ABSTRACT
BACKGROUND: Mechanical circulatory support (MCS) with temporary, extracorporeal assist devices restores hemodynamics in patients with refractory cardiogenic shock. These devices are frequently used in community hospitals, with subsequent referral to tertiary care centers. We sought to determine the outcomes of such referrals and identify prognostic variables that may influence management decisions. METHODS: We performed a single-institution retrospective review of 59 consecutive patients transferred on temporary, extracorporeal MCS from 1997 to 2008. Demographics, medical history, laboratory data, and clinical status were obtained, with survival determined from the medical record and the Social Security Death Index. Univariable and multivariable analysis were performed and survival estimates were determined using the Kaplan-Meier method. RESULTS: Median age was 49.6 years (range, 14 to 77 years). Forty-five patients (76%) were supported for postcardiotomy failure, and 34 (58%) required biventricular support. Twenty-five (42%) survived to hospital discharge, 11 after cardiac recovery (44%), 9 with long-term implantable MCS devices (39%), and 5 after heart transplantation (22%). Eight patients discharged with implantable MCS devices underwent heart transplantation and 1 remains alive on long-term implantable MCS support. Survival was 42% +/- 6% at 1 year and 38% +/- 6% at 5 years. Age and renal function were independent predictors of death. CONCLUSIONS: Nearly half of all patients transferred on temporary extracorporeal MCS survive to discharge. Most of the long-term survivors received a heart transplant. Age and renal function were independent predictors of death, suggesting that survival is maximized by considering eligibility for cardiac transplantation.
Subject(s)
Heart-Assist Devices , Hospital Mortality , Patient Transfer/statistics & numerical data , Shock, Cardiogenic/mortality , Shock, Cardiogenic/surgery , Adolescent , Adult , Aged , Cohort Studies , Female , Heart Transplantation , Heart-Assist Devices/statistics & numerical data , Hospitals, University/statistics & numerical data , Humans , Kaplan-Meier Estimate , Male , Michigan , Middle Aged , Multivariate Analysis , Postoperative Complications/mortality , Postoperative Complications/surgery , Prognosis , Referral and Consultation/statistics & numerical data , Retrospective Studies , Shock, Cardiogenic/etiology , Survivors/statistics & numerical data , Young AdultABSTRACT
Flap endonuclease-1 (FEN1) is a key enzyme involved in base excision repair (BER), a primary pathway utilized by mammalian cells to repair DNA damage. Sensitization to DNA damaging agents is a potential method for the improvement of the therapeutic window of traditional chemotherapeutics. In this paper, we describe the identification and SAR of a series of low nanomolar FEN1 inhibitors. Over 1000-fold specificity was achieved against a related endonuclease, xeroderma pigmentosum G (XPG). Two compounds from this series significantly potentiate the action of methyl methanesulfonate (MMS) and temozolamide in a bladder cancer cell line (T24). To our knowledge, these are the most potent endonuclease inhibitors reported to date.
Subject(s)
Dacarbazine/analogs & derivatives , Enzyme Inhibitors/chemistry , Flap Endonucleases/antagonists & inhibitors , Urea/analogs & derivatives , Cell Line, Tumor , DNA Damage , Dacarbazine/chemistry , Enzyme Inhibitors/pharmacology , Humans , Methyl Methanesulfonate/chemistry , Structure-Activity Relationship , Temozolomide , Urea/pharmacology , Urinary Bladder Neoplasms , Xeroderma PigmentosumABSTRACT
There have been several recent reports of chemopotentiation via inhibition of DNA repair processes. Flap endonuclease 1 (FEN1) is a key enzyme involved in base excision repair (BER), a primary pathway utilized by mammalian cells to repair DNA damage. In this report, we describe the identification and SAR of a series of 2,4-diketobutyric acid FEN1 inhibitors.
