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Introduction Variation in treatment and survival outcomes for Non–Small Cell Lung Cancer (NSCLC) is high among patients with stage III or IV, but untreated NSCLC patients have not been critically analyzed to evaluate for improvable outcomes. We evaluated treatment trends and their association with oncologic outcomes for NSCLC, hypothesizing that there are a substantial number of untreated patients who are similar to patients who undergo treatment. Methods Linear regression was used to calculate trends in utilization of treatment. Kaplan-Meier and Cox regression modeling were used to determine predictors of receiving treatment. Propensity-matching was used to compare survival among subsets of treated versus untreated patients. Results Patients with primary NSCLC were identified from the National Cancer Data base from 1998–2012 and 21% (190,539) of patients received no treatment. For stage IIIA and IV, the proportion of untreated patients increased over the study period by 0.21% and 0.4% respectively (p= 0.003, <0.0001). Regardless of stage, untreated patients had significantly shorter OS (p<0.0001). Propensity-matched analyses of 6,144 stage IIIA patient pairs treated with chemoradiation vs no treatment confirmed shorter OS for untreated patients (Median, 16.5 vs 6.1 months, p <0.0001). For 19,046 stage IV patient pairs treated with chemotherapy vs no treatment, similar results were obtained (Median OS, 9.3 vs 2.0 months, p<0.0001). Conclusions The proportion of untreated stage IIIA and IV patients is increasing. Survival outcomes among advanced stage patients are superior with treatment, independent of selection bias. The benefits and risks of treatment should be carefully assessed prior to choosing to forego treatment.

Mucopolysaccharidosis type II is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS) and characterized by the accumulation of the primary storage substrate, glycosaminoglycans (GAGs). Understanding central nervous system (CNS) pathophysiology in neuronopathic MPS II (nMPS II) has been hindered by the lack of CNS biomarkers. Characterization of fluid biomarkers has been largely focused on evaluating GAGs in cerebrospinal fluid (CSF) and the periphery; however, GAG levels alone do not accurately reflect the broad cellular dysfunction in the brains of MPS II patients. We utilized a preclinical mouse model of MPS II, treated with a brain penetrant form of IDS (ETV:IDS) to establish the relationship between markers of primary storage and downstream pathway biomarkers in the brain and CSF. We extended the characterization of pathway and neurodegeneration biomarkers to nMPS II patient samples. In addition to the accumulation of CSF GAGs, nMPS II patients show elevated levels of lysosomal lipids, neurofilament light chain, and other biomarkers of neuronal damage and degeneration. Furthermore, we find that these biomarkers of downstream pathology are tightly correlated with heparan sulfate. Exploration of the responsiveness of not only CSF GAGs but also pathway and disease-relevant biomarkers during drug development will be crucial for monitoring disease progression, and the development of effective therapies for nMPS II.

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Lysosomal dysfunction is a hallmark of Parkinson's disease (PD), and variants in several PD-associated genes, including LRRK2, perturb lysosomal homeostasis. Based on this, LRRK2 kinase inhibition is being explored as a therapeutic approach for the treatment of PD. LRRK2 inhibitors reduce levels of BMP, an endolysosomal lipid involved in glycosphingolipid (GSL) catabolism, in urine from preclinical models and clinical subjects, however, the mechanisms by which LRRK2 regulates BMP and the functional significance of this change to disease are undefined. We establish that LRRK2 regulates secretion of BMP- and GSL-containing vesicles from kidney into urine and modulates BMP and GSL levels in the brain. BMP accumulates within lysosomes as a secondary response to LRRK2's effects on the activity of glucocerebrosidase (GCase), a PD-linked enzyme involved in GSL catabolism. Alterations in BMP and GCase substrate turnover are observed in CSF from LRRK2-PD patients, highlighting the relevance of LRRK2-dependent lysosomal dysfunction in disease.