Citations

Abstract Positive interim positron emission tomography (PET) scans are thought to be associated with inferior outcomes in diffuse large B-cell lymphoma. In the E3404 diffuse large B-cell lymphoma study, PET scans at baseline and after 3 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone were centrally reviewed by a single reader. To determine the reproducibility of interim PET interpretation, an expert panel of 3 external nuclear medicine physicians visually scored baseline and interim PET scans independently and were blinded to clinical information. The binary Eastern Cooperative Oncology Group (ECOG) study criteria were based on modifications of the Harmonization Criteria; the London criteria were also applied. Of 38 interim scans, agreement was complete in 68% and 71% by ECOG and London criteria, respectively. The range of PET+ interim scans was 16% to 34% (P = not significant) by reviewer. Moderate consistency of reviews was observed: κ statistic = 0.445 using ECOG criteria, and κ statistic = 0.502 using London criteria. These data, showing only moderate reproducibility among nuclear medicine experts, indicate the need to standardize PET interpretation in research and practice. This trial was registered at www.clinicaltrials.gov as #NCT00274924.

Advances in extracorporeal life support have expanded indications for use extending beyond patients undergoing cardiac surgery. The approach to cannulation in patients requiring extracorporeal membrane oxygenation should be individualized and based on the specific clinical scenario in which the need arises. Adherence to proper techniques of vessel visualization, exposure, and cannulation along with accurate placement of cannulae will optimize flows and minimize complications in this setting. Patients in need of mechanical circulatory support require input from a multidisciplinary team approach with systematic clinical evaluation to optimize outcome. If hemodynamics do not initially permit the successful separation from mechanical support, then a systematic search for potentially reversible patient and/ or pump related factors should be undertaken. The success of this therapy is predicated on patient selection, a multidisciplinary team approach in the intensive care unit, adherence to precise technical principles, and repeated patient evaluation.

The technical evolution of extracorporeal membrane oxygenation (ECMO) coincides with the vast improvement in intensive care medicine of the past 4 decades. Extracorporeal circulatory technology substitutes for acutely failed cardiac or pulmonary function until these organs regain sustainable function through goal-oriented intensive care practice. The technology has been validated to improve survival in select patients who would otherwise have 100% mortality. This is by far the most complex life-sustaining technology employed and thus can contribute significant risks such that the decision to institute ECMO requires prompt risk and benefit analysis. Delaying the institution of ECMO may cause irreversible pulmonary and cardiac injuries in addition to other organs. Therefore, the optimal time of initiating ECMO support is crucial to the survival of a critically ill patient.

Though much has been surveyed and written about the equipment aspects of extracorporeal life support (ECLS) in the past 10 years, there is value in reviewing the use and nonuse of multiple safety devices and techniques. Minimally equipped ECLS circuits for adult and pediatric bridge to decision during cardiac and respiratory failure are rapidly gaining popularity to maintain simplicity and portability. ECLS circuits employed for long-term therapy are outfitted differently and should include more safety devices. The purpose of this review is to compare and contrast the spectrum of minimally equipped ECLS circuits to circuits with maximum flexibility and safety device protection. Due to the lack of high-level, well-controlled scientific studies regarding ECLS equipment and safety devices, this study reviews the basis for how we use ECLS circuits and devices in our institution to provide safe patient support.

