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.     

Computerized anatomy of the distal radius and its relevance to volar plating,research, and teaching

Distal radius fractures are common and fracture patterns and fixation can be complex. Computerized anatomy evaluation (CAE) might offer non‐invasive and enhanced anatomy assessment that might help with implant selection and placement and screw length determination. Our goal was to test the accuracy of two CAE methods for anatomical volar plate positioning and screw lengths measurement of the distal radius. We included 56 high‐resolution peripheral quantitative computed tomography scans of intact, human distal radii. Plates were placed manually onto 3D printed models (method 1), which was compared with automated computerized plate placement onto the 3D computer models (method 2). Subsequently, screw lengths were determined digitally for both methods. Screw lengths evaluations were compared via Bland–Altman plots. Both CAE methods resulted in identical volar plate selection and in anatomical plate positioning. For screw length the concordance correlation coefficient was ≥0.91, the location shift ≤0.22 mm, and the scale shift ≤0.16. The differences were smaller than ±1 mm in all samples. Both CAE methods allow for comparable plate positioning and subsequent screw length measurement in distal radius volar plating. Both can be used as a non‐invasive teaching environment for volar plate fixation. Method 2 even offers fully computerized assessments. Future studies could compare our models to other anatomical areas, post‐operative volar plate positioning, and model performance in actual distal radius fracture instead of intact radii. Clin. Anat. 32:361–368, 2019. © 2018 The Authors. Clinical Anatomy published by Wiley Periodicals, Inc. on behalf of American Association of Clinical Anatomists.     

Conserved pan-cancer microenvironment subtypes predict response to immunotherapy

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Separation anxiety: Extreme dehiscence of a mitral annuloplasty ring

We report a patient admitted with acute pulmonary edema 3 months after mitral valve repair, with no history of inter‐current febrile illness. Transesophageal echocardiography (TEE) demonstrated severe mitral regurgitation (MR) and an abnormally positioned annuloplasty ring, suggestive of dehiscence. The extreme extent of ring dehiscence was visualized on 3‐dimensional TEE (3D), with near‐complete separation of the ring. Strept.Mitis and Cristatus were isolated from the ring following redo mitral valve surgery, confirming endocarditis as the mechanism for dehiscence. This report highlights the additive role and superior ability of 3D TEE in the identification and anatomic delineation of mitral ring dehiscence.     

An assessment of the correlation between robust CT-derived ventilation and pulmonary function test in a cohort with no respiratory symptoms

Objective:To evaluate CT-ventilation imaging (CTVI) within a well-characterized, healthy cohort with no respiratory symptoms and examine the correlation between CTVI and concurrent pulmonary function test (PFT).Methods:CT scans and PFTs from 77 Caucasian participants in the NORM dataset (clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00848406","term_id":"NCT00848406"}}NCT00848406) were analyzed. CTVI was generated using the robust Integrated Jacobian Formulation (IJF) method. IJF estimated total lung capacity (TLC) was computed from CTVI. Bias-adjusted Pearson’s correlation between PFT and IJF-based TLC was computed.Results:IJF- and PFT-measured TLC showed a good correlation for both males and females [males: 0.657, 95% CI (0.438–0.797); females: 0.667, 95% CI (0.416–0.817)]. When adjusting for age, height, smoking, and abnormal CT scan, correlation moderated [males: 0.432, 95% CI (0.129–0.655); females: 0.540, 95% CI (0.207–0.753)]. Visual inspection of CTVI revealed participants who had functional defects, despite the fact that all participant had normal high-resolution CT scan.Conclusion:In this study, we demonstrate that IJF computed CTVI has good correlation with concurrent PFT in a well-validated patient cohort with no respiratory symptoms.Advances in knowledge:IJF-computed CTVI’s overall numerical robustness and consistency with PFT support its potential as a method for providing spatiotemporal assessment of high and low function areas on volumetric non-contrast CT scan.     

Fatal neonatal nephrocutaneous syndrome in 18 Roma children with EGFR deficiency

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with tyrosine-kinase signaling activity, involved in many cellular functions including cell growth and differentiation. Germ line loss-of-function mutations in EGFR lead to a severe neonatal skin disorder (Online Mendelian Inheritance in Man #131550). We report 18 premature Roma children from 16 families with birthweights ranging 440–1470 g and multisystem diseases due to the homozygous mutation c.1283G˃A (p.Gly428Asp) in EGFR. They presented with thin, translucent, fragile skin (14/15), skin desquamation (10/17), ichthyosis (9/17), recurrent skin infections and sepsis (9/12), nephromegaly (10/16) and congenital heart defects (7/17). Their prognosis was poor, and all died before the age of 6 months except one 13-year-old boy with a severe skin disorder, dentinogenesis imperfecta, Fanconi-like syndrome and secondary hyperaldosteronism. Management of ion and water imbalances and extremely demanding skin care may improve the unfavorable outcome of such patients.     

Skin closure with 2-octyl cyanoacrylate and polyester mesh after primary total knee arthroplasty offers superior cosmetic outcomes and patient satisfaction compared to staples: a prospective trial

European Journal of Orthopaedic Surgery & Traumatology - The goals of this study were to compare patient satisfaction and wound-related complications in patients receiving 2-octyl cyanoacrylate...