Search

Background A post-operative MRI (MRIpost-op) performed within 72 h is routinely used for radiation treatment planning in glioblastoma (GBM) patients, with radiotherapy starting about 4–6 weeks after surgery. Some patients undergo an additional pre-radiotherapy MRI (MRIpre-RT) about 2–6 weeks after surgery. We sought to analyze the incidence of rapid early progression (REP) between surgery and initiation of radiotherapy seen on MRIpre-RT and the impact on radiation target volumes. Methods Patients with GBM diagnosed between 2018 and 2020 who had an MRIpost-op and MRIpre-RT were retrospectively identified. Criteria for REP was based on Modified RANO criteria. Radiation target volumes were created and compared using the MRIpost-op and MRIpre-RT. Results Fifty patients met inclusion criteria. The median time between MRIpost-op and MRIpre-RT was 26 days. Indications for MRIpre-RT included clinical trial enrollment in 41/50 (82%), new symptoms in 5/50 (10%), and unspecified in 4/50 (8%). REP was identified in 35/50 (70%) of patients; 9/35 (26%) had disease progression outside of the MRIpost-op-based high dose treatment volumes. Treatment planning with MRIpost-op yielded a median undertreatment of 27.1% of enhancing disease and 11.2% of surrounding subclinical disease seen on MRIpre-RT. Patients without REP had a 38% median volume reduction of uninvolved brain if target volumes were planned with MRIpre-RT. Conclusion Given the incidence of REP and its impact on treatment volumes, we recommend using MRIpre-RT for radiation treatment planning to improve coverage of gross and subclinical disease, allow for early identification of REP, and decrease radiation treatment volumes in patients without REP.

The aim of this study was to understand the use of chemotherapy (CMT) and radiotherapy (RT) in pilocytic astrocytoma (PA) and their impact on overall survival (OS). Data from the National Cancer Database (NCDB) for patients with non-metastatic WHO grade I PA from 2004 to 2014 were analyzed. Pearson’s chi-squared test and multivariate logistic regression analyses were performed to assess the distribution of demographic, clinical, and treatment factors. Inverse probability of treatment weighting (IPTW) was used to account for differences in baseline characteristics. Kaplan–Meier analyses and doubly-robust estimation with multivariate Cox proportional hazards modeling were used to analyze OS. Of 3865 patients analyzed, 294 received CMT (7.6%), 233 received RT (6.0%), and 42 (1.1%) received both. On multivariate analyses, decreasing extent of surgical resection was associated with receipt of both CMT and RT. Brainstem tumors were associated with RT, optic nerve tumors were associated with CMT. Cerebellar tumors were inversely associated with both CMT and RT. Younger age was associated with receipt of CMT; conversely, older age was associated with receipt of RT. After IPTW, receipt of CMT and/or RT were associated with an OS decrement compared with matched patients treated with surgery alone or observation (HR 3.29, p

A BSTRACT: PURPOSE: Optimal treatment for primary central nervous system lymphoma (PCNSL) comprises polychemotherapy induction with high-dose methotrexate followed by consolidation therapy, but there is no standard treatment regimen because of a lack of comparative trials examining efficacy or relative value. We performed a retrospective outcome and relative cost analysis on consolidation regimens to gain perspective on how cost and benefit can be weighed in medical decisions for patients with PCNSL.Patients with newly diagnosed PCNSL who completed consolidation at our institution from July 1, 2012, to March 1, 2019, were included. Patients completed etoposide/cytarabine (EA), high-dose cytarabine (HIDAC), or high-dose chemotherapy with autologous stem-cell rescue (HDC-ASCR) as consolidation regimen. Data were collected from the electronic medical record and our institution's Value Driven Outcomes tool. Survival was analyzed as date of diagnosis to last known date of survival.Of the 22 patients included in the study, 12 completed the EA regimen, 4 completed HDC-ASCR, and 6 completed HIDAC. Facility and pharmacy costs contributed most to the cost of each treatment. HDC-ASCR treatment was 50× the cost of the cheapest treatment, HIDAC. Outcomes were numerically superior with HDC-ASCR and HIDAC compared with EA (2-year progression-free survival 100% vs. 100% vs. 63.6%, respectively, p = 0.1915).This small retrospective cost-benefit analysis provides evidence that HDC-ASCR may be a superior treatment for PCNSL but at a higher cost than other consolidation regimens. HIDAC may increase value for patients, including elderly patients, who are not appropriate candidates for HDC-ASCR when compared with EA.

