Citations

The mucin MUC1 is typically aberrantly glycosylated by epithelial cancer cells manifested by truncated O -linked saccharides. The resultant glycopeptide epitopes can bind cell surface major histocompatibility complex (MHC) molecules and are susceptible to recognition by cytotoxic T lymphocytes (CTLs), whereas aberrantly glycosylated MUC1 protein on the tumor cell surface can be bound by antibodies to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Efforts to elicit CTLs and IgG antibodies against cancer-expressed MUC1 have not been successful when nonglycosylated MUC1 sequences were used for vaccination, probably due to conformational dissimilarities. Immunizations with densely glycosylated MUC1 peptides have also been ineffective due to impaired susceptibility to antigen processing. Given the challenges to immuno-target tumor-associated MUC1, we have identified the minimum requirements to consistently induce CTLs and ADCC-mediating antibodies specific for the tumor form of MUC1 resulting in a therapeutic response in a mouse model of mammary cancer. The vaccine is composed of the immunoadjuvant Pam 3 CysSK 4 , a peptide T helper epitope and an aberrantly glycosylated MUC1 peptide. Covalent linkage of the three components was essential for maximum efficacy. The vaccine produced CTLs, which recognized both glycosylated and nonglycosylated peptides, whereas a similar nonglycosylated vaccine gave CTLs which recognized only nonglycosylated peptide. Antibodies elicited by the glycosylated tripartite vaccine were significantly more lytic compared with the unglycosylated control. As a result, immunization with the glycosylated tripartite vaccine was superior in tumor prevention. Besides its own aptness as a clinical target, these studies of MUC1 are likely predictive of a covalent linking strategy applicable to many additional tumor-associated antigens.

Abstract:Post‐transplantation histoplasmosis may be acquired via inhalation, may result from endogenous reactivation, or may be derived from the allograft. The Histoplasma and Aspergillus enzyme‐linked immunoassays are increasingly being relied upon for rapid diagnosis of fungal infections, especially in immunocompromised patients. We describe 4 cases of solid organ transplant recipients who had histoplasmosis and a falsely positive Aspergillus galactomannan (GM) obtained from the serum or bronchoalveolar lavage (BAL) fluid. We also report our experience, testing for Histoplasma antigen (Ag) in specimens positive for Aspergillus GM. From January 2007 through December 2010, of 2432 unique patients who had positive Aspergillus GM tests, 514 (21%) were tested for Histoplasma Ag, and 27 were found to be positive. Most specimens that tested positive for both Aspergillus and Histoplasma were obtained by BAL. False‐positive tests for Aspergillus GM can occur in immunosuppressed patients who have histoplasmosis, and may obscure the correct diagnosis.

Abstract Background Accelerated recovery pathways may reduce length of hospital stay after surgery but there are few data on minimally invasive colorectal operations. Methods An enhanced recovery pathway (ERP) was instituted, including preoperative analgesia, limited intravenous fluids and opiates, and early feeding. Intrathecal analgesia was administered as needed, but epidural analgesia was not used. The first 66 patients subjected to the ERP were case-matched by surgeon, procedure and age (within 5 years) with patients treated previously in a fast-track pathway (FTP). Short-term and postoperative outcomes to 30 days were compared. Results Hospital stay was shorter with the ERP than the FTP: median (interquartile range, i.q.r.) 3 (2–3) versus 3 (3–5) days (P < 0·001). A 2-day hospital stay was achieved in 44 and 8 per cent of patients respectively (P < 0·001). Patients in the ERP had a shorter time to recovery of bowel function: median (i.q.r.) 1 (1–2) versus 2 (2–3) days (P < 0·001). Thirty-day complication rates were similar (32 per cent ERP, 27 per cent FTP; P = 0·570). Readmissions within 30 days were more common with ERP, but the difference was not statistically significant (10 versus 5 patients; P = 0·170). Total hospital stay for those readmitted was shorter in the ERP group (18 versus 23 days). Conclusion ERP decreased the length of hospital stay after minimally invasive colorectal surgery. Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Abstract We tested whether the association between bone mineral density (BMD) and coronary artery calcification (CAC) varies according to dyslipidemia in community-living individuals. Between 2002 and 2005, 305 women and 631 men (mean age of 64 years), who were not taking lipid-lowering medications or estrogen were assessed for spine BMD, CAC, and total (TC), HDL- and LDL-cholesterol and triglycerides. Participants were a random sample from the Multi-Ethnic Study of Atherosclerosis (MESA) without clinical cardiovascular disease. Spine BMD at the L3 vertebrate was performed by computer tomography (CT). CAC prevalence was measured by CT. The total cholesterol to HDL ratio (TC:HDL) ≥ 5.0 was used as the primary marker of hyperlipidemia. The association of BMD with CAC differed in women with TC:HDL < 5.0 versus higher (p-interaction = 0.01). In age- and race-adjusted models, among women with TC:HDL < 5.0, each SD (43.4 mg/cc) greater BMD was associated with a 25% lower prevalence of CAC (prevalence ratio [PR] 0.75, 95% confidence interval [CI] 0.63–0.89), whereas among women with higher TC:HDL, higher BMD was not significantly associated with CAC (PR 1.22, 95% CI 0.82–1.82). Results were similar using other definitions of hyperlipidemia. In contrast, no consistent association was observed between BMD and CAC in men, irrespective of the TC:HDL ratio (p interaction 0.54). The inverse association of BMD with CAC is stronger in women without dyslipidemia. These data argue against the hypothesis that dyslipidemia is the key factor responsible for the inverse association of BMD with atherosclerosis. © 2011 American Society for Bone and Mineral Research

