Citations

Purpose Romidepsin (depsipeptide or FK228) is a member of a new class of antineoplastic agents active in T-cell lymphoma, the histone deacetylase inhibitors. On the basis of observed responses in a phase I trial, a phase II trial of romidepsin in patients with T-cell lymphoma was initiated. Patients and Methods The initial cohort was limited to patients with cutaneous T-cell lymphoma (CTCL), or subtypes mycosis fungoides or Sézary syndrome, who had received no more than two prior cytotoxic regimens. There were no limits on other types of therapy. Subsequently, the protocol was expanded to enroll patients who had received more than two prior cytotoxic regimens. Results Twenty-seven patients were enrolled onto the first cohort, and a total of 71 patients are included in this analysis. These patients had undergone a median of four prior treatments, and 62 patients (87%) had advanced-stage disease (stage IIB, n = 15; stage III, n= 6; or stage IV, n = 41). Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Pharmacokinetics were evaluated with the first administration of romidepsin. Complete responses were observed in four patients, and partial responses were observed in 20 patients for an overall response rate of 34% (95% CI, 23% to 46%). The median duration of response was 13.7 months. Conclusion The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable responses in patients with CTCL.

We compared measures of ID coronary atherosclerosis between diabetic and non-diabetic patients enrolled in a prospective multinational IVUS registry. The region of interest was the most diseased 10 mm segment of a single coronary artery. Coronary plaque was quantified using greyscale IVUS and further classified by phenotype (ID-adaptive intimal thickening, ID-pathological intimal thickening, ID-TCFA, ID-fibroatheroma, or ID-fibrocalcific) using VH-IVUS. There was a non-significant trend for greater total plaque volume in diabetic (n=191) compared with non-diabetic (n=584) patients (94.8 vs. 88.1 mm 3 , p=0.36, adjusted for multiple comparisons). There was a greater proportion of ID-TCFA among diabetic patients (21.6 vs. 13.6%, p=0.01 after adjustment for multiple comparisons; p=0.08 following multivariable adjustment for age and clinical demographics), while differences in pathological intimal thickening, fibroatheroma and fibrocalcific plaque were not significant between groups. ID-TCFA was more common in the most diseased 10 mm segment of diabetic than in non-diabetic coronary arteries. Multivariable adjustment demonstrated age and possibly the presence of diabetes to be independent predictors of ID-TCFA.

Abstract Our preclinical and clinical trials using a replication-defective adenoviral vector expressing IFN-β have shown promising results for the treatment of malignant mesothelioma. Based on the hypotheses that a replication-competent vesicular stomatitis virus (VSV) oncolytic vector would transduce more tumor cells in vivo, that coexpression of the immunostimulatory IFN-β gene would enhance the immune-based effector mechanisms associated both with regression of mesotheliomas and with VSV-mediated virotherapy, and that virus-derived IFN-β would add further safety to the VSV platform, we tested the use of IFN-β as a therapeutic transgene expressed from VSV as a novel treatment for mesothelioma. VSV-IFN-β showed significant therapy against AB12 murine mesotheliomas in the context of both local and locoregional viral delivery. Biologically active IFN-β expressed from VSV added significantly to therapy compared with VSV alone, dependent in part on host CD8+ T-cell responses. Immune monitoring suggested that these antitumor T-cell responses may be due to a generalized T-cell activation rather than the priming of tumor antigen–specific T-cell responses. Finally, IFN-β also added considerable extra safety to the virus by providing protection from off-target viral replication in nontumor tissues and protected severe combined immunodeficient mice from developing lethal neurotoxicity. The enhanced therapeutic index provided by the addition of IFN-β to VSV therefore provides a powerful justification for the development of this virus for future clinical trials. [Cancer Res 2009;69(19):7713–20]

