IMPORTANCE Neurological complications are an increasingly recognized consequence of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established.OBJECTIVE To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti-PD-1 therapy. DESIGN, SETTING, AND PARTICIPANTSThis single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016. All patients receiving anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patients with development of neurological symptoms within 12 months of anti-PD-1 therapy were included. Patients with neurological complications directly attributable to metastatic disease or other concurrent cancer-related treatments were excluded.MAIN OUTCOMES AND MEASURES Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score.RESULTS Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti-PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.CONCLUSIONS AND RELEVANCE Neurological adverse events associated with anti-PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti-PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti-PD-1 therapy is recommended....
PCV produces tumor regressions in a meaningful proportion of patients with LGO/LGOA. Toxicity, especially myelosuppression, is significant. Loss of 1p and 19q seems limited to patients with pure LGO and is inversely related to p53 alterations.
Pilocytic astrocytoma is a WHO grade 1 brain tumor common in children. Relatively little is known about the behavior of pilocytic astrocytomas in adult patients, largely due to the rarity of pilocytic astrocytoma in this population. Some data suggest that adults share the excellent prognosis seen in children, while other reports suggest more aggressive tumor behavior in adult patients. Patients diagnosed with pilocytic astrocytoma between 1973 and 2008 were identified in the National Cancer Institute Surveillance, Epidemiology, and End Results Program database. Age-group specific survival was analyzed with overall, expected, and cancer-specific survival rates. Further survival analyses were performed with the Kaplan-Meier method and Cox Proportional Hazards models. 3,066 patients with pilocytic astrocytoma were identified, including 865 patients aged 20 years and older. Survival rates declined significantly with age, from 96.5% 60-month survival in patients 5-19 years (95% CI 95.3-97.4) to 52.9% 60-month survival in adult patients 60+ years of age (95% CI 38.4-65.5), with a corresponding decrease in relative and cancer-specific survival rates. Gross total resection was a positive prognostic indicator in adults, while patients receiving radiation had shorter survival regardless of extent of resection. Pilocytic astrocytoma is associated with higher mortality in adult patients than in children and teens, and survival decreases with increasing age in adults. The morbidity of pilocytic astrocytoma in adults provides rationale for future trials of adjuvant treatment in high-risk patients.
Tricyclic antidepressants have been reported to relieve the paresthesiae associated with peripheral neuropathies of many etiologies. We designed a randomized, double-blind, placebo-controlled, crossover trial to establish the efficacy of nortriptyline in the treatment of cis-diamminedichloroplatinum (CDDP)-induced paresthesiae. The study included 51 evaluable patients with CDDP-induced peripheral neuropathy and painful paresthesiae. The study consisted of two 4 week phases, separated by a 1 week 'wash-out' period, in which patients received escalating dosages of either placebo or nortriptyline. The target maximum dose of nortriptyline was 100 mg/day. Each patient filled out pre-randomization and then weekly questionnaires assessing paresthesiae severity, hours of sleep, quality of life, and adverse effects over the 9 week study. No significant differences in paresthesia were observed in the first treatment period between nortriptyline and placebo (means of 49 and 55 respectively on a 0-100 point scale, P=0.78). Although some evidence of a modest effect in favor of nortriptyline was observed during the second treatment period (about one patient in five got a 10-point reduction in pain from drug above placebo effect), this occurred in the presence of a strong carryover effect. Linear models analysis and Bayes methods confirmed that the effect of nortriptyline on paresthesia was modest at best. Hours of sleep increased in the nortriptyline phase (P=0.02). There was no significant difference in measures of quality of life and the effect of paresthesiae on patients' daily activities between nortriptyline and placebo. There was no major toxicity associated with nortriptyline, but dry mouth, dizziness, and constipation were more common with nortriptyline. In summary, nortriptyline failed to demonstrate strong evidence of any effect on paresthesia or pain. The presence of a potential effect which appeared in the second period of the crossover design is questionable due to the observed carryover effect. Cross-validation sensitivity analysis of results support the conclusion that nortriptyline provides modest improvement at best over placebo in terms of chemotherapy-related neuropathy.
BACKGROUND: Advances in glioblastoma care have resulted in a larger proportion of patients surviving beyond 2 years after diagnosis. It is not clear how long-term survivors should be counseled with respect to future prognosis, or what factors influence that prognosis. The conditional probability of survival was evaluated from multiple time points in patients with glioblastoma, using Surveillance, Epidemiology, and End Results (SEER) data. METHODS: Patients diagnosed with glioblastoma from 1998 to 2008 who were treated with radiation-containing regimens were identified within SEER data. Conditional survival probabilities from multiple survival points were calculated. Cox proportional hazards models were constructed to identify predictors of survival from diagnosis and from 1 and 2 years after diagnosis. RESULTS: A total of 10,022 patients with glioblastoma met study inclusion criteria; median survival was 12.61 months. Conditional probability of surviving an additional 2 years ranged from 19.8% at diagnosis to 65.9% at 5 years after diagnosis. The proportion of patients surviving 12 months from time of diagnosis as well as from 6, 12, and 18 months after diagnosis was significantly higher in patients diagnosed in 2005 through 2008 than those diagnosed in 1998 through 2004. Of demographic and treatment-related factors evaluated, only age was associated with hazard of death at diagnosis and 1 and 3 years after diagnosis (P < .0001 at each time point). CONCLUSIONS: Patients surviving past 2 years from diagnosis have a relatively favorable conditional probability of survival into the future compared to newly diagnosed patients. This effect becomes more pronounced with increasing time
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