Recent Phase Research Articles

PMON329 Survey of physician experience with once weekly somatrogon vs once daily somatropin regimen for the treatment of pediatric patients with growth hormone deficiency: results from a cross sectional, observational study

Abstract Background Somatrogon is a long-acting recombinant human growth hormone (hGH) currently being developed as a once-weekly subcutaneous injectable treatment for pediatric patients with growth hormone deficiency (GHD). A recent global Phase 3 study compared the efficacy and safety of somatrogon administered once weekly with Genotropin administered once daily in pediatric patients with GHD (ClinicalTrials.gov: NCT02968004). Aims To understand and describe physicians’ experiences using once-weekly somatrogon injections compared with once-daily hGH injections during the Phase 3 study. Methods In this quantitative, cross-sectional, observational study, a 14-item multiple choice questionnaire was administered to physicians who were clinical investigators in the Phase 3 study. The questionnaire was designed to assess physicians’ experiences, preferences and satisfaction regarding the use of the once-weekly somatrogon regimen compared with the standard once-daily hGH injection regimen. Survey results were analyzed quantitatively using descriptive statistics. Results A total of 24 physicians who were part of the global Phase 3 study (mean age [SD]: 58.5 [10.1] years; 10 males, 14 females) in 12 different countries completed the on-line survey. Compared with daily injections, most physicians preferred somatrogon (n=18, 75.0%) and reported that somatrogon was more convenient (n=19, 79.2%), less burdensome (n=19, 79.2%) and that they would be more likely to prescribe somatrogon to patients in the future (n=20, 83.3%). In terms of being more likely to support positive long-term growth outcomes, 37.5% (n=9) of physicians selected somatrogon; the remaining physicians (n=15, 62.5%) reported no difference between treatments. The proportion of physicians who were satisfied or very satisfied with somatrogon was 95.8% (n=23), compared with 87.5% (n=21) for daily hGH injections. Most physicians (n=15, 62.5%) reported that daily hGH injections required more effort/much more effort to monitor adherence, compared with somatrogon. Some physicians (n=7, 29.2%) reported that explaining the device instructions to patient/caregivers required more/much more effort for somatrogon compared with daily hGH injections; more than half (n=14, 58.3%) reported no difference in effort required for either regimen. Physicians were divided as to which treatment needed more/much more effort to: (i) explain the injection regimen (n=7 [29.2%] daily injection; n=7 [29.2%] no difference; n=10 [41.7%] somatrogon), (ii) explain what to do if an injection is missed (n=7 [29.2%] daily injection; n=9 [37.5%] no difference; n=8 [33.3%] somatrogon), and (iii) address patient/caregiver questions (n=8 [33.3%] daily injection; n=11 [45.8%] no difference; n=5 [20.8%] somatrogon). Conclusions Overall, physicians from the global Phase 3 study were positive about their experience using somatrogon for the treatment of children with GHD. Physicians generally preferred the once-weekly somatrogon injection regimen, with most physicians reporting somatrogon to be more convenient and less burdensome to patients, indicating that they would be more likely to prescribe somatrogon to their patients in the future. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

The role of gas flushing on magma reservoir crystallization and its consequences for the growth of planetary crust

