Alteration of DNA methyltransferases by eribulin elicits broad DNA methylation changes with potential therapeutic implications for triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options. Eribulin, a chemotherapeutic drug, induces epigenetic changes in cancer cells, suggesting a unique mechanism of action. Materials & methods: MDA-MB 231 cells were treated with eribulin and paclitaxel, and the samples from 53 patients treated with neoadjuvant eribulin were compared with those from 14 patients who received the standard-of-care treatment using immunohistochemistry. Results: Eribulin treatment caused significant DNA methylation changes in drug-tolerant persister TNBC cells, and it also elicited changes in the expression levels of epigenetic modifiers (DNMT1, TET1, DNMT3A/B) in vitro and in primary TNBC tumors. Conclusion: These findings provide new insights into eribulin's mechanism of action and potential biomarkers for predicting TNBC treatment response.

Real-world treatment patterns and clinical outcomes in patients treated with eribulin after prior phosphoinositide 3-Kinase inhibitor treatment for metastatic breast cancer.

PURPOSE: In 2010, the US Food and Drug Administration approved eribulin for the treatment of metastatic breast cancer (MBC). Since then, the treatment landscape has evolved with many new therapy classes, a more recent one being the small molecule inhibitors of phosphoinositide 3 kinase (PI3K). We sought to characterize the treatment patterns and clinical outcomes of patients with MBC who received eribulin following prior treatment with a PI3K inhibitor. METHODS: A retrospective cohort study based on medical record review included MBC patients who initiated eribulin between March 2019 and September 2020 following prior treatment with a PI3K inhibitor was conducted. Patient demographics, treatment characteristics, and clinical outcomes were analyzed descriptively. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated from the initiation of eribulin therapy using Kaplan-Meier analyses. RESULTS: 82 eligible patients were included. Patients' median age at eribulin initiation was 62 years; 86.5% had hormone receptor-positive, human epidermal growth factor receptor 2-negative tumors. Eribulin was most often administered in the second or third line (82.9%) in the metastatic setting. Best overall response on eribulin was reported as complete or partial response in 72% of the patients. The median rwPFS was 18.9 months (95% confidence interval [CI], 12.4-not estimable); median OS was not reached. The estimated rwPFS and OS rates at 12 months were 63.3% (95% CI, 50.5-73.7) and 82.6% (95% CI, 72.4-89.3), respectively. CONCLUSION: Our real-world study suggests that eribulin may be a potential treatment option for MBC patients who fail a prior PI3K inhibitor.

Effect of the ketone beta-hydroxybutyrate on markers of inflammation and immune function in adults with type 2 diabetes.

Pre-clinical and cell culture evidence supports the role of the ketone beta-hydroxybutyrate (BHB) as an immunomodulatory molecule that may inhibit inflammatory signalling involved in several chronic diseases such as type 2 diabetes (T2D), but studies in humans are lacking. Therefore, we investigated the anti-inflammatory effect of BHB in humans across three clinical trials. To investigate if BHB suppressed pro-inflammatory cytokine secretion, we treated LPS-stimulated leukocytes from overnight-fasted adults at risk for T2D with BHB (Study 1). Next (Study 2), we investigated if exogenously raising BHB acutely in vivo by ketone monoester supplementation (KME) in adults with T2D would suppress pro-inflammatory plasma cytokines. In Study 3, we investigated the effect of BHB on inflammation via ex vivo treatment of LPS-stimulated leukocytes with BHB and in vivo thrice-daily pre-meal KME for 14 days in adults with T2D. Ex vivo treatment with BHB suppressed LPS-stimulated IL-1ß, TNF-α, and IL-6 secretion and increased IL-1RA and IL-10 (Study 1). Plasma IL-10 increased by 90 min following ingestion of a single dose of KME in T2D, which corresponded to peak blood BHB (Study 2). Finally, 14 days of thrice-daily KME ingestion did not significantly alter plasma cytokines or leukocyte subsets including monocyte and T-cell polarization (Study 3). However, direct treatment of leukocytes with BHB modulated TNF-α, IL-1ß, IFN-γ, and MCP-1 secretion in a time- and glucose-dependent manner (Study 3). Therefore, BHB appears to be anti-inflammatory in T2D, but this effect is transient and is modulated by the presence of disease, glycaemia, and exposure time.