The aim of this study was to understand the use of chemotherapy (CMT) and radiotherapy (RT) in pilocytic astrocytoma (PA) and their impact on overall survival (OS).Data from the National Cancer Database (NCDB) for patients with non-metastatic WHO grade I PA from 2004 to 2014 were analyzed. Pearson's chi-squared test and multivariate logistic regression analyses were performed to assess the distribution of demographic, clinical, and treatment factors. Inverse probability of treatment weighting (IPTW) was used to account for differences in baseline characteristics. Kaplan-Meier analyses and doubly-robust estimation with multivariate Cox proportional hazards modeling were used to analyze OS.Of 3865 patients analyzed, 294 received CMT (7.6%), 233 received RT (6.0%), and 42 (1.1%) received both. On multivariate analyses, decreasing extent of surgical resection was associated with receipt of both CMT and RT. Brainstem tumors were associated with RT, optic nerve tumors were associated with CMT. Cerebellar tumors were inversely associated with both CMT and RT. Younger age was associated with receipt of CMT; conversely, older age was associated with receipt of RT. After IPTW, receipt of CMT and/or RT were associated with an OS decrement compared with matched patients treated with surgery alone or observation (HR 3.29, p 0.01).This is the largest study to date to examine patterns of care and resultant OS outcomes in PA. We identified patient characteristics associated with receipt of CMT and RT. After propensity score matching, receipt of CMT and/or RT was associated with decreased OS.

Neurologic complications of cancer may involve both the central nervous system (CNS) and peripheral nervous system (PNS) manifesting as brain, leptomeningeal, intramedullary, intradural, epidural, plexus, and skull base metastases. Excluding brain involvement, neurologic complications affecting these other sites are relatively infrequent, but collectively they affect more than 25% of patients with metastatic cancer causing significant morbidity and mortality. Early diagnosis and intervention optimize quality of life and improve survival.

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma that is typically confined to the brain, eyes, and cerebrospinal fluid (CSF) without evidence of systemic spread. PCNSL is an uncommon tumor, and only four randomized trials and one phase III trial have been completed so far, all in the first-line setting. The prognosis of patients with PCNSL has improved during the past few decades with the introduction of high-dose methotrexate (HD-MTX), which now serves as the backbone of all first-line treatment regimens. Despite recent progress, results after treatment are durable in half of patients, and therapy can be associated with late neurotoxicity. Novel insights into the pathophysiology of PCNSL have identified the B-cell receptor (BCR) pathway as a key mechanism in the pathogenesis of PCNSL. The use of novel agents targeting components of the BCR pathway, namely the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, and immunomodulatory drugs (IMIDs) like lenalidomide and pomalidomide, has so far been limited to patients who have recurrent/refractory PCNSL with promising high response rates. Within the past 5 years, there has been a peak in clinical trials investigating small molecules and novel reagents in the recurrent/refractory setting, including immune checkpoint inhibitors, IMIDs, and BTK and PI3K/AKT/mTOR inhibitors.

BACKGROUND: There has been significant improvement in treatment outcomes of primary central nervous system lymphoma (PCNSL) at specialized centers over the past several decades; however, it is unclear if these changes have translated to benefits in the general population. METHODS: In this study, we utilized 2 national databases to examine survival trends over time for PCNSL: the Central Brain Tumor Registry of the United States (CBTRUS, 2000–2013) and 18 registries from the Surveillance, Epidemiology, and End Results program (SEER, 1973–2013). RESULTS: The annual incidence of PCNSL in 2013 was 0.4 per 100000 population (CBTRUS/SEER). Incidence increased from 0.1 per 100000 in the 1970s to 0.4 per 100000 in the 1980s, correlating with an increase in the diagnosis of patients ≥70 years (1973: 0.2 vs 2013: 2.1 [SEER]). Incidence rates differed greatly between young and elderly patients (age 20–29 y: 0.08 vs 70–79 y: 4.32 [CBTRUS]). Even though the median overall survival of all patients doubled from 12.5 months in the 1970s to 26 months in the 2010s, this survival benefit was limited to patients