Many crustal magmatic reservoirs are fundamentally powered by basalt injection at their base. Asides from transfer of silicate liquid and crystals and accompanying heat, basaltic magma also provides large amounts of fluids to the overlying magma. This work explores how water activity and temperature, hence degree of crystallisation , of magmatic reservoirs are affected by such a mechanism at various levels in the crust. By using recent experimental phase equilibria , thermodynamic relationships between gas and silicate melts , and heat balance, it is shown that, depending on the level of magma storage, diffusive exchange during bubble uprise and stalling may produce either crystallisation or melting of magmas. Long term fluxing of felsic to intermediate magma bodies stored in upper crust by mafic volatiles will generally lead to their near isothermal solidification. Conversely, for bodies stagnating in the mid to deep crust, such a process almost inevitably enhances melting, driving or maintaining magmas beyond the threshold of mobility needed for upward material transfer, unless the percolating fluid is very CO 2 -rich. Compilation of basaltic melt inclusion data gathered in arc, hot-spot and ridge settings, shows that the two last categories coexist with CO 2 -rich fluids at high pressures (XH 2 O fluid < 0.1), which will almost always enhance crystallisation. In contrast arc basalts record a wide and continuous range of fluid compositions, from dry to almost H 2 O-saturated conditions, which may either favour (low pressure) or inhibit (high pressure) the crystallisation of felsic reservoirs which they underplate. Crustal growth may thus be in part limited by the difficulty of crystallising deep-seated magma bodies, in particular in arc settings. This pressure controlled effect is related to the contrasted solubilities of H 2 O and CO 2 in silicate melts, and to the much stronger non-ideal behaviour of CO 2 relative to H 2 O as pressure increases. Asides from tectonic and density inversion processes, a thick crust may fundamentally reflect the fact that basalt underplating in the lower crust has proceeded at a rate sufficiently slow so as to prevent remelting of earlier intrusions (or melting of lower crust lithologies) or that the outcoming fluid was CO 2 -rich, or both. Application to other terrestrial planets is hindered by the paucity of data regarding crust thickness and composition, and it can be only conjectured that the thin crust of large planets (Earth, Venus) reflects in part the operation of subduction process during their evolution, while the comparatively thicker crust inferred for smaller bodies (e.g. Mars, the Moon, Vesta) primarily reflects processes related to a primordial crust. • Long term fluxing of felsic magma bodies in upper crust by mafic volatiles generally leads to their solidification. • Conversely, in the deep crust, such a process almost inevitably enhances melting, unless the mafic fluid is very CO2-rich. • Crustal growth may thus be limited by the difficulty of crystallising deep-seated magma bodies, in particular in arc settings. • A relatively thin crust on large planets may reflect the operation of subduction

399P Role of denosumab as targeted therapy in treatment of unresectable or recurrent cases of giant cell tumor of the bone

The primary modality of treatment of Giant cell tumor of bone (GCTB) is surgical resection; which is not always possible given the location and extent of the neoplasm. A recent phase II data have demonstrated denosumab's (RANKL inhibitor) activity concerning disease and symptom control, without significant adverse effects.

Immune modulatory vaccines: time to move into infectious diseases

Immune modulatory vaccines represent a new treatment modality that is currently under intense investigation in patients with cancer. This is best exemplified by a recent phase 2 clinical trial in patients with metastatic melanoma; clinical efficacy as first-line treatment was shown with an immune modulatory vaccine based on T-cell epitopes from indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand (PD-L1) in combination with immune checkpoint blockade.1 The objective response rate was 80% (95% CI 62·7–90·5), complete response rate was 43% (27·4–60·8), and median progression-free survival was 26 months (15·4–69·0), which is superior to any other therapy in patients with previously untreated metastatic melanoma.

Dose-Response Effects of 7-Dehydrocholesterol Reductase Inhibitors on Sterol Profiles and Vesicular Stomatitis Virus Replication.

Cholesterol is ubiquitous in cells; it plays a critical role in membrane structure and transport as well as in intracellular trafficking processes. There are suggestions that cholesterol metabolism is linked to innate immunity with inhibitors of DHCR7, the last enzyme in the cholesterol pathway, suggested to have potential as viral therapeutics nearly a decade ago. In fact, there are a number of highly prescribed pharmaceuticals that are off-target inhibitors of DHCR7, causing increased cellular levels of 7-dehydrodesmosterol (7-DHD) and 7-dehydrocholesterol (7-DHC). We report here dose-response studies of six such inhibitors on late-stage cholesterol biosynthesis in Neuro2a cells as well as their effect on infection of vesicular stomatitis virus (VSV). Four of the test compounds are FDA-approved drugs (cariprazine, trazodone, metoprolol, and tamoxifen), one (ifenprodil) has been the object of a recent Phase 2b COVID trial, and one (AY9944) is an experimental compound that has seen extensive use as a DHCR7 inhibitor. The three FDA-approved drugs inhibit replication of a GFP-tagged VSV with efficacies that mirror their effect on DHCR7. Ifenprodil and AY9944 have complex inhibitory profiles, acting on both DHCR7 and DHCR14, while tamoxifen does not inhibit DHCR7 and is toxic to Neuro2a at concentrations where it inhibits the Δ7-Δ8 isomerase of the cholesterol pathway. VSV itself affects the sterol profile in Neuro2a cells, showing a dose-response increase of dehydrolathosterol and lathosterol, the substrates for DHCR7, with a corresponding decrease in desmosterol and cholesterol. 7-DHD and 7-DHC are orders of magnitude more vulnerable to free radical chain oxidation than other sterols as well as polyunsaturated fatty esters, and the effect of these sterols on viral infection is likely a reflection of this fact of Nature.

