PD-L1 and tumor-associated macrophages in de novo DLBCL.

Programmed death-ligand 1 (PD-L1) and its receptor, programmed cell death-1 (PD-1), are important negative regulators of immune cell activation. Therapeutically targeting PD-1/PD-L1 in diffuse large B-cell lymphoma (DLBCL) patients with a single agent has limited activity, meriting a deeper understanding of this complex biology and of available PD-L1 clinical assays. In this study, we leveraged 2 large de novo DLBCL phase 3 trials (GOYA and MAIN) to better understand the biologic and clinical relevance of PD-L1 in de novo DLBCL. PD-L1 was expressed on myeloid cells in 85% to 95% of DLBCL patients (depending on staining procedure), compared with 10% on tumor cells, and correlated with macrophage gene expression. PD-L1 did not identify high-risk patients in de novo DLBCL; it correlated with STAT3, macrophage gene expression, and improved outcomes among a subset of patients. These results may help identify immunologically distinct DLBCL subsets relevant for checkpoint blockade. GOYA and MAIN trials were registered at www.clinicaltrials.gov as #NCT01287741 and #NCT00486759, respectively.

Mutation load and an effector T-cell gene signature may distinguish immunologically distinct and clinically relevant lymphoma subsets.

Identifying follicular lymphoma (FL) patients with preexisting antitumor immunity will inform precision medicine strategies for novel cancer immunotherapies. Using clinical and genomic data from 249 FL patients, we determined the clinical impact of mutation load and an effector T-cell (Teff) gene signature as proxies for the likelihood of a functional immune response. The FL mutation load estimate varied between 0 and 33 mutations per Mb (median, 6.6), and 92% of FL patients with a high mutation load had high Teff gene expression (P = .001). The mutation load was associated with a benefit from rituximab maintenance: FL patients with low mutation loads experienced a profound benefit from rituximab maintenance (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.15-0.54; P < .001). The Teff gene signature was prognostic as a continuous predictor (P = .008), and was used to separate FL patients into 2 groups, an "inflamed" subset (Teff-high; n = 74) and an "uninflamed" subset (Teff-low; n = 75), with longer progression-free survival (PFS) in the inflamed FL subset (PFS HR, 0.39; 95% CI, 0.21-0.70; P = .002). Furthermore, the subset of inflamed FL tumors demonstrated high expression of other T-cell signatures and counterregulatory genes, which also correlate with PFS. Mutation load and Teff gene expression may help identify immunologically distinct lymphoma subsets relevant for modern immunotherapies.

SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair.

The Sir2 chromatin regulatory factor links maintenance of genomic stability to life span extension in yeast. The mammalian Sir2 family member SIRT6 has been proposed to have analogous functions, because SIRT6-deficiency leads to shortened life span and an aging-like degenerative phenotype in mice, and SIRT6 knockout cells exhibit genomic instability and DNA damage hypersensitivity. However, the molecular mechanisms underlying these defects are not fully understood. Here, we show that SIRT6 forms a macromolecular complex with the DNA double-strand break (DSB) repair factor DNA-PK (DNA-dependent protein kinase) and promotes DNA DSB repair. In response to DSBs, SIRT6 associates dynamically with chromatin and is necessary for an acute decrease in global cellular acetylation levels on histone H3 Lysine 9. Moreover, SIRT6 is required for mobilization of the DNA-PK catalytic subunit (DNA-PKcs) to chromatin in response to DNA damage and stabilizes DNA-PKcs at chromatin adjacent to an induced site-specific DSB. Abrogation of these SIRT6 activities leads to impaired resolution of DSBs. Together, these findings elucidate a mechanism whereby regulation of dynamic interaction of a DNA repair factor with chromatin impacts on the efficiency of repair, and establish a link between chromatin regulation, DNA repair, and a mammalian Sir2 factor.

SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin.

The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomyces cerevisiae. In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened lifespan and a premature ageing-like phenotype. However, the molecular mechanisms of SIRT6 function are unclear. SIRT6 is a chromatin-associated protein, but no enzymatic activity of SIRT6 at chromatin has yet been detected, and the identity of physiological SIRT6 substrates is unknown. Here we show that the human SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin. SIRT6 associates specifically with telomeres, and SIRT6 depletion leads to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence. Moreover, SIRT6-depleted cells exhibit abnormal telomere structures that resemble defects observed in Werner syndrome, a premature ageing disorder. At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome. We propose that SIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metabolism and function. Our findings constitute the first identification of a physiological enzymatic activity of SIRT6, and link chromatin regulation by SIRT6 to telomere maintenance and a human premature ageing syndrome.

