Evaluation of Changes in Activities of Daily Living and Quality of Life of Patients with Bone Metastasis Who Underwent Conservative Therapy through Bone Metastasis Cancer Boards.

Background and Objectives: Changes in activities of daily living (ADL) and quality of life (QOL) of patients with bone metastasis who underwent surgical treatment through Bone Metastasis Cancer Boards (BMCBs), a recent multidisciplinary approach for managing bone metastases, have been reported; however, no reports exist on patients who undergo conservative treatment. In this study, we aimed to evaluate these patients' ADL and QOL and examine the factors influencing changes in these parameters. Materials and Methods: We retrospectively reviewed 200 patients with bone metastases who underwent conservative therapy through BMCBs between 2013 and 2021. A reassessment was conducted within 2-8 weeks after the initial assessment. Patients' background and changes in performance status (PS), Barthel Index (BI), EuroQol five-dimension (EQ-5D) scores, and Numerical Rating Scale (NRS) scores were initially assessed. Furthermore, we categorized patients into two groups based on improvements or deteriorations in ADL and QOL and performed comparative analyses. Results: Significant improvements in EQ-5D (0.57 ± 0.02 versus [vs.] 0.64 ± 0.02), NRS max (5.21 ± 0.24 vs. 3.56 ± 0.21), and NRS average (2.98 ± 0.18 vs. 1.85 ± 0.13) scores were observed between the initial assessment and reassessment (all p < 0.001). PS (1.84 ± 0.08 vs. 1.72 ± 0.08) and BI (83.15 ± 1.68 vs. 84.42 ± 1.73) also showed improvements (p = 0.06, and 0.054, respectively). In addition, spinal cord paralysis (odds ratio [OR]: 3.69, p = 0.049; OR: 8.42, p < 0.001), chemotherapy (OR: 0.43, p = 0.02; OR: 0.25, p = 0.007), and NRS average scores (OR: 0.38, p = 0.02; OR: 0.14, p < 0.001) were independent factors associated with ADL and QOL. Conclusions: Patients with bone metastases who underwent conservative treatment through BMCBs exhibited an increase in QOL without a decline in ADL. The presence of spinal cord paralysis, absence of chemotherapy, and poor pain control were associated with a higher risk of deterioration in ADL and QOL.

Effect of Bone Metastasis Cancer Board on Spinal Surgery Outcomes: A Retrospective Study.

Background and Objectives: Bone metastasis cancer boards (BMCBs) focusing on the management of bone metastases have been gathering much attention. However, the association of BMCBs with spinal surgery in patients with spinal metastases remains unclear. In this retrospective single-center observational study, we aimed to clarify the effect of a BMCB on spinal metastasis treatment. Materials and Methods: We reviewed consecutive cases of posterior decompression and/or instrumentation surgery for metastatic spinal tumors from 2008 to 2019. The BMCB involved a team of specialists in orthopedics, rehabilitation medicine, radiation oncology, radiology, palliative supportive care, oncology, and hematology. We compared demographics, eastern cooperative oncology group performance status (ECOGPS), Barthel index (BI), number of overall versus emergency surgeries, and primary tumors between patients before (2008-2012) and after (2013-2019) BMCB establishment. Results: A total of 226 patients including 33 patients before BMCB started were enrolled; lung cancer was the most common primary tumor. After BMCB establishment, the mean patient age was 5 years older (p = 0.028), the mean operating time was 34 min shorter (p = 0.025), the mean hospital stay was 34.5 days shorter (p < 0.001), and the mean BI before surgery was 12 points higher (p = 0.049) than before. Moreover, the mean number of surgeries per year increased more than fourfold to 27.6 per year (p < 0.01) and emergency surgery rates decreased from 48.5% to 29.0% (p = 0.041). Patients with an unknown primary tumor before surgery decreased from 24.2% to 9.3% (p = 0.033). Postoperative deterioration rates from 1 to 6 months after surgery of ECOGPS and BI after BMCB started were lower than before (p = 0.045 and p = 0.027, respectively). Conclusion: The BMCB decreased the emergency surgery and unknown primary tumor rate despite an increase in the overall number of spinal surgeries. The BMCB also contributed to shorter operation times, shorter hospital stays, and lower postoperative deterioration rates of ECOGPS and BI.

Human Non-Hypertrophic Nonunion Tissue Contains Osteoblast Lineage Cells and E-BMP-2 Activates Osteogenic and Chondrogenic Differentiation.