An analysis of deficiencies in the ethics committee data of certain interventional trials registered with the Clinical Trials Registry-India.

There is widespread agreement that clinical trials should be registered in a public registry, preferably before the trial commences. It is also important that details of each trial in the public record are complete and accurate. In this study, we examined the trial sites and ethics committee (EC) data for 1359 recent Phase 2 or Phase 3 interventional trials registered with Clinical Trials Registry-India (CTRI), to identify categories of problems that prevent the clear identification of which EC approved a given site. We created an SQLite database that hosted the relevant CTRI records, and queried this database, as needed. We identified two broad categories of problems: those pertaining to the understanding of an individual trial and those to adopting a data analytics approach for a large number of trials. Overall, about 30 problems were identified, such as an EC not being listed; an uninformative name of the EC that precluded its clear identification; ambiguity in which EC supervised a particular site; repetition of a site or an EC; the use of a given acronym for different organizations; site name not clearly listed, etc. The large number of problems with the data in the EC or site field creates a challenge to link particular sites with particular ECs, especially if a programme is used to find the matches. We make a few suggestions on how the situation could be improved. Most importantly, list the EC registration number for each EC, merge the site and EC tables so that it is clear which EC is linked to which site; and implement logic rules that would prevent a trial from being registered unless certain conditions were met. This will raise user confidence in CTRI EC data, and enable data based public policy and inferences. This will also contribute to increased transparency, and trust, in clinical trials, and their oversight, in India.

Oligometastatic Prostate Cancer in the Modern Era: Post-SBRT Chronicle

<h3>Purpose/Objective(s)</h3> Recent randomized phase II trials have demonstrated the clinical benefit of incorporating modern functional radionuclide imaging modalities and stereotactic body radiotherapy (SBRT) in the management of oligometastatic prostate cancers. An improved understanding of the clinical course following metastasis-directed therapy can assist in the role and timing of systemic treatment as a part of complex management decisions. Here, we provide long-term follow-up data for oligometastatic castration-sensitive (CSPC) and resistant (CRPC) prostate cancer following SBRT. <h3>Materials/Methods</h3> We retrospectively evaluated patients with oligometastatic prostate cancer (≤3 lesions) identified on 11C-Choline PET who were treated with SBRT. Outcomes reported were biochemical progression-free (BPFS), local (LPFS), distant (DPFS), and overall (OS) survival. Survival curves were generated by Kaplan-Meier analysis and compared by Cox proportional hazards. <h3>Results</h3> A total of 139 patients were analyzed, 31 (22%) with CSPC and 107 (78%) with CRPC (78%). Median follow-up after SBRT was 49 months (range 6.7 to 143.5 months). 124 patients (89%) were treated with SBRT at multiple sites for their oligometastatic disease and most treated lesions (96.7%) were osseous metastases. In addition, 76% of CRPC and 58% of CSPC patients had previously received chemotherapy (p=0.09) and 82% of CRPC and 48% of CSPC had previously received a second-generation antiandrogen (p<0.001). The median BPFS defined by PCWG-3 was 48.1 months (95% CI 10.5-NR) in CSPC versus 20.5 months (95% CI 17.5-34.4) in CRPC (p=0.2). DPFS and LPFS were very similar, with excellent long-term local control in both CSPC and CRPC (75% LPFS versus 38% DPFS at 2 years, 66% LPFS and 19% DPFS at 4 years). Overall survival was significantly longer in CSPC patients compared to CRPC patients (median OS not reached versus 64.4 months, p=0.016). Overall survival after radiotherapy trended worse among patients with CRPC previously exposed to chemotherapy (death HR 2.32, p=0.075) or second-generation antiandrogen (death HR 2.1, p=0.12) as would be expected; this trend was not present in CSPC. <h3>Conclusion</h3> In our study of oligometastatic prostate cancer patients treated with SBRT to a site of metastatic disease, patients with CSPC had better outcomes for progression-free survival and overall survival compared to CRPC patients. Pre-treatment with chemotherapy or second-generation antiandrogens did not significantly impact overall survival in patients with CSPC. Local control was excellent in both CSPC and CRPC, suggesting that highly sensitive imaging modalities may best select patients for effective SBRT.