Abstract Multiple genome-wide association studies have identified several susceptibility variants for colon cancer at 8q24. However, the functional roles of these variants have yet to be elucidated. Here, we evaluated the potential role of these markers in tumor progression and examined association with commonly observed structural abnormalities in this region, c-MYC amplification and chromosome fragility at FRA8C and FRA8D. We first replicated the previously reported association by testing 1,178 cases and 1,009 clinic-based controls with eight markers localized to three specific regions at 8q24. We observed significant associations with colon cancer risk with markers rs13254738 (ordinal odds ratio, 0.82; 95% confidence interval, 0.072-0.94; Ptrend = 0.0037) and rs6983267 (ordinal odds ratio, 1.17; 95% confidence interval, 1.03-1.32, Ptrend = 0.013). Survival analysis was done using a separate set of 460 cases to evaluate the clinical significance of these markers. Overall, univariate analysis did not detect survival differences for any of the markers. We also tested a subset of the 460 cases (n = 380) for structural abnormalities at or near the c-MYC locus using fluorescence in situ hybridization analysis. Furthermore, we evaluated a small number of cases homozygous for the rs6983267 alleles to test for differences in fragile site induction. None of the 8q markers correlated with amplification at the c-MYC locus as detected by fluorescence in situ hybridization, and no clear pattern of breakage was observed at the FRA8C and FRA8D sites. In this study, we confirm the association for several single nucleotide polymorphisms at 8q24 in colon cancer but have not detected any structural role relating to c-MYC amplification or chromosomal fragility. Finally, these risk alleles do not seem to be associated with survival. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2492–500)

OBJECTIVE The negative results of two randomized controlled trials (RCTs) have challenged current guideline recommendations for using aspirin for primary prevention of cardiovascular events among patients with diabetes. We therefore sought to determine if the effect of aspirin for primary prevention of cardiovascular events and mortality differs between patients with and without diabetes. RESEARCH DESIGN AND METHODS We conducted a systematic search of MEDLINE, EMBASE, Cochrane Library, Web of Science, and Scopus since their inceptions until November 2008 for RCTs of aspirin for primary prevention of cardiovascular events. Blinded pairs of reviewers evaluated studies and extracted data. Random-effects meta-analysis and Bayesian logistic regression were used to estimate the ratios of relative risks (RRs) of outcomes of interest among patients with and without diabetes. A 95% CI that crosses 1.00 indicates that the effect of aspirin does not differ between patients with and without diabetes. RESULTS Nine RCTs with moderate to high methodological quality contributed data to the analyses. The ratios of RRs comparing the benefit of aspirin among patients with diabetes compared with patients without diabetes for mortality, myocardial infarction, and ischemic stroke were 1.12 (95% CI 0.92–1.35), 1.19 (0.82–1.17), and 0.70 (0.25–1.97), respectively. CONCLUSIONS Whereas estimates of benefit among patients with diabetes remain imprecise, our analysis suggests that the relative benefit of aspirin is similar in patients with and without diabetes.