Eribulin for patients with metastatic extramammary Paget disease: Study protocol for a single-arm phase II trial.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy that predominantly affects the anogenital areas of the elderly. Although the efficacy of docetaxel and other cytotoxic agents for advanced EMPD has been reported in small retrospective case studies, no treatment has been proven effective in prospective clinical trials. We established the world's first in vivo EMPD experimental model (a patient-derived xenograft model). In our treatment experiment, xenograft tumours showed a remarkable response to eribulin. This study evaluates the efficacy of eribulin for patients with advanced EMPD. In October 2022, we started a single-arm phase II trial to evaluate the efficacy of eribulin as a treatment for adult patients with unresectable EMPD with measurable lesions. Enrolment in this clinical trial is open to patients with any prior treatment for EMPD. The primary endpoint is overall response rate; the secondary endpoints include disease control rate, overall survival, progression-free survival and adverse events. The study protocol was approved by the Ethics Committee of Hokkaido University and the other collaborating institutions. If the primary endpoint is met, it is our hope that eribulin will be regarded as a standard medication for patients with advanced EMPD.

Therapeutic efficacy of vancomycin-loaded carbon fiber-reinforced polyetheretherketone hip stem for periprosthetic joint infection: A pilot study.

A carbon fiber-reinforced polyetheretherketone (CFR/PEEK) hip stem with a special antibiotic elution mechanism is under development to treat periprosthetic joint infection (PJI). The antibiotic elution characteristics of intramedullary implants were experimentally investigated, and the efficacy of revision surgery using a therapeutic stem in treating ovine PJI was examined. To evaluate elution characteristics, the intramedullary vancomycin-loaded CFR/PEEK cylindrical implants were inserted in the distal femur of nine sheep, and the vancomycin elution rate was measured at 2, 7, and 21 days. To evaluate therapeutic efficacy, the PJI model with staphylococcus aureus was attempted to create for five sheep. Moreover, the therapeutic vancomycin-loaded CFR/PEEK stem was implanted during one-stage revision surgery. Three weeks after revision surgery, the treatment efficacy was evaluated based on bacterial cultures and wound findings. In addition, the vancomycin elution rate from the stem was measured. On average, the cylindrical implants eluted approximately 70% vancomycin in 21 days. Of the five sheep attempting to create a PJI model, three were successfully infected with S. aureus as intended for verification of treatment efficacy. In all three joints, negative bacterial cultures and no purulence were observed 3 weeks after revision surgery. The vancomycin elution rates from the stems were >70%. Efficient elution of vancomycin was confirmed by the experimental implant inserted into the bone marrow and the stem in actual PJI treatment. Using a novel therapeutic stem with an antibiotic elution mechanism in one-stage revision surgery, successful treatment was demonstrated in all S. aureus-induced PJIs.

Comparison between Three-Dimensional Printed Titanium and PEEK Cages for Cervical and Lumbar Interbody Fusion: A Prospective Controlled Trial.

OBJECTIVES: The three-dimensional printing titanium (3DPT) cage with excellent biomechanical properties and osseointegration capabilities has been initially used in spinal fusion, while the polyetheretherketone (PEEK) cage, a bioinert material device, has been a widely used for decades with relatively excellent clinical outcomes. This study was performed to investigate the early radiographic and clinical outcomes of 3DPT cage versus PEEK cage in patients undergoing anterior cervical discectomy and fusion (ACDF) and transforaminal lumbar interbody fusion (TLIF). METHODS: This prospective controlled trial, from December 2019 to June 2022, included patients undergoing ACDF and TLIF with 3DPT cages and compared them to patients using PEEK cages for treating spinal degenerative disorders. The outcome measures included radiographic parameters (intervertebral height [IH], subsidence, fusion status, and bone-cage interface contact) and clinical outcomes (Japanese Orthopaedic Association [JOA], Neck Disability Index [NDI], Oswestry Disability Index [ODI], Short Form 12-Item Survey [SF-12], Visual Analog Scale [VAS], and Odom's criteria). Student's independent samples t test and Pearson's chi-square test were used to compare the outcome measures between the two groups before surgery and at 1 week, 3 and 6 months after surgery. RESULTS: For the patients undergoing ACDF, the 3DPT (18 patients/[26 segments]) and PEEK groups (18 patients/[26 segments]) had similar fusion rates at 3 months and 6 months follow-up (3 months: 96.2% vs. 83.3%, p = 0.182; 6 months: 100% vs. 91.7%, p = 0.225). The subsidence in the 3DPT group was significantly lower than that in the PEEK group (3 months: 0.4 ± 0.2 mm vs. 0.9 ± 0.7 mm p = 0.004; 6 months: 0.7 ± 0.3 mm vs. 1.5 ± 0.8 mm, p < 0.001). 3DPT and PEEK cage all achieved sufficient contact with the cervical endplates. For the patients undergoing TLIF, the 3DPT (20 patients/[26 segments]) and PEEK groups (20 patients/[24 segments]) had no statistical difference in fusion rate (3 months: 84.6% vs. 58.3%, p = 0.059; 6 months: 92.3% vs. 75%, p = 0.132). The subsidence was lower than that in the PEEK group without significantly difference (3 months: 0.9 ± 0.7 mm vs.1.2 ± 0.9 mm p = 0.136; 6 months: 1.6 ± 1.0 mm vs. 2.0 ± 1.0 mm, p = 0.200). At the 3-month follow-up, the bone-cage interface contact of the 3DPT cage was significantly better than that of the PEEK cage (poor contact: 15.4% vs. 75%, p < 0.001). The values of UAR were higher in the 3DPT group than in the PEEK group during the follow-up in cervical and lumbar fusion, there were more statistical differences in lumbar fusion. There were no significant differences in the clinical assessment between 3DPT or PEEK cage in spinal fusion. CONCLUSION: The 3DPT cage and PEEK cage can achieve excellent clinical outcomes in cervical and lumbar fusion. The 3DPT cage has advantage in fusion quality, subsidence severity, and bone-cage interface contact than PEEK cage.