e14544 Background: Treatment for Primary Central Nervous System Lymphoma (PCNSL) includes induction therapy consisting of polychemotherapy including high-dose methotrexate followed by consolidation therapy. There are various induction and consolidation regimens with wide variability in their treatment duration, inpatient vs outpatient administration, and the number of chemotherapeutic agents utilized. We performed a comparative cost and efficacy analysis of three consolidation techniques in an effort to provide insight into the cost-benefit of these treatment regimens. Methods: Patients treated for newly diagnosed PCNSL at our institution after July 1, 2012 were retrospectively reviewed. Patients who completed one of the following regimens and received consolidation therapy at our institution were included: rituximab/methotrexate/vincristine/procarbazine (R-MVP), rituximab/methotrexate/temozolomide (R-MT), or rituximab/methotrexate (R-M) for induction followed by consolidation with etoposide/cytarabine (EA), high-dose cytarabine (HIDAC), or high-dose chemotherapy with autologous stem cell rescue (HDC-ASCR). Cost to health system was derived from a Value Driven Outcomes tool and filtered to compare major costs of treatment. Survival was calculated from the date of diagnosis and last date of known survival. Results: Twenty-two patients met eligibility criteria and received the following four treatment regimens: R-MT+EA (12), R-MT+ HDC-ASCR (3), R-M+ HDC-ASCR (1), and R-MVP+HIDAC (6). Patients receiving HDC-ASCR (4) had a trend towards a more favorable overall survival (p = 0.0880) compared to the other two consolidation therapies with no recurrence or death in those patients treated with HDC-ASCR. Comparative cost analysis of facility and pharmacy costs of the three consolidation techniques found that HDC-ASCR was 40 times the cost of the cheapest treatment, HIDAC. Conclusions: This small retrospective review provides evidence that HDC-ASCR may be a superior consolidation strategy but with a profound increase in financial cost. To our knowledge this is the first study completed in the U.S. comparing treatment outcomes and cost in PCNSL. Based on our results, it is clear that a larger and prospective review could potentially shed light on selecting a standard of care based on cost-benefit analysis.

Mitral valve leaflets and chordae have been shown to contain different amounts and proportions of glycosaminoglycans (GAGs) and proteoglycans (PGs) corresponding to in vivo normal or diseased cyclic strain patterns. To understand the effect of cyclic strains on GAG/PG synthesis by valvular interstitial cells (VICs) isolated from valve leaflet and chordae separately, porcine VICs were seeded within collagen gels and alternately stretched or relaxed for 24 h periods for one week in a custom-designed tissue engineering bioreactor. We found cyclic-stretch-induced upregulation of total GAGs and of individual GAG classes secreted into the culture medium. Leaflet cells showed a delayed response to stretching compared to chordal cells, but altered the proportions of various GAG classes they secreted during the culture duration. Decorin and biglycan PGs were slightly responsive to stretch. We demonstrated that mechanical stretch and relaxation conditions reversibly regulate GAG and PG production in a novel 3D model of valve tissues. This is the first study using cyclic strains to modulate GAG/PG synthesis by valve cells and our results may have implications for the remodeling of the mitral valve as well as other tissues.

Management of patients with glioblastoma (GBM) often includes radiation (RT) and temozolomide (TMZ). The association between severe treatment-related lymphopenia (TRL) after the standard chemoradiation and reduced survival has been reported in GBM patients with the median age of 57. Similar findings were described in patients with head and neck, non-small cell lung, and pancreatic cancers. This retrospective study is designed to evaluate whether elderly GBM patients (age ≥65) develop similar TRL after RT/TMZ and whether such TRL is associated with decreased survival. Serial total lymphocyte counts (TLC) were retrospectively reviewed in patients (age ≥65) with newly diagnosed GBM undergoing RT/TMZ and associated with treatment outcomes. Seventy-two patients were eligible: median KPS 70, median age 71 years (range 65-86) with 56 % of patients >70 years, 53% female, 31% received RT ≤45 Gy. Baseline median TLC was 1100 cells/mm(3) which fell by 41% to 650 cells/mm(3) 2 months after initiating RT/TMZ (p < 0.0001). Patients with TLC

The cytotoxic response of cells in culture is dependant on the degree of functionalization of the single-walled carbon nanotube (SWNT). After characterizing a set of water-dispersible SWNTs, we performed in vitro cytotoxicity screens on cultured human dermal fibroblasts (HDF). The SWNT samples used in this exposure include SWNT-phenyl-SO3H and SWNT-phenyl-SO3Na (six samples with carbon/-phenyl-SO3X ratios of 18, 41, and 80), SWNT-phenyl-(COOH)2 (one sample with carbon/-phenyl-(COOH)2 ratio of 23), and underivatized SWNT stabilized in 1% Pluronic F108. We have found that as the degree of sidewall functionalization increases, the SWNT sample becomes less cytotoxic. Further, sidewall functionalized SWNT samples are substantially less cytotoxic than surfactant stabilized SWNTs. Even though cell death did not exceed 50% for cells dosed with sidewall functionalized SWNTs, optical and atomic force microscopies show direct contact between cellular membranes and water-dispersible SWNTs; i.e. the SWNTs in aqueous suspension precipitate out and selectively deposit on the membrane. © 2005 Elsevier Ireland Ltd. All rights reserved.