Patients with worry: presentation of concerns and expectations for response.

Patients with the same underlying concern express this with different styles that predict preference for physician responses. One hundred primary care patients imagined having chest pain and selected from a videotape, the most likely response which they would tell their physician: (1) symptoms only--no disclosure of underlying concern; (2) symptoms and a "Clue" to an underlying concern; or (3) symptom with an explicit concern. Depending on their preferred expression, they were presented videotaped doctors responses to that disclosure and ranked their response preferences. Patients stating they would present with symptoms only (17%) preferred a biomedical question response; patients selecting a symptom and a clue (43%) were equally comfortable with a biomedical question, facilitation or, an exploration of the clue. Of patients presenting with an explicit concern (40%), most wanted the physician to acknowledge and explore the origins of that concern.

Communication assessment using the common ground instrument: psychometric properties.

BACKGROUND AND OBJECTIVES: Recent guidelines from the Association of American Medical Colleges and from the Accreditation Council for Graduate Medical Education strongly suggest that communications teaching and assessment be part of medical education at all levels. This study's objective was to validate an instrument to assess communications skills. This instrument, Common Ground, is linked to the core, generic communication skills emphasized by the consensus statements of Toronto and Kalamazoo. METHODS: A total of 100 medical students were recruited from two medical schools and tested with four-station, communications-focused objective structured clinical examinations. Using Common Ground, trained raters performed checklist and global rating assessments. Experts globally assessed 20 representative interviews. RESULTS: Inter-rater reliability for Common Ground was 0.85 for the overall global ratings and 0.92 for the overall checklist assessment. Generalizability coefficient was 0.80 for 50 minutes of testing. The correlation between the ratings of trained raters and a panel of communication experts was 0.84. CONCLUSIONS: The Common Ground assessment instrument assesses core communication skills with sufficient reliability, validity, and generalizablity to make decisions on medical students' performance.

Determining Component Weights in a Communications Assessment Using Judgmental Policy Capturing.

OBJECTIVES: Tools are needed for determining appropriate weights for complex performance assessment components in medical education. The feasibility of using judgmental policy capturing (JPC), a procedure to statistically describe the information processing strategies of experts, for this purpose was investigated. METHODS: Iterative JPC was used to determine appropriate weighting for the six core communication skill scores from a communications objective structured clinical examination (OSCE) for medical students using a panel of four communication skill experts. RESULTS: The mean regression weights from the panel indicated they placed less importance on information management (8.5%), moderate and nearly equal importance on rapport building (15.8%), agenda setting (15.4%), and addressing feelings (14.1%), and greater importance on active listening (20.1%) and reaching common ground with the patient (25.5%). DISCUSSION: JPC is an effective procedure for determining appropriate weights for complex clinical assessment components. The derived weights may be very different for those assessment components.

Responding effectively to patient anger directed at the physician.

BACKGROUND AND OBJECTIVES: Patient anger because of a long wait is a common occurrence, but few studies have looked at how the anger should be addressed. This study determined patient levels of satisfaction, rating of importance, and preference for a variety of approaches for addressing anger being directed toward a physician. METHODS: A video trigger tape of an angry patient and 12 physician responses to the angry patient were shown to 130 participants who then rated the physician responses based on four approaches, alone or in combination (apology, explanation, self disclosure, and acknowledgment) for satisfaction and importance of the response. Participants also evaluated four physician follow-up questions. RESULTS: An apology combined with an explanation was rated highest in satisfaction and importance and individually ranked as the best approaches for physicians to use. "I apologize for your long wait" was rated significantly higher than "I am sorry you have been kept waiting." Although gender and prior high anger with clinicians affected the ratings of some responses, participants consistently preferred an apology and/or an apology combined with explanation as the best response. Participants also preferred physician follow-up questions that facilitated segue to the medical interview rather than questions that explored patient feelings. CONCLUSIONS: Participants clearly indicated that they would like a physician to apologize, explain the reason for the delay, and then quickly move along with the interview.