Are the Cytotoxic Properties of Conjugated Unsaturated Ketones Inactivated by Thiols?

The focus of this study was to examine whether the conversion of cytotoxic conjugated unsaturated ketones (or enones) into the corresponding thiol adducts leads to a reduction or abolition of cytotoxic potencies. A number of enones and related thiol adducts were evaluated against human HCT116 and HT29 colon cancer cells. Some 63% of the IC50 values are less than 10 µM and several compounds are more toxic than 5-FU. The thiol adducts are either more potent or are equipotent with the corresponding enones. A number of compounds are far more toxic to HCT116 and HT29 neoplasms than non-malignant CRL1790 cells leading to impressive Selectivity Index figures. An additional positive feature of these compounds is that they have favorable ADME properties.

Multifunctional modifications of polyetheretherketone implants for bone repair: A comprehensive review.

Polyetheretherketone (PEEK) has emerged as a highly promising orthopedic implantation material due to its elastic modulus which is comparable to that of natural bone. This polymer exhibits impressive properties for bone implantation such as corrosion resistance, fatigue resistance, self-lubrication and chemical stability. Significantly, compared to metal-based implants, PEEK implants have mechanical properties that are closer to natural bone, which can mitigate the "stress shielding" effect in bone implantation. Nevertheless, PEEK is incapable of inducing osteogenesis due to its bio-inert molecular structure, thereby hindering the osseointegration process. To optimize the clinical application of PEEK, researchers have been working on promoting its bioactivity and endowing this polymer with beneficial properties, such as antibacterial, anti-inflammatory, anti-tumor, and angiogenesis-promoting capabilities. Considering the significant growth of research on PEEK implants over the past 5 years, this review aims to present a timely update on PEEK's modification methods. By highlighting the latest advancements in PEEK modification, we hope to provide guidance and inspiration for researchers in developing the next generation bone implants and optimizing their clinical applications.

Safety and Efficacy of Polyetheretherketone (PEEK) Cages and Cadaveric Allografts in Transforaminal Lumbar Interbody Fusion (TLIF) for Treating Lumbar Pyogenic Spondylodiscitis.

Purpose: There have been many studies in the operative management of pyogenic spondylodiscitis with foreign materials. However, it still remains an issue of debate on whether the allografts may be used in pyogenic spondylodiscitis. This study sought to evaluate the safety and effectiveness of PEEK cages and the cadaveric allograft in transforaminal lumbar interbody fusion (TLIF) for treating lumbar pyogenic spondylodiscitis. Methods: From January 2012 to December 2019, 56 patients underwent surgery for lumbar pyogenic spondylodiscitis. The posterior debridement of all patients and their fusion with allografts, local bone grafts, and bone chip cages were performed before posterior pedicle screw fusion. An assessment of the residual pain, the grade of neurological injury, and the resolution of infection was conducted on 39 patients. The clinical outcome was evaluated using a visual analog scale (VAS) and the Oswestry Disability Index (ODI), and neurological outcomes were appraised based on Frankel grades. The radiological outcomes were evaluated via focal lordosis, lumbar lordosis, and the state of the fusion. Results: Staphylococcus aureus and Staphylococcus epidermidis were the most common causative organisms. The mean preoperative focal lordosis was -1.2° (-11.4° to 5.7°), and the mean postoperative focal lordosis increased to 10.3° (4.3°-17.2°). At the final follow-up, there were five cases with subsidence of the cage, no case of recurrence, and no case with cage and screw loosening or migration. The mean preoperative VAS and ODI scores were 8.9 and 74.6%, respectively, and improvements in VAS and ODI were 6.6 ± 2.2 and 50.4 ± 21.3%, respectively. The Frankel grade D was found in 10 patients and grade C in 7. Following the final follow-up, only one patient improved from Frankel grade C to grade D while the others recovered completely. Conclusion: The PEEK cage and cadaveric allograft combined with local bone grafts is a safe and effective choice for intervertebral fusion and restoring sagittal alignment without increased incidence of relapse for treating lumbar pyogenic spondylodiscitis.