There has been significant improvement in treatment outcomes of Primary Central Nervous System Lymphoma (PCNSL) at specialized centers over the past several decades. However, it is unclear if these changes have translated to benefits in the general population. In this study, we utilized two national databases to examine incidence and survival trends over time for PCNSL (Central Brain Tumor Registry of the United States (CBTRUS, 2000 – 2013) and 18 Surveillance, Epidemiology and End Results (SEER, 1973 – 2013) registries). The annual incidence of PCNSL in 2013 was 0.4 per 100,000 population (CBTRUS/SEER). Incidence increased from 0.1 per 100,000 in the 1970s to 0.4 per 100,000 in the 1980s, correlating with an increase in the diagnosis of patients ≥70 years (1973:0.2 vs 2013:2.1 – SEER). Incidence rates differed greatly between young and elderly patients (age 20–29 years: 0.08 vs 70–79: 4.32 – CBTRUS). Even though the median overall survival of all patients doubled from 12.5 months in the 1970s to 26 months in the 2010s, this survival benefit was limited to patients

2040 Background: There has been significant improvement in treatment outcomes of Primary Central Nervous System Lymphoma (PCNSL) at specialized centers over past decades, and it is unclear if these changes have translated to benefits in the general population. In this study, we utilized national databases to examine survival trends over time. Methods: Incidence rates were obtained from the Central Brain Tumor Registry of the United States (CBTRUS, 2000 – 2013) and 18 Surveillance, Epidemiology and End Results (SEER, 1973 – 2013) registries. Data for survival analysis was obtained from SEER and analyzed using SEER*STAT. To focus on non-HIV-associated PCNSL, patients with “other infectious and parasitic diseases including HIV” as cause of death and follow up were excluded. CBTRUS identified 19,027 patients over 13 years and SEER 6,765 over 40 years. Results: The annual incidence of PCNSL in 2013 was 0.4 per 100,000 population (CBTRUS/SEER). Incidence increased from 0.1 per 100,000 in the 1970s to 0.4 per 100,000 in the 1980s, correlating with an increase in the diagnosis of elderly patients, ≥70 (1973:0.2 vs 2013:2.1 – SEER). Incidence rates differed greatly between young and elderly patients (20-29: 0.08 vs 70-79: 4.32 – CBTRUS). The median overall survival (mOS) of all patients is 17 months (m) with no survival benefit based on sex. Survival doubled from 12.5 m in the 1970s to 26 m in the 2010s. There was a significant difference in survival based on age: < 50: 83 m vs 50-69: 25 m vs ≥70: 6 m (p-value < 0.0001). In patients < 50, mOS increased from 35.5 m in the 1970s to 134 m in the 2000s (mOS not achieved in 2010s). In patients 50-69, mOS increased from 8 m in the 1970s to 35 m in the 2010s. However, mOS in the elderly population, ≥70, has not changed in the last 40 years (6 m in the 1970s vs 7 m in the 2010s, p-value = 0.1). Conclusions: PCNSL is a disease that more frequently affects the elderly. Although overall survival has increased over the past 4 decades, reflecting current literature in PCNSL, survival in the elderly has not changed since the 1970s. Identification of this vulnerable patient population highlights the need for clinical trials targeting the elderly in hopes of improving treatment strategies and ultimately outcomes.

