Ineffective control of Epstein-Barr-virus-induced autoimmunity increases the risk for multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the CNS. Epstein-Barr virus (EBV) contributes to the MS pathogenesis because high levels of EBV EBNA386-405-specific antibodies cross react with the CNS-derived GlialCAM370-389. However, it is unclear why only some individuals with such high autoreactive antibody titers develop MS. Here, we show that autoreactive cells are eliminated by distinct immune responses, which are determined by genetic variations of the host, as well as of the infecting EBV and human cytomegalovirus (HCMV). We demonstrate that potent cytotoxic NKG2C+ and NKG2D+ natural killer (NK) cells and distinct EBV-specific T cell responses kill autoreactive GlialCAM370-389-specific cells. Furthermore, immune evasion of these autoreactive cells was induced by EBV-variant-specific upregulation of the immunomodulatory HLA-E. These defined virus and host genetic pre-dispositions are associated with an up to 260-fold increased risk of MS. Our findings thus allow the early identification of patients at risk for MS and suggest additional therapeutic options against MS.

The genetic basis for cancer treatment decisions.

Personalized cancer medicine is based on increased knowledge of the cancer mutation repertoire and availability of agents that target altered genes or pathways. Given advances in cancer genetics, technology, and therapeutics development, the timing is right to develop a clinical trial and research framework to move future clinical decisions from heuristic to evidence-based decisions. Although the challenges of integrating genomic testing into cancer treatment decision making are wide-ranging and complex, there is a scientific and ethical imperative to realize the benefits of personalized cancer medicine, given the overwhelming burden of cancer and the unprecedented opportunities for advancements in outcomes for patients.

HLA-E-restricted immune responses are crucial for the control of EBV infections and the prevention of PTLD.

Primary Epstein-Barr virus (EBV) infections may cause infectious mononucleosis (IM), whereas EBV reactivations in solid organ and hematopoietic stem cell transplant recipients are associated with posttransplantation lymphoproliferative disorders (PTLDs). It is still unclear why only a minority of primary EBV-infected individuals develop IM, and why only some patients progress to EBV+PTLD after transplantation. We now investigated whether nonclassic human leukocyte antigen E (HLA-E)-restricted immune responses have a significant impact on the development of EBV diseases in the individual host. On the basis of a large study cohort of 1404 patients and controls as well as on functional natural killer (NK) and CD8+ T-cell analyses, we could demonstrate that the highly expressed HLA-E∗0103/0103 genotype is protective against IM, due to the induction of potent EBV BZLF1-specific HLA-E-restricted CD8+ T-cell responses, which efficiently prevent the in vitro viral dissemination. Furthermore, we provide evidence that the risk of symptomatic EBV reactivations in immunocompetent individuals as well as in immunocompromised transplant recipients depends on variations in the inhibitory NKG2A/LMP-1/HLA-E axis. We show that EBV strains encoding for the specific LMP-1 peptide variants GGDPHLPTL or GGDPPLPTL, presented by HLA-E, elicit strong inhibitory NKG2A+ NK and CD8+ T-cell responses. The presence of EBV strains encoding for both peptides was highly associated with symptomatic EBV reactivations. The further progression to EBV+PTLD was highly associated with the presence of both peptide-encoding EBV strains and the expression of HLA-E∗0103/0103 in the host. Thus, HLA-E-restricted immune responses and the NKG2A/LMP-1/HLA-E axis are novel predictive markers for EBV+PTLD in transplant recipients and should be considered for future EBV vaccine design.

A Phase I Dose-Escalation Study of LY3405105, a Covalent Inhibitor of Cyclin-Dependent Kinase 7, Administered to Patients With Advanced Solid Tumors.

