Much focus has been on the interaction of programmed cell death ligand 1 (PD-L1) on malignant B cells with programmed cell death 1 (PD-1) on effector T cells in inhibiting antilymphoma immunity. We sought to establish the contribution of natural killer (NK) cells and inhibitory CD163 monocytes/macrophages in Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL). Levels of PD-1 on NK cells were elevated in cHL relative to DLBCL. Notably, CD3CD56CD16 NK cells had substantially higher PD-1 expression relative to CD3CD56CD16 cells and were expanded in blood and tissue, more marked in patients with cHL than patients with DLBCL. There was also a raised population of PD-L1-expressing CD163 monocytes that was more marked in patients with cHL compared with patients with DLBCL. The phenotype of NK cells and monocytes reverted back to normal once therapy (ABVD [doxorubicin 25 mg/m, bleomycin 10 000 IU/m, vinblastine 6 mg/m, dacarbazine 375 mg/m, all given days 1 and 15, repeated every 28 days] or R-CHOP [rituximab 375 mg/m, cyclophosphamide 750 mg/m IV, doxorubicin 50 mg/m IV, vincristine 1.4 mg/m (2 mg maximum) IV, prednisone 100 mg/day by mouth days 1-5, pegfilgrastim 6 mg subcutaneously day 4, on a 14-day cycle]) had commenced. Tumor-associated macrophages (TAMs) expressed high levels of PD-L1/PD-L2 within diseased lymph nodes. Consistent with this, CD163/PD-L1/PD-L2 gene expression was also elevated in cHL relative to DLBCL tissues. An in vitro functional model of TAM-like monocytes suppressed activation of PD-1 NK cells, which was reversed by PD-1 blockade. In line with these findings, depletion of circulating monocytes from the blood of pretherapy patients with cHL and patients with DLBCL enhanced CD3CD56CD16 NK-cell activation. We describe a hitherto unrecognized immune evasion strategy mediated via skewing toward an exhausted PD-1-enriched CD3CD56CD16 NK-cell phenotype. In addition to direct inhibition of NK cells by the malignant B cell, suppression of NK cells can occur indirectly by PD-L1/PD-L2-expressing TAMs. The mechanism is more prominent in cHL than DLBCL, which may contribute to the clinical sensitivity of cHL to PD-1 blockade.

BackgroundMedical education must adapt to different health care contexts, including digitalized health care systems and a digital generation of students in a hyper-connected world. The aims of this study are to identify and synthesize the values that medical educators need to implement in the curricula and to introduce representative educational programs.MethodsAn integrative review was conducted to combine data from various research designs. We searched for articles on PubMed, Scopus, Web of Science, and EBSCO ERIC between 2011 and 2017. Key search terms were “undergraduate medical education,” “future,” “twenty-first century,” “millennium,” “curriculum,” “teaching,” “learning,” and “assessment.” We screened and extracted them according to inclusion and exclusion criteria from titles and abstracts. All authors read the full texts and discussed them to reach a consensus about the themes and subthemes. Data appraisal was performed using a modified Hawker ‘s evaluation form.ResultsAmong the 7616 abstracts initially identified, 28 full-text articles were selected to reflect medical education trends and suggest suitable educational programs. The integrative themes and subthemes of future medical education are as follows: 1) a humanistic approach to patient safety that involves encouraging humanistic doctors and facilitating collaboration; 2) early experience and longitudinal integration by early exposure to patient-oriented integration and longitudinal integrated clerkships; 3) going beyond hospitals toward society by responding to changing community needs and showing respect for diversity; and 4) student-driven learning with advanced technology through active learning with individualization, social interaction, and resource accessibility.ConclusionsThis review integrated the trends in undergraduate medical education in readiness for the anticipated changes in medical environments. The detailed programs introduced in this study could be useful for medical educators in the development of curricula. Further research is required to integrate the educational trends into graduate and continuing medical education, and to investigate the status or effects of innovative educational programs in each medical school or environment.

Leukaemia Foundation of Queensland, Kasey-Anne Oklobdzijato Memorial Fund, the Australasian Leukaemia and Lymphoma Group (Malcolm Broomhead Bequest), the Australian Cancer Research Foundation, and the Cancer Council of Queensland.

