Current State of Compassionate Phage Therapy.

There is a current unmet medical need for the treatment of antibiotic-resistant infections, and in the absence of approved alternatives, some clinicians are turning to empirical ones, such as phage therapy, for compassionate treatment. Phage therapy is ideal for compassionate use due to its long-standing historical use and publications, apparent lack of adverse effects, and solid support by fundamental research. Increased media coverage and peer-reviewed articles have given rise to a more widespread familiarity with its therapeutic potential. However, compassionate phage therapy (cPT) remains limited to a small number of experimental treatment centers or associated with individual physicians and researchers. It is possible, with the creation of guidelines and a greater central coordination, that cPT could reach more of those in need, starting by increasing the availability of phages. Subsequent steps, particularly production and purification, are difficult to scale, and treatment paradigms stand highly variable between cases, or are frequently not reported. This article serves both to synopsize cPT publications to date and to discuss currently available phage sources for cPT. As the antibiotic resistance crisis continues to grow and the future of phage therapy clinical trials remains undetermined, cPT represents a possibility for bridging the gap between current treatment failures and future approved alternatives. Streamlining the process of cPT will help to ensure high quality, therapeutically-beneficial, and safe treatment

Interobserver variability in target definition for stereotactic arrhythmia radioablation

Background: Stereotactic arrhythmia radioablation (STAR) is a potential new therapy for patients with refractory ventricular tachycardia (VT). The arrhythmogenic substrate (target) is synthesized from clinical and electro-anatomical information. This study was designed to evaluate the baseline interobserver variability in target delineation for STAR. Methods: Delineation software designed for research purposes was used. The study was split into three phases. Firstly, electrophysiologists delineated a well-defined structure in three patients (spinal canal). Secondly, observers delineated the VT-target in three patients based on case descriptions. To evaluate baseline performance, a basic workflow approach was used, no advanced techniques were allowed. Thirdly, observers delineated three predefined segments from the 17-segment model. Interobserver variability was evaluated by assessing volumes, variation in distance to the median volume expressed by the root-mean-square of the standard deviation (RMS-SD) over the target volume, and the Dice-coefficient. Results: Ten electrophysiologists completed the study. For the first phase interobserver variability was low as indicated by low variation in distance to the median volume (RMS-SD range: 0.02–0.02 cm) and high Dice-coefficients (mean: 0.97 ± 0.01). In the second phase distance to the median volume was large (RMS-SD range: 0.52–1.02 cm) and the Dice-coefficients low (mean: 0.40 ± 0.15). In the third phase, similar results were observed (RMS-SD range: 0.51–1.55 cm, Dice-coefficient mean: 0.31 ± 0.21). Conclusions: Interobserver variability is high for manual delineation of the VT-target and ventricular segments. This evaluation of the baseline observer variation shows that there is a need for methods and tools to improve variability and allows for future comparison of interventions aiming to reduce observer variation, for STAR but possibly also for catheter ablation

KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors

Background: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C. Methods: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Results: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. Conclusions: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)

Phage Biobank: Present Challenges and Future Perspectives.

After a century of use in human infection, the preparation and administration of therapeutic bacteriophages (phages) still relies on ad hoc partnerships of researchers, biotech companies, clinicians and regulators. There is a clear need to improve the reproducibility, safety and speed of the provision of suitable phages. Here we discuss the specific characteristics and challenges of a sustainable phage biobank and, as we build a national consortium aimed at delivering phage therapeutics, suggest a roadmap toward national biobanking and phage therapy initiatives using the Australian context as a&nbsp;model.</p

2019 ESC Guidelines on the Treatment of Patients With Supraventricular Tachycardia

Cardiolog

The Drosophila Cog5 Homologue Is Required for Cytokinesis, Cell Elongation, and Assembly of Specialized Golgi Architecture during Spermatogenesis

The multisubunit conserved oligomeric Golgi (COG) complex has been shown previously to be involved in Golgi function in yeast and mammalian tissue culture cells. Despite this broad conservation, several subunits, including Cog5, were not essential for growth and showed only mild effects on secretion when mutated in yeast, raising questions about what functions these COG complex subunits play in the life of the cell. Here, we show that function of the gene four way stop (fws), which encodes the Drosophila Cog5 homologue, is necessary for dramatic changes in cellular and subcellular morphology during spermatogenesis. Loss-of-function mutations in fws caused failure of cleavage furrow ingression in dividing spermatocytes and failure of cell elongation in differentiating spermatids and disrupted the formation and/or stability of the Golgi-based spermatid acroblast. Consistent with the lack of a growth defect in yeast lacking Cog5, animals lacking fws function were viable, although males were sterile. Fws protein localized to Golgi structures throughout spermatogenesis. We propose that Fws may directly or indirectly facilitate efficient vesicle traffic through the Golgi to support rapid and extensive increases in cell surface area during spermatocyte cytokinesis and polarized elongation of differentiating spermatids. Our study suggests that Drosophila spermatogenesis can be an effective sensitized genetic system to uncover in vivo functions for proteins involved in Golgi architecture and/or vesicle transport

Outcomes Associated With Catheter Ablation of Ventricular Tachycardia in Patients With Cardiac Sarcoidosis

IMPORTANCE Ventricular tachycardia (VT) is associated with high mortality in patients with cardiac sarcoidosis (CS), and medical management of CS-associated VT is limited by high failure rates. The role of catheter ablation has been investigated in small, single-center studies.OBJECTIVE To investigate outcomes associated with VT ablation in patients with CS.DESIGN, SETTING, AND PARTICIPANTS This cohort study from the Cardiac Sarcoidosis Consortium registry (2003-2019) included 16 tertiary referral centers in the US, Europe, and Asia. A total of 158 consecutive patients with CS and VT were included (33% female; mean [SD] age, 52 [11] years; 53% with ejection fraction [EF] <50%).EXPOSURES Catheter ablation of CS-associated VT and, as appropriate, medical treatment.MAIN OUTCOMES AND MEASURES Immediate and short-term outcomes included procedural success, elimination of VT storm, and reduction in defibrillator shocks. The primary long-term outcome was the composite of VT recurrence, heart transplant (HT), or death.RESULTS Complete procedural success (no inducible VT postablation) was achieved in 85 patients (54%). Sixty-five patients (41%) had preablation VT storm that did not recur postablation in 53 (82%). Defibrillator shocks were significantly reduced from a median (IQR) of 2 (1-5) to 0 (0-0) in the 30 days before and after ablation (P < .001). During median (IQR) follow-up of 2.5 (1.1-4.9) years, 73 patients (46%) experienced VT recurrence and 81 (51%) experienced the composite primary outcome. One- and 2-year rates of survival free of VT recurrence, HT, or death were 60% and 52%, respectively. EF less than 50% and myocardial inflammation on preprocedural F-18-fluorodeoxyglucose positron emission tomography were significantly associated with adverse prognosis in multivariable analysis for the primary outcome (HR, 2.24; 95% CI, 1.37-3.64; P = .001 and HR, 2.93; 95% CI, 1.31-6.55; P = .009, respectively). History of hypertension was associated with a favorable long-term outcome (adjusted HR, 0.51; 95% CI, 0.28-0.92; P = .02).CONCLUSIONS AND RELEVANCE In this observational study of selected patients with CS and VT, catheter ablation was associated with reductions in defibrillator shocks and recurrent VT storm. Preablation LV dysfunction and myocardial inflammation were associated with adverse long-term prognosis. These data support the role of catheter ablation in conjunction with medical therapy in the management of CS-associated VT.Cardiolog