Citations

Abstractβ‐Blockers’ heart rate (HR)‐lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among β‐blocker–treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to β‐blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single‐nucleotide polymorphisms (SNPs) previously associated with the HR response to β‐blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following β‐blocker used in the PEAR (n = 757), PEAR‐2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR‐2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both β‐blockers in whites (rs1042714 C‐allele carriers, meta‐analysis β = –0.95 beats per minute [bpm], meta‐analysis P = 3×10–4; rs1042713 A‐allele carriers, meta‐analysis β = –1.15 bpm, meta‐analysis P = 2×10–3). In conclusion, the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective β‐blockade in hypertensive patient cohorts.

Abstract Background: TAK-228 is an investigational, oral and highly selective ATP-competitive inhibitor of TORC1/2. Targeting the PI3K/AKT/mTOR pathway with the dual TORC1/2 inhibitor TAK-228 may restore sensitivity to endocrine therapies in patients (pts) with breast cancer who have progressed on the combination of an endocrine agent plus a TORC1 inhibitor. Here we report data from the phase 2 portion of a phase 1b/2 study of TAK-228 plus exemestane (E) or fulvestrant (F). Methods: Postmenopausal women with ER+ and HER2-, inoperable or metastatic breast cancer (MBC) following everolimus (EVE) plus E or F after progression, received oral TAK-228 (4 mg QD) plus E (25 mg QD) or F (500 mg monthly) for 28-day cycles until progressive disease (PD) or unacceptable toxicity (NCT02049957). Pts were enrolled into parallel cohorts based on prior response to EVE plus E or F and were given the same prior therapy (E or F) at their established dose: EVE-sensitive, defined as disease progression after complete response (CR), partial response (PR), or ≥6 mos stable disease (SD); or EVE-resistant, defined as disease progression without a CR or PR, or after <6 mos SD. Primary endpoint was clinical benefit rate at 16 wks (CR, PR, or SD at 16 wks; CBR-16). Secondary endpoints included CBR at 24 wks (CBR-24), overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. Results: From Oct 2015 to Dec 2017, 94 pts were enrolled. Median age was 58 y (range 32–83). At baseline, most pts (67%) had stage IV disease and others were stage IA–IIIC (24%), other (3%) or unknown (5%); 94% of EVE-sensitive (93% E vs 100% F) and 88% of EVE-resistant pts (91% E vs 75% F) had received ≥4 prior lines of therapy. Pts received a median of 3 cycles (1–15) of TAK-228. At data cutoff (24 Apr 2018), 98% of pts had discontinued treatment, mainly due to PD (76%) or adverse events (AEs; 14%). CBR-16 was 41% (n=21) in EVE-sensitive and 26% (n=11) in EVE-resistant pts (table). CBR-24 was 24% in EVE-sensitive (19% E vs 50% F) and 23% in EVE-resistant (23% E vs 25% F) pts. Eleven of 21 pts who achieved CBR-16 also achieved CBR-24 (6 SD, 5 PR) in the EVE-sensitive cohort and 8 of 11 pts in the EVE-resistant cohort (6 SD, 2 PR). The ORR was 12% in EVE-sensitive pts and 9% in EVE-resistant pts (table). Median PFS (95% CI) was 4.1 mos (2.2–5.5) and 3.4 mos (1.9–5.4), and median OS (95% CI) was 15.9 mos (14.1–19.5) and 14.0 mos (13.0–16.0) in the EVE-sensitive and -resistant cohorts, respectively. Drug-related any grade and grade ≥3 AEs were seen in 90% and 29% of pts, respectively. Most common drug-related any grade AEs were nausea (50%), fatigue (38%), hyperglycemia and diarrhea (each 29%); 22% of pts reported a serious AE. No deaths were reported. Treatment is ongoing in two pts. Conclusion: TAK-228 plus E or F showed modest clinical benefit in pts with previously treated, EVE-sensitive or -resistant MBC, with an acceptable safety profile. EVE-sensitive (N=51)EVE-resistant (N=43) TAK-228+TAK-228+Best response, n (%)E (n=43)F (n=8)E (n=35)F (n=8)ORR=CR+PR4 (9)2 (25)3 (9)1 (13)CR001 (3)0PR4 (9)2 (25)2 (6)1 (13)CBR-1617 (40)4 (50)9 (26)2 (25) Citation Format: Diamond JR, Potter D, Salkeni M, Silverman P, Haddad T, Forget F, Awada A, Canon J-L, Danso M, Lortholary A, Bourgeois H, Tan-Chiu E, Patel C, Neuwirth R, Leonard EJ, Lim B. Phase 2 safety and efficacy results of TAK-228 in combination with exemestane or fulvestrant in postmenopausal women with ER-positive/HER2-negative metastatic breast cancer previously treated with everolimus [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-09.

Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cell has changed the treatment landscape of B-cell non-Hodgkin’s lymphoma (NHL), especially for aggressive B-cell lymphomas. Single-center and multicenter clinical trials with anti-CD19 CAR T-cell therapy have shown great activity and long-term remissions in poor-risk diffuse large B-cell lymphoma (DLBCL) when no other effective treatment options are available. Two CAR T-cell products [axicabtagene ciloleucel (axi-cel) and tisagenlecleucel] have obtained US Food and Drug Administration approval for the treatment of refractory DLBCL after two lines of therapy. A third product, liso-cel, is currently being evaluated in clinical trials and preliminary results appear very promising. CAR T-cell-related toxicity with cytokine-release syndrome and neurotoxicity remain important potential complications of this therapy. Here, we review the s biology, structure, clinical trial results and toxicity of two commercially approved CAR T-cell products and others currently being studied in multicenter clinical trials in B-cell NHLs.

The aim of this study is to review all the published clinical trials on autologous bone marrow mesenchymal stem cells (BM-MSCs) in the repair of cartilage lesions of the knee. We performed a comprehensive search in three electronic databases: PubMed, Medline via Ovid, and Web of Science. A systematic review was conducted according to the guidelines of PRISMA protocol and the Cochrane Handbook for Systematic Reviews of Interventions. The modified Coleman methodology score was used to assess the quality of the included studies. Meta-analysis was conducted to estimate the effect size for Pain and function change after receiving BM-MSCs. Thirty-three studies—including 724 patients of mean age 44.2 years—were eligible. 50.7% of the included patients received cultured BM-MSCs for knee cartilage repair. There was improvement in the MINORS quality score over time with a positive correlation with the publication year. Meta-analysis indicated better improvement and statistical significance in the Visual Analog Scale for Pain, IKDC Function, Tegner Activity Scale, and Lysholm Knee Score after administration of noncultured BM-MSCs when compared to evaluation before the treatment. Meanwhile, there was a clear methodological defect in most studies with an average modified Coleman methodology score (MCMS) of 55. BM-MSCs revealed a clinically relevant improvement in pain, function, and histological regeneration.

ObjectiveThe present study was undertaken to evaluate changes in knee magnetic resonance imaging (MRI) findings over the course of 18 months in subjects with osteoarthritic change and meniscal tear treated with arthroscopic partial meniscectomy (APM) or nonoperatively with physical therapy (PT).MethodsWe used 18‐month follow‐up data from the Meniscal Tear in Osteoarthritis Research Trial. MRI results were read with reference to the MRI Osteoarthritis Knee Score. We focused on 18‐month change in bone marrow lesions (BMLs), cartilage thickness, cartilage surface area, osteophyte size, effusion‐synovitis, and Hoffa‐synovitis. We used multinomial logistic regression to assess associations between MRI‐based changes in each feature and treatment type.ResultsA total of 351 subjects were randomized, and 225 had both baseline and 18‐month MRI results. In both treatment groups, patients experienced substantial changes in several MRI‐based markers. In 60% of the APM group, versus 33% of the PT group, cartilage surface area damage advanced in ≥2 subregions (adjusted odds ratio 4.2 [95% confidence interval 2.0–9.0). Patients who underwent APM also had greater advancement in scores for osteophytes and effusion‐synovitis. We did not find significant associations between treatment type and change in cartilage thickness, BMLs, or Hoffa‐synovitis.ConclusionThis cohort of patients with meniscal tear and osteoarthritis showed marked advancement in MRI‐based features over 18 months. Patients treated with APM showed more advancement in some features compared to those treated nonoperatively. The clinical relevance of these early findings is unknown and requires further study.