BACKGROUND: This study aimed to evaluate the safety, pharmacokinetics (PKs), and preliminary activity of LY3405105, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), in patients with advanced solid tumors. MATERIALS AND METHODS: LY3405105 monotherapy was given once daily (QD; part A1) or thrice weekly (TIW; part A2) starting at 1 and 2 mg orally, respectively, and escalated per a Bayesian design in adult patients. The primary endpoint was safety, and secondary endpoints included PKs and antitumor activity. RESULTS: Fifty-four patients were enrolled: 43 in part A1 and 11 in part A2. Seven patients had dose-limiting toxicities, all in part A1 (45 mg: n = 3; 35 mg: n = 3; 25 mg: n = 1). Thirty-five patients (64.8%) reported at least one treatment-related adverse event (TRAE). TRAEs (≥10%) were diarrhea, nausea, fatigue, vomiting, abdominal pain, anemia, asthenia, and decreased platelet count. QD dosing showed sustained exposure with less peak-trough fluctuation compared to TIW dosing. Median time to maximum concentration was 1-2 hours and half-life was 15-19 hours. CDK7-target occupancy in skin and peripheral blood on day 15 was dose-dependent and reached near maximal occupancy of 75% at ≥15 mg QD. The maximum tolerated dose (MTD) was 20 mg QD. Twelve patients in part A1 (27.9%) and 5 patients in part A2 (45.5%) had a best overall response of stable disease. No complete response or partial response was observed. CONCLUSION: The MTD of LY3405105 monotherapy was 20 mg QD. The most common toxicities were gastrointestinal adverse events, myelosuppression, fatigue, and asthenia. Limited clinical activity was observed in this phase I trial, and there are no plans for further development. CLINICALTRIALS.GOV IDENTIFIER: NCT03770494.

Ziv-aflibercept plus pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment.

BACKGROUND: Vascular endothelial growth factor is associated with reduced immune response and impaired anti-tumor activity. Combining antiangiogenic agents with immune checkpoint inhibition can overcome this immune suppression and enhance treatment efficacy. METHODS: This study investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment. Baseline and on-treatment plasma and PBMC samples were analyzed by multiplex protein assay and mass cytometry, respectively. RESULTS: In this Phase 1B study (NCT02298959), ten patients with advanced PD-1-resistant melanoma were treated with a combination of ziv-aflibercept (at 2-4 mg/kg) plus pembrolizumab (at 2 mg/kg), administered intravenously every 2 weeks. Two patients (20%) achieved a partial response, and two patients (20%) experienced stable disease (SD) as the best response. The two responders had mucosal melanoma, while both patients with SD had ocular melanoma. The combination therapy demonstrated clinical activity and acceptable safety, despite the occurrence of adverse events. Changes in plasma analytes such as platelet-derived growth factor and PD-L1 were explored, indicating potential alterations in myeloid cell function. Higher levels of circulating CXCL10 in non-responding patients may reflect pro-tumor activity. Specific subsets of γδ T cells were associated with poor clinical outcomes, suggesting impaired γδ T-cell function in non-responding patients. CONCLUSIONS: Although limited by sample size and follow-up, these findings highlight the potential of the combination of ziv-aflibercept antiangiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment and the need for further research to improve outcomes in anti-PD-1-resistant melanoma. TRIAL REGISTRATION NUMBER: NCT02298959.

Sensitive tumour detection and classification using plasma cell-free DNA methylomes.

The use of liquid biopsies for cancer detection and management is rapidly gaining prominence1. Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations2-5. By contrast, large-scale epigenetic alterations-which are tissue- and cancer-type specific-are not similarly constrained6 and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns.

Women Anesthesiologists in Sub-Saharan Africa in the Pre-COVID Era: A Multinational Demographic Study.

BACKGROUND: Gender imbalance and poor representation of women complicate the anesthesiology workforce crisis in sub-Saharan Africa (SSA). This study was performed to obtain a better understanding of gender disparity among medical graduates and anesthesiologists in SSA. METHODS: Using a quantitative, participatory, insider research study, led by female anesthesiologists as the national coordinators in SSA, we collected data from academic or national health authorities and agencies. National coordinators were nominees of anesthesiology societies that responded to our email invitations. Data gathered from 13 countries included information on medical graduates, anesthesiologists graduating between 1998 and 2021, and number of anesthesiologists licensed to practice in 2018. We compared data between Francophone and Anglophone countries, and between countries in East Africa and West Africa/Central Africa. We calculated anesthesiology workforce densities and compared representation of women among graduating anesthesiologists and medical graduates.Data analysis was performed using linear regression. We used F-tests on regression slopes to assess the trends in representation of women over the years and the differences between the slopes. A value of P < .050 was considered statistically significant. RESULTS: Over a 20-year period, the representation of female medical graduates in SSA increased from 29% (1998) to 41% (2017), whereas representation of female anesthesiologists was inconsistent, with an average of 25%, and lagged behind. Growth and gender disparity patterns were different between West Africa/Central Africa and East Africa. Representation of female anesthesiologists was higher in East Africa (39.4%) than West Africa/Central Africa (19.7%); and the representation of female medical graduates in East Africa (42.5%) was also higher that West Africa/Central Africa (33.1%). CONCLUSIONS: On average, in SSA, female medical graduates (36.9%), female anesthesiologists (24.9%), and female anesthesiology residents projected to graduate between 2018 and 2022 (25.2%) were underrepresented when compared to their male counterparts. Women were underrepresented in SSA, despite evidence that their representation in medicine and anesthesiology in East African countries was rising.

