Publications

Immune Checkpoint Inhibitor Myocarditis and Left Ventricular Systolic Dysfunction

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, but ICI myocarditis (ICI-M) remains a potentially fatal complication. The clinical implications and predictors of left ventricular ejection fraction (LVEF) <50% in ICI-M are not well understood. The aim of this study was to identify factors associated with LVEF <50% vs ≥50% at the time of hospitalization for ICI-M. A secondary objective was to evaluate the relationship between LVEF and 30-day all-cause mortality. The International ICI-Myocarditis Registry, a retrospective, international, multicenter database, included 757 patients hospitalized with ICI-M. Patients were stratified by LVEF as reduced LVEF (<50%) or preserved LVEF (≥50%) on admission. Cox proportional hazards models were used to assess the associations between LVEF and clinical events, and multivariable logistic regression was conducted to examine factors linked to LVEF. Of 757 patients, 707 had documented LVEFs on admission: 244 (35%) with LVEF <50% and 463 (65%) with LVEF ≥50%. Compared with patients with LVEF ≥50%, those with LVEF <50% were younger (<70 years), had a body mass index of <25 kg/m2, and were more likely to have received chest radiation (24.2% vs 13.5%; P < 0.001). Multivariable analysis identified predictors of LVEF <50%, including exposure to v-raf murine sarcoma viral oncogene homolog B1/mitogen-activated protein kinase inhibitors, pre-existing heart failure, dyspnea at presentation, and at least 40 days from ICI initiation to ICI-M onset. Conversely, myositis symptoms were associated with LVEF ≥50%. LVEF <50% was marginally associated with 30-day all-cause mortality (unadjusted log-rank P = 0.062; adjusted for age, cancer types, and ICI therapy, HR: 1.50; 95% CI: 1.02-2.20). Dyspnea, time from ICI initiation, a history of heart failure, and prior cardiotoxic therapy may be predictors of an initial LVEF <50% in patients with ICI-M.

First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study

RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m2, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar-plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable. SIGNIFICANCE: CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies.This article is highlighted in the In This Issue feature, p. 983.

Evaluation of the reporting quality of clinical practice guidelines on prostate cancer using the RIGHT checklist

The International Reporting Items for Practice Guidelines in Healthcare (RIGHT) statement is a set of recommendations for reporting in clinical practice guidelines (CPGs). We aimed to use RIGHT to evaluate the reporting quality of CPGs on prostate cancer.We systematically searched literature databases and websites from January 1, 2018 to December 1, 2020 to identify CPGs on prostate cancer. Two investigators reviewed the identified articles and assessed the reporting quality independently by using the RIGHT checklist. We reported the proportions of guidelines that complied with each of the 35 RIGHT checklist item and the mean reporting compliance percentages for each of the seven domains of RIGHT.A total of 38 CPGs were included. The mean overall reporting rate over the included CPGs was 51.6%. Eighteen items were reported by more than half of the guidelines four items (1a 3, 7a and 13a) were reported by all guidelines. Items 7b (10.5%), 13b (10.5%), 14c (13.2%), and 18b (7.9%) had the lowest reporting proportions. The mean reporting rates in each RIGHT domain were 74.6% for "Basic Information", 26.3% for "Review and quality assurance", 59.9% for "Background", 43.7% for "Evidence", 43.2% for "Recommendations", 43.4% for "Funding and declaration and management of interests", and 43.0% for "Other information".The overall adherence of CPGs on prostate cancer to RIGHT checklist is poor. Following the RIGHT checklist during the development of the guideline could improve the quality of reporting in the future.

Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma

Abstract Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I–mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K–AKT–mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYC-driven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eμ-Myc lymphoma–bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies. Significance: Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eμ-Myc lymphoma–bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer. Cancer Discov; 6(1); 59–70. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 1

Microbiota-derived butyrate promotes a FOXO1-induced stemness program and preserves CD8+ T cell immunity against melanoma

Strength prediction of concrete-filled steel tubular columns using Categorical Gradient Boosting algorithm

Due to complexities from the interaction between steel tube and concrete filling of concrete-filled steel tubular (CFST) columns, their strengths are very complicated, which is a highly nonlinear relation with material strengths and geometry. Categorical gradient Boosting (CatBoost), which is advanced boosting machine, is presented to solve the problems. A total of 3103 tests, which is divided in four datasets, is trained and tested the learners to determine the ultimate axial strength as the output variable while the strength of materials (concrete and steel) and geometry (e.g., diameters/width/heights, thickness, effective length, eccentricities) are the input ones. The comparison of the present results from 10-fold cross validation and those from the code predictions (AISC 360-16, Eurocode 4 and AS/NZS 2327) and previous study shows very high prediction accuracy in terms of coefficient of determination (R2), which is the lowest value (R2 = 0.964) for Dataset 2 and the highest one (R2 = 0.996) for Dataset 1. While the predictions from three codes beyond material limit and slenderness are less conservative than those within it, CatBoost provides nearly similar experiment results with the mean values as unity without any limits. This algorithm can be used to predict an accurate strength of CFST columns.

