Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.Experimentele farmacotherapi

The Physics of Star Cluster Formation and Evolution

© 2020 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/s11214-020-00689-4.Star clusters form in dense, hierarchically collapsing gas clouds. Bulk kinetic energy is transformed to turbulence with stars forming from cores fed by filaments. In the most compact regions, stellar feedback is least effective in removing the gas and stars may form very efficiently. These are also the regions where, in high-mass clusters, ejecta from some kind of high-mass stars are effectively captured during the formation phase of some of the low mass stars and effectively channeled into the latter to form multiple populations. Star formation epochs in star clusters are generally set by gas flows that determine the abundance of gas in the cluster. We argue that there is likely only one star formation epoch after which clusters remain essentially clear of gas by cluster winds. Collisional dynamics is important in this phase leading to core collapse, expansion and eventual dispersion of every cluster. We review recent developments in the field with a focus on theoretical work.Peer reviewe

Elevation of von Willebrand factor is independent of erythrocyte sedimentation rate and persists after glucocorticoid treatment in giant cell arteritis

Von Willebrand factor (vWF) antigen levels were measured in 39 patients with biopsy-proven giant cell arteritis (GCA), 16 patients with polymyalgia rheumatica (PMR), 12 patients with Sj\uf6gren's syndrome, and 7 with choroiditis, as well as in 20 age- and sex-matched controls. Among GCA patients, 31 (group A) had clinically inactive disease and were taking low-dose glucocorticoids for at least 1 year; their vWF levels were high even in the presence of a normalized erythrocyte sedimentation rate (ESR). When the ESR and vWF were analyzed in another 8 GCA patients (group B) before and after treatment with glucocorticoids, vWF remained elevated even though the ESR returned to normal. Among the highest levels of vWF were those of 3 GCA patients who presented with ocular symptoms and positive temporal artery biopsies, but normal ESR. The presence of elevated vWF was not specific for GCA since elevated levels were also found in patients with PMR, Sj\uf6gren's syndrome, and choroiditis. The levels of vWF in GCA were significantly higher (P less than 0.01) than in these other conditions associated with myalgias and eye symptoms. Elevation of vWF levels may help in the differential diagnosis of GCA, particularly when the ESR is normal and ocular symptoms are present

Nonlinear Control and Trajectory Tracking of an Unmanned Aircraft System Based on a Complete State Space Representation

International audienceConventional control strategies for holonomic Unmanned Aircraft Systems (UASs) require that, while executing a mission, the UAS attitude dynamics remains very close to zero in order to satisfy the assumption of small angles approximation. This requirement may be valid for hover flight, but not for translational flights or aggressive maneuvers. To overcome this issue, this paper presents the controllability analysis for a non-linear representation of a holonomic UAS. Under the proposed scheme, it is shown that it is possible to design control schemes for stabilizing the complete UAS state space without the necessity of separating the system in attitude and translation subsystems. A set of simulations are presented to evaluate the effectiveness of the proposed control laws. These results show that the proposed strategy enables the UAS to track a desired trajectory while keeping the attitude close to a desired value

Acute infection of Toxoplasma gondii and cytomegalovirus reactivation in a pediatric patient receiving liver transplant

A 7-year-old Mexican boy with end-stage cirrhosis underwent liver transplantation and was maintained with cyclosporine and prednisolone. No specific data about Toxoplasma gondii or cytomegalovirus (CMV) infections in the cadaver donor were available. The recipient was seronegative for Toxoplasma, but CMV-IgG positive before transplantation. Ganciclovir was administered for prophylaxis during 3 months, but 5 months later he presented with icterus and increased transaminases. Acute transplant rejection was ruled out by biopsy. A seroconversion for T. gondii IgM and IgG and a small increase in CMV-IgM antibodies were observed, although the CMV-polymerase chain reaction (PCR) was negative. Ganciclovir was re-started, and the patient improved, but 6 months later he relapsed, and chorioretinitis lesions compatible both with T. gondii and CMV infections appeared. Pyrimethamine, sulfadiazine, folinic acid, and ganciclovir were administered. The boy showed favorable clinical improvement and remained stable for 12 months. Then, new retinal CMV lesions appeared in both eyes and the PCR for CMV became positive; therefore, the patient received a new regimen of ganciclovir, and clinically improved. From these data we concluded that the child presented a reactivation of CMV and a primary infection with T. gondii after transplantion. Copyright Zapotitlán Blackwell Munksgaard 2006