Exploring the circum-global teleconnection—Indian summer monsoon interactions in the interannual and multidecadal timescales

The Northern hemispheric circum global teleconnection (CGT) pattern is thought to be maintained by two main forcings—viz-diabatic heating associated with the Indian summer monsoon (ISM) and barotropic instability generation over the jet exit region over the North Atlantic. The CGT and ISM impacts one another through the circulation responses over West central Asia (WCA). In this study we revisit the CGT-ISM interactions focusing on the WCA region and try to understand whether the downstream impact of CGT on ISM dominates over the ISM feedback on CGT. Analysis indicates that the Atlantic forced CGT responses play a lead role in modulating the ISM in the interannual timescale, by modulating the upper-level anticyclones over WCA and in turn affecting the ISM easterly vertical wind shear. Atlantic multi-decadal oscillation (AMO) is a major driver of ISM variability in the multi-decadal time scale and the AMO is associated with an arching wave-train of teleconnection across Eurasia. Our analysis indicates significant modulation of WCA anomalies by the AMO in the multi-decadal time scale, implying that the Atlantic-CGT-WCA-ISM pathway of teleconnection has a low frequency counterpart. We further demonstrate that the observed out of phase relationship between AMO and ISM in the recent decades, may be attributed to the relatively stronger high latitude warming over the north Atlantic during the recent AMO warm phase. The equivalent barotropic responses to the extra-tropical north Atlantic sea surface temperature (SST) anomalies alter the entire downstream teleconnection pattern producing cyclonic anomalies over WCA and in turn weakening the ISM.

Phase III, randomised, double-blind, placebo-controlled, multicentre trial to evaluate the efficacy and safety of rhGAD65 to preserve endogenous beta cell function in adolescents and adults with recently diagnosed type 1 diabetes, carrying the genetic HLA DR3-DQ2 haplotype: the DIAGNODE-3 study protocol

IntroductionType 1 diabetes (T1D) is an autoimmune disease leading to the destruction of the insulin-producing beta cells resulting in insulin deficiency and hyperglycaemic. Today, no approved therapy exists to halt...

How we (will) treat PNH?

Clinical signs arising from intravascular hemolysis, hemolysis-related transfusions and thrombosis are indications for treatment initiation in paroxysmal nocturnal hemoglobinuria (PNH), whereas clone size per se is not. Eculizumab prevents intravascular hemolysis and reduces significantly thromboembolic risk resulting in a five-year overall survival of >90%. Hemoglobin value, LDH and reticulocyte count are used to define treatment response. Residual intravascular hemolysis is mainly caused by an incomplete C5 blockage and can lead to continuous low‐grade hemolysis or transient breakthrough hemolysis episodes in 10-15% of PNH patients. Additional complement‐amplifying conditions such as infections, surgery or pregnancy may overcome efficient therapeutic levels of Eculizumab and therefore require dose adjustments. C3‐mediated extra‐vascular hemolysis represents the main reason for residual anemia during anti‐C5 treatment. Patients with an inherited C5-variant lack response to Eculizumab and have been directed (in past) towards allogeneic HSCT. Transplantation has an overall mortality of up to 30%, with a higher risk in patients with previous thrombosis. A plethora of novel therapeutic agents are reported to impact on both; residual intravascular hemolysis and C3‐mediated extra‐vascular hemolysis. The new C5 inhibitor Ravalizumab with an eight‐week i.v. dosing interval showed non-inferiority to Eculizumab. Crovalimab, binding on the single missense C5 heterozygous mutation is injected s.c. monthly; two large phase III trials are ongoing as add on- and mono-therapy. Others, such as Pozelimab, injected subcutaneously on a weekly basis after an initial IV loading dose or Tesidolumab are still under current investigation. Currently investigated proximal inhibitors are acting towards: (i) the C3 complement; (ii) complement factor D or (iii) the complement factor B. They are aiming in particular to prevent C3‐mediated extra‐vascular hemolysis. Pegcetacoplan is a PEGylated version of compstatin which binds to C3 and is injected s.c. in monotherapy 4 weeks after initial concomitant therapy with Eculizumab. In a recent phase III trial, pegcetacoplan showed superiority to eculizumab in hemoglobin change from baseline and is now approved by the FDA for patients with PNH who are either treatment‐naive or switching from anti‐C5 monoclonal antibodies. Danicopan is an oral first‐in‐class factor D complement alternative pathway inhibitor and decreased significantly transfusion requirement, as shown in a phase II trial (phase III ongoing). BCX9930, another FD inhibitor in early development is given orally and demonstrated initial clinical efficacy both as add‐on therapy in patients with inadequate response to eculizumab as well as in monotherapy in treatment‐naive patients. In conclusion, novel proximal and distal complement inhibitors with different application modalities, in part as add-on or monotherapy seem to improve significantly intra- and extra‐vascular hemolysis in PNH, resulting in a better hematological benefit. Before choosing specific treatment, hematologists have to assess hemolysis, thrombosis and patients‘ bone marrow function. Future studies will help to explore long-term efficacy and safety of these novel agents.

