Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, and despite optimized treatment options, median survival remains dismal. Contemporary evidence suggests disease recurrence results from expansion of a robustly radioresistant subset of GBM progenitor cells, termed GBM stem cells (GSCs). In this study, we utilized transmission electron microscopy to uncover ultrastructural effects on patient-derived GSC lines exposed to supratherapeutic radiotherapy levels. Elevated autophagosome formation and increased endoplasmic reticulum (ER) internal diameter, a surrogate for ER stress and activation of unfolded protein response (UPR), was uncovered. These observations were confirmed via protein expression through Western blot. Upon interrogating genomic data from an open-access GBM patient database, overexpression of UPR-related chaperone protein genes was inversely correlated with patient survival. This indicated controlled UPR may play a role in promoting radioresistance. To determine if potentiating UPR further can induce apoptosis, we exposed GSCs to radiation with an ER stress-inducing drug, 2-deoxy-D-glucose (2-DG), and found dose-dependent decreases in viability and increased apoptotic marker expression. Taken together, our results indicate GSC radioresistance is, in part, achieved by overexpression and overactivation of ER stress-related pathways, and this effect can be overcome via potentiation of UPR, leading to loss of GSC viability.

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Background The economic burden of cancer in the United States is substantial, and better understanding it is essential in informing healthcare policy and innovation. Leptomeningeal carcinomatosis (LC) represents a late complication of primary cancer spreading to the leptomeninges. Methods The IBM MarketScan® Research databases were queried for adults diagnosed with LC from 2001-2015, secondary to four primary cancers (breast, lung, gastrointestinal, and melanoma). Healthcare resource utilization (HCRU) and treatment utilization were quantified at baseline (1-year pre-LC diagnosis) and 30, 90, and 365 days post-LC diagnosis. Results We identified 4,961 cases of LC (46.3% breast cancer, 34.8% lung cancer, 13.5% gastrointestinal cancer, and 5.4% melanoma). The median age was 57.0 years, with 69.7% female and 31.1% residing in the South. Insurance status included Commercial (71.1%), Medicare (19.8%) and Medicaid (9.1%). Median follow-up was 66.0 days (Q1: 24.0, Q3: 186.0) and total cumulative costs were highest for the gastrointestinal subgroup ($167,768) and lowest for the lung cancer subgroup ($145,244). There was considerable variation in the 89.6% of patients who utilized adjunctive treatments at 1 year, including the use of chemotherapy (64.3%), radiotherapy (57.6%), therapeutic lumbar puncture (31.5%), and Ommaya reservoir (14.5%). The main cost drivers at 1 year were chemotherapy ($62,026), radiation therapy ($37,076), and specialty drugs ($29,330). The prevalence of neurologic impairments was 46.9%, including radiculopathy (15.0%), paresthesia (12.3%), seizure episode/convulsive disorder not otherwise specified (11.0%), and ataxia (8.0%). Conclusions LC is a devastating condition with an overall poor prognosis. We present the largest study of LC in this real-world study, including current treatments, with an emphasis on healthcare resource utilization. There is considerable variation in the treatment of LC and significant healthcare costs.

INTRODUCTION The economic burden of low back pain (LBP) in the US is estimated between $84.1 and $624.8 billion. Some patients with LBP that persists despite conventional medical management are ineligible for spine surgery and are considered to have non-surgical refractory back pain (NSRBP). We investigated the healthcare resource utilization (HCRU) of patients with NSRBP. METHODS The IBM MarketScan® Research databases were queried for adult patients with a diagnosis of LBP, excluding instability (eg, spondylolisthesis) and non-mechanical etiologies, and negative history of failed back surgery syndrome or spine surgery within the study period (2009-2016). For a patient to qualify as refractory, we required utilization for >30 d of pain medications (prescribed within 2 wk of diagnosis) or non-pharmacologic therapies within the 3 to 24 mo following initial diagnosis. Annual total costs, including inpatient and outpatient service costs and outpatient medication costs, were calculated for 2 yr. RESULTS Among 50 801 patients, median total cost was $3,755 (IQR $1,299, $9,108) at 1 yr pre-diagnosis, reached $6,622 (IQR $2,723, $13,978) at 1 yr, and decreased to $5,977 (IQR $2,311, $13,307) at 2 yr. Costs were highest for patients with Medicare Supplemental (N = 7,053): median total cost was $10,198 (IQR $5,517, $18,584) at 1 yr, decreasing in the second year to $9,407 (IQR $4,737, $18,330). Outpatient services accounted for the majority of all costs. The proportion of patients with ≥4 outpatient visits for LBP was 56.6% within the first 6 mo, 50.0% in the 1st year, and 68.5% in the 2nd year. CONCLUSION For patients with NSRBP, the median annual total cost at 1 yr almost doubled the 1-yr prediagnosis cost and decreased for the 2nd year; most costs were due to outpatient services. Patients with Medicare Supplemental incurred the highest total costs. Most patients saw outpatient providers multiple times in the first 6 mo and throughout the 2 yr.

INTRODUCTION Leptomeningeal carcinomatosis (LC) represents a late complication of primary cancer spreading to the leptomeninges. METHODS The IBM MarketScan® Research databases were queried for adult patients diagnosed with LC between 2001 and 2015, secondary to four primary solid tumors (breast, lung, gastrointestinal, and melanoma). The primary outcome was overall healthcare resource utilization (HCRU) for each primary cancer subgroup, quantified as the total cost at baseline (1-year pre-LC diagnosis) and 30, 90, and 365 days post-LC diagnosis. The secondary outcome was interventional treatments for LC. RESULTS We identified 4,961 cases of LC (46% breast cancer, 35% lung cancer, 14% GI cancer, and 5% melanoma). The median baseline Elixhauser comorbidity index was lower for patients with LC secondary to breast cancer (19) relative to those with primary lung, GI, or melanoma (22). The overall median follow-up length was 66 days. The breast and lung cancer groups had the longest and shortest post-LC diagnosis follow-up at 84 and 51 days, respectively. Cost data demonstrated high baseline total costs for the year preceding LC diagnosis (median $117,219). Cumulative median service and medication costs at 365 days post-LC diagnosis were the highest for the GI subgroup ($167,768) and lowest for the lung cancer subgroup ($145,244). In the first 30 days post-diagnosis, 66.9% sought treatments of any kind: 40% radiotherapy, 28% therapeutic lumbar puncture (TLP), and 14% Ommaya insertion. Of the 747 (15%) patients surviving and continuously enrolled to 365 days post-diagnosis, 78.8% had at least one encounter for treatments: 58% radiotherapy, 30% TLP, and 15% Ommaya insertion. CONCLUSION In this large nationwide study of LC associated with four major primary cancers, breast cancer patients had the fewest comorbidities at baseline and the longest follow-up, while those with GI cancer had the highest cost both at baseline and one year after LC diagnosis.