In this study, we examined the proliferation capability and osteogenic and chondrogenic differentiation potential of non-hypertrophic nonunion cells (NHNCs), and the effect of Escherichia coli-derived BMP-2 (E-BMP-2) on them. We enrolled five patients with non-hypertrophic nonunion. NHNCs isolated from nonunion tissue sampled during surgery were cultured, passaged, counted every 14 days, and analyzed. NHNCs were homogenous fibroblastic adherent cells and long-lived through at least 10 passages, with a slight decline. The cells were consistently positive for mesenchymal stem cell-related markers CD73 and CD105, and negative for the hematopoietic markers CD14 and CD45. NHNCs could differentiate into osteoblast lineage cells; however, they did not have strong calcification or sufficient chondrogenic differentiation capability. E-BMP-2 did not affect the proliferative capability of the cells but improved their osteogenic differentiation capability by increasing alkaline phosphatase activity and upregulating the gene expression of osterix, bone sialoprotein, and osteocalcin. E-BMP-2 enhanced their chondrogenic differentiation capability by upregulating the gene expression of aggrecan and collagen type II. We showed, for the first time, that NHNCs have the capacity to differentiate into osteoblast-lineage cells, although the chondrogenic differentiation potential was poor. Local application of E-BMP-2 with preservation of nonunion tissue is a potential treatment option for non-hypertrophic nonunion.

Clinical Outcome of Patients with Bone Metastases in a Convalescent Rehabilitation Ward: A Case Series of Six Patients.

Background: Advances in cancer treatment have led to an increase in the number of cancer survivors and, likewise, cancer patients in convalescent rehabilitation wards. It is difficult for patients with bone metastases to recover their motor functions and be discharged. However, cancer treatments, such as anti-cancer drug therapy and radiation therapy, are not generally provided in convalescent rehabilitation wards. Cases: This study retrospectively reviewed six cases of bone metastases in our convalescent rehabilitation ward from April 2018 to October 2019. The ages of the patients ranged from 58 to 85 years, and all patients were male. The primary cancers were lung cancer (two cases), renal cancer (one case), esophageal cancer (one case), prostate cancer (one case), and double lung and kidney cancer (one case). Bone metastases were observed in the spine (six cases), pelvis (two cases), and femur (one case). All patients were admitted to our convalescent rehabilitation ward for postoperative management of imminent fracture risk and rehabilitation of pathological fracture or spinal cord compression caused by bone metastasis. None of the patients received treatment for primary cancer or bone metastases during their hospitalization. Two patients had new bone metastases in load-bearing bones. Five patients were transferred to acute care hospitals for the treatment of cancer or infection. Discussion: Before transferring patients with bone metastases to convalescent rehabilitation wards, clinicians should assess the risk of skeletal-related events and the rate of progression of their cancer. Indications for hospitalization should be carefully determined in cooperation with acute care hospitals.

Low-Intensity Pulsed Ultrasound Promotes Osteogenic Differentiation of Reamer-Irrigator-Aspirator Graft-Derived Cells in Vitro.

Recently, reamer-irrigator-aspirator (RIA) systems have been increasingly used to harvest autologous bone grafts. RIA graft materials contain bone marrow, which provides a viable source to derive large numbers of mesenchymal stem cells. Low-intensity pulsed ultrasound (LIPUS) significantly accelerates the differentiation of stem cells derived from bone marrow. This in vitro study investigated the effect of LIPUS on the osteogenic activity and differentiation of RIA graft-derived cells. A small amount of RIA graft was obtained from seven patients. After the cells derived from RIA grafts were cultured, they were divided into two groups: the LIPUS and control groups. LIPUS was applied once daily for 20 min (1.5 MHz, pulse duration: 200 µs, pulse repetition rate: 1 kHz, spatial average-temporal average intensity: 30 mW/cm2). Alkaline phosphatase activity (113.4% and 130.1% on days 7 and 14), expression of osteoblast-related genes (ALP, Runx2) and mineralization (135.2% on day 21) of the RIA graft-derived cells were significantly higher in the LIPUS group than in the control group. However, LIPUS did not affect the cell proliferation of RIA graft-derived cells. This study indicates that LIPUS may enhance the healing of non-union and critical bone defects treated by autologous bone grafting using the RIA system.

The multi-kinase inhibitor dasatinib suppresses autoinflammation and increases bone density in a mouse model for chronic recurrent multifocal osteomyelitis.

Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disease that presents with bone destruction and pain. Although genetic studies have identified signalling pathways involving CRMO, molecularly targeted drugs remain unavailable. We used an animal model of CRMO as an in vivo screening system for candidate therapeutic agents. A gain-of-function mutation in Fgr, a member of Src family kinases (SFKs), causes peripheral paw inflammation and reduced bone mineral density (BMD) in Ali18 mice. The SFK inhibitor dasatinib was selected for administration to Ali18 mice daily for 2 weeks. Local inflammation and BMD were assessed by clinical scoring and computed tomography, respectively. Pilot studies in a small number of animals showed that dasatinib administration effectively suppressed the early phase of autoinflammation in Ali18 mice. Serial oral gavage of dasatinib to a group of Ali18 mice confirmed significant suppression of paw swelling with no side effects. Histological analysis revealed that abnormal proliferative bone marrow cells and inflammatory infiltration into the skin in the affected area were clearly reduced in the animals with dasatinib administration. Further, trabecular BMD in Ali18 long bones was restored to levels similar to that found in wild type mice. Our results indicate that autoinflammation and related-bone phenotypes were completely suppressed by the dasatinib kinase inhibitor in CRMO model animals. Thus, it is strongly suggested that dasatinib can be used for clinical treatments of CRMO with the combination of molecular diagnosis of the FGR locus. SIGNIFICANCE OF THE STUDY: Autoinflammation and related-bone phenotypes were effectively suppressed by the kinase inhibitor dasatinib in CRMO model animals. In combination with molecular analysis of the FGR locus, dasatinib is a strong candidate for the clinical treatments of CRMO. We propose that the animal model employed in this study can be used to screen this and other potential drugs for CRMO.

Staged Bilateral Total Knee Arthroplasty in a Patient with Charcot Knees: A Case Report.

INTRODUCTION: Charcot arthropathy causes severe progressive and destructive joint disease. With the development of prostheses and surgical techniques, orthopedic surgeons have a greater opportunity to use total knee arthroplasty (TKA) to treat Charcot knee. However, consensus is lacking regarding prosthesis choice. Here, we present a case of staged bilateral TKA in a patient with bilateral Charcot knees in a different way. CASE REPORT: We report a case of a 64-year-old woman with bilateral Charcot knees. Her knee joints had become increasingly unstable with severe deformity over 1 year, and she has been unable to walk for1 month before hospitalization. We performed the first TKA of the right knee using rotating hinge prosthesis with a combination of autologous bone graft and metal tibial block augmentation; lateral release and patellar replacement were also performed. Three months after the first surgery, we performed the second TKA for her left knee using a constrained condylar prosthesis with a combination of lateral retinaculum release and patella replacement. At the 6-month follow-up, both knees were stable and in good alignment. There were no signs of loosening or fracture. The patient experienced no pain and was able to ambulate in her household using a walker. CONCLUSION: TKA using constrained condylar or rotating hinge prosthesis effectively treats Charcot knee. Surgeons must acquire both appropriate alignment and ligament stability rather than the range of motion to ensure increased longevity of the prosthesis by performing various surgical techniques. Careful follow-up is needed, but Charcot knee patients can have good outcomes with TKA.

The Medial Eminence Line for Predicting Tibial Fracture Risk after Unicompartmental Knee Arthroplasty.

BACKGROUD: Tibial fracture after cementless Oxford unicompartmental knee arthroplasty (OUKA) is a rare but serious complication. It is reported more frequently in Asian countries. The aim of this retrospective study was to assess the morphological characteristics of the tibia by using a simple novel measurement method in patients with tibial fractures after OUKA. METHODS: Six knees (all women) with tibial fractures after cementless OUKA (fracture group) and 150 knees without an obvious complication after cementless OUKA (control group) were examined retrospectively at our institution between January 2016 and April 2017. We drew a medial eminence line (ME line) defined as a line extending from the tip of the medial intercondylar eminence parallel to the tibial axis. The ME line was classified into two types (intramedullary type [type I] and extramedullary type [type E]), and the proportion of each type was compared between fracture patients and controls. RESULTS: In the fracture group, there were four (66.7%) type E cases and two (33.3%) type I cases; in the control group, there were 18 (12%) type E cases and 132 (88%) type I cases. Fisher exact tests showed that the proportion of type E was higher in the fracture group than in the control group (p < 0.01). CONCLUSIONS: Measurement of the ME line can be recommended as a useful method to assess the risk of postoperative fracture after cementless OUKA.

Impact of Machine Perfusion on Sinusoid Microcirculation of Liver Graft Donated After Cardiac Death.