Purpose: To investigate the relationship between the intratumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in de novo diffuse large B-cell lymphoma (DLBCL) and the impact of TCR on survival.Experimental Design: We performed high-throughput unbiased TCRb sequencing on a population-based cohort of 92 patients with DLBCL treated with conventional (i.e., non-checkpoint blockade) frontline "R-CHOP" therapy. Key immune checkpoint genes within the TME were digitally quantified by nanoString. The primary endpoints were 4-year overall survival (OS) and progression-free survival (PFS).Results: The TCR repertoire within DLBCL nodes was abnormally narrow relative to non-diseased nodal tissues (P < 0.0001). In DLBCL, a highly dominant single T-cell clone was associated with inferior 4-year OS rate of 60.0% [95% confidence interval (CI), 31.7%-79.6%], compared with 79.8% in patients with a low dominant clone (95% CI, 66.7%-88.5%; P ¼ 0.005). A highly dominant clone also predicted inferior 4-year PFS rate of 46.6% (95% CI, 22.5%-76.6%) versus 72.6% (95% CI, 58.8%-82.4%, P ¼ 0.008) for a low dominant clone. In keeping, clonal expansions were most pronounced in the EBV þ DLBCL subtype that is known to express immunogenic viral antigens and is associated with particularly poor outcome. Increased T-cell diversity was associated with significantly elevated PD-1, PD-L1, and PD-L2 immune checkpoint molecules. Conclusions: Put together, these findings suggest that the TCR repertoire is a key determinant of the TME. Highly dominant T-cell clonal expansions within the TME are associated with poor outcome in DLBCL treated with conventional frontline therapy.

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Peer-assisted learning encourages students to participate more actively in the dissection process and promotes thoughtful dissection. We implemented peer-assisted dissection in 2012 and compared its effects on students’ self-assessments of learning and their academic achievement with those of faculty-led dissection. All subjects performed dissections after a lecture about upper-limb gross anatomy. Experimental group (n = 134) dissected a cadaver while guided by peer tutors who had prepared for the dissection in advance, and control group (n = 71) dissected a cadaver after the introduction by a faculty via prosection. Self-assessment scores regarding the learning objectives related to upper limbs were significantly higher in experimental group than in control group. Additionally, experimental group received significantly higher academic scores than did control group. The students in peer-assisted learning perceived themselves as having a better understanding of course content and achieved better academic results compared with those who participated in faculty-led dissection. Peer-assisted dissection contributed to self-perception and to the ability to retain and explain anatomical knowledge.

PurposeSkin allergies through type 1 and 4 hypersensitivity reactions are the most frequent manifestations of drug allergies. We had previously experienced a case of a nurse with cefotiam-induced contact urticaria syndrome. To aid in preventing the progression of drug-induced allergic disease in nurses, we conducted a survey of tertiary hospital nurses who were likely to have been exposed professionally to antibiotics.MethodsAll 539 staff nurses at a tertiary hospital were asked to respond to a questionnaire regarding antibiotic exposure. Of the 457 nurses (84.8%) who responded, 427 (79.2%) received a physical examination of the hands and 318 (59.0%) received skin prick tests with the β-lactam antibiotics cefotiam, cefoperazone, ceftizoxime, flomoxef, piperacillin and penicillin G.ResultsA positive response to at least one of the antibiotics occurred in 8 (2.6%) of the 311 subjects included in the analysis and stages 1 and 2 contact urticaria syndrome were observed in 38 (8.9%) and 3 (0.7%) of 427 nurses, respectively. The frequencies of a positive antibiotic skin test (6.9 versus 1.3%, χ2=7.15, P=0.018), stage 1 contact urticaria syndrome (14.4 versus 7.4%, χ2=4.33, P=0.038) and drug allergy (15.3 versus 3.6%, χ2=18.28, P=0.000) were higher in subjects with a positive skin allergy history than in those without. Allergic rhinitis (P=0.02, OR=3.86, CI=1.23-12.06), night cough (P=0.04, OR=3.12, CI=1.03-9.41) and food allergy (P=0.00, OR=9.90, CI=3.38-29.98) were significant risk factors for drug allergy.ConclusionsAntibiotic sensitization and drug allergy occurred more frequently in nurses with a positive skin allergy history. Atopy may be an important risk factor for drug allergy.

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