Activity of PD-1 blockade with nivolumab among patients with recurrent atypical/anaplastic meningioma: phase II trial results

BackgroundProgrammed death ligand 1 (PD-L1) contributes to tumor immunosuppression and is upregulated in aggressive meningiomas. We performed a phase II study of nivolumab, a programmed death 1 (PD-1) blocking antibody among patients with grade ≥2 meningioma that recurred after surgery and radiation therapy.MethodsTwenty-five patients received nivolumab (240 mg biweekly) until progression, voluntary withdrawal, unacceptable toxicity, or death. Tumor mutational burden (TMB) and quantification of tumor-infiltrating lymphocytes (TIL) were evaluated as potential immunocorrelative biomarkers. Change in neurologic function was prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale.ResultsEnrolled patients had multiple recurrences including ≥3 prior surgeries and ≥2 prior courses of radiation in 60% and 72%, respectively. Nivolumab was well tolerated with no unexpected adverse events. Six-month progression-free survival (PFS-6) rate was 42.4% (95% CI: 22.8, 60.7) and the median OS was 30.9 months (95% CI: 17.6, NA). One patient achieved radiographic response (ongoing at 4.5 years). TMB was >10/Mb in 2 of 15 profiled tumors (13.3%). Baseline TIL density was low but increased posttreatment in 3 patients including both patients with elevated TMB. Most patients who achieved PFS-6 maintained neurologic function prior to progression as assessed by NANO.ConclusionNivolumab was well tolerated but failed to improve PFS-6, although a subset of patients appeared to derive benefit. Low levels of TMB and TIL density were typically observed. NANO assessment of neurologic function contributed to outcome assessment. Future studies may consider rationally designed combinatorial regimens.     

Control of Lytic Function by Mitogen-activated Protein Kinase/Extracellular Regulatory Kinase 2 (ERK2) in a Human Natural Killer Cell Line: Identification of Perforin and Granzyme B Mobilization by Functional ERK2

The signal pathways that control effector function in human natural killer (NK) cells are little known. In this study, we have identified the critical role of the mitogen-activated protein kinase (MAPK) pathway in NK lysis of tumor cells, and this pathway may involve the mobilization of granule components in NK cells upon interaction with sensitive tumor target cells. Evidence was provided by biological, biochemical, and gene transfection methods. NK cell binding to tumor cells for 5 min was sufficient to maximally activate MAPK/extracellular signal–regulatory kinase 2 (ERK2), demonstrated by its tyrosine phosphorylation and by its ability to function as an efficient kinase for myelin basic protein. MAPK activation was achieved in NK cells only after contact with NK-sensitive but not NK-resistant target cells. In immunocytochemical studies, cytoplasmic perforin and granzyme B were both maximally redirected towards the tumor contact zone within 5 min of NK cell contact with tumor cells. A specific MAPK pathway inhibitor, PD098059, could block not only MAPK activation but also redistribution of perforin/granzyme B in NK cells, which occur upon target ligation. PD098059 also interfered with NK lysis of tumor cells in a 5-h ⁵¹Cr-release assay, but had no ability to block NK cell proliferation. Transient transfection studies with wild-type and dominant-negative MAPK/ERK2 genes confirmed the importance of MAPK in NK cell lysis. These results document a pivotal role of MAPK in NK effector function, possibly by its control of movement of lytic granules, and clearly define MAPK involvement in a functional pathway unlinked to cell growth or differentiation.     

Synthesis and pharmacology of new camptothecin drugs

Camptothecin (CPT) drugs exhibit antineoplastic activity against colorectal, breast, lung and ovarian cancers. This review briefly summarizes the pharmacology of CPT drugs, examines four strategies and methods for the synthesis of camptothecins, and finally discusses homocamptothecins and silatecans, two new classes of CPT analog.     

A qualitative study of the experiences of people who identify themselves as having adjusted positively to a visible difference

Individual and group interviews explored experiences of positive adjustment among 12 people with a range of visible differences. Thematic analysis identified four main themes: importance of appearance; personal growth; relationships with others; and coping (factors in the coping theme considered to be paramount to positive adjustment were inner strength and positivity, active coping techniques, downward social comparisons, taking things day-by-day, spirituality and humour). The findings provide insight into behaviours and personal outlooks that may contribute to adaptive coping and have implications for future research and interventions aimed at those who exhibit poor adjustment to visible difference. The article reflects on the use of both individual and group interviews for research in this field.     

Priming of color and position during visual search in unilateral spatial neglect

We examined priming of visual search by repeated target location or color in two patients with left visual neglect and extinction, following strokes centered on the right inferior parietal lobe. Both patients, like the healthy controls we tested, showed intact priming, with performance speeded when either the location or color of a singleton target was repeated over successive trials in a standard search condition (Experiment 1). This was observed both from and to targets on the contralesional (left) side. Moreover, priming of search was still observed even when a return of fixation back to display-center was required between successive trials (Experiment 2). When briefer displays were used (Experiment 3), the patients often failed to detect left targets. This situation revealed an important dissociation: Whereas location priming only arose from preceding left targets that had been consciously detected, color priming (possibly arising within the intact ventral stream) did not depend on awareness of the preceding target. There was considerable color priming from missed targets. These findings demonstrate relatively intact priming of visual search by color and location in patients with right parietal damage, and also reveal that location priming may differ from color priming in requiring awareness.