Unfortunately, the middle name of Olufemi R. Ayeni was accidentally omitted in the original publication and the author name is corrected here. The original article has been corrected.

AbstractIncreasing rates of chronic wound infections caused by antibiotic‐resistant bacteria are a crisis in healthcare settings. Biofilms formed by bacterial communities in these wounds create a complex environment, enabling bacteria to persist, even with antibiotic treatment. Wound infections caused by methicillin‐resistant Staphylococcus aureus (MRSA) are major causes of morbidity in clinical practice. There is a need for new therapeutic interventions not based on antibiotics. Hydrogen peroxide (H2O2) is a known antibacterial/antibiofilm agent, continuous delivery of which has been challenging. A conductive electrochemical scaffold (e‐scaffold) is developed, which is composed of carbon fabric that electrochemically reduces dissolved oxygen into H2O2 when polarized at −0.6 VAg/AgCl, as a novel antibiofilm wound dressing material. In this study, the in vitro antibiofilm activity of the e‐scaffold against MRSA is investigated. The developed e‐scaffold efficiently eradicates MRSA biofilms, based on bacterial quantitation and ATP measurements. Moreover, imaging hinted at the possibility of cell‐membrane damage as a mechanism of action. These results suggest that an H2O2‐generating e‐scaffold may be a novel platform for eliminating MRSA biofilms without using antibiotics and may be useful to treat chronic MRSA wound infections.

Study Design. Case–control analysis and systematic literature review. Objective. To illustrate the prognosis and perioperative risk factors associated with this condition. Summary of Background Data. Ischemic optic neuropathy (ION) is the most common pathological diagnosis underlying postoperative vision loss. It comes in two primary forms—anterior (AION)—affecting the optic disc or posterior (PION) affecting the optic nerve proximal to the disc. Spine surgery remains one of the largest sources of acute perioperative visual loss. Methods. We performed a 1:4 case–control analysis (by age and year of surgery) for patients with ION and those who didn’t develop ION following spine surgery at our institution. A systematic literature search of Medline, Embase, Scopus from inception to September 2017 as also performed. Results. We identified 12 cases from our institution. Comparison to 48 matched controls revealed fusion, higher number of operative levels, blood loss, and change in hemoglobin, hematocrit to be significantly associated with ION. Majority were diagnosed with PION (83%, 10/12) and had bilateral presentation (75%, 9/12). Only 30% patients (3/10) demonstrated improvement in visual acuity while the rest remained either unchanged (40%, 4/10) or worsened (20%, 2/10) at last follow-up. Literature review identified 182 cases from 42 studies. Posterior ischemic optic neuropathy (PION) was found in 58.7% (114/194) of cases, anterior ischemic optic neuropathy (AION) in 17% (33/19) and unspecified ION in 24% (47/194). PION was associated with higher odds of severe visual deficit at immediate presentation (odds ratio [OR]: 6.45, confidence interval [CI]: 1.04–54.3, P = 0.04) and last follow-up. Conclusion. PION is the most common cause of vision loss following spine surgery and causes more severe visual deficits compared with AION. Prone spine surgery especially multi-level fusions with longer operative time, higher blood loss, and intraoperative hypotension are most associated with the development of this devastating complication. Level of Evidence: 3