Supplementary Data from γδ T Cells in Merkel Cell Carcinomas Have a Proinflammatory Profile Prognostic of Patient Survival

&lt;p&gt;RNA-seq and scRNA-seq count data and TCR contigs&lt;/p&gt;

30 Weight change analysis in advanced castration resistant prostate cancer (CRPC) patients treated with Abiraterone Acetate (AA) single agent and in combination with steroids

Patient-reported acute and chronic toxicities from adjuvant therapies post resection of melanoma.

e21568 Background: One year ofadjuvant anti-programmed cell death protein-1 (anti-PD1) or dabrafenib-trametinib are standards of care for patients (pts) with resected stage III-IV melanoma. There is limited data regarding the incidence, spectrum and resolution or persistence of toxicities from the pt’s perspective. We describe this in a real-world population up to 2 years post initiation of adjuvant therapy. Methods: A prospective, longitudinal study of pts with resected stage IIB-IV melanoma receiving adjuvant anti-PD1 or dabrafenib-trametinib at an Australian comprehensive cancer center. Fourteen items from the Patient-Reported Outcome version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) reflecting potential toxicities were collected pre-treatment and at 1, 3, 6, 12, and 24 months post treatment initiation using Research Electronic Data Capture (REDCap). PRO-CTCAE responses were converted to CTCAE-equivalent grades using a published algorithm. Chronic toxicities were defined as those persisting &gt;3 months after treatment cessation. Results: From September 2021-December 2024 , 70 pts were eligible and 52 (74%) consented: 17 (33%) female, median age 64 years (IQR 60-71), 46 (89%) had resected stage III, 32 (62%) adjuvant anti-PD1. 41 pts had completed treatment and 11 were still receiving treatment at data cut off (17 December 2024). The table shows the most common toxicities by PRO-CTCAE composite grade up to 2 years post initiation of adjuvant therapy. Most toxicities reported at 12 months persisted at 24 months (71/103 reported toxicities, 71%). Fatigue was the most commonly reported toxicity at 12 and 24 months. Of the 18 pts with data at both 12 and 24 months, 15 pts had fatigue at 12 months, persisting at 24 months in 14 pts (93%). In terms of chronic toxicities, 19 pts completed at least one survey &gt;3 months post treatment cessation and 18 (95%) reported ongoing toxicities. 16 (84%) had chronic fatigue, including 9 (82%) on adjuvant anti-PD1 and 7 (88%) on adjuvant targeted therapy. Conclusions: Both acute and chronic toxicities from adjuvant therapy are common. This data can inform shared decision-making regarding risks, benefits and expectations from adjuvant therapy and identify priorities for supportive care interventions. PRO-CTCAE term (n, %) Pre-treatment (n=51) 12 months (n=31) 24 months (n=18) No. of pts who completed item Any grade G1 &gt; G2 No. of pts who completed item Any grade G1 &gt; G2 No. of pts who completed item Any grade G1 &gt; G2 Fatigue 50 30 (60%) 23 (46%) 7 (14%) 31 24 (77%) 10 (32%) 14 (45%) 18 14 (78%) 5 (28%) 9 (50%) Skin dryness 51 13 (26%) 10 (20%) 3 (6%) 31 20 (65%) 14 (45%) 6 (20%) 18 12 (67%) 7 (39%) 5 (28%) Itching 51 12 (24%) 10 (20%) 2 (4%) 31 18 (58%) 14 (45%) 4 (13%) 18 10 (56%) 5 (28%) 5 (28%) Muscle pain 50 17 (34%) 11 (22%) 6 (12%) 30 17 (57%) 10 (33%) 7 (24%) 18 10 (56%) 4 (22%) 6 (34%) Joint pain 51 21 (41%) 13 (25%) 8 (16%) 31 17 (55%) 9 (29%) 8 (26%) 18 8 (44%) 2 (11%) 6 (33%)

Potentiation of tonic GABAergic inhibition by activation of postsynaptic kainate receptors

Multiplex immunohistochemistry accurately defines the immune context of metastatic melanoma