Extracellular matrix changes occur in many heart valve pathologies. For example, myxomatous mitral valves are reported to contain excess proteoglycans and hyaluronan. However, it is unknown which specific proteoglycans are altered in myxomatous valves. Because proteoglycans perform varied functions in connective tissues, this study was designed to identify and localize three matrix-associated proteoglycans, as well as hyaluronan and the hyaluronan receptor for endocytosis, within myxomatous and normal mitral valves.Human mitral posterior leaflets (control, n=6-9; myxomatous, n=14-21; mean age, 61 years for all groups) were histochemically stained for proteoglycan core proteins, hyaluronan, and the hyaluronan receptor for endocytosis. Stain intensity was semiquantitatively graded to determine differences in marker abundance between normal and myxomatous valves. The proteoglycans were localized to different regions of the leaflet by correspondence to parallel Movat-stained sections.The proteoglycans decorin, biglycan, and versican were more abundant in myxomatous valves than in normal controls (P.03). There was a gender effect on proteoglycan presence, but no age-related trends were observed. Hyaluronan and the hyaluronan receptor for endocytosis were distributed throughout all valves. There was no significant difference in hyaluronan between groups, but expression of the hyaluronan receptor for endocytosis was reduced in myxomatous valves compared to normal controls (P.002).Excess decorin, biglycan, and versican may be associated with the remodeling of other matrix components in myxomatous mitral valves. Decreased expression of the hyaluronan receptor for endocytosis in myxomatous valves suggests that hyaluronan metabolism could be altered in myxomatous mitral valve disease. These findings contribute towards elucidating the pathogenesis of myxomatous mitral valve disease and developing potential new therapies.

Differently loaded regions of the mitral valve contain distinct amounts and types of proteoglycans (PGs); these PG profiles are altered in abnormal loading and disease conditions. We developed an in vitro three-dimensional model to analyze PGs secreted by valvular interstitial cells (VICs) isolated from distinct regions of porcine mitral valves (leaflet or chordae) and subjected to either biaxial or uniaxial mechanical constraints. In addition, the PGs, DNA and collagen content of the collagen gels was monitored over time. All three PGs previously found in heart valves (decorin, biglycan and versican) were present in the collagen gels and the conditioned medium. Compared to unconstrained gels, the constrained collagen gels (whether biaxially or uniaxially loaded) retained more decorin and biglycan but less versican. However, the conditioned medium from constrained collagen gels contained higher amounts of all three PGs than did medium from unconstrained gels. Constrained collagen gels containing leaflet cells retained more decorin and biglycan than did those containing chordal cells. DNA content was maintained early in the culture period but was reduced by 55–80% after 7 days, whereas PG synthesis increased over time. At the end of the culture period, the cell density was highest in the biaxial region of gels seeded with leaflet cells. In contrast, collagen content in both constrained and unconstrained gels remained consistent over culture duration. This study provides valuable information about the role of applied loading on proteoglycan segregation, which should aid in tissue engineering applications and for understanding valve biology and pathology.

BACKGROUND: Management of elderly patients with high grade glioma often includes radiation therapy (RT) +/- temozolomide (TMZ). A previous report showed that standard RT/TMZ resulted in severe lymphopenia in 40% of patients (median age of 57) with an associated shorter survival (Grossman, 2011). Similar findings were described in patients with head and neck, non-small cell lung, and pancreatic cancer. This study is designed to evaluate whether elderly patients (age ≥65) with glioblastoma (GBM) develop severe treatment related lymphopenia (TRL) after RT +/- TMZ and whether TRL is associated with reduced survival. METHODS: Elderly patients (age ≥65) newly diagnosed with GBM and followed-up at Washington University (2000-2013) were eligible. Radiation parameters and serial total lymphocyte counts (TLC) were collected. RESULTS: Seventy-seven patients were eligible: median KPS 70, median age 71 years (range 65 - 86) with 57% of patients >70 years, 52% female, 32% received RT

This study examines the biological effects of water-soluble fullerene aggregates in an effort to evaluate the fundamental mechanisms that contribute to the cytotoxicity of a classic engineered nanomaterial. For this work we used a water-soluble fullerene species, nano-C60, a fullerene aggregate that readily forms when pristine C60 is added to water. Nano-C60 was cytotoxic to human dermal fibroblasts, human liver carcinoma cells (HepG2), and neuronal human astrocytes at doses>or= 50 ppb (LC50=2-50 ppb, depending on cell type) after 48 h exposure. This water-soluble nano-C60 colloidal suspension disrupts normal cellular function through lipid peroxidation; reactive oxygen species are responsible for the membrane damage. Cellular viability was determined through live/dead staining and LDH release. DNA concentration and mitochondrial activity were not affected by the nano-C60 inoculations to cells in culture. The integrity of cellular membrane was examined by monitoring the peroxy-radicals on the lipid bilayer. Subsequently, glutathione production was measured to assess the cell's reaction to membrane oxidation. The damage to cell membranes was observed both with chemical assays, and confirmed physically by visualizing membrane permeability with high molecular weight dyes. With the addition of an antioxidant, L-ascorbic acid, the oxidative damage and resultant toxicity of nano-C60 was completely prevented.