New Horizons of Macrophage Immunomodulation in the Healing of Diabetic Foot Ulcers.

Diabetic foot ulcers (DFUs) are one of the most costly and troublesome complications of diabetes mellitus. The wound chronicity of DFUs remains the main challenge in the current and future treatment of this condition. Persistent inflammation results in chronic wounds characterized by dysregulation of immune cells, such as M1 macrophages, and impairs the polarization of M2 macrophages and the subsequent healing process of DFUs. The interactive regulation of M1 and M2 macrophages during DFU healing is critical and seems manageable. This review details how cytokines and signalling pathways are co-ordinately regulated to control the functions of M1 and M2 macrophages in normal wound repair. DFUs are defective in the M1-to-M2 transition, which halts the whole wound-healing machinery. Many pre-clinical and clinical innovative approaches, including the application of topical insulin, CCL chemokines, micro RNAs, stem cells, stem-cell-derived exosomes, skin substitutes, antioxidants, and the most recent Phase III-approved ON101 topical cream, have been shown to modulate the activity of M1 and M2 macrophages in DFUs. ON101, the newest clinically approved product in this setting, is designed specifically to down-regulate M1 macrophages and further modulate the wound microenvironment to favour M2 emergence and expansion. Finally, the recent evolution of macrophage modulation therapies and techniques will improve the effectiveness of the treatment of diverse DFUs.

Linking North Atlantic and Alpine Last Glacial Maximum climates via a high-resolution pollen-based subarctic forest steppe record

During the last glaciation the Eurasian continent was impacted by the global reorganization of atmospheric circulation caused by North Atlantic events, through changes in moisture storm tracks modulated by orography. Our research explores the linkages between climate evolution in the North Atlantic and in the Alps between 30.6 and 12.5 ka, This period, centered on the Last Glacial Maximum, experienced the most recent phase of maximum global ice volume, corresponding to a millennia-long phase of sea-level lowstand, minima in reconstructed sea surface temperatures and isotopic values from polar ice. We present a high-resolution multiproxy record from Lake Fimon at the southern Alpine foothills, where a larch forest-steppe persisted throughout the coldest spells. We analyse the fine climate structure of the MIS 3–2 transition, of the Alpine Last Glacial Maximum stepped by HS2, and provide an unprecedented fine resolution and accurate 14C dating of the Last Glacial Maximum and the early Alpine Lateglacial. We reconstructed quantitative climate parameters based on sensitive pollen descriptors, and derived co-registered sedimentary proxies for dust flux. Reconstructed series suggest that extreme continental spells in the Alps and cold boreal winters match the timing of Heinrich Stadials 2 and 1, episodes of iceberg discharge and release of rock fragments (Ice Rafted Debris) in the North Atlantic. The initiation of the LGM at 27.3 ka is marked by a 4 °C drop in July temperatures, likely responsible for the onset of glacial build-up in the Southern Alpine piedmont. The first extreme continental spell coincides with the British-Irish-sourced IRD event at 26.2 ka and with glacier retreat in the Southern Alps, persisting in the subsequent HS2. Late Glacial glacier collapse and extreme drought occurred during the first half of the HS1, 17.4–16.2 ka. The comparison of the results obtained at Lake Fimon with other terrestrial Eurasian records and with recalibrated marine chronologies from the North Atlantic suggests in-phase reactions of the British-Irish Ice Sheet and of Alpine glaciers and ecosystems to changes in the Atlantic Meridional Circulation. Asymmetric ecoclimatic effects produced by North Atlantic events at the windward and leeward sides of the Alps confirm a southern provenance of moist air masses throughout the LGM.