Psychological distress following multi-gene panel testing for hereditary breast and ovarian cancer risk.

Advances in our understanding of the genetic landscape of hereditary breast and ovarian cancer (HBOC) have led to the clinical adoption of multi-gene panel testing. Panel testing introduces new sources of genetic uncertainty secondary to the inclusion of moderate- and low-penetrance genes, as well as the increased likelihood of identifying a variant of uncertain significance (VUS). This cross-sectional study explored the post-test psychological functioning of women who underwent multi-gene panel testing for HBOC susceptibility genes. Two hundred and ninety-five women who underwent panel testing within the previous 2 years completed a study questionnaire to measure levels of cancer-related and genetic testing-related distress using the Impact of Events Scale (IES) and the Multidimensional Impact of Cancer Risk Assessment (MICRA), respectively. Multiple regression analyses were conducted to evaluate the relationship between genetic test results and levels of psychological distress captured by the IES and MICRA. In this cohort, a pathogenic variant (PV) was identified in 41 (14%) of participants, and 77 (26%) participants were found to have a VUS. In the multi-variate model, higher mean levels of genetic testing-related distress were observed in individuals with a PV (p < 0.001) or a VUS (p = 0.007) compared to those with a negative result. Furthermore, participants with a PV in a moderate-penetrance gene were found to have higher levels of genetic testing-related distress compared to those with a PV in a high-risk gene (p = 0.03). Overall, participants were highly satisfied with their genetic testing experience, with 92% of individuals reporting they would recommend testing to others. Our findings highlight differences in psychological outcomes based on both variant pathogenicity and gene penetrance, which contribute to our understanding of the impact of panel testing and sources of both cancer-related and genetic testing-related distress secondary to testing.

A tailored phase I-specific patient-reported outcome (PRO) survey to capture the patient experience of symptomatic adverse events.

BACKGROUND: Patient perspectives are fundamental to defining tolerability of investigational anti-neoplastic therapies in clinical trials. Phase I trials present a unique challenge in designing tools for efficiently collecting patient-reported outcomes (PROs) given the difficulty of anticipating adverse events of relevance. However, phase I trials also offer an opportunity for investigators to optimize drug dosing based on tolerability for future larger-scale trials and in eventual clinical practice. Existing tools for comprehensively capturing PROs are generally cumbersome and are not routinely used in phase I trials. METHODS: Here, we describe the creation of a tailored survey based on the National Cancer Institute's PRO-CTCAE for collecting patients' perspectives on symptomatic adverse events in phase I trials in oncology. RESULTS: We describe our stepwise approach to condensing the original 78-symptom library into a modified 30 term core list of symptoms which can be efficiently applied. We further show that our tailored survey aligns with phase I trialists' perspectives on symptoms of relevance. CONCLUSIONS: This tailored survey represents the first PRO tool developed specifically for assessing tolerability in the phase I oncology population. We provide recommendations for future work aimed at integrating this survey into clinical practice.

Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase. METHODS: We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety. RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group. CONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.).

The natural killer cell-associated rs9916629-C allele is a novel genetic risk factor for fatal COVID-19.

The severity of COVID-19 is associated with individual genetic host factors. Among these, genetic polymorphisms affecting natural killer (NK) cell responses, as variations in the HLA-E- (HLA-E*0101/0103), FcγRIIIa- (FcγRIIIa-158-F/V), and NKG2C- (KLRC2wt/del ) receptor, were associated with severe COVID-19. Recently, the rs9916629-C/T genetic polymorphism was identified that indirectly shape the human NK cell repertoire towards highly pro-inflammatory CD56bright NK cells. We investigated whether the rs9916629-C/T variants alone and in comparison to the other risk factors are associated with a fatal course of COVID-19. We included 1042 hospitalized surviving and 159 nonsurviving COVID-19 patients as well as 1000 healthy controls. rs9916629-C/T variants were genotyped by TaqMan assays and were compared between the groups. The patients' age, comorbidities, HLA-E*0101/0103, FcγRIIIa-158-F/V, and KLRC2wt/del variants were also determined. The presence of the rs9916629-C allele was a risk factor for severe and fatal COVID-19 (p < 0.0001), independent of the patients' age or comorbidities. Fatal COVID-19 was more frequent in younger patients (<69.85 years) carrying the FcγRIIIa-158-V/V (p < 0.006) and in older patients expressing the KLRC2del variant (p < 0.003). Thus, patients with the rs9916629-C allele have a significantly increased risk for fatal COVID-19 and identification of the genetic variants may be used as prognostic marker for hospitalized COVID-19 patients.

