Concepts of Regeneration for Spinal Diseases in 2023.

It is our pleasure to announce the publication of the Special Issue "Regeneration for Spinal Diseases 3.0" in the International Journal of Molecular Sciences (ISSN 1422-0067) [...].

Cytokine Inhibitors Upregulate Extracellular Matrix Anabolism of Human Intervertebral Discs under Alginate Beads and Alginate-Embedded Explant Cultures.

We investigated the effects of the cytokine inhibitors IL-1 receptor antagonist (IL-1Ra) and soluble tumor necrosis factor receptor-1 (sTNFR1) on the extracellular matrix metabolism of human intervertebral discs (IVDs) and the roles of IL-1ß and TNF in the homeostasis of IVD cells. The 1.2% alginate beads and the explants obtained from 35 human lumbar discs were treated with cytokine inhibitors. Extracellular matrix metabolism was evaluated by proteoglycan (PG) and collagen syntheses and IL-1ß, TNF, and IL-6 expressions after three days of culture in the presence or absence of IL-1Ra, sTNFR1, and cycloheximide. Simultaneous treatment with IL-1Ra and sTNFR1 stimulated PG and collagen syntheses in the NP and AF cells and explants. The IL-1ß concentration was significantly correlated to the relative increase in PG synthesis in AF explants after simultaneous cytokine inhibitor treatment. The relative increase in PG synthesis induced by simultaneous cytokine treatment was significantly higher in an advanced grade of MRI. Expressions of IL-1ß and TNF were upregulated by each cytokine inhibitor, and simultaneous treatment suppressed IL-1ß and TNF productions. In conclusion, IL-1Ra and sTNFR1 have the potential to increase PG and collagen synthesis in IVDs. IL-1ß and TNF have a feedback pathway to maintain optimal expression, resulting in the control of homeostasis in IVD explants.

Anti-Inflammatory Effects of Adiponectin Receptor Agonist AdipoRon against Intervertebral Disc Degeneration.

Adiponectin, a hormone secreted by adipocytes, has anti-inflammatory effects and is involved in various physiological and pathological processes such as obesity, inflammatory diseases, and cartilage diseases. However, the function of adiponectin in intervertebral disc (IVD) degeneration is not well understood. This study aimed to elucidate the effects of AdipoRon, an agonist of adiponectin receptor, on human IVD nucleus pulposus (NP) cells, using a three-dimensional in vitro culturing system. This study also aimed to elucidate the effects of AdipoRon on rat tail IVD tissues using an in vivo puncture-induced IVD degeneration model. Analysis using quantitative polymerase chain reaction demonstrated the downregulation of gene expression of proinflammatory and catabolic factors by interleukin (IL)-1ß (10 ng/mL) in human IVD NP cells treated with AdipoRon (2 µM). Furthermore, western blotting showed AdipoRon-induced suppression of p65 phosphorylation (p < 0.01) under IL-1ß stimulation in the adenosine monophosphate-activated protein kinase (AMPK) pathway. Intradiscal administration of AdipoRon was effective in alleviating the radiologic height loss induced by annular puncture of rat tail IVD, histomorphological degeneration, production of extracellular matrix catabolic factors, and expression of proinflammatory cytokines. Therefore, AdipoRon could be a new therapeutic candidate for alleviating the early stage of IVD degeneration.

Clinical and Radiological Characteristics of Cervical Spondylotic Myelopathy in Young Adults: A Retrospective Case Series of Patients under Age 30.

Background and Objectives: Cervical spondylotic myelopathy (CSM) is a degenerative disease and occurs more frequently with age. In fact, the development of non-herniated CSM under age 30 is uncommon. Therefore, a retrospective case series was designed to clarify clinical and radiological characteristics of young adult patients with CSM under age 30. Materials and Methods: A total of seven patients, all men, with non-herniated, degenerative CSM under age 30 were retrieved from the medical records of 2598 hospitalized CSM patients (0.27%). Patient demographics and backgrounds were assessed. The sagittal alignment, congenital canal stenosis, dynamic canal stenosis, and vertebral slips in the cervical spine were radiographically evaluated. The presence of degenerative discs, intramedullary high-signal intensity lesions, and sagittal spinal cord compression on T2-weighted magnetic resonance images (MRIs) and axial spinal cord deformity on T1-weighted MRIs was identified. Results: All patients (100.0%) had relatively high daily sports activities and/or jobs requiring frequent neck extension. Cervical spine radiographs revealed the sagittal alignment as the "reverse-sigmoid" type in 57.1% of patients and "straight" type in 28.6%. All patients (100.0%) presented congenital cervical stenosis with the canal diameter ≤12 mm and/or Torg-Pavlov ratio <0.80. Furthermore, all patients (100.0%) developed dynamic stenosis with the canal diameter ≤12 mm and/or posterior vertebral slip ≥2 mm at the neurologically responsible segment in full-extension position. In MRI examination, all discs at the neurologically responsible level (100.0%) were degenerative. Intramedullary abnormal intensity lesions were detected in 85.7% of patients, which were all at the neurologically responsible disc level. Conclusions: Patients with non-herniated, degenerative CSM under age 30 are rare but more common in men with mild sagittal "reverse-sigmoid" or "straight" deformity and congenital canal stenosis. Relatively high daily activities, accumulating neck stress, can cause an early development of intervertebral disc degeneration and dynamic canal stenosis, leading to CSM in young adults.