Objective:This guideline provides evidence‐based recommendations on managing hoarseness (dysphonia), defined as a disorder characterized by altered vocal quality, pitch, loudness, or vocal effort that impairs communication or reduces voice‐related quality of life (QOL). Hoarseness affects nearly one‐third of the population at some point in their lives. This guideline applies to all age groups evaluated in a setting where hoarseness would be identified or managed. It is intended for all clinicians who are likely to diagnose and manage patients with hoarseness.Purpose:The primary purpose of this guideline is to improve diagnostic accuracy for hoarseness (dysphonia), reduce inappropriate antibiotic use, reduce inappropriate steroid use, reduce inappropriate use of anti‐reflux medications, reduce inappropriate use of radiographic imaging, and promote appropriate use of laryngoscopy, voice therapy, and surgery. In creating this guideline the American Academy of Otolaryngology—Head and Neck Surgery Foundation selected a panel representing the fields of neurology, speech‐language pathology, professional voice teaching, family medicine, pulmonology, geriatric medicine, nursing, internal medicine, otolaryngology–head and neck surgery, pediatrics, and consumers.ResultsThe panel made strong recommendations that 1) the clinician should not routinely prescribe antibiotics to treat hoarseness and 2) the clinician should advocate voice therapy for patients diagnosed with hoarseness that reduces voice‐related QOL. The panel made recommendations that 1) the clinician should diagnose hoarseness (dysphonia) in a patient with altered voice quality, pitch, loudness, or vocal effort that impairs communication or reduces voice‐related QOL; 2) the clinician should assess the patient with hoarseness by history and/or physical examination for factors that modify management, such as one or more of the following: recent surgical procedures involving the neck or affecting the recurrent laryngeal nerve, recent endotracheal intubation, radiation treatment to the neck, a history of tobacco abuse, and occupation as a singer or vocal performer; 3) the clinician should visualize the patient's larynx, or refer the patient to a clinician who can visualize the larynx, when hoarseness fails to resolve by a maximum of three months after onset, or irrespective of duration if a serious underlying cause is suspected; 4) the clinician should not obtain computed tomography or magnetic resonance imaging of the patient with a primary complaint of hoarseness prior to visualizing the larynx; 5) the clinician should not prescribe anti‐reflux medications for patients with hoarseness without signs or symptoms of gastroesophageal reflux disease; 6) the clinician should not routinely prescribe oral corticosteroids to treat hoarseness; 7) the clinician should visualize the larynx before prescribing voice therapy and document/communicate the results to the speech‐language pathologist; and 8) the clinician should prescribe, or refer the patient to a clinician who can prescribe, botulinum toxin injections for the treatment of hoarseness caused by adductor spasmodic dysphonia. The panel offered as options that 1) the clinician may perform laryngoscopy at any time in a patient with hoarseness, or may refer the patient to a clinician who can visualize the larynx; 2) the clinician may prescribe anti‐reflux medication for patients with hoarseness and signs of chronic laryngitis; and 3) the clinician may educate/counsel patients with hoarseness about control/preventive measures.Disclaimer:This clinical practice guideline is not intended as a sole source of guidance in managing hoarseness (dysphonia). Rather, it is designed to assist clinicians by providing an evidence‐based framework for decision‐making strategies. The guideline is not intended to replace clinical judgment or establish a protocol for all individuals with this condition, and may not provide the only appropriate approach to diagnosing and managing this problem.

AbstractPurpose: This study aimed to evaluate the safety of, immune response induced by, and efficacy of treatment with lapuleucel-T (APC8024) in patients with HER-2/neu–expressing tumors. Lapuleucel-T is an investigational active immunotherapy product consisting of autologous peripheral blood mononuclear cells, including antigen presenting cells, which are cultured ex vivo with BA7072, a recombinant fusion antigen consisting of portions of the intracellular and extracellular regions of HER-2/neu linked to granulocyte-macrophage colony-stimulating factor.Experimental Design: Patients with metastatic breast, ovarian, or colorectal cancer whose tumors expressed HER-2 were eligible. Patients underwent leukapheresis in week 0 and received lapuleucel-T infusions in weeks 0, 2, and 4. Patients who achieved a partial response or had stable disease through week 48 were eligible for re-treatment using the same protocol and dose as their initial treatment.Results: Eighteen patients were enrolled and treated. Patients showed an immune response to the immunizing antigen (BA7072) at week 8 compared with week 0 as measured by T lymphocyte proliferation and IFN-γ enzyme-linked immunospot assay. Therapy was well tolerated. The majority (94.7%) of adverse events associated with treatment were grade 1 or 2. Two patients experienced stable disease lasting >48 weeks.Conclusions: Autologous active cellular immunotherapy with lapuleucel-T stimulated an immune response specific to the immunizing antigen and seemed to be well tolerated. Further clinical studies to assess the clinical benefit for patients with HER/2-neu–expressing breast, ovarian, and colorectal cancer are warranted. (Clin Cancer Res 2009;15(18):5937–44)