Join us on an amazing journey towards next-generation treatments for CNS disorders: Launch of Neuroprotection, a new high-quality journal in translational neuroscience.

Join us on an amazing journey towards next-generation treatments for CNS disorders: Launch of Neuroprotection, a new high-quality journal in translational neuroscience.

Incorporating a palaeo-perspective into Andean montane forest restoration

Reference ecosystems used in tropical forest restoration lack the temporal dimension required to characterise a mature or intact vegetation community. Here we provide a practical ‘palaeo-reference ecosystem’ for the eastern Andean forests of Ecuador to complement the standard ‘reference ecosystem’ approach. Pollen assemblages from sedimentary archives recovered from Ecuadorian montane forests are binned into distinct time periods and characterised as 1) Ancient (pre-human arrival), 2) Pre-European (Indigenous cultivation), 3) Successional (European arrival/Indigenous depopulation), 4) Mature (diminished human population), 5) Deforested (re-colonisation), and 6) Modern (industrial agriculture). A multivariate statistical approach is then used to identify the most recent period in which vegetation can be characterised as mature. Detrended correspondence analysis indicates that the pollen spectra from CE 1718-1819 (time bin 4 – Mature (diminished human population)) is most similar to that of a pre-human arrival mature or intact state. The pollen spectra of this period are characterised by Melastomataceae, Fabaceae, Solanaceae and Weinmannia. The vegetation of the 1700s, therefore, provides the most recent phase of substantial mature vegetation that has undergone over a century of recovery, representing a practical palaeo-reference ecosystem. We propose incorporating palynological analyses of short cores spanning the last 500 years with botanical inventory data to achieve more realistic and long-term restoration goals.

Postcolonial politics of elimination?

A common view is that states formulate and administer policy. However, there is much in the classification and administration of persons that is not narrowly governmental. As an example, this article traces long-term developments in Australia and the United States which have made possible recent broadening and “de-racializing” of governmental formulations of Indigenous identity. This most recent phase has seen emergent kinds of “new politics,” here called “hyper-identification.” This is the self-identification of significant numbers of people as Indigenous, well beyond strictly “demographic” factors. It is easy, and probably partly accurate, to regard such hyper-identification as opportunistic, given the range of entitlements that Indigenous identification may permit. Yet an explanation in terms of opportunity, strategy, or psychology does not treat the conditions that enable that process. This paper attempts to do so in its focus on the relation between state classifications and shifts in the public sphere.

33181 C5a and C5aR is prominently associated with tunnels in severe hidradenitis suppurativa

Complement dysregulation and neutrophil activation have been implicated in the pathogenesis of hidradenitis suppurativa (HS). The presence of tunnels (subcutaneous cavities lined with squamous epithelium) is a feature of the moderate and severe forms of HS. The complement 5a (C5a) receptor (C5aR) is highly expressed on neutrophils and is a major driver of the proinflammatory functions. Avacopan is a potent and specific inhibitor of human C5aR, and was shown to be efficacious and well tolerated in patients with severe HS in a recent phase 2 clinical trial.

The Current and Evolving Role of Immunotherapy in Metastatic Colorectal Cancer.

Immunotherapy can be considered a therapeutic revolution in oncology, with great impact on many tumor types, such as melanoma and non-small cell lung cancer. However, in metastatic colorectal cancer, the benefits in terms of prolonged tumor control and high response rate are limited to the rare subgroup of tumors with high mutation burden - mostly tumors that harbor microsatellite instability (MSI) or a deficient mismatch repair system (dMMR), or tumor microsatellite stability and damaging mutations in the exonuclease domains of POLE or POLD. The KEYNOTE-028 uncontrolled phase II trial demonstrated an impressive antitumor activity of pembrolizumab in patients with treatmentrefractory Lynch-associated tumors, including colorectal cancer. Nivolumab with or without ipilimumab confirmed the efficacy of immune checkpoint inhibitors in patients with previously treated dMMR / MSI metastatic colorectal cancer. The recent KEYNOTE-177 phase III trial demonstrated that pembrolizumab significantly reduced the relative risk of disease progression or death and improved progression-free survival in patients with treatment-naive dMMR / MSI metastatic colorectal cancer in comparison with first-line chemotherapy with or without biologics. Unfortunately, current pharmacological strategies with immunotherapy have not been successful for most patients with microsatellite stable metastatic colorectal cancer. In this review, we critically appraise the applicability of immune checkpoint inhibitors in dMMR/MSI metastatic colorectal cancer. We also discuss the recent negative trials of immunotherapy combinations in microsatellite stabl.