Cost-utility Analysis of Anterior Cervical Discectomy and Fusion for Cervical Spondylosis Patients Comparing Polyetheretherketone Versus Tricortical Iliac Crest Bone Graft.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: To perform a cost-utility analysis and to investigate the clinical outcomes and patient's quality of life after anterior cervical discectomy and fusion (ACDF) to treat cervical spondylosis compared between fusion with polyetheretherketone (PEEK) and fusion with tricortical iliac bone graft (IBG) in Thailand. SUMMARY OF BACKGROUND DATA: ACDF is one of the standard treatments for cervical spondylosis. The fusion material options include PEEK and tricortical IBG. No previous studies have compared the cost-utility between these 2 fusion material options. PATIENTS AND METHODS: Patients with cervical spondylosis who were scheduled for ACDF at Siriraj Hospital (Bangkok, Thailand) during 2019-2020 were prospectively enrolled. Patients were allocated to the PEEK or IBG fusion material group according to the patient's choice of fusion material. EuroQol-5 dimensions 5 levels and relevant costs were collected during the operative and postoperative periods. A cost-utility analysis was performed using a societal perspective. All costs were converted to 2020 United States dollars (USD), and a 3% discount rate was used. The outcome was expressed as the incremental cost-effectiveness ratio. RESULTS: Thirty-six patients (18 ACDF-PEEK and 18 ACDF-IBG) were enrolled. Except for Nurick grading, there was no significant difference in patient baseline characteristics between groups. The average utility at 1 year after ACDF-PEEK and ACDF-IBG were 0.939 ± 0.061 and 0.798 ± 0.081, respectively ( P < 0.001). The total lifetime cost of ACDF-PEEK and ACDF-IBG was 83,572 USD and 73,329 USD, respectively. The incremental cost-effectiveness ratio of ACDF-PEEK when compared with that of ACDF-IBG showed a gain of 4468.52 USD/quality-adjusted life-years, which is considered cost-effective at the Thailand willingness-to-pay threshold of 5115 USD/quality-adjusted life-year gained. CONCLUSIONS: ACDF-PEEK was found to be more cost-effective than ACDF-IBG for treating cervical spondylosis in Thailand. LEVEL OF EVIDENCE: Level II.

Patient-Specific Facial Implants in Polyetheretherketone and Their Stability: A Preliminary Study.

BACKGROUND: Polyetheretherketone (PEEK) is a synthetic material with many favorable characteristics; PEEK implants are increasingly used for a variety of applications ranging from cranioplasty to orthopedic surgery and facial implants. METHODS: This study is a retrospective review of patients who underwent PEEK implant placement in our department over the last 5 years. Polyetheretherketone computer-aided design and manufacture facial implants were designed from high-resolution computed tomography (CT) scans of each patient. The implants placed were onlay implants used for facial rehabilitation purposes to correct malformative and posttraumatic malformations. RESULTS: Twenty-eight consecutive patients (11 males and 17 females) underwent PEEK implant positioning between January 2015 and December 2020. Common indications were anterior plagiocephaly, hemifacial microsomia, and residual facial imbalance after orthognathic surgery. No complications of implant breakdown, exposure, infection, or displacement were noticed during the follow-up period. During routine controls on 3 patients, we requested a craniomaxillofacial CT scan for reasons unrelated to the implanted prostheses. The CT scans were all high resolution (<1-mm slices). The CT images indicated that bone was starting to form around the implant in all 3 patients as well as in the penetrating holes that were planned in the implants. CONCLUSIONS: In our experience, computer-designed, patient-specific PEEK onlay implants are a valid option for the treatment of malformative and posttraumatic malformations. This is, to the best of our knowledge, the first clinical report on bone reaction to PEEK implantation in the maxillofacial field. Moreover, based on the signs of bone regrowth that we observed in CT controls we can presume that the design of this type of prosthesis can probably take advantage of some technical stratagems not yet codified and fully exploited. Despite our preliminary favorable results, further multicentric and comparative studies are necessary to evaluate outcomes and better understand the behavior of this promising material and thus optimize its use in craniomaxillofacial surgery.

