Summary Detection of MUM1+ cells in follicular lymphoma (FL) tissues was previously found to be associated with poor prognosis in a single report, whereas the usefulness of Ki-67 immunostaining ...remains debated. Our goal was to establish whether these markers have predictive value for patients with FL. We analyzed MUM1 and Ki-67 expression using immunohistochemistry in biopsy samples from 434 patients from the PRIMA randomized trial. The MUM1 prognostic value was then validated in a cohort of 138 patients from the FL2000 randomized trial, using the optimal cutoff value obtained from the PRIMA cohort. The surface of positive staining was quantified using computerized image analysis. In the PRIMA cohort, both high levels of MUM1 positivity (cutoff value of 0.80%) and high levels of Ki-67 positivity (cutoff value of 10.25%) were significantly associated with a shorter progression-free survival (PFS) ( P = .004 and P = .007 for MUM1 and Ki-67, respectively). In a multivariate Cox proportional hazards regression model, only MUM1 retained a statistical significance (hazards ratio 1.56; 95% confidence interval, 1.02-2.37; P = .038) after adjustment for the maintenance arm of treatment and the follicular lymphoma international prognostic index score. In the FL2000 cohort, high levels of MUM1 positivity were significantly associated to a shorter PFS ( P = .004) and to a trend toward a shorter overall survival ( P = .043). This remained significant using a multivariate Cox regression model after adjustment for the follicular lymphoma international prognostic index and the treatment arm for PFS ( P = .016). These results show that MUM1 is a strong and robust predictive immunohistochemical marker in patients with FL.
...little is known about the mechanisms by which homozygous JAK3 R117C missense mutations impair JAK3 signaling in lymphocyte ontogeny to result in the persistence of dysfunctional NK cells, although ...a hypomorphic mutation could be possible. ...the present study describes a case of T-B+NK+ SCID caused by a homozygous JAK3 missense mutation, resulting in leaky SCID.
Study objective Randomized trials suggest that nonoperative treatment of uncomplicated appendicitis with antibiotics-first is safe. No trial has evaluated outpatient treatment and no US randomized ...trial has been conducted, to our knowledge. This pilot study assessed feasibility of a multicenter US study comparing antibiotics-first, including outpatient management, with appendectomy. Methods Patients aged 5 years or older with uncomplicated appendicitis at 1 US hospital were randomized to appendectomy or intravenous ertapenem greater than or equal to 48 hours and oral cefdinir and metronidazole. Stable antibiotics-first-treated participants older than 13 years could be discharged after greater than or equal to 6-hour emergency department (ED) observation with next-day follow-up. Outcomes included 1-month major complication rate (primary) and hospital duration, pain, disability, quality of life, and hospital charges, and antibiotics-first appendectomy rate. Results Of 48 eligible patients, 30 (62.5%) consented, of whom 16 (53.3%) were randomized to antibiotics-first and 14 (46.7%) to appendectomy. Median age was 33 years (range 9 to 73 years), median WBC count was 15,000/μL (range 6,200 to 23,100/μL), and median computed tomography appendiceal diameter was 10 mm (range 7 to 18 mm). Of 15 antibiotic-treated adults, 14 (93.3%) were discharged from the ED and all had symptom resolution. At 1 month, major complications occurred in 2 appendectomy participants (14.3%; 95% confidence interval CI 1.8% to 42.8%) and 1 antibiotics-first participant (6.3%; 95% CI 0.2% to 30.2%). Antibiotics-first participants had less total hospital time than appendectomy participants, 16.2 versus 42.1 hours, respectively. Antibiotics-first-treated participants had less pain and disability. During median 12-month follow-up, 2 of 15 antibiotics-first-treated participants (13.3%; 95% CI 3.7% to 37.9%) developed appendicitis and 1 was treated successfully with antibiotics; 1 had appendectomy. No more major complications occurred in either group. Conclusion A multicenter US trial comparing antibiotics-first to appendectomy, including outpatient management, is feasible to evaluate efficacy and safety.
Summary Programmed death 1 (PD-1) is a lymphoid receptor that negatively regulates immune responses. PD-1 expression was recently reported in some T-cell non-Hodgkin lymphoma (NHL) subtypes, but the ...expression profile of PD-1 and its ligands (PD-L1 and PD-L2) in B-NHLs remains largely to be characterized. To investigate this issue, monoclonal antibodies against PD-1, PD-L1, and PD-L2 were generated by immunization of balb-c mice. A series of 161 lymphoma tissue and 11 blood samples was analyzed using either immunohistochemistry or flow cytometry. In reactive lymph nodes, PD-1 was mainly expressed in follicular T cells. In B-NHLs, PD-1 was mainly expressed in reactive T cells; but expression was also noted in neoplastic B cells from small lymphocytic lymphoma (SLL, 12/13), grade III follicular lymphoma (3/3), and diffuse large cell lymphoma (2/25). In contrast, neoplastic B cells from mantle cell lymphoma (0/11), marginal zone lymphoma (0/12), Burkitt lymphoma (0/3), and grade 1 to 2 follicular lymphoma (0/40) were PD-1 negative. PD-L1 and PD-L2 were negative in small B-cell lymphomas, including B-SLL. Flow cytometry showed that blood cells from chronic lymphocytic leukemia (B-CLL) also displayed PD-1 expression, which could be increased by CD40 stimulation. PD-1 expression in T-NHLs was restricted to the angioimmunoblastic subtype (8/8). These results show that PD-1 expression among B-NHLs is mainly associated with SLL/CLL and is influenced by activation of the CD40/CD40L pathway. Because the anti–PD-1.6.4 antibody works on paraffin sections, it represents a useful tool to differentiate SLL/CLL from other small B-cell lymphomas.
Background Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on ...tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells. Objective We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. Methods We performed multiparametric cytofluorimetric analysis of PD-1+ NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. Results We provide unequivocal evidence that PD-1 is highly expressed (PD-1bright ) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56dim but not CD56bright NK cells and is confined to fully mature NK cells characterized by the NKG2A− KIR+ CD57+ phenotype. Proportions of PD-1bright NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their possible induction/expansion in tumor environments. Functional analysis revealed a reduced proliferative capability in response to cytokines, low degranulation, and impaired cytokine production on interaction with tumor targets. Conclusions We have identified and characterized a novel subpopulation of human NK cells expressing high levels of PD-1. These cells have the phenotypic characteristics of fully mature NK cells and are increased in patients with ovarian carcinoma. They display low proliferative responses and impaired antitumor activity that can be partially restored by antibody-mediated disruption of PD-1/programmed death ligand interaction.
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