p-S6. Furthermore, enzastaurin demonstrated additive cytotoxicity in combination with bortezomib, and synergistic cytotoxicity in combination with fludarabine. Finally, in an in vivo xenograft model of human WM, significant inhibition of tumor growth was observed in the enzastaurin-treated mice (P = .028). Our studies therefore show that enzastaurin has significant antitumor activity in WM both in vitro and in vivo, providing the framework for clinical trials to improve patient outcome in WM.

Abstract The aims of this study were to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials of bortezomib in multiple myeloma and to develop predictive classifiers of response and survival with bortezomib. Patients with relapsed myeloma enrolled in phase 2 and phase 3 clinical trials of bortezomib and consented to genomic analyses of pretreatment tumor samples. Bone marrow aspirates were subject to a negative-selection procedure to enrich for tumor cells, and these samples were used for gene expression profiling using DNA microarrays. Data quality and correlations with trial outcomes were assessed by multiple groups. Gene expression in this dataset was consistent with data published from a single-center study of newly diagnosed multiple myeloma. Response and survival classifiers were developed and shown to be significantly associated with outcome via testing on independent data. The survival classifier improved on the risk stratification provided by the International Staging System. Predictive models and biologic correlates of response show some specificity for bortezomib rather than dexamethasone. Informative gene expression data and genomic classifiers that predict clinical outcome can be derived from prospective clinical trials of new anticancer agents.