A Prospective, Phase 1 Trial of Nivolumab, Ipilimumab, and Radiotherapy in Patients with Advanced Melanoma.

PURPOSE: Preclinical data suggest that radiotherapy (RT) is beneficial in combination with immune checkpoint blockade. Clinical trials have explored RT with single-agent immune checkpoint blockade, but no trials have reported RT with the combination of nivolumab and ipilimumab. PATIENTS AND METHODS: We conducted a phase 1 study of patients with stage IV melanoma receiving nivolumab and ipilimumab with two different dose-fractionation schemes of RT. Patients had at least one melanoma metastasis that would benefit from palliative RT and one metastasis that would not be irradiated. Nivolumab 1 mg/kg + ipilimumab 3 mg/kg and extracranial RT with a dose of 30 Gy in 10 fractions was administered in Cohort A, and then 27 Gy in 3 fractions was administered in Cohort B. The primary outcome was safety. RESULTS: Twenty patients were treated (10 in each cohort). The rates of treatment-related grade 3-4 adverse events in Cohort A and B were 40% and 30%, respectively. There were no grade ≥3 adverse events attributed to RT. Patients responded to treatment outside of the irradiated volume (Cohort A 5/10; Cohort B 1/9). No evaluable patients had progression of irradiated metastases. Immunologic changes were seen in the peripheral blood with increases in T-cell receptor diversity in some responding patients. CONCLUSIONS: RT with nivolumab and ipilimumab was safe compared with historical data of nivolumab and ipilimumab alone. Immunologic effects were observed in the peripheral blood. Randomized studies are ongoing to assess whether RT increases the efficacy of nivolumab and ipilimumab.

An event-related potential study of attention deficits in posttraumatic stress disorder during auditory and visual Go/NoGo continuous performance tasks.

Posttraumatic stress disorder (PTSD) is characterized by disturbances in attention, such as increased arousal and hypervigilance. This study examined the event-related potential (ERP) P3 component to target detection (Go), response inhibition (NoGo) and irrelevant nontarget stimuli during auditory and visual A-X continuous performance tasks. NoGo N2 amplitude effects were also analyzed. Participants were 23 Vietnam veterans with PTSD and 13 civilian controls. No group differences were present for N2 or P3 amplitude to Go and NoGo stimuli. The PTSD group, however, had longer P3 latency to NoGo stimuli than controls, regardless of modality. The PTSD group also had greater frontal P3 amplitude to irrelevant nontarget stimuli than controls. Significant P3 amplitude and latency findings were associated with higher hyperarousal and reexperiencing scores from the Clinician-Administered PTSD Scale. The findings suggest that attentional problems in PTSD are related to slowed central processing when response inhibition is required, and to an impaired ability to screen irrelevant information. This study provides further evidence that the attentional impairments in PTSD are not confined to trauma-related stimuli. Heightened arousal appears to enhance the attentional dysregulation seen in PTSD.

The effects of covert attention and stimulus complexity on the P3 response during an auditory continuous performance task.

This study examined the effects of motor responding and stimulus complexity on the event-related potential (ERP) P3 amplitude and latency during an auditory continuous performance task (A-CPT). Subjects were presented with undegraded and degraded syllables during two experimental conditions. In the motor attention (MA) condition participants performed a button press to target syllables. In the covert attention (CA) condition, participants listened for target syllables without responding. The ERP P3 amplitude for targets during MA and CA showed the expected anterior-to-posterior scalp topography, with the greatest amplitude at Pz. Although amplitudes across all scalp sites were greater for MA than CA target P3 responses, both MA and CA targets had greater P3 amplitudes than the P3 for the nontarget syllables (NT). There was no effect of stimulus complexity (degraded vs. undegraded) on P3 amplitude. However, stimulus complexity did affect P3 latency. Degraded syllables elicited longer P3 latency than undegraded syllables for both the MA and CA conditions. The amplitude and topography findings show that when stimulus probability is controlled through the use of a CPT paradigm, a reliable P3 component is present even when the task does not require a motor response to target stimuli.

Working memory and processing speed deficits in systemic lupus erythematosus as measured by the paced auditory serial addition test.

As many as 66% of systemic lupus erythematosus (SLE) patients have been reported to have cognitive deficits. These deficits are often associated with information processing speed and working memory. Similarly, processing speed and working memory impairments are the hallmark of cognitive dysfunction in multiple sclerosis (MS). The Paced Auditory Serial Addition Test (PASAT) places high demands on processing speed and working memory. Fisk and Archibald, however, demonstrated that the total score of the PASAT does not accurately reflect impairments in these cognitive processes. They found that MS patients used a chunking strategy to obtain correct responses and reduce the cognitive demands of the task. In the present study, PASAT performance was examined for 45 SLE patients and 27 controls using alternative scoring procedures. Although the total number of correct responses did not differ between SLE and controls at the 2.4 or 2.0 s presentation rates, SLE patients had fewer dyads (correct consecutive responses) than controls at the faster rate, and more chunking responses than controls at both rates. Disease activity, disease duration, depression, fatigue, and corticosteroids could not account for these differences. The findings suggest that SLE patients, like MS patients, chunk responses more often than controls, and that this scoring procedure may better reflect the working memory and processing speed deficits present in SLE.