Tumor mutational burden and PTEN alterations as molecular correlates of response to PD-1/L1 blockade in metastatic triple-negative breast cancer

Purpose: Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICI). On the basis of immunotherapy response correlates in other cancers, we evaluated whether high tumor mutational burden (TMB) ≥10 nonsynonymous mutations/megabase and PTEN alterations, defined as nonsynonymous mutations or 1 or 2 copy deletions, were associated with clinical benefit to anti-PD-1/L1 therapy in mTNBC. Experimental design: We identified patients with mTNBC, who consented to targeted DNA sequencing and were treated with ICIs on clinical trials between April 2014 and January 2019 at Dana-Farber Cancer Institute (Boston, MA). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were correlated with tumor genomic features. Results: Sixty-two women received anti-PD-1/L1 inhibitors alone (23%) or combined with targeted therapy (19%) or chemotherapy (58%). High TMB (18%) was associated with significantly longer PFS (12.5 vs. 3.7 months; P = 0.04), while PTEN alterations (29%) were associated with significantly lower ORR (6% vs. 48%; P = 0.01), shorter PFS (2.3 vs. 6.1 months; P = 0.01), and shorter OS (9.7 vs. 20.5 months; P = 0.02). Multivariate analyses confirmed that these associations were independent of performance status, prior lines of therapy, therapy regimen, and visceral metastases. The survival associations were additionally independent of PD-L1 in patients with known PD-L1 and were not found in mTNBC cohorts treated with chemotherapy (n = 90) and non-ICI regimens (n = 169). Conclusions: Among patients with mTNBC treated with anti-PD-1/L1 therapies, high TMB and PTEN alterations were associated with longer and shorter survival, respectively. These observations warrant validation in larger datasets

An investigation of overlap in children's speech

The simultaneous speech of six 4-year-old girls was investigated within three-party conversation. The data reveal two major types of overlap, one providing instances of turn completion projections and the other reflecting tension for the turn at speaking. The data are discussed in terms of the Sacks, Schegloff, and Jefferson (1974) model of conversational interaction.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45101/1/10936_2005_Article_BF01067502.pd

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Topical silver diamine fluoride (SDF) for preventing and managing dental caries in children and adults