Abstract Objective: The aim was to formulate practice guidelines for endocrine evaluation and treatment of pituitary incidentalomas. Consensus Process: Consensus was guided by systematic reviews of evidence and discussions through a series of conference calls and e-mails and one in-person meeting. Conclusions: We recommend that patients with a pituitary incidentaloma undergo a complete history and physical examination, laboratory evaluations screening for hormone hypersecretion and for hypopituitarism, and a visual field examination if the lesion abuts the optic nerves or chiasm. We recommend that patients with incidentalomas not meeting criteria for surgical removal be followed with clinical assessments, neuroimaging (magnetic resonance imaging at 6 months for macroincidentalomas, 1 yr for a microincidentaloma, and thereafter progressively less frequently if unchanged in size), visual field examinations for incidentalomas that abut or compress the optic nerve and chiasm (6 months and yearly), and endocrine testing for macroincidentalomas (6 months and yearly) after the initial evaluations. We recommend that patients with a pituitary incidentaloma be referred for surgery if they have a visual field deficit; signs of compression by the tumor leading to other visual abnormalities, such as ophthalmoplegia, or neurological compromise due to compression by the lesion; a lesion abutting the optic nerves or chiasm; pituitary apoplexy with visual disturbance; or if the incidentaloma is a hypersecreting tumor other than a prolactinoma.

Abstract Introduction Cytidine drugs, such as gemcitabine, undergo rapid, inactivating catabolism by cytidine deaminase (CD). 3,4,5,6-tetrahydrouridine (THU), a potent CD inhibitor, has been applied preclinically and clinically as a modulator of cytidine drug metabolism. However, p.o. THU is at most 20% bioavailable (Beumer et al.), which limits its preclinical evaluation and clinical use. Therefore, the more lipophilic prodrug triacetyl THU (taTHU) was developed. We characterized THU pharmacokinetics after administration of taTHU to mice. Methods Mice were dosed 150 mg/kg taTHU i.v. or p.o. Plasma and urine THU concentrations were quantitated with a validated LC-MS/MS assay. Plasma and urine pharmacokinetic parameters and p.o. bioavailability were calculated non-compartmentally and compartmentally. We assessed taTHU inhibition of metabolism of gemcitabine by recombinant CD. ResultsTHU parameterstaTHU i.v. 150 mg/kgtaTHU p.o. 150 mg/kgCmax (µg/mL)10611.8Tmax (min)560Half-life (min)235122AUC0-inf (mg/mL*min)7.553.36Vd/F (L/kg)4.495.26Cl/F (mL/min/kg)13.229.8F-THUi.v. (%)68.030.3% dose in 0-16 h urine405.6% dose in 0-24 h urine5512 THU, after 150 mg/kg taTHU i.v., had a 235 min terminal half-life and produced plasma THU concentrations >1 µg/mL, the concentration shown to inhibit CD, for 10 h. A multi-compartment model fit the data best. 150 mg/kg p.o. taTHU produced a concentration versus time profile with a plateau of approximately 10 µg/mL from 0.5-2 h, followed by a decline with a 122 min half-life. Approximately 68% of i.v. taTHU was converted to THU. Approximately 30% of p.o. taTHU reached the systemic circulation as THU. After i.v dosing, renal excretion accounted for 40-55% of the taTHU dose, 26-35% as THU and an additional 14-19% as acetylated forms of THU. After p.o. dosing, the renal excretion percentages were 6-12%, 5.2-11%, and 0.42-0.71%, respectively. taTHU did not inhibit recombinant CD. Conclusion The availability of THU after p.o. taTHU in mice is 30%, as compared to the 20% achieved after p.o. THU. Clinical studies are warranted to evaluate availability of THU from taTHU in humans. Support: N01-CM07106, N01-CM52202, P30-CA47904 from the NCI and P41-EB001978. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4549.