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.

Concepts of Regeneration for Spinal Diseases in 2022.

It is our pleasure to announce the publication of the Special Issue "Regeneration for Spinal Diseases 2 [...].

Influence of the Preoperative Duration of Symptoms on Patients' Clinical Outcomes after Minimally Invasive Surgery-Transforaminal Lumbar Interbody Fusion for Degenerative Lumbar Spinal Diseases.

Background and Objectives: The impact of the duration of symptoms (DOS) on postoperative clinical outcomes of patients with degenerative lumbar spinal diseases is important for determining the optimal timing of surgical intervention; however, the timing remains controversial. This prospective case−control study aimed to investigate the influence of the preoperative DOS on surgical outcomes in minimally invasive surgery-transforaminal lumbar interbody fusion (MIS-TLIF). Materials and Methods: Patients who underwent single-level TLIF for lumbar degenerative diseases between 2017 and 2018 were reviewed. Only patients with full clinical data during the 1-year follow-up period were included. The patients were divided into two groups (DOS < 12 months, group S; DOS ≥ 12 months, group L). The clinical outcomes, including the Oswestry disability index (ODI) and visual analog scale (VAS) for lower back pain, leg pain, and numbness, were investigated preoperatively and at 1, 3, and 6 months, as well as 1 year, after surgery. Furthermore, postoperative patient satisfaction 1 year after surgery was also surveyed. Results: A total of 163 patients were assessed: 60 in group S and 103 in group L. No differences in baseline characteristics and clinical outcomes were found. The ODI and VAS significantly improved from the baseline to each follow-up period (all p < 0.01). Group S had significantly lower ODI scores at 3 months (p = 0.019) and 6 months (p = 0.022). In addition, group S had significantly lower VAS scores for leg pain at 3 months (p = 0.027). In a comparison between both groups, only the patients with cauda equina symptoms showed that ODI and leg pain VAS scores at 3 months after surgery were significantly lower in group S (19.9 ± 9.1 vs. 14.1 ± 12.5; p = 0.037, 7.4 ± 13.9 vs. 14.7 ± 23.1; p = 0.032, respectively). However, the clinical outcomes were not significantly different between both groups 1 year after surgery. Patient satisfaction was also not significantly different between both groups. Conclusions: Patients with a shorter DOS tended to have a significantly slower recovery; however, clinical outcomes 1 year after surgery were good, regardless of the DOS.

Surgical Outcome of Spinal Fusion for Osteogenesis Imperfecta With Scoliosis: Is the Hybrid System With Pedicle Screws Applicable to Weak, Tiny, and Fragile Vertebrae?

INTRODUCTION: Corrective surgery for spinal deformity associated with osteogenesis imperfecta (OI) is challenging due to the severe and rigid deformity combined with extreme bone fragility. However, surgical outcomes still remain unclear. In addition, the applicability of pedicle screws (PSs) to the tiny and fragile vertebrae in patients with OI is poorly understood. This study evaluated the surgical outcome, and the accuracy and safety of PS placement in patients with OI. METHODS: Twenty-five patients with OI were included in this study. Mean age was 21.0±9.3 (10 to 49) years. Mean follow-up was 5.8±2.0 years. The Sillence classification showed 16 patients had the mildest type I, 1 patient had moderate type IV, and 8 patients had the most severe type III. Fifteen patients underwent anterior release followed by posterior fusion, and 10 patients underwent only posterior fusion. The accuracy of PS placement was evaluated with postoperative computed tomography. RESULTS: Scoliosis was corrected from 95.6 to 65.8 degrees after surgery (correction rate 32.5%) and 68.1 degrees at final follow-up (both, P<0.01). Space available for the lung was improved from 76.3% to 84.9% (P<0.05). No implant dislodgement occurred after surgery. A total of 290 screws were placed, of which 213 screws (73.4%) were placed completely. However, 30 screws (10.3%) penetrated >2 mm. In particular, rates of >2 mm penetration was much higher in type III than type I and IV (27.8% vs. 3.0%; P<0.01). Complications related to spinal surgery included 2 transient neurological disturbances. CONCLUSIONS: PSs were applicable to spinal fusion surgery in patients with OI. However special care should be taken in placing PSs because of the weakness of the pedicle cortex, which was easily penetrated especially in Sillence type III. LEVEL OF EVIDENCE: Level IV.

Concepts of Regeneration for Spinal Diseases in 2021.

It is our pleasure to announce the publication of the Special Issue "Regeneration for Spinal Diseases" in the International Journal of Molecular Sciences