Background Dental caries is the world's most prevalent disease. Untreated caries can cause pain and negatively impact psychosocial health, functioning, and nutrition. It is important to identify cost‐effective, easy‐to‐use agents, which can prevent or arrest caries. This review evaluates silver diamine fluoride (SDF). Objectives To assess the effects of silver diamine fluoride for preventing and managing caries in primary and permanent teeth (coronal and root caries) compared to any other intervention including placebo or no treatment. Search methods We searched CENTRAL, MEDLINE, Embase, Cochrane Oral Health's Trial Register and two clinical trials registers in June 2023. Selection criteria We included randomised controlled trials (RCTs), with parallel‐group or split‐mouth design, in children and adults (with or without carious lesions) that compared SDF with placebo or no treatment; different frequencies, concentrations or duration of SDF; or any other intervention. Data collection and analysis We used standard methodological procedures expected by Cochrane, and GRADE to assess the certainty of the evidence. We collected data for primary caries prevention (change in caries increment), arrest of carious lesions, secondary prevention of caries (lesions do not progress from initial classification), adverse effects, dental pain or sensitivity, and aesthetics at the end of study follow‐up. Main results We included 29 RCTs (13,036 participants; 12,020 children, 1016 older adults). We summarise outcome data for the five most clinically relevant comparisons. All studies included high risks of bias, and some findings were imprecise (e.g. because of small sample sizes). SDF versus placebo or no treatment (14 studies; 2695 children, 905 older adults) Compared to placebo or no treatment, SDF may help prevent new caries in the primary dentition (1 study, 373 participants), or on the coronal surfaces of permanent dentition (1 study, 373 participants) but the evidence is very uncertain. SDF likely prevents new root caries (mean difference (MD) −0.79 surfaces, 95% confidence interval (CI) −1.40 to −0.17; 3 studies, 439 participants; moderate‐certainty evidence). SDF may help arrest caries in the primary dentition (MD 0.86 surfaces, 95% CI 0.39 to 1.33; 2 studies, 841 participants; low‐certainty evidence) and the permanent dentition (coronal: 1 study, 373 participants; root: 1 study, 158 participants) but the evidence is very uncertain. The evidence is very uncertain for secondary prevention of caries (primary dentition: 1 study, 128 participants; permanent dentition (coronal): 1 study, 663 participants), for adverse effects (5 studies, 1299 participants), and aesthetics (1 study, 43 participants). Different approaches to SDF application (5 studies, 1808 children) Studies compared different frequencies or intervals of application, different concentrations of SDF, and different durations of treatment. Some studies included multiple comparisons of different approaches. Because of the different approaches, we could not combine findings from these studies. Due to very low‐certainty evidence, we were unsure whether any approach to SDF application was better than another for caries arrest (4 studies, including 8 comparisons of different approaches, 1360 participants); secondary prevention of caries (1 study, 203 participants), or led to differences in adverse effects (3 studies, 1121 children) or aesthetics (1 study, 119 children). SDF versus fluoride varnish (8 studies, 2868 children, 223 older adults) Compared to flouride varnish, SDF may result in little or no difference to the prevention of new caries in the primary dentition (MD 0.00, 95% CI ‐0.26 to 0.26; 1 study, 434 participants; low‐certainty evidence). The evidence is very uncertain for this outcome measure in the permanent dentition (coronal: 1 study, 237 participants; root: 1 study, 100 participants; very low‐certainty evidence). Due to very low‐certainty evidence, we were unsure whether or not there were any differences between flouride varnish (applied weekly for three applications) and SDF for caries arrest and secondary prevention of caries in the primary dentition (1 study, 309 participants). Similarly, we were unsure of adverse effects (3 studies, 980 children), dental pain or sensitivity (1 study, 62 children), or aesthetics (1 study, 263 children). SDF versus sealants and resin infiltration (2 studies, 343 children) Very low‐certainty evidence in this comparison meant we were unsure if either treatment was better than the other for primary prevention of caries in permanent dentition (coronal: 1 study, 242 participants), or adverse effects (2 studies, 336 participants). SDF versus atraumatic restorative treatment (ART) with glass ionomer cement (GIC) or GI material (4 studies, 610 children) Very low‐certainty evidence in this comparison meant we were unsure if either treatment was better than the other at arresting caries in the primary dentition (1 study, 143 participants). We were also unsure whether there were any differences between treatments in adverse effects (3 studies, 482 participants), dental pain or sensitivity (1 study, 234 participants), or aesthetics (2 studies, 248 participants). Authors' conclusions In the primary dentition, evidence remains uncertain whether SDF prevents new caries or progression of existing caries compared to placebo or no treatment, but it may offer benefit over placebo or no treatment in caries arrest. Compared to placebo or no treatment, SDF probably also helps prevent new root caries. However, the evidence is uncertain for other caries outcome measures in this dentition and in all caries outcomes for coronal surfaces of permanent dentition. Compared to flouride varnish, SDF may offer little or no benefit in preventing new caries in the primary dentition, but the evidence is very uncertain for other caries outcome measures in the primary dentition and for preventing new caries in the permanent dentition. We were unable to establish whether one SDF treatment approach was better than another, or how SDF compared to other treatments, because of very low‐certainty evidence. The impact of SDF staining of teeth was poorly reported and the evidence for adverse effects is very uncertain. Additional well‐conducted studies are needed. These should measure the impact of staining and be analysed to take account of clustering issues within participants

Phase Ib study of pembrolizumab in combination with trastuzumab emtansine for metastatic HER2-positive breast cancer

Background Preclinical and clinical data support potential synergy between anti-HER2 therapy plus immune checkpoint blockade. The safety and tolerability of trastuzumab emtansine (T-DM1) combined with pembrolizumab is unknown.Methods This was a single-arm phase Ib trial (registration date January 26, 2017) of T-DM1 plus pembrolizumab in metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Eligible patients had HER2-positive, metastatic breast cancer previously treated with taxane, trastuzumab, and pertuzumab, and were T-DM1-naïve. A dose de-escalation design was used, with a dose-finding cohort followed by an expansion cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies. The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Immune biomarkers were assessed using histology, protein/RNA expression, and whole exome sequencing. Associations between immune biomarkers and treatment response, and biomarker changes before and during treatment, were explored.Results 20 patients received protocol therapy. There were no dose-limiting toxicities. The RP2D was 3.6 mg/kg T-DM1 every 21 days plus 200 mg pembrolizumab every 21 days. 85% of patients experienced treatment-related adverse events (AEs) ≥grade 2, 20% of patients experienced grade 3 AEs, and no patients experienced grade >4 AEs. Four patients (20%) experienced pneumonitis (three grade 2 events; one grade 3 event). ORR was 20% (95% CI 5.7% to 43.7%), and median PFS was 9.6 months (95% CI 2.8 to 16.0 months). Programmed cell death ligand-1 and tumor infiltrating lymphocytes did not correlate with response in this small cohort.Conclusions T-DM1 plus pembrolizumab was a safe and tolerable regimen. Ongoing trials will define if there is a role for checkpoint inhibition in the management of HER2-positive metastatic breast cancer.Trial registration number NCT03032107