Impact of Acute Exacerbation of Idiopathic Pulmonary Fibrosis on Lung Transplant Outcomes.

BACKGROUND: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are acute, significant respiratory deteriorations in patients with IPF and can lead to increased morbidity and mortality. It remains unclear how AE-IPF impacts lung transplant (LTX) outcomes. METHODS: All adult patients who were listed for LTX between July 2005 and October 2020 at the Loyola University Medical Center with a diagnosis of IPF were included. Pretransplant characteristics and posttransplant outcomes were gathered via retrospective chart review. The primary outcome was short- and long-term survival for patients transplanted during stable IPF versus those with AE-IPF. RESULTS: One hundred fifty-nine patients were included in this study, 17.6% of whom were transplanted during AE-IPF. AE-IPF patients were more likely to have higher oxygen needs pretransplant, have higher lung allocation score, and were more likely to be intubated or be on extracorporeal membrane oxygenation as compared with stable IPF patients. Survival by AE status at transplant did not differ at 90 d or 1 y posttransplantation. There were also no significant differences in rates of severe primary graft dysfunction or acute rejection within 1 y. CONCLUSIONS: Patients with AE-IPF were more likely to have higher oxygenation requirements and higher lung allocation score at the time of LTX than those with stable IPF. Despite this, there were no differences in survival at 90 d, 1 y, or 3 y, or differences in incidence of severe primary graft dysfunction or acute cellular rejection. Transplantation of patients with AE-IPF has clinical outcomes comparable with transplantation of patients with stable IPF. This contrasts with previous studies examining LTX in patients with AE-IPF.

Assessment of CBCT-based synthetic CT generation accuracy for adaptive radiotherapy planning.

PURPOSE: Cone-beam CT (CBCT)-based synthetic CT (sCT) dose calculation has the potential to make the adaptive radiotherapy (ART) pathway more efficient while removing subjectivity. This study assessed four sCT generation methods using 15 head-and-neck rescanned ART patients. Each patient's planning CT (pCT), rescan CT (rCT), and CBCT post-rCT was acquired with the CBCT deformably registered to the rCT (dCBCT). METHODS: The four methods investigated were as follows: method 1-deformably registering the pCT to the dCBCT. Method 2-assigning six mass density values to the dCBCT. Method 3-iteratively removing artifacts and correcting the dCBCT Hounsfield units (HU). Method 4-using a cycle general adversarial network machine learning model (trained with 45 paired pCT and CBCT). Treatment plans were created on the rCT and recalculated on each sCT. Planning target volume (PTV) and organ-at-risk (OAR) structures were contoured by clinicians on the rCT (high-dose PTV, low-dose PTV, spinal canal, larynx, brainstem, and parotids) to allow the assessment of dose-volume histogram statistics at clinically relevant points. RESULTS: The HU mean absolute error (MAE) and minimum dose gamma index pass rate (2%/2 mm) were calculated, and the generation time was measured for 15 patients using the rCT as the comparator. For methods 1-4 the MAE, gamma index analysis, and generation time were as follows: 59.7 HU, 100.0%, and 143 s; 164.2 HU, 95.2%, and 232 s; 75.7 HU, 99.9%, and 153 s; and 79.4 HU, 99.8%, and 112 s, respectively. Dose differences for PTVs and OARs were all <0.3 Gy except for method 2 (<0.5 Gy). CONCLUSION: All methods were considered clinically viable. The machine learning method was found to be most suitable for clinical implementation due to its high dosimetric accuracy and short generation time. Further investigation is required for larger anatomical changes between the CBCT and pCT and for other anatomical sites.

Preclinical evaluation of an anti-alpha5beta1 integrin antibody as a novel anti-angiogenic agent.

Integrin alpha5beta1, the principal fibronectin receptor, is an important survival factor, playing a key role in angiogenesis. Angiogenesis is critical for tumor growth, and anti-angiogenic therapies have met clinical success. To validate the therapeutic potential of an anti-alpha5beta1 strategy, we generated volociximab (M200) a chimeric human IgG4 version of the alpha5beta1 function-blocking murine antibody IIA1; and F200, the Fab derivative. Volociximab, F200 and IIA1 showed similar activity by ELISA (EC50= 0.2nM), Biacore (Kd= 0.1-0.4nM) and inhibition of fibronectin binding (IC50= 2-3nM). The inhibitory potential of alpha5beta1 antibodies was compared to HuMV833, an anti-VEGF antibody. Both volociximab and HuMV833 inhibited HUVEC proliferation (IC50 of volociximab = 0.2-0.5nM; IC50 of HuMV833 = 45nM). However, IIA1, volociximab and F200 were also potent inhibitors of an in vitro model of angiogenesis (HUVEC tube formation assay), unlike HuMV833. Additionally, volociximab inhibited in vitro tube formation induced by VEGF and/or bFGF, suggesting a mechanism of action independent of growth factor stimulus. In fact, inhibition of alpha5beta1 function by volociximab induced apoptosis of actively proliferating, but not resting, endothelial cells. Volociximab does not cross-react with rodent alpha5beta1, therefore in vivo validation of an anti-alpha5beta1 approach was conducted in a cynomolgus model of choroidal revascularization. Volociximab and F200 were potent inhibitors of neovessel formation in this model. These data demonstrate that volociximab has therapeutic potential in diseases in which new vessel formation is a component of the pathology.