Comparison of Long-Term Outcomes between the n-HA/PA66 Cage and the PEEK Cage Used in Transforaminal Lumbar Interbody Fusion for Lumbar Degenerative Disease: A Matched-Pair Case Control Study.

OBJECTIVE: The nanohydroxyapatite/polyamide-66 (n-HA/PA66) cage is a novel bioactive nonmetal cage that is now used in some medical centers, while the polyetheretherketone (PEEK) cage is a typical device that has been widely used for decades with excellent clinical outcomes. This study was performed to compare the long-term radiographic and clinical outcomes of these two different cages used in transforaminal lumbar interbody fusion (TLIF). METHODS: In this retrospective and matched-pair case control study, we included 200 patients who underwent TLIF from January 2010 to December 2014 with a minimum 7-year follow-up. One hundred patients who used n-HA/PA66 cages were matched with 100 patients who used PEEK cages for age, sex, diagnosis, and fusion level. The independent student's t-test and Pearson's chi-square test were used to compare the two groups regarding radiographic (fusion status, cage subsidence rate, segmental angle [SA], and interbody space height [IH]) and clinical (Oswestry Disability Index [ODI], and Visual Analog Scale [VAS] for back and leg) parameters preoperatively, postoperatively, and at the final follow-up. RESULTS: The n-HA/PA66 and PEEK groups had similar fusion rates of bone inside and outside the cage at the final follow-up (95.3% vs 91.8%, p = 0.181, 92.4% vs 90.1%, p = 0.435). The cage union ratios exposed to the upper and lower endplates of the n-HA/PA66 group were significantly larger than those of the PEEK group (p < 0.05). The respective cage subsidence rates in the n-HA/PA66 and PEEK groups were 10.5% and 17.5% (p = 0.059). There were no significant differences between the two groups in the SA, IH, ODI scores, or VAS scores at any time point. The n-HA/PA66 group showed high fusion and low subsidence rates during long-term follow-up. CONCLUSION: Both n-HA/PA66 and PEEK cages can achieve satisfactory long-term clinical and radiographic outcomes in TLIF. However, the n-HA/PA66 group showed significantly larger cage union ratios than the PEEK group. Therefore, the results indicated that the n-HA/PA66 cage is an ideal alternative material comparable to the PEEK cage in TLIF.

Clinical value of offering multiple chemotherapy lines to a luminal-like metastatic breast cancer: A case report with eribulin.

INTRODUCTION: The achievement of complete response with chemotherapy after multiple treatment lines in metastatic breast cancer and the chemosensitivity in a luminal-like breast cancer are two important issues as it is often asked whether there is a potential limit to the number of therapeutic lines offered and what clinical value they may have. In this setting, eribulin mesylate is a chemotherapy option available. Several randomized and observational studies demonstrated eribulin's meaningful improvement on prolongation of survival, chronicling the disease and preventing the onset of new metastases, although the rate of complete responses is rather limited. CASE DESCRIPTION: We report the five-year history of a luminal A breast cancer, stage IV at diagnosis, metastasized to bone and brain. After undergoing four chemotherapy lines and several radiotherapy sessions with partial response as the best response on bone and with a complete response on brain, our patient finally achieved a metabolic complete response also on bone after about a year of fifth-line treatment with eribulin. Currently the patient is in close clinical and radiological follow-up. CONCLUSIONS: This case report aims to emphasize the clinical value of a chronic chemotherapy treatment also in heavily pretreated and luminal-like metastatic breast cancer, supporting eribulin as a good choice to consider.

HMGCS2 Mediation of Ketone Levels Affects Sorafenib Treatment Efficacy in Liver Cancer Cells.