BACKGROUND: The present study examined the impact of oxygenated machine perfusion on preservation of liver grafts donated after cardiac death by measuring sinusoidal endothelial injury and microcirculatory disturbances. MATERIALS AND METHODS: Fifteen porcine livers were retrieved 60 min after warm ischemia and allocated into three groups as follows: (1) CS group: static cold storage, (2) HMP group: oxygenated hypothermic perfusion preservation, (3) SNMP group: oxygenated subnormothermic perfusion preservation. The liver grafts donated after cardiac death were preserved for 4 h in different treatment conditions mentioned previously, then subject to ex vivo reperfusion for 2 h using diluted allogeneic blood. The hemodynamic parameters, liver function tests, tissue adenosine triphosphate (ATP) levels, and immunohistochemical findings were investigated. RESULTS: The number of sinusoidal epithelial cells and trabecular structures were maintained after 4 h of preservation in the CS, HMP, and SNMP group. Liver tissue ATP levels after 4 h of preservation in the HMP and SNMP groups were significantly higher compared with that in the CS group. The sinusoidal epithelial cells were significantly exfoliated to a more severe extent in the CS group than in the HMP and SNMP groups. Intrasinusoidal platelet aggregation occurred more frequently in the CS group than in the HMP and SNMP groups. CONCLUSIONS: The results indicated that oxygenated machine perfusion preservation was important to prevent the depletion of tissue ATP and maintain sinusoidal homeostasis regardless of the perfusate temperature. Our findings suggest oxygenated machine perfusion preservation as an effective alternative to static cold storage.

Approximately 30% of Functioning Anterior Cruciate Ligaments Are Sacrificed for Knee Arthroplasty.

The anterior cruciate ligament (ACL) plays an important role in knee kinematics. Unicompartmental knee arthroplasty (UKA) preserves the ACL, an advantage over total knee arthroplasty (TKA), where it is sacrificed. This study aims to evaluate how often functional ACLs are sacrificed in arthroplasty. The type of arthroplasty (TKA or UKA) and condition of the ACL were studied in a total of 1,586 knees in 1,052 patients who underwent knee arthroplasties. Of 1,586 knees, TKA was performed on 653 knees (41%) and UKA on 933 knees (59%). The ACL was functioning in 77% of all knees. Of the TKA knees, the ACL was functioning in 357 knees (55%). Of these, around 30% of the functioning ACLs were sacrificed to perform TKA. To improve postoperative patient satisfaction after knee arthroplasty, further study regarding relationship between ACL preservation and clinical outcome will be required.

Impact of human-derived hemoglobin based oxygen vesicles as a machine perfusion solution for liver donation after cardiac death in a pig model.

The recent clinical application of perfusion technology for the machine preservation of donation after cardiac death (DCD) grafts has some advantages. Oxygenation has been proposed for the preservation of DCD liver grafts. The aim of this study is to clarify whether the use of HbV-containing preservation solution during the subnormothermic machine perfusion (SNMP) of the liver graft improves the graft function of DCD porcine livers in an ex vivo reperfusion model. Pig livers were excised after 60 minutes of warm ischemic time and were preserved under one of three preservation conditions for 4 hours. The preservation conditions were as follows: 4°C cold storage (CS group; N = 5), Hypothermic machine preservation (HMP) with UW gluconate solution (HMP group; N = 5), SNMP (21°C) with UW gluconate solution (SNMP group; N = 5), SNMP (21°C) with HbVs (Hb; 1.8 mg/dl) perfusate (SNMP+HbV group; N = 5). Autologous blood perfusion was performed for 2 hours in an isolated liver reperfusion model (IRM). The oxygen consumption of the SNMP and SNMP+HbV group was higher than the HMP groups (p < 0.05). During the reperfusion, the AST level in the SNMP+HbV group was lower than that in the CS, HMP and SNMP groups. The changes in pH after reperfusion was significantly lower in SNMP+HbV group than CS and HMP groups. The ultrastructural findings indicated that the mitochondria of the SNMP+HbV group was well maintained in comparison to the CS, HMP and SNMP groups. The SNMP+HbVs preservation solution protected against metabolic acidosis and preserved the liver function after reperfusion injury in the DCD liver.

Synthesis of histone proteins by CPE ligation using a recombinant peptide as the C-terminal building block.

The post-translational modification of histones plays an important role in gene expression. We report herein on a method for synthesizing such modified histones by ligating chemically prepared N-terminal peptides and C-terminal recombinant peptide building blocks. Based on their chemical synthesis, core histones can be categorized as two types; histones H2A, H2B and H4 which contain no Cys residues, and histone H3 which contains a Cys residue(s) in the C-terminal region. A combination of native chemical ligation and desulphurization can be simply used to prepare histones without Cys residues. For the synthesis of histone H3, the endogenous Cys residue(s) must be selectively protected, while keeping the N-terminal Cys residue of the C-terminal building block that is introduced for purposes of chemical ligation unprotected. To this end, a phenacyl group was successfully utilized to protect endogenous Cys residue(s), and the recombinant peptide was ligated with a peptide containing a Cys-Pro ester (CPE) sequence as a thioester precursor. Using this approach it was possible to prepare all of the core histones H2A, H2B, H3 and H4 with any modifications. The resulting proteins could then be used to prepare a core histone library of proteins that have been post-translationally modified.