Symptom screening with Targeted Early Palliative care (STEP) versus usual care for patients with advanced cancer: a mixed methods study.

PURPOSE: Although early palliative care is recommended, resource limitations prevent its routine implementation. We report on the preliminary findings of a mixed methods study involving a randomized controlled trial (RCT) of Symptom screening with Targeted Early Palliative care (STEP) and qualitative interviews. METHODS: Adults with advanced solid tumors and an oncologist-estimated prognosis of 6-36 months were randomized to STEP or symptom screening alone. STEP involved symptom screening at each outpatient oncology visit; moderate to severe scores triggered an email to a palliative care nurse, who offered referral to in-person outpatient palliative care. Patient-reported outcomes of quality of life (FACT-G7; primary outcome), depression (PHQ-9), symptom control (ESAS-r-CS), and satisfaction with care (FAMCARE P-16) were measured at baseline and 2, 4, and 6 months. Semi-structured interviews were conducted with a subset of participants. RESULTS: From Aug/2019 to Mar/2020 (trial halted due to COVID-19 pandemic), 69 participants were randomized to STEP (n = 33) or usual care (n = 36). At 6 months, 45% of STEP arm patients and 17% of screening alone participants had received palliative care (p = 0.009). Nonsignificant differences for all outcomes favored STEP: difference in change scores for FACT-G7 = 1.67 (95% CI: -1.43, 4.77); ESAS-r-CS = -5.51 (-14.29, 3.27); FAMCARE P-16 = 4.10 (-0.31, 8.51); PHQ-9 = -2.41 (-5.02, 0.20). Sixteen patients completed qualitative interviews, describing symptom screening as helpful to initiate communication; triggered referral as initially jarring but ultimately beneficial; and referral to palliative care as timely. CONCLUSION: Despite lack of power for this halted trial, preliminary results favored STEP and qualitative results demonstrated acceptability. Findings will inform an RCT of combined in-person and virtual STEP.

Pharmacogenetics-guided dalcetrapib therapy after an acute coronary syndrome: the dal-GenE trial.

AIMS: In a retrospective analysis of dal-Outcomes, the effect of dalcetrapib on cardiovascular events was influenced by an adenylate cyclase type 9 (ADCY9) gene polymorphism. The dal-GenE study was conducted to test this pharmacogenetic hypothesis. METHODS AND RESULTS: dal-GenE was a double-blind trial in patients with an acute coronary syndrome within 1-3 months and the AA genotype at variant rs1967309 in the ADCY9 gene. A total of 6147 patients were randomly assigned to receive dalcetrapib 600 mg or placebo daily. The primary endpoint was the time from randomization to first occurrence of cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, or non-fatal stroke. After a median follow-up of 39.9 months, the primary endpoint occurred in 292 (9.5%) of 3071 patients in the dalcetrapib group and 327 (10.6%) of 3076 patients in the placebo group [hazard ratio 0.88; 95% confidence interval (CI) 0.75-1.03; P = 0.12]. The hazard ratios for the components of the primary endpoint were 0.79 (95% CI 0.65-0.96) for myocardial infarction, 0.92 (95% CI 0.64-1.33) for stroke, 1.21 (95% CI 0.91-1.60) for death from cardiovascular causes, and 2.33 (95% CI 0.60-9.02) for resuscitated cardiac arrest. In a pre-specified on-treatment sensitivity analysis, the primary endpoint event rate was 7.8% (236/3015) in the dalcetrapib group and 9.3% (282/3031) in the placebo group (hazard ratio 0.83; 95% CI 0.70-0.98). CONCLUSION: Dalcetrapib did not significantly reduce the risk of occurrence of the primary endpoint of ischaemic cardiovascular events at end of study. A new trial would be needed to test the pharmacogenetic hypothesis that dalcetrapib improves the prognosis of patients with the AA genotype. CLINICAL TRIAL REGISTRATION: Trial registration dal-GenE ClinicalTrials.gov Identifier: NCT02525939.

