Heart transplantation research in the next decade--a goal to achieving evidence-based outcomes: National Heart, Lung, And Blood Institute Working Group

The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group (WG) on August 5 to 6, 2010 in Bethesda, Maryland to discuss future directions of research in heart transplantation (HT). The WG was composed of researchers with expertise in the basic science, clinical science, and epidemiological aspects of advanced heart failure and HT. These experts were asked to identify the highest priority research gaps in the field and make recommendations for future research strategies. The WG was also asked to include approaches that capitalize on current scientific opportunities and focus on areas that required unique NHLBI leadership. Finally, the WG was charged with developing recommendations that would have short- and long-term impact on the field of HT. The WG participants reviewed key areas in HT and identified the most urgent knowledge gaps. These gaps were then organized into the following 4 specific research directions: 1) enhanced phenotypic characterization of the pre-transplant population; 2) donor-recipient optimization strategies; 3) individualized immunosuppression therapy; and, 4) investigations of immune and non-immune factors affecting late cardiac allograft outcomes. Finally, because the HT population is relatively small compared with other patient groups, the WG strongly urged concerted efforts to enroll every transplant recipient into a clinical study and to increase collaborative networks to optimize research in this field.     

Transsaccadic integration relies on a limited memory resource

Saccadic eye movements cause large-scale transformations of the image falling on the retina. Rather than starting visual processing anew after each saccade, the visual system combines post-saccadic information with visual input from before the saccade. Crucially, the relative contribution of each source of information is weighted according to its precision, consistent with principles of optimal integration. We reasoned that, if pre-saccadic input is maintained in a resource-limited store, such as visual working memory, its precision will depend on the number of items stored, as well as their attentional priority. Observers estimated the color of stimuli that changed imperceptibly during a saccade, and we examined where reports fell on the continuum between pre- and post-saccadic values. Bias toward the post-saccadic color increased with the set size of the pre-saccadic display, consistent with an increased weighting of the post-saccadic input as precision of the pre-saccadic representation declined. In a second experiment, we investigated if transsaccadic memory resources are preferentially allocated to attentionally prioritized items. An arrow cue indicated one pre-saccadic item as more likely to be chosen for report. As predicted, valid cues increased response precision and biased responses toward the pre-saccadic color. We conclude that transsaccadic integration relies on a limited memory resource that is flexibly distributed between pre-saccadic stimuli.     

Liver transplantation in the critically ill: donation after cardiac death compared to donation after brain death grafts

Patients with end stage liver disease may become critically ill prior to LT requiring admission to the intensive care unit (ICU). The high acuity patients may be thought too ill to transplant; however, often LT is the only therapeutic option. Choosing the correct liver allograft for these patients is often difficult and it is imperative that the allograft work immediately. Donation after cardiac death (DCD) donors provide an important source of livers, however, DCD graft allocation remains a controversial topic, in critically ill patients. Between January 2003-December 2008, 1215 LTs were performed: 85 patients at the time of LT were in the ICU. Twelve patients received DCD grafts and 73 received donation after brain dead (DBD) grafts. After retransplant cases and multiorgan transplants were excluded, 8 recipients of DCD grafts and 42 recipients of DBD grafts were included in this study. Post-transplant outcomes of DCD and DBD liver grafts were compared. While there were differences in graft and survival between DCD and DBD groups at 4 month and 1 year time points, the differences did not reach statistical significance. The graft and patient survival rates were similar among the groups at 3-year time point. There is need for other large liver transplant programs to report their outcomes using liver grafts from DCD and DBD donors. We believe that the experience of the surgical, medical and critical care team is important for successfully using DCD grafts for critically ill patients.     

Sequential mTOR inhibitor treatment with temsirolimus in metastatic renal cell carcinoma following failure of VEGF receptor tyrosine kinase inhibitors

Purpose

Agents targeting the mammalian target of rapamycin (mTOR) pathway, e. g. everolimus, can provide clinical benefit in pretreated patients with metastatic renal cell carcinoma (mRCC), but data from randomized trials on the sequential use of temsirolimus are lacking. We retrospectively studied the efficacy and safety of temsirolimus therapy following failure of rTKI therapy.

Methods

Twenty-nine patients treated with temsirolimus (25 mg/week) following progression on rTKI therapy were studied at four institutions. All patients had failed at least one prior rTKI therapy (sunitinib, n = 6; sorafenib, n = 1; both, n = 22). Over 80% had two or more prior therapies. Data on efficacy (response assessment, progression-free survival [PFS], overall survival [OS]) and safety (NCI-CTC) were analyzed.

Results

Adverse events occurred in 90% of patients with the majority being grade 1 (n = 4, 14%) or grade 2 (n = 12, 41%). Most grade 3/4 toxicities (n = 10, 34%) were manageable and included anemia (n = 4, 14%), leukopenia/neutropenia (n = 2, 7%), hyperglycemia (n = 1, 3%), acidosis/alkalosis (n = 2, 7%), and infection (n = 1, 3%). One patient discontinued temsirolimus for grade 3 pneumonitis. Median (range) PFS and OS were 5.1 months (1–10.4) and 18.0 months (12.6–23.3), respectively. Best response included partial response (n = 1) and stable disease (n = 15) for a disease control rate of 55%, and disease progression of 45% (n = 13).

Conclusions

Temsirolimus after rTKI failure appears to provide promising safety and efficacy comparable to other treatment options in pretreated patients with mRCC.