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.     

Patient Blood Management in der Geburtsvorbereitung,Geburtshilfe und postpartalen Phase

Die Anaesthesiologie - Die Implementierung eines Patient Blood Management (PBM) wird zunehmender Standard in der operativen Medizin. Seit einiger Zeit gilt das Interesse auch den vulnerablen...     

The impact of a total knee arthroplasty on jaw movements,upper body posture,plantar pressure distribution,and postural control

ABSTRACT

Objective: The purpose of this study was to examine the influence of a total knee arthroplasty (TKA) on linked cranial and caudal structures.

Methods: Thirty-five (14f/21m) subjects participated in this study: 15 subjects (9f, 6m) pre- and post- TKA and a control group of 20 subjects (5f, 15m). The measurements included: jaw condyle position and movement, back scan, plantar pressure distribution, and body sway.

Results: There were no significant differences in electronic position analysis of the jaw; however, the protrusion of the TKA group improved (p = 0.001). The test group had a more anteriorly inclined thoracic spine and a less pronounced lumbar lordosis. Before and after surgery, the body sway in the test group was larger.

Conclusion: The TKA affected most prominently the static mechanisms of the postural control and the spine position. The trajectories of the mandible during protrusion also changed slightly.     

Development of a core outcome set for venous leg ulceration (CoreVen) research evaluations (protocol)

BackgroundA venous leg ulcer is a chronic leg wound caused by poor venous blood circulation in the lower limbs. It is a recurring condition causing pain, malodour, reduced mobility, and depression. Randomised controlled trials evaluating treatments for venous leg ulcers provide important evidence to inform clinical decision-making. However, for findings to be useful, outcomes need to be clinically meaningful, consistently reported across trials, and fully reported. Research has identified the large number of outcomes reported in venous leg ulcer trials, impacting both synthesis of results, and clinical decision-making. To address this, a core outcome set will be developed. A core outcome set is an agreed standardised set of outcomes which should be, as a minimum, measured and reported in all trials which evaluate treatment effectiveness for a given indication. A core outcome set has the potential to reduce research waste, improve the utility of RCTs, reduce reporting bias, facilitate treatment comparisons across different sources of evidence and expedite the production of systematic reviews, meta-analyses and evidence-based clinical guidelines.AimThe aim of this project is to develop a core outcome set for research evaluating the effectiveness of interventions for treating venous leg ulceration.MethodsThrough a scoping review of the literature on venous leg ulceration, we will firstly identify a list of candidate outcome domains (broad categories in relation to what is being measured) from randomised controlled trials and qualitative research, and outcomes (specific methods in relation to what is being measured). In two further stages, we will use the resulting lists of outcome domains and outcomes to design two online surveys. A range of stakeholders will be invited to participate in the surveys and they will be asked to indicate which outcome domains and outcomes are most important and should be considered as core in future research reports.     

Repeated hepatic resection for colorectal liver metastases: is this concept safe and feasible?

European Surgery - The beneficial outcomes of hepatectomy in patients with colorectal metastases have encouraged the attempts of repeated hepatectomy in patients with recurrent disease. Although...     

TGF-β superfamily co-receptors in cancer

Transforming growth factor-β (TGF-β) superfamily signaling via their cognate receptors is frequently modified by TGF-β superfamily co-receptors. Signaling through SMAD-mediated pathways may be enhanced or depressed depending on the specific co-receptor and cell context. This dynamic effect on signaling is further modified by the release of many of the co-receptors from the membrane to generate soluble forms that are often antagonistic to the membrane-bound receptors. The co-receptors discussed here include TβRIII (betaglycan), endoglin, BAMBI, CD109, SCUBE proteins, neuropilins, Cripto-1, MuSK, and RGMs. Dysregulation of these co-receptors can lead to altered TGF-β superfamily signaling that contributes to the pathophysiology of many cancers through regulation of growth, metastatic potential, and the tumor microenvironment. Here we describe the role of several TGF-β superfamily co-receptors on TGF-β superfamily signaling and the impact on cellular and physiological functions with a particular focus on cancer, including a discussion on recent pharmacological advances and potential clinical applications targeting these co-receptors.     

Komplikationen bei skleranahtfixierter Kunstlinsenimplantation

Die Sklerafixation einer Kunstlinse ist bei insuffizientem Kapselapparat eine häufig gewählte Versorgung. Als nachteilig gilt das potenzielle Komplikationsprofil. Analyse des postoperativen Komplikationsprofils. In dieser monozentrischen, retrospektiven Analyse einer konsekutiven Fallserie von Patienten mit standardisierter, skleranahtfixierter Kunstlinsenimplantation (2007 bis 2017) wurden die dokumentierten Komplikationen in „dauerhaft visusbedrohend“ (Endophthalmitis, Aderhautblutung, Ablatio retinae) und „klinisch relevant, aber nicht dauerhaft visusbedrohend“ (z. B. Blutungen, Hypotonie) kategorisiert. Zudem wurde der Zeitpunkt der erstmaligen Dokumentation der Komplikationen erfasst und in 3 Zeiträume eingeordnet (0 bis 3, 4 bis 30 und ≥31 Tage). Vorliegend handelt es sich um das bislang größte publizierte Patientenkollektiv einer Studie mit Skleranahtfixierung einer Hinterkammerlinse (HKL). Es wurden 338 Augen von 338 Patienten in die Studie eingeschlossen (Frauen: 47 %), die mediane Nachbeobachtungszeit betrug 60 Tage (min.: 1 Tag, max.: 5833 Tage). In 68 % der Fälle wurden Komplikationen dokumentiert. „Dauerhaft visusbedrohende Komplikationen“ traten bei 3 % (n = 10) der Patienten auf. Als „klinisch relevante Komplikationen“ wurden ermittelt: okuläre Hypotension auf Werte ≤10 mm Hg (n = 119; 35 %), entrundete Pupille (n = 93; 28 %), Hyphäma, Iris- oder Glaskörperblutungen (n = 34; 10 %), Sekundärglaukom (n = 32; 9 %) und Iris-Capture (n = 17; 5 %); 41 % der Komplikationen traten innerhalb der ersten 3 Tage und 70 % innerhalb der ersten 30 Tage auf. Zu Revisionsoperationen kam es bei 4,5 % (n = 15) der Patienten. Obwohl bei ca. zwei Dritteln aller Eingriffe Komplikationen auftraten, war die Zahl der dauerhaft visusbedrohenden Komplikationen gering. Die Sklerafixation der Kunstlinse ist weiterhin ein vertretbarer Eingriff.