Objective: To summarize the role of pharmacotherapy in the management of phenylketonuria (PKU) and to review the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and safety profile of sapropterin for this indication. Data Sources: A literature search was conducted using MEDLINE (1966–May 2009), International Pharmaceutical Abstracts (1970–May 2009), and Cochrane database (2008) for the following key words: sapropterin, tetrahydrobiopterin, phenylketonurias, and phenylalanine. Study Selection and Data Extraction: English-language studies involving humans examining the role of tetrahydrobiopterin (BH4) in the management of PKU were reviewed to evaluate the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and safety profile for sapropterin. All Phase 2 and 3 randomized controlled trials assessing the safety and efficacy of sapropterin were included in this literature evaluation. Data Synthesis: Sapropterin represents the only Food and Drug Administration–approved medication for BH4-responsive PKU, marking an important advance in the treatment of this condition. Among individuals with hyperphenylalaninemia and some residual phenylalanine hydroxylase function, sapropterin can enhance activity of this enzyme to decrease serum phenylalanine concentrations. Sapropterin has been compared with placebo in one Phase 2 and one Phase 3 clinical trial, demonstrating significantly better response rates. Based on available studies, this agent appears to be safe and well tolerated, with adverse event rates similar to those of placebo. However, additional studies are warranted to assess the long-term safety and efficacy of sapropterin therapy. Conclusions: Sapropterin offers a promising therapeutic option for select individuals with BH4-responsive PKU, although long-term data are limited evaluating its safety and efficacy in traditional clinical practice settings. When considering sapropterin therapy, clinicians must consider factors such as cost and patient adherence to drug therapy and/or diet.

Nuclear factor κB (NF-κB) is one of the main transcription factors involved in regulating apoptosis, inflammation, chronic liver disease, and cancer progression. The IKK complex mediates NF-κB activation and deletion of its regulatory subunit NEMO in hepatocytes (NEMOΔhepa) triggers chronic inflammation and spontaneous hepatocellular carcinoma development. We show that NEMOΔhepa mice were resistant to Fas-mediated apoptosis but hypersensitive to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as the result of a strong up-regulation of its receptor DR5 on hepatocytes. Additionally, natural killer (NK) cells, the main source of TRAIL, were activated in NEMOΔhepa livers. Interestingly, depletion of the NK1.1+ cells promoted a significant reduction of liver inflammation and an improvement of liver histology in NEMOΔhepa mice. Furthermore, hepatocyte-specific NEMO deletion strongly sensitized the liver to concanavalin A (ConA)–mediated injury. The critical role of the NK cell/TRAIL axis in NEMOΔhepa livers during ConA hepatitis was further confirmed by selective NK cell depletion and adoptive transfer of TRAIL-deficient−/− mononuclear cells. Our results uncover an essential mechanism of NEMO-mediated protection of the liver by preventing NK cell tissue damage via TRAIL/DR5 signaling. As this mechanism is important in human liver diseases, NEMOΔhepa mice are an interesting tool to give insight into liver pathophysiology and to develop future therapeutic strategies.

Abstract Data on long-term follow-up for definitive therapy of prostate cancer are limited, especially for radiation therapy. Either surgery or radiation was used in 322 patients for treatment with curative intent, and follow-up was for a minimum of 15 years. Overall survival was nearly identical to that in an age-matched cohort. 5-, 10-, and 15-year recurrence-free survival rates were 77%, 63% and 53%, respectively. Grade and stage were significant prognostic factors for both recurrence and survival. More than 60% of the initial failures were local, and more than 25% of the failures occurred after 10 years. Radiation therapy was used in 137 patients with clinically staged disease. Radical retropubic prostatectomy and perineal prostatectomy were performed in 133 and 44 patients, respectively. In this group, pathological staging was used. Survival rates for surgically treated patients were better than those in the cohort population. In conclusion, overall long-term follow-up demonstrates that definitive treatment does not have an adverse effect on survival from prostate cancer. Local recurrence is a frequent cause of failure. Caution must be used in interpreting any prostate study with less than 10 years of follow-up, because 25% to 50% of the failures occur after that time.

ABSTRACT Because of the bioterrorism threat posed by agents such as variola virus, considerable time, resources, and effort have been devoted to biodefense preparation. One avenue of this research has been the development of rapid, sensitive, high-throughput assays to validate immune responses to poxviruses. Here we describe the adaptation of a β-galactosidase reporter-based vaccinia virus neutralization assay to large-scale use in a study that included over 1,000 subjects. We also describe the statistical methods involved in analyzing the large quantity of data generated. The assay and its associated methods should prove useful tools in monitoring immune responses to next-generation smallpox vaccines, studying poxvirus immunity, and evaluating therapeutic agents such as vaccinia virus immune globulin.