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 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).
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 <70 years. Survival in the elderly population has not changed in the last 40 years (6 mo in the 1970s vs 7 mo in the 2010s, P = 0.1).
The poor outcome seen in the particularly vulnerable elderly patient population highlights the need for clinical trials targeting the elderly in hopes of improving treatment strategies and survival.
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 <500 cells/mm
3
at 2 months had a shorter survival than those with higher TLCs with a median overall survival of 4.6 versus 11.6 months, respectively. Multivariate analysis revealed a significant association between TRL and survival (HR 2.76, 95 % CI 1.30–5.86, p = 0.008). Treatment-related lymphopenia is frequent, severe, and an independent predictor for survival in elderly patients with GBM. These findings add to the body of evidence that immunosuppression induced by chemoradiation is associated with inferior clinical outcomes. Prospective studies are needed to confirm these findings suggesting that immune preservation is important in this cancer.
The authors sought to determine the incidence, time course, and risk factors for overall adverse radiation effect (ARE) and symptomatic ARE after stereotactic radiosurgery (SRS) for brain metastases.
...All cases of brain metastases treated from 1998 through 2009 with Gamma Knife SRS at UCSF were considered. Cases with less than 3 months of follow-up imaging, a gap of more than 8 months in imaging during the 1st year, or inadequate imaging availability were excluded. Brain scans and pathology reports were reviewed to ensure consistent scoring of dates of ARE, treatment failure, or both; in case of uncertainty, the cause of lesion worsening was scored as indeterminate. Cumulative incidence of ARE and failure were estimated with the Kaplan-Meier method with censoring at last imaging. Univariate and multivariate Cox proportional hazards analyses were performed.
Among 435 patients and 2200 brain metastases evaluable, the median patient survival time was 17.4 months and the median lesion imaging follow-up was 9.9 months. Calculated on the basis of 2200 evaluable lesions, the rates of treatment failure, ARE, concurrent failure and ARE, and lesion worsening with indeterminate cause were 9.2%, 5.4%, 1.4%, and 4.1%, respectively. Among 118 cases of ARE, approximately 60% were symptomatic and 85% occurred 3-18 months after SRS (median 7.2 months). For 99 ARE cases managed without surgery or bevacizumab, the probabilities of improvement observed on imaging were 40%, 57%, and 76% at 6, 12, and 18 months after onset of ARE. The most important risk factors for ARE included prior SRS to the same lesion (with 20% 1-year risk of symptomatic ARE vs 3%, 4%, and 8% for no prior treatment, prior whole brain radiotherapy WBRT, or concurrent WBRT) and any of these volume parameters: target, prescription isodose, 12-Gy, or 10-Gy volume. Excluding lesions treated with repeat SRS, the 1-year probabilities of ARE were < 1%, 1%, 3%, 10%, and 14% for maximum diameter 0.3-0.6 cm, 0.7-1.0 cm, 1.1-1.5 cm, 1.6-2.0 cm, and 2.1-5.1 cm, respectively. The 1-year probabilities of symptomatic ARE leveled off at 13%-14% for brain metastases maximum diameter > 2.1 cm, target volume > 1.2 cm(3), prescription isodose volume > 1.8 cm(3), 12-Gy volume > 3.3 cm(3), and 10-Gy volume > 4.3 cm(3), excluding lesions treated with repeat SRS. On both univariate and multivariate analysis, capecitabine, but not other systemic therapy within 1 month of SRS, appeared to increase ARE risk. For the multivariate analysis considering only metastases with target volume > 1.0 cm(3), risk factors for ARE included prior SRS, kidney primary tumor, connective tissue disorder, and capecitabine.
Although incidence of ARE after SRS was low overall, risk increased rapidly with size and volume, leveling off at a 1-year cumulative incidence of 13%-14%. This study describes the time course of ARE and provides risk estimates by various lesion characteristics and treatment parameters to aid in decision-making and patient counseling.
Abstract
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.
Methods
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.
Results
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).
Conclusion
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.
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.
Purpose
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).
Methods
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.
Results
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).
Conclusions
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.
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.
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-SO
3H and SWNT-phenyl-SO
3Na (six samples with carbon/-phenyl-SO
3X 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.
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