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Abstract Background Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS). Methods FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied. Results There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (−7.6 points, P = 0.02) and mobility (−4.2, P = 0.02), the number of reported symptoms was associated with worse depression (−2.7 per symptom, P = 0.009) and anxiety (−2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (−2.8 per visit, P < 0.001) and fatigue (−2.4, P = 0.03). Multivariable analyses among adults found the number of reported symptoms was associated with worse function in all eight PROMIS measures and the number of ER visits was associated with worse fatigue, pain interference, sleep impairment, depression, anxiety and social satisfaction. Laboratory markers of disease severity (i.e. proteinuria, estimated glomerular filtration rate and serum albumin) did not predict PRO in multivariable analyses, with the single exception of complete remission and better pain interference scores among children (+9.3, P = 0.03). Conclusions PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.

Intrapulmonary arteriovenous anastomoses (IPAVA) are large diameter (>50 μm) vascular conduits, present in >95% of healthy humans. Because IPAVA are large diameter pathways that allow blood flow to bypass the pulmonary capillary network, blood flow through IPAVA (QIPAVA) can permit the transpulmonary passage of particles larger than pulmonary capillaries. IPAVA have been known to exist for over 50 years, but their physiological and clinical significance are still being established; although, currently suggested roles for QIPAVA include allowing emboli to reach the systemic circulation and providing a source of shunt. Studying QIPAVA is an important area of research and as the suggested roles become better established, detecting and quantifying QIPAVA may become significantly more important in the clinic. Several techniques that can be used to quantify and/or detect QIPAVA in animals, ex vivo human/animal lungs, and intact healthy humans; microspheres, radiolabeled macroaggregated albumin particles, and saline contrast echocardiography, are reviewed with limitations and advantages to each. The current body of literature using these techniques to study QIPAVA in animals, ex vivo lungs, and healthy humans has established conditions when QIPAVA is present, such as during exercise or with arterial hypoxemia and conditions when QIPAVA is absent, such as at rest or during exercise breathing 100% O2. Many of these physiological studies have direct application to patient populations and we discuss each of these findings in the context of their potential to influence the clinical utility, and interpretation, of the results from these techniques highlighted in this review.

Significance Long noncoding RNAs (lncRNAs) are involved in numerous biological roles including epigenetic regulation, apoptosis, and cell cycle. Whereas lncRNAs contribute to epigenetic gene regulation, metastasis, and prognosis in solid tumors, their role in acute myeloid leukemia (AML) has not been hitherto reported. Here, we show that lncRNA expression profiles are associated with recurrent mutations, clinical features, and outcome in AML. A fraction of these lncRNAs may have a functional role in leukemogenesis. Furthermore, lncRNAs could be used as biomarkers for outcome in AML. The identification of patients likely to achieve complete remission with standard therapy alone, based on lncRNA expression, is a significant advance potentially sparing such patients from other toxicities and focusing investigational approaches on postremission studies.

AbstractIntrapulmonary arteriovenous anastomoses (IPAVA) have been known to exist in human lungs for over 60 years. The majority of the work in this area has largely focused on characterizing the conditions in which IPAVA blood flow (IPAVA) is either increased, e.g. during exercise, acute normobaric hypoxia, and the intravenous infusion of catecholamines, or absent/decreased, e.g. at rest and in all conditions with alveolar hyperoxia ( = 1.0). Additionally, IPAVA is present in utero and shortly after birth, but is reduced in older (>50 years) adults during exercise and with alveolar hypoxia, suggesting potential developmental origins and an effect of age. The physiological and pathophysiological roles of IPAVA are only beginning to be understood and therefore these data remain controversial. Although evidence is accumulating in support of important roles in both health and disease, including associations with pulmonary arterial pressure, and adverse neurological sequelae, there is much work that remains to be done to fully understand the physiological and pathophysiological roles of IPAVA. The development of novel approaches to studying these pathways that can overcome the limitations of the currently employed techniques will greatly help to better quantify IPAVA and identify the consequences of IPAVA on physiological and pathophysiological processes. Nevertheless, based on currently published data, our proposed working model is that IPAVA occurs due to passive recruitment under conditions of exercise and supine body posture, but can be further modified by active redistribution of pulmonary blood flow under hypoxic and hyperoxic conditions.

PurposeThis multicenter, dose-escalation study evaluates the safety, pharmacokinetics, and efficacy of galiximab (anti-CD80 monoclonal antibody) in patients with relapsed or refractory follicular lymphoma.Patients and MethodsPatients had follicular lymphoma that had relapsed or failed to respond to primary therapy; the majority (90%) presented with stage III or IV disease. Four weekly intravenous infusions of galiximab were administered at doses of 125, 250, 375, or 500 mg/m2.ResultsThirty-seven patients received galiximab treatment and were evaluated for safety; 35 were assessable for response. Antibody infusions were safe and well tolerated with no dose-limiting toxicities. A total of 22 (60%) of 37 patients experienced adverse events related to galiximab. All but one of the events were grade 1 or 2; the most common were fatigue, nausea, and headache. Cytopenias were rare; only one patient experienced anemia and febrile neutropenia, which were unrelated to galiximab and resolved after treatment. No patient developed antigaliximab antibody formation. The mean serum half-life ranged from 13 to 24 days. The overall response rate was 11% (two complete responses and two partial responses). Time to best response was delayed (months 3, 6, 9, and 12). Twelve patients (34%) maintained stable disease. Nearly half of all patients (49%) had a decrease in indicator lesions. Two responders remain on study without progression (22 and 24.4 months).ConclusionThe favorable safety profile of galiximab and evidence of single-agent biologic activity and dose-dependent pharmacokinetics support further evaluation of galiximab as a treatment for follicular lymphoma, possibly in combination with other lymphoma therapies.