PURPOSE Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. METHODS In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692 ) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990 ) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. RESULTS The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. CONCLUSION Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.
Condensing osteitis (CO) is a common lesion of the jaw bone. This study surveyed the occurrence of mandible CO and its distribution in the mandible in a Taiwanese population. Panoramic radiographs and clinical information of 1098 patients at the Dental Department of Tri-Service General Hospital (Taipei, Taiwan) were collected. The patient data were analyzed to determine the CO disease status, patient age distribution, sex, CO location in the mandible, and the status of the affected tooth. Seventy-five CO lesions were identified in 63 patients. The prevalence of CO in the mandible was 5.7%. Eight (10.7%) CO cases were associated with teeth that had crowns and/or bridges, 16 (21.3%) CO cases were associated with teeth that had caries or restorations; 22 (29.3%) CO cases were associated with teeth that had received root canal therapy, nine (12%) CO cases were associated with teeth with periodontal diseases, and 20 (26.7%) CO cases were located in the tooth extraction area. The percentage of females and males was 65.3% and 34.7%, respectively. Ten (13.3%) CO cases and 65 (86.7%) CO cases were identified in the premolar and molar area, respectively. The most common site of CO was in the first molar region. In our study population, the CO lesion occurs more commonly in female patients who were in their 60s. The mandibular 1st molar and teeth that had received root canal therapy had the highest association with CO. The CO distribution, as determined from this study, can provide valuable information for future clinical references.
PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity, despite promising efficacy and evidence that toxicity is associated with improved clinical outcomes. Prior phenotypic evaluation by CyTOF has identified increases in activated CD8 T cells with activation of Th17 T cells, as well as decreases in Tregs, particularly in patients with toxicity. Here we sought to further understand the effects of idelalisib and duvelisib in vitro, and demonstrate that both idelalisib and duvelisib can inhibit T cell proliferation as well as Th1 and Treg differentiation in vitro, while promoting Th2 and Th17 differentiation. We further demonstrate directly using intracellular flow cytometry that autoimmune toxicity in patients is associated with higher absolute numbers of CD4 and CD8 T cells with Th17 differentiation in peripheral blood prior to therapy, and that gastrointestinal tissues from patients with active autoimmune complications of PI3Kδ inhibitors show infiltration with Th17+ T cells. These same tissues show depletion of Tregs as compared to CLL patients without toxicity, suggesting that loss of Tregs may be permissive for Th17 activation to lead to autoimmune toxicity. Clinical trials to restore this balance are warranted.
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