No evidence of disease versus residual disease in long-term responders to first-line HER2-targeted therapy for metastatic breast cancer.

BACKGROUND: Long-term response to HER2-targeted therapies is infrequent in metastatic breast cancer (MBC). We evaluated clinical characteristics of HER2-positive MBC patients with no evidence of disease (NED) vs residual disease (RES) experiencing long-term response to first-line HER2-targeted therapy. METHODS: Patients receiving first-line chemotherapy-trastuzumab (CT) or taxane-trastuzumab-pertuzumab (THP) with response duration ≥2-fold higher than in phase II/III trials (CT [18.2 months]; THP [40.4 months]) were included. Clinical characteristics and radiographic review for NED or RES was evaluated by Cox-regression (hazard ratio; HR) or Kaplan-Meier (log-rank). Characteristics associated with NED were evaluated by logistic regression (Odds; OR). RESULTS: From 01/2005-01/2016, N = 103 (4.6%) patients were identified. In multivariate analyses, NED (N = 46) showed improved progression-free (PFS) and overall survival (OS) [p < 0.001] versus RES (N = 57), with high 5-year PFS/OS for NED (93.2%/97.4%) relative to RES (10.6%/61.3%). Premenopausal status (p = 0.006), de-novo metastases (p = 0.002), and no palliative radiotherapy (p = 0.01) were associated with NED. Overall, 6/7 (85.7%) patients with NED were alive and disease-free after discontinuing HER2 treatment (≥1 year) versus 1/17 (5.9%) with RES. CONCLUSIONS: Long-term responders with NED have better survival compared to RES. Premenopausal status and de novo metastatic disease are associated with NED. Prospective studies of HER2 therapy discontinuation with NED in MBC are warranted.

Evaluation of the patient experience of symptomatic adverse events on Phase I clinical trials using PRO-CTCAE.

BACKGROUND: Adverse event (AE) reporting in early-phase clinical trials is essential in determining the tolerability of experimental anticancer therapies. The patient-reported outcome version of the CTCAE (PRO-CTCAE) evaluates AE components such as severity and interference in daily life. The aim of this study was to correlate the grade of clinician-reported AEs with patients' reported experience of these toxicities using PRO-CTCAE. METHODS: Patients with advanced solid tumours enrolled on Phase I clinical trials were surveyed using the PRO-CTCAE. Symptomatic AEs were recorded by physicians using the CTCAE. A logistic regression model was used to assess associations between CTCAE grade and PRO responses. RESULTS: Of 219 evaluable patients, 81 experienced a high-grade (3/4) clinician-reported symptom, and of these, only 32 (40%) and 26 (32%) patients concordantly reported these as either severe or very severe, and interfering with daily life either 'quite a bit' or 'very much', respectively. Of the 137 patients who experienced a low-grade (1/2) clinician-reported AE as their worst symptom, 98 (72%) and 118 (86%) patients concordantly reported these as either mild-moderate severity and minimally interfering with daily life, respectively. There was a statistically significant association between clinician-reported AE grade and interference. Interference scores were also associated with dose reductions. CONCLUSION: This is the first study to explore patient-reported severity and interference from symptomatic toxicities and compare clinician grading of the same toxicities. The study provided further evidence to support the added value of the PRO-CTCAE in Phase I oncology trials, which would make AE reporting patient-centred. Further work is needed to determine how this would affect the assessment of tolerability.

Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction.

BACKGROUND: Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis. METHODS: We performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed. RESULTS: A total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P = 0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P = 0.03). CONCLUSIONS: Among patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.).

Novel classes of immunotherapy for breast cancer.

Immune-checkpoint inhibitors have profoundly changed the treatment landscape for many tumor types. Despite marked improvements in disease control for highly immunogenic cancers, the clinical impact of checkpoint inhibitors in breast cancers to date is limited. Breast cancer is a heterogeneous disease with different levels of PD-L1 expression and variable tumor microenvironment (TME) composition according to molecular subtype. With emerging evidence of the role of different factors involved in immune evasion, there are promising new immunotherapy targets that will reshape early drug development for metastatic breast cancer. This review examines the available evidence for existing and emerging immuno-oncology (IO) approaches including small molecules targeting different regulators of the cancer-immunity cycle.

A phase III trial of alpelisib + trastuzumab ± fulvestrant versus trastuzumab + chemotherapy in HER2+ PIK3CA-mutated breast cancer.