Primary liver cancer is the fifth leading death of cancers in men, and hepatocellular carcinoma (HCC) accounts for approximately 90% of all primary liver cancer cases. Sorafenib is a first-line drug for advanced-stage HCC patients. Sorafenib is a multi-target kinase inhibitor that blocks tumor cell proliferation and angiogenesis. Despite sorafenib treatment extending survival, some patients experience side effects, and sorafenib resistance does occur. 3-Hydroxymethyl glutaryl-CoA synthase 2 (HMGCS2) is the rate-limiting enzyme for ketogenesis, which synthesizes the ketone bodies, ß-hydroxybutyrate (ß-HB) and acetoacetate (AcAc). ß-HB is the most abundant ketone body which is present in a 4:1 ratio compared to AcAc. Recently, ketone body treatment was found to have therapeutic effects against many cancers by causing metabolic alternations and cancer cell apoptosis. Our previous publication showed that HMGCS2 downregulation-mediated ketone body reduction promoted HCC clinicopathological progression through regulating c-Myc/cyclin D1 and caspase-dependent signaling. However, whether HMGCS2-regulated ketone body production alters the sensitivity of human HCC to sorafenib treatment remains unclear. In this study, we showed that HMGCS2 downregulation enhanced the proliferative ability and attenuated the cytotoxic effects of sorafenib by activating expressions of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-P38, and p-AKT. In contrast, HMGCS2 overexpression decreased cell proliferation and enhanced the cytotoxic effects of sorafenib in HCC cells by inhibiting ERK activation. Furthermore, we showed that knockdown HMGCS2 exhibited the potential migratory ability, as well as decreasing zonula occludens protein (ZO)-1 and increasing c-Myc expression in both sorafenib-treated Huh7 and HepG2 cells. Although HMGCS2 overexpression did not alter the migratory effect, expressions of ZO-1, c-Myc, and N-cadherin decreased in sorafenib-treated HMGCS2-overexpressing HCC cells. Finally, we investigated whether ketone treatment influences sorafenib sensitivity. We showed that ß-HB pretreatment decreased cell proliferation and enhanced antiproliferative effect of sorafenib in both Huh7 and HepG2 cells. In conclusion, this study defined the impacts of HMGCS2 expression and ketone body treatment on influencing the sorafenib sensitivity of liver cancer cells.

[Short-term safety and effectiveness of domestic polyether-ether-ketone suture anchors for rotator cuff repair: A multicenter, randomized, single-blind, parallel-controlled noninferiority study].

Objective: A multicenter, randomized, single-blind, parallel-controlled noninferiority study was used to evaluate the short-term safety and effectiveness of domestic polyether-ether-ketone (PEEK) suture anchor for rotator cuff repair by comparing with the imported PEEK suture anchor commonly used in clinical practice. Methods: A total of 59 patients with rotator cuff tears who were admitted between May 2019 and October 2019 were selected as the research objects. Among them, 3 patients were excluded because they did not meet the selection criteria, and 1 patient withdrew from the study because of serious adverse events. A total of 55 patients were included in the study. They were randomly divided into trial group ( n=27) and control group ( n=28). The trial group used PEEK suture anchors produced from REJOIN Company, and the control group used PEEK suture anchors from American Arthrex Company. Two patients in control group were lost to follow-up. Twenty-seven patients in trial group and 26 patients in control group were included in the final quantitative analysis. There was no significant difference ( P>0.05) in gender, age, disease duration, side and sizes of rotator cuff tears, composition ratio of patients with type 2 diabetes, and preoperative American Shoulder and Elbow Surgeons (ASES) score, Constant-Murley score, University of California at Los Angeles (UCLA) score, and visual analogue scale (VAS) score. The patients were followed up regularly after operation. The postoperative follow-up included safety evaluation (complications, anchor position, and anchor bone reaction) and effectiveness evaluation (shoulder joint function and pain scores, rotator cuff integrity based on Sugaya classification criteria). Results: The operations in both groups were successfully completed, and there was no complication related to the operation and suture anchor. All incisions healed by first intention. There was no significant difference in follow-up time between trial group [(5.85±0.77) months] and control group [(5.96±0.72) months] ( t=0.535, P=0.595). MRI examination indicated that the repaired tendons were fixed and the anchors did not get loose or torn. At 1 day, 3 months, and 6 months after operation, there was no patient with grade 3-4 anchor bone reaction in the two groups, and there was no significant difference in the bone reaction grading between groups ( P>0.05). After operation, the VAS scores of the two groups gradually decreased, and the ASES scores, Constant-Murley scores, and UCLA scores gradually increased, and there were significant differences between groups at each time point ( P<0.05). There was no significant difference between groups at different time points ( P>0.05). There was no significant difference in Sugaya classification of rotator cuff integrity at 1 day, 3 months, and 6 months after operation between groups ( P>0.05). Conclusion: The short-term safety and effectiveness of domestic PEEK suture anchors in rotator cuff tear repair are not significant different from those of imported PEEK suture anchors commonly used in clinical practice.