A prospective study explored the heterogeneous nature of metastatic melanoma using Multiplex immunohistochemistry (IHC) and flow cytometry (FACS). Multiplex IHC data quantitated immune subset number present intra-tumoral (IT) vs the tumor stroma, plus distance of immune subsets from the tumor margin (TM). In addition, mIHC showed a close association between the presence of IT CD8+ T cells and PDL1 expression in melanoma, which was more prevalent on macrophages than on melanoma cells. In contrast, FACS provided more detailed information regarding the T cell subset differentiation, their activation status and expression of immune checkpoint molecules. Interestingly, mIHC detected significantly higher Treg numbers than FACS and showed preferential CD4+ T cell distribution in the tumor stroma. Based on the mIHC and FACS data, we provide a model which defines metastatic melanoma immune context into four categories using the presence or absence of PDL1+ melanoma cells and/or macrophages, and their location within the tumor or on the periphery, combined with the presence or absence of IT CD8+ T cells. This model interprets melanoma immune context as a spectrum of tumor escape from immune control, and provides a snapshot upon which interpretation of checkpoint blockade inhibitor (CBI) therapy responses can be built.

Characteristics of Clinical Trials relating to COVID‐19 registered at ClinicalTrials.gov

What is known and objective Since the beginning of the COVID-19 outbreak in China in December 2019, the epidemic has continued to spread globally. Despite continuous reports of clinical trials being launched, no studies have yet systematically summarized and analysed their characteristics. Our objective is to do this by reviewing trials registered at ClinicalTrials.gov. Methods We searched the ClinicalTrials.gov database and retrieved all clinical trials on COVID-19 registered up to and including 3 April 2020. We summarized the characteristics of the trials, presenting the results of all trials, all intervention trials and drug intervention (including vaccines and traditional Chinese medicine) trials. Results and discussion We identified 306 COVID-19-related clinical trials. Seven of the studies had been withdrawn, leaving 299 active trials. Of the trials, 28.8% were planned to be conducted in Asia, 26.8% in Europe and 18.7% in North America. Most (73.0%) proposed trials expected to recruit fewer than 500 people, and only 22.1% of the studies included children (aged <18 years). About two-thirds (67.2%) of the studies were funded by the own resources of medical or research institutions. Of intervention trials, 73.9% used random allocation, and 73.4% used parallel assignment. Only 36.7% of the intervention trials used blinding. In terms of drug trials, 147 trials were drug intervention studies, covering 80 conventional drugs and seven traditional Chinese medicine drugs. Antiviral drugs and antimalarial drugs were the most commonly studied drugs with 52 and 45 trials registered, respectively. Five registered clinical trials were on vaccines. What is new and conclusion A large number of COVID-19-related trials have been registered within the first 4 months since the first infection was reported. These involve a large number of different drugs, the most common being antiviral drugs and antimalarial drugs. More attention should be paid to adequate blinding in future trials.

Characterizations of gut bacteriome, mycobiome, and virome of healthy individuals living in sea-level and high-altitude areas

Table S1 from Gene Copy Number Estimation from Targeted Next-Generation Sequencing of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification

&lt;p&gt;Genomic regions used for the targeted panel sequencing in this study.&lt;/p&gt;

Figure 1 from Phase Ib Study of Immunocytokine Simlukafusp Alfa (FAP-IL2v) Combined with Pembrolizumab for Treatment of Advanced and/or Metastatic Melanoma

&lt;p&gt;Antitumor activity following treatment with FAP-IL2v of CPI-experienced patients in the extension part with at least one postbaseline tumor assessment (&lt;i&gt;n&lt;/i&gt; = 62). Best percentage change in the sum of diameters of target lesion from baseline (column color indicates confirmed best overall response) in CPI-experienced patients in the Q3W extension part (&lt;i&gt;n&lt;/i&gt; = 41; &lt;b&gt;A&lt;/b&gt;) and in the QW/Q3W extension part (&lt;i&gt;n&lt;/i&gt; = 21; &lt;b&gt;B&lt;/b&gt;). &lt;b&gt;C,&lt;/b&gt; Kaplan–Meier estimate of progression-free survival in patients in the Q3W (blue) and QW/Q3W (red) extension part. Tick marks on the Kaplan–Meier plot show censoring of the data at the last time the patient was known to be alive. NE, not evaluable; PD, progressive disease; SD, stable disease; SLD, sum of longest diameters.&lt;/p&gt;

LBA84 Enzalutamide and 177Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer (mCRPC): A randomised, phase II trial: ENZA-p (ANZUP 1901)

Supplementary Figure S2 from Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition

&lt;p&gt;Plots showing percentage changes in total cfDNA concentration for each patient at weeks 4 and 8 of treatment, compared to same-patient baseline value. The left plot includes non-responding patients and the right plot includes patients who responded to olaparib in the clinical trial. Below, Mann-Whitney test comparing these changes at each time point for responders and non-responder patients.&lt;/p&gt;

Supplementary Methods and References from UV-Associated Mutations Underlie the Etiology of MCV-Negative Merkel Cell Carcinomas

&lt;p&gt;Description of additional methods and procedures used in the study. Also includes Supplementary References.&lt;/p&gt;