ALPHABET is a randomized phase III trial assessing alpelisib + trastuzumab with or without fulvestrant in previously treated HER2-positive PIK3CA-mutated advanced breast cancer. Patients will be included in two cohorts according to hormone receptor (HR) status. In the experimental arms, patients in the HR-negative cohort will receive trastuzumab + alpelisib, and patients in the HR-positive cohort will receive the same treatment plus fulvestrant. Patients in the control arms will receive trastuzumab + physician's choice chemotherapy (eribuline, capecitabine or vinorelbine). Key eligibility criteria include 1-4 previous lines of anti-HER2 therapy and prior trastuzumab emtansine. The primary end point is investigator-assessed progression-free survival. The study aims to recruit a total of 300 patients.

ALPHABET is a clinical study investigating the potential use of alpelisib for the treatment of certain subtypes of breast cancer. Alpelisib is a novel drug that is given orally. It specifically targets a protein called PI3K. PI3K is hyperactivated in some tumors, allowing uncontrolled growth. This study is enrolling patients with HER2-positive advanced breast cancer whose tumor tests positive for a mutation in the PIK3CA gene, which encodes PI3K. Patients are allocated at random to receive either a combination treatment of trastuzumab (an anti-HER2-targeted therapy) with alpelisib or standard chemotherapy and trastuzumab without alpelisib. The efficacy of each treatment will be determined by comparing how long patients in each group live for without further tumor growth. Additional analyses will also look at the side effects experienced by patients, as well as their quality of life.

Neurological Determination of Death Following Infratentorial Stroke: A Population-Based Cohort Study.

BACKGROUND: There is international variability in whether neurological determination of death (NDD) is conceptually defined based on permanent loss of brainstem function or "whole brain death." Canadian guidelines are not definitive. Patients with infratentorial stroke may meet clinical criteria for NDD despite persistent cerebral blood flow (CBF) and relative absence of supratentorial injury. METHODS: We performed a multicenter cohort study involving patients that died from ischemic or hemorrhagic stroke in Alberta intensive care units from 2013 to 2019, focusing on those with infratentorial involvement. Medical records were reviewed to determine the incidence and proportion of patients that met clinical criteria for NDD; whether ancillary testing was performed; and if so, whether this demonstrated the absence of CBF. RESULTS: There were 95 (27%) deaths from infratentorial and 263 (73%) from supratentorial stroke. Sixteen patients (17%) with infratentorial stroke had neurological examination consistent with NDD (0.55 cases per million per year). Among patients that underwent confirmatory evaluation for NDD with an apnea test, ancillary test (radionuclide scan), or both, ancillary testing was more common with infratentorial compared with supratentorial stroke (10/12 (85%) vs. 25/47 (53%), p = 0.04). Persistent CBF was detected in 6/10 (60%) patients with infratentorial compared with 0/25 with supratentorial stroke (p = 0.0001). CONCLUSIONS: Infratentorial stroke leading to clinical criteria for NDD occurs with an annual incidence of about 0.55 per million. There is variability in clinicians' use of ancillary testing. Persistent CBF was detected in more than half of patients that underwent radionuclide scans. Canadian consensus is needed to guide clinical practice.

Indirect x-ray photodesorption of N215 and CO13 from mixed and layered ices.

X-ray photodesorption yields of N215 and CO13 are derived as a function of the incident photon energy near the N (∼400 eV) and O K-edge (∼500 eV) for pure N215 ice and mixed CO13:N215 ices. The photodesorption spectra from the mixed ices reveal an indirect desorption mechanism for which the desorption of N215 and CO13 is triggered by the photoabsorption of CO13 and N215, respectively. This mechanism is confirmed by the x-ray photodesorption of CO13 from a layered CO13/N215 ice irradiated at 401 eV on the N 1s → π* transition of N215. This latter experiment enables us to quantify the relevant depth involved in the indirect desorption process, which is found to be 30-40 monolayers in that case. This value is further related to the energy transport of Auger electrons emitted from the photoabsorbing N215 molecules that scatter toward the ice surface, inducing the desorption of CO13. The photodesorption yields corrected from the energy that can participate in the desorption process (expressed in molecules desorbed by eV deposited) do not depend on the photon energy; hence, they depend neither on the photoabsorbing molecule nor on its state after Auger decay. This demonstrates that x-ray induced electron stimulated desorption, mediated by Auger scattering, is the dominant process explaining the desorption of N215 and CO13 from the ices studied in this work.