Eribulin Treatment for Patients with Metastatic Breast Cancer: The UK Experience - A Multicenter Retrospective Study.

INTRODUCTION: This study examined real-world data from patients who received eribulin for metastatic breast cancer (MBC) collected from 14 hospitals across the UK. METHODS: Anonymized data were collected retrospectively from patients with MBC who had received eribulin. The data included the hormone-receptor status, histological diagnosis, age, prior chemotherapy, response to eribulin, progression-free survival (PFS), and overall survival (OS). RESULTS: Among 577 patients analyzed, the median age was 56 years, and most patients (73%) were estrogen-receptor positive. The median OS was 288 days (95% confidence interval [CI]: 261-315), and the PFS was 117 days (95% CI: 105-129). The median OS was higher among older patients (≥65 vs. <65 years: 325 days [95% CI: 264-385] vs. 285 days [95% CI: 252-317]; p = 0.028). The median OS was also higher in patients who received eribulin after fewer prior lines of chemotherapy (≤2 vs. >2 prior: 328 days [95% CI: 264-385] vs. 264 days [95% CI: 229-298]; p = 0.042). DISCUSSION/CONCLUSION: These retrospective data suggest that eribulin can be successfully used in older patients with MBC. Eribulin treatment was more effective in earlier-line settings, which, while predictable, supports consideration of eribulin as a second-line treatment option.

Prospective, Randomized, Blinded Clinical Trial Comparing PEEK and Allograft Spacers in Patients Undergoing Anterior Cervical Discectomy and Fusion Surgeries.

STUDY DESIGN: Prospective, randomized, blinded clinical trial. OBJECTIVE: To examine clinical and radiological outcomes in patients undergoing anterior cervical discectomy and fusion (ACDF) surgeries randomized to receive either polyether-ether-ketone (PEEK) or structural bone allografts. SUMMARY OF BACKGROUND DATA: The biomechanical qualities as well as osteoconductive, osteogenic, and osteoinductive properties of various graft materials have been previously evaluated. There remain questions, however, as to whether there are any clinical and/or radiographic outcome differences in the selection of interbody graft types for ACDF. METHODS: Patients undergoing one- to three-level ACDF with single anterior plate fixation were randomized (1:1 ratio) to receive either cortical allograft or PEEK interbody spacers. Radiographic and clinical outcomes were assessed at 3, 6, 12, and 24 months with an additional postoperative radiographic assessment. RESULTS: A total of 120 patients were enrolled and randomized. Comparing clinical outcomes, no differences in arm or neck pain scores were noted; however, there was a statistically significant (≤0.041) improvement in SF-36 PCS scores for the allograft group at all follow-up time points and a tendency toward lower disability scores. Overall, evidence of radiographic fusion was achieved in 87 (91.6%) patients: five (10.2%) and three (6.5%) patients had pseudoarthrosis (P = 0.72) in the PEEK and allograft groups, respectively. At 24 months' follow-up time, any cervical or segmental alignment restoration achieved with surgery was lost and no statistically significant changes were detected when all levels of surgery were included. Likewise, there were no statistically significant differences between the groups for anterior or posterior body height measurements at the 24 months' follow-up. Approximately 20% of patients had anterior and posterior subsidence, all grade 0 regardless of the group assignment. CONCLUSION: Comparable radiographic outcomes were observed for patients undergoing one- to three-level PEEK versus allograft-assisted ACDF surgeries. Although MCID comparisons suggest that allograft and PEEK-treated patients have similar clinical outcomes, testing that incorporates the magnitude of the change suggests that there may be a statistically significant greater magnitude of improvement for the allograft group patients, but further studies with a larger sample size would be helpful to determine if a true effect exists.

Prevention of New Metastatic Lesions by Eribulin Monotherapy Is Associated with Better Prognosis in Patients with Metastatic Breast Cancer.