An innovative phase change composite with high thermal conductivity and sensitive light response rate for thermal energy storage

In recent years paraffin-based organic phase change materials have been widely employed in thermal-energy storage systems due to their relatively high latent thermal capacity. However, the risk of leaks, low thermal conductivity, and low light-to-thermal conversion capacity has, to date, limited their use in the storage of solar thermal energy. To address these issues, we have developed a novel bio-based shape-stable organic phase change composite (SSOPCC) by encapsulating paraffin C22 with the double-supporting component consisting of poly (styrene-b-ethylene-co-butylene-b-styrene) (SEBS) and expanded perlite (EP), and improving the thermal conductivity and increasing the sensitive light response rate by introducing boron nitride (BN) and a lignin biomass-derived carbon material carbonized lignin (CL). Our investigations show that, with the introduction of the BN sheets and biomass CL into the SSOPCCs, the thermal conductivity of the composites is improved (from 0.407 W/mK to 0.596 W/mK), and the light-to-thermal conversion ability is also considerably enhanced. The obtained SSOPCCs possess not only good thermal storage performance, such as high latent heat enthalpy (as large as 185.5 J/g) and high relative enthalpy efficiency (>95%) but also exhibit excellent thermal stability and reliability after multiple heating-cooling cycles. The findings of this study will both provide a promising way for fabricating new bio-based phase change composites for real solar energy storage and conversion applications and broaden the high-value utilization of lignin-based biomass.

Posttraumatischer Stress in der Kardiologie

Although fascinating improvements in surgical, interventional and medical treatment of patients with coronary artery disease have been achieved, a growing number of patients present with refractory angina despite optimal treatment. Currently, different approaches are being investigated to reduce angina and to improve quality of life in these patients with “no options”. Slowing of coronary venous drainage by implantation of a stent device that reduces the diameter of the coronary sinus is a promising approach, as demonstrated by a recent phase II trial. In this report we document the first implantation of this novel device at our institution in Switzerland, give a stepwise description of the implantation procedure and discuss the currently available literature with regard to the physiology and clinical indications for the so-called (coronary sinus) Reducer™ device.

AcT Trial: Protocol for a Pragmatic Registry‐Linked Randomized Clinical Trial

Background Intravenous thrombolysis with alteplase is widely used in patients with acute ischemic stroke presenting early after symptom onset. Recent phase II trials have suggested that intravenous tenecteplase may be safer and associated with higher early reperfusion rates as compared with alteplase. This study investigates whether intravenous tenecteplase is noninferior to intravenous alteplase for the treatment of acute ischemic stroke. Methods This is a pragmatic, registry‐linked, prospective, randomized (1:1) controlled, open‐label parallel group clinical trial (AcT [Alteplase Compared to Tenecteplase in Patients With Acute Ischemic Stroke]) with blinded end point assessment of 1600 patients to test if intravenous tenecteplase (0.25 mg/kg body weight, maximum dose 25 mg) is noninferior to intravenous alteplase (0.9 mg/kg body weight; maximum dose, 90 mg) in patients with acute ischemic stroke eligible for intravenous thrombolysis in clinical routine. Patients are recruited from comprehensive and primary stroke centers and enrolled using deferral of consent. The proposed sample has at least 90% power with a noninferiority margin of 5%, assuming incidence of the 90‐day modified Rankin Scale score of 0 to 1 is 38% in the tenecteplase and 35% in the alteplase groups, and a loss to follow‐up rate &lt;5%. Results The blinded primary end point is the proportion of subjects achieving a 90‐day modified Rankin Scale score of 0 to 1. Key safety outcomes include 24‐hour symptomatic intracerebral hemorrhage and 90‐day all‐cause mortality. All serious adverse events within a 24‐hour period will be reported and coded using the Medical Dictionary for Regulatory Activities. Outcomes are collected either centrally (primary, key secondary, and safety end points) or through ongoing Canadian stroke registries. The primary analysis is a simple unadjusted comparison of proportions. Conclusions Results from the trial will provide real‐world evidence of the effectiveness of intravenous tenecteplase versus alteplase in patients with acute ischemic stroke presenting early after stroke onset.