Purpose Nonhormonal pharmacologic interventions are recommended for the treatment of hot flashes in breast cancer survivors. Antidepressants and gabapentin have been shown to be both effective and well tolerated; however, it is not clear which is preferred. Patients and Methods This was a group-sequential, open-label, randomized, cross-over trial of 4 weeks of venlafaxine (37.5 mg daily for 7 days followed by 75 mg daily for 21 days) versus gabapentin (300 mg once per day for 3 days, then 300 mg twice per day for 3 days, then 300 mg three times per day for 22 days), with patient preference as the primary outcome. Postmenopausal women with at least 14 bothersome hot flashes per week for the prior month were eligible. A 2-week baseline period and a 2-week tapering/washout time was used before the first and second treatment periods, respectively. Diaries were used to measure hot flashes and potential toxicities throughout the study. Participants completed a preference questionnaire at the end of the study. A predefined Pocock stopping rule was applied. Patient preference and hot flash and toxicity outcomes were compared between treatments. Results Sixty-six patients were randomly assigned, 56 of whom provided a preference (eight dropped out and two had no preference); 18 (32%) preferred gabapentin and 38 (68%) preferred venlafaxine (P = .01). Both agents reduced hot flash scores to a similar extent (66% reduction). Venlafaxine was associated with increased nausea, appetite loss, constipation, and reduced negative mood changes compared with gabapentin, whereas gabapentin was associated with increased dizziness and appetite compared with venlafaxine (all P < .05). Conclusion Breast cancer survivors prefer venlafaxine over gabapentin for treating hot flashes.

Background— Health status is a key outcome for comparing treatments, particularly when mortality does not differ significantly. Methods and Results— Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) randomized 2368 patients with type 2 diabetes mellitus and stable ischemic heart disease to (1) prompt revascularization versus medical therapy and (2) insulin sensitization versus insulin provision. Randomization was stratified by the intended method of revascularization, coronary artery bypass graft surgery or percutaneous coronary intervention. The Duke Activity Status Index and RAND Energy, Health Distress, and Self-Rated Health scales were assessed at study entry and annually thereafter; linear mixed models were used to evaluate the effect of randomized treatment on these measures. Health status improved significantly from baseline to 1 year ( P <0.001) in each randomized treatment group. Compared with medical therapy, prompt revascularization was associated with significantly greater improvements in Duke Activity Status Index (1.32 points; P <0.001), Energy (1.36 points; P =0.02), and Self-rated Health (1.77 points; P =0.007) but not Health Distress (−0.47; P =0.46). These treatment effects were largely maintained over 4 years of follow-up. The effect of revascularization on the Duke Activity Status Index was significantly larger in the subgroup of patients intended for coronary artery bypass graft surgery compared with the subgroup intended for percutaneous coronary intervention. Health status did not differ significantly on any of the 4 measures between the insulin provision and insulin sensitization strategies. Conclusions— Prompt coronary revascularization was associated with small yet statistically significant improvements in health status compared with initial medical therapy among patients with diabetes mellitus and stable ischemic heart disease. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT00006305.