BACKGROUND: Eribulin therapy has been reported to prolong overall survival (OS) but not progression-free survival, probably because it prevents the development of metastatic lesions; however, this effect has not yet been confirmed. METHODS: We reviewed the medical charts of 50 patients with metastatic breast cancer who underwent eribulin monotherapy at our hospital between 2014 and 2019. Patients were divided into two groups, namely, those who discontinued eribulin because of disease progression due to development of new lesions (NL group) and those who discontinued eribulin for other reasons, such as lesion growth and unacceptable side effects (non-NL group). Survival times were estimated for both groups and we investigated if eribulin-mediated suppression of new metastasis increased OS. RESULTS: Median OS for all patients, from eribulin initiation, was 14.4 months (range 1.2-60.1), whereas it was 4.6 months (range 1.7-24.7) in the NL group and 16.8 months (range 1.2-60.1) in the non-NL group. OS was significantly poorer in the NL group than in the non-NL group (p < 0.05). CONCLUSION: Eribulin monotherapy-mediated suppression of new metastatic lesions results in a better prognosis in patients with metastatic breast cancer.

Intravitreal injection of EV11, a novel aryl ketone amide, inhibits choroidal neovascularization via AKT/ERK1/2 pathway.

PURPOSE: Choroidal neovascularization (CNV) is the major cause of irreversible vision loss associated with age-related macular disease (AMD). The currently clinical chemical therapeutic strategies are of high cost and facing supply chain shortage. In our study, we aim to investigate EV11, a novel derivative from Sorafenib, as a new approach to inhibit the formation of CNV. METHODS: Cell viability assay, wound healing assay, transwell assay and tube formation assay were applied to explore the effects of EV11 on human vascular endothelial cells (HUVECs). Western blotting analysis was performed to investigate the pathways when EV11 acts on HUVECs. Laser-induced CNV in mice and intravitreal injection of EV11 were applied to find out the efficacy of the drug in vivo. Histological examination and electroretinogram (ERG) evaluated the retinal morphology and visual function after drug application. RESULTS: EV11 influenced the HUVECs cell viability as the concentration increasing after 24 hour incubation. It influenced HUVECs through suppressing AKT and ERK1/2 pathway. EV11 reduced CNV area with the optimal concentration of 200uM in mice eyes and compared with Bevacizumab, it had the same effect. The retinal thickness around the optic in each group was not influenced. The amplitudes of the a- and b-waves on scotopic and photopic ERG were not reduced after intravitreal injection. CONCLUSION: The present study indicated that EV11 affected the proliferation, migration and tube formation of HUVECs, inhibited the area of neovascular of laser induced choroidal neovascularization in mice eyes with no toxicity. EV11 could block the AKT/ERK1/2 signaling pathway in effects of HUVECs. This study unveiled a novel perspective drug EV11 to be a potential candidate for neovascularization.

Trends of glucose, lactate and ketones during anaerobic and aerobic exercise in subjects with type 1 diabetes: The ACTION-1 study.

BACKGROUND: Exercise is part of type 1 diabetes (T1D) management due to its cardiovascular and metabolic benefits. However, despite using continuous glucose monitoring, many patients are reluctant to exercise because of fear for hypoglycaemia. AIMS: We assessed trends in glucose, lactate and ketones during anaerobic and aerobic exercise in people with T1D and compared incremental area under the curve (AUC) between both exercises. METHODS: Twenty-one men with T1D (median [IQR]: age 29 years [28-38], body mass index (BMI) 24.4 kg/m2 [22.3-24.9], HbA1c 7.2% [6.7-7.8]), completed a cardiopulmonary exercise test (CPET) and a 60-min aerobic exercise (AEX) at 60% VO2 peak on an ergometer bicycle within a 6-week period. Subjects consumed a standardised breakfast (6 kcal/kg, 20.2 g CHO/100 ml) before exercise without pre-meal insulin and basal insulin for pump users. RESULTS: During CPET, glucose levels increased, peaking at 331 mg/dl [257-392] 1-3 h after exercise and reaching a nadir 6 h after exercise at 176 mg/dl [118-217]. Lactate levels peaked at 6.0 mmol/L [5.0-6.6] (max 13.5 mmol/L). During AEX, glucose levels also increased, peaking at 305 mg/dl [245-336] 80 min after exercise and reaching a nadir 6 h after exercise at 211 mg/dl [116-222]. Lactate levels rose quickly to a median of 4.3 mmol/L [2.7-6.7] after 10 min. Ketone levels were low during both tests (median ≤ 0.2 mmol/L). Lactate, but not glucose or ketone AUC, was significantly higher in CPET compared to AEX (p = 0.04). CONCLUSIONS: Omitting pre-meal insulin and also basal insulin in pump users, did prevent hypoglycaemia but induced hyperglycaemia due to a too high carbohydrate ingestion. No ketosis was recorded during or after the exercises. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT05097339.