Citations

SummaryThere is a need for efficacious, convenient treatments with long‐term tolerability for patients with relapsed/refractory multiple myeloma (RRMM). This phase 2 study evaluated the all‐oral combination of ixazomib, cyclophosphamide and dexamethasone (ICd). Patients with RRMM received ixazomib 4 mg and cyclophosphamide 300 mg/m2 on days 1, 8 and 15, and dexamethasone 40 mg on days 1, 8, 15 and 22 in 28‐day cycles. The primary endpoint was overall response rate (ORR). Seventy‐eight patients were enrolled (median age 63·5 years). At data cut‐off, patients had received a median of 12 treatment cycles; 31% remained on treatment. ORR was 48% [16% very good partial response or better (≥VGPR)]. ORR was 64% and 32% in patients aged ≥65 and <65 years (25% and 16% ≥VGPR), respectively. At a median follow‐up of 15·2 months, median progression‐free survival (PFS) was 14·2 months, with a trend towards better PFS in patients aged ≥65 years vs. <65 years (median 18·7 months vs. 12·0 months; hazard ratio 0·62, P = 0·14). ICd was well tolerated. The most common treatment‐emergent adverse events were diarrhoea (33%), nausea (24%), upper respiratory tract infection (24%), and thrombocytopenia (22%); 10 patients (13%) had peripheral neuropathy (one grade 3). This study is registered at ClinicalTrials.gov (NCT02046070).

The incidence of reinfarction, death and systemic thromboembolism is greatest in the first 2 months after acute myocardial infarction and decreases with time after infarction. Reasons for this are unknown, but increased platelet vascular wall interaction may be a contributing factor. Thirteen patients, mean age 53 years, had a platelet survival determination (platelet half-life calculated by least square analysis) within 1 month (mo) after acute, uncomplicated myocardial infarction (10 transmural, 3 subendocardial); a platelet survival study was repeated 3-8 mo (average 4 mo) later. All patients were on oral anticoagulants and during the time of observation none of the patients had any clinical thromboembolic events.Ten of the 13 patients had a shortened (<92 hours) platelet survival half-life of 75 hours (avg) within 1 mo after myocardial infarction which increased significantly (P<.01) to 94 hours (avg) four mo (avg) later. Ten control patients with angiographically proven coronary artery disease, stable angina pectoris, and a shortened platelet survival of 85 hours (avg) had a repeat platelet survival 6 mo later that was not significantly changed (mean variability 5%).The shortened platelet survival that improves with time after myocardial infarction is compatible with the increased incidence of reinfarction, death and thromboembolism early after myocardial infarction. Whether the increased platelet consumption reflects platelet deposition in the coronary vessels or in the left ventricle (as a mural thrombus) is at present under investigation with imaging of III-Indium-labeled platelets.

Abstract This Consensus Document is the first of two reports summarizing the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on the clinical use of intracoronary imaging including intravascular ultrasound (IVUS) and optical coherence tomography (OCT). The first document appraises the role of intracoronary imaging to guide percutaneous coronary interventions (PCIs) in clinical practice. Current evidence regarding the impact of intracoronary imaging guidance on cardiovascular outcomes is summarized, and patients or lesions most likely to derive clinical benefit from an imaging-guided intervention are identified. The relevance of the use of IVUS or OCT prior to PCI for optimizing stent sizing (stent length and diameter) and planning the procedural strategy is discussed. Regarding post-implantation imaging, the consensus group recommends key parameters that characterize an optimal PCI result and provides cut-offs to guide corrective measures and optimize the stenting result. Moreover, routine performance of intracoronary imaging in patients with stent failure (restenosis or stent thrombosis) is recommended. Finally, strengths and limitations of IVUS and OCT for guiding PCI and assessing stent failures and areas that warrant further research are critically discussed.

Abstract Analysis of non‐Gal antibody induced after pig‐to‐baboon cardiac xenotransplantation identified the glycan produced by porcine beta‐1,4‐N‐acetyl‐galactosaminyltransferase 2 (B4GALNT2) as an immunogenic xenotransplantation antigen. The porcine B4GALNT2 enzyme is homologous to the human enzyme, which synthesizes the human SDa blood group antigen. Most humans produce low levels of anti‐SDa IgM which polyagglutinates red blood cells from rare individuals with high levels of SDa expression. The SDa glycan is also present on GM2 gangliosides. Clinical GM2 vaccination studies for melanoma patients suggest that a human antibody response to SDa can be induced. Expression of porcine B4GALNT2 in human HEK293 cells results in increased binding of anti‐SDa antibody and increased binding of Dolichos biflorus agglutinin (DBA), a lectin commonly used to detect SDa. In pigs, B4GALNT2 is expressed by vascular endothelial cells and endothelial cells from a wide variety of pig backgrounds stain with DBA, suggesting that porcine vascular expression of B4GALNT2 is not polymorphic. Mutations in B4GALNT2 have been engineered in mice and pigs. In both species, the B4GALNT2‐KO animals are apparently normal and no longer show evidence of SDa antigen expression. Pig tissues with a mutation in B4GALNT2, added to a background of alpha‐1,3‐galactosyltransferase deficient (GGTA1‐KO) and cytidine monophosphate‐N‐acetylneuraminic acid hydroxylase deficient (CMAH‐KO), show reduced antibody binding, confirming the presence of B4GALNT2‐dependent antibodies in both humans and non‐human primates. Preclinical xenotransplantation using B4GALNT2‐deficient donors has recently been reported. Elimination of this source of immunogenic pig antigen should minimize acute injury by preformed anti‐pig antibody and eliminate an induced clinical immune response to this newly appreciated xenotransplantation antigen.

Purpose To perform a systematic review to determine if there is (1) an association between decreased hip internal rotation and anterior cruciate ligament (ACL) tear rates; (2) an association between radiographic femoroacetabular impingement (FAI) and ACL tear rates; and (3) biomechanical evidence demonstrating increased strain in the ACL of patients with decreased hip internal rotation. Methods A systematic review was performed using Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Studies investigating relationships between hip motion, hip radiographs, and ACL tear were sought. Studies with Levels of evidence I‐IV were eligible for inclusion. Study methodology/evidence were evaluated using Methodological Index for Non‐Randomized Studies (MINORS), Strengthening the Reporting of Observational Studies in Epidemiology (STROBE), and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Results Eleven studies were analyzed (2 cadaveric in vitro models, 8 clinical studies measuring hip internal rotation (2 concurrently assessing radiographic FAI), and 1 clinical study assessing radiographic FAI alone). Mean MINORS, STROBE, and GRADE for the studies was 82.4%, 20.9 out of 22, and “low,” respectively. A total of 959 subjects (84.8% male; mean age 23.6 ± 3.8 years) were analyzed. Overall, 378 subjects sustained 427 ACL tears (399 primary ACL ruptures, 28 reruptures). Six of 8 clinical studies identified a significant association between limited rotation (internal rotation [IR; loss greater than 10°‐20°], external rotation [ER], or combined IR + ER [loss greater than 20°]) and ACL tears. Two studies found an association between ACL ruptures and radiographic cam/pincer impingement. Two cadaveric models found a significant association between ACL strain and limited hip internal rotation. Conclusions This systematic review identified a significant association between ACL tear and both limited hip rotation and radiographic FAI. Level of Evidence Level IV, systematic review of Levels II‐IV studies.

Cardiac xenotransplantation (CXTx) is a promising solution to the chronic shortage of donor hearts. Recent advancements in immune suppression have greatly improved the survival of heterotopic CXTx, now extended beyond 2 years, and life-supporting kidney XTx. Advances in donor genetic modification (B4GALNT2 and CMAH mutations) with proven Gal-deficient donors expressing human complement regulatory protein(s) have also accelerated, reducing donor pig organ antigenicity. These advances can now be combined and tested in life-supporting orthotopic preclinical studies in nonhuman primates and immunologically appropriate models confirming their efficacy and safety for a clinical CXTx program. Preclinical studies should also allow for organ rejection to develop xenospecific assays and therapies to reverse rejection. The complexity of future clinical CXTx presents a substantial and unique set of regulatory challenges which must be addressed to avoid delay; however, dependent on these prospective life-supporting preclinical studies in NHPs, it appears that the scientific path forward is well defined and the era of clinical CXTx is approaching.