Both prostacyclin analogs and phosphodiesterase 5 (PDE5) inhibitors are effective treatments for pulmonary arterial hypertension (PAH). In addition to direct effects on vascular smooth muscle, prostacyclin analogs increase cAMP levels and ATP release from healthy human erythrocytes. We hypothesized that UT-15C, an orally available form of the prostacyclin analog, treprostinil, would stimulate ATP release from erythrocytes of humans with PAH and that this release would be augmented by PDE5 inhibitors. Erythrocytes were isolated and the effect of UT-15C on cAMP levels and ATP release were measured in the presence and absence of the PDE5 inhibitors, zaprinast or tadalafil. In addition, the ability of a soluble guanylyl cyclase inhibitor to prevent the effects of tadalafil was determined. Erythrocytes of healthy humans and humans with PAH respond to UT-15C with increases in cAMP levels and ATP release. In both groups, UT-15C-induced ATP release was potentiated by zaprinast and tadalafil. The effect of tadalafil was prevented by pre-treatment with an inhibitor of soluble guanylyl cyclase in healthy human erythrocytes. Importantly, UT-15C-induced ATP release was greater in PAH erythrocytes than in healthy human erythrocytes in both the presence and the absence of PDE5 inhibitors. The finding that prostacyclin analogs and PDE5 inhibitors work synergistically to enhance release of the potent vasodilator ATP from PAH erythrocytes provides a new rationale for the co-administration of these drugs in this disease. Moreover, these results suggest that the erythrocyte is a novel target for future drug development for the treatment of PAH.

Background The shortage in intensivist workforce has been long recognized but no solution has been identified. Meanwhile, fellowships in pulmonary and critical care medicine (PCCM) are expanding, other critical care medicine (CCM) programs are contracting. No explanation exists for this contradictory trend, although understanding contributory factors may lead to a solution for the shortage. The fundamental difference between PCCM and other CCM programs lies in the residency training of trainees. We tested the hypothesis that the nature of CCM practice determines its attractiveness to potential candidates. Methods A questionnaire‐based survey was administered recording all daily activities in four different kinds of ICUs at two teaching hospitals one was public, and one was private. Activities were categorized into conventional CCM, respiratory, medical, and surgical interventions. Results The average daily census was 17.6 ± 6.6. Across two MICU, one trauma/surgical and one cardiothoracic ICU the average daily activity ranged from 152 to 203 of these CCM formed 27%‐36%, respiratory 10%‐13%, medical 43%‐59%, and surgical 1%‐15%. The combination of medical and respiratory interventions represented >50% of daily activities among all the ICUs. Conclusions Quantitative description of ICU activities indicates that the majority of the ICU daily practice relies on medical and respiratory interventions, which may explain why PCCM remains popular.

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4157 Introduction: We initiated an aggressive treatment protocol for newly diagnosed and relapsed follicular lymphoma in March 2006. This is an IRB approved prospective study registered at clinicaltrials.gov as NCT01130194, which sequentially utilizes three treatment modalities: immunochemotherapy, radioimmunotherapy, and autologous transplantation, in an effort to cure the disease. We report preliminary results of the first twenty patients. Methods: Patients' whose diagnosis of follicular lymphoma was confirmed by our hematopathologists in accordance with the 2008 World Health Organization criteria signed informed consent, and were enrolled in our study. Patients must have had an indication for treatment, stage II-IV disease, any grade, ECOG performance status of 0–1, and adequate organ function to participate. PET/CT has been the standard response tool for follicular lymphoma at our institution since study initiation, and responses were assessed by Cheson criteria. Treatment consisted of six cycles of C-MOPP-R every 28 days: cyclophosphamide 650mg/m2 IV day 1 and 8, vincristine 1.4mg/m2 IV day 1 and 8, procarbazine 100mg/m2 PO daily day 1–14, prednisone 40mg/m2 PO daily day 1–14, rituximab 375mg/m2 IV day 1 and 8, and pegylated filgrastim 6mg SC day 9. Prophylaxis consisted of a quinolone, TMP-SMX, acyclovir, and fluconazole. Chemotherapy alterations were made at the discretion of the treating physician. Mobilization and collection of hematopoietic stem cells with growth factor was performed in patients with documented response and no residual bone marrow disease after four to six cycles of C-MOPP-R. After completion of C-MOPP-R and recovery of ANC >1000 cells/mcL and platelets to 100K, patients received ibritumomab tiuxetan at standard dosing. Upon second recovery, patients were admitted for BEAM(C) conditioned autologous transplant. Results: See Table 1 for baseline characteristics. 45% (n=9) of patients received all 3 modalities, 35% (n=7) received C-MOPP-R + radioimmunotherapy, and 20% (n=4) received C-MOPP-R only. The ORR (CR+PR) was 95% (n=19, CR n=18, PR n=1). All responses occurred during C-MOPP-R therapy. The lone non-responder had progressive disease after two cycles of C-MOPP-R. With a median follow-up of 27 months (range 7–54 months), the median event-free survival and overall survival for all 20 patients has not yet been reached. See Figures 1 and 2 for EFS and OS, respectively. See Table 2 for toxicity rates during the treatment. Thirty-five percent of patients required a dose reduction or discontinuation of vincristine for peripheral neuropathy. In addition to our lone non-responder, two patients on protocol have died; one of pulmonary hemorrhage thought to be related to BEAC conditioning, and one due to pulmonary embolism and sepsis. One patient received 2 cycles of C-MOPP-R, refused further therapy, relapsed, and is still alive. The main reason for not completing protocol therapy was insurance denial of ibritumomab tiuxetan or autologous transplantation. Conclusion: Based on our interim analysis of this prospective, ongoing study we propose this therapeutic protocol is an effective and feasible regimen with the possibility of cure for patients with follicular lymphoma. Response rates with C-MOPP-R are excellent and overall, the treatment protocol is well tolerated. Further updates of this cohort and ongoing prospective enrollment on this protocol will help clarify the ultimate role of aggressive therapy in upfront and relapsed follicular lymphoma. Disclosures: Fesler: Spectrum Pharmaceuticals: Research Funding. Off Label Use: Ibritumomab tiuxetan was utilized off-label for some patients on this study prior to FDA approval in untreated patients. Procarbazine was utilized off-label for patients in this study in spite of proven efficacy as a single agent in non-Hodgkin lymphoma. Petruska:Spectrum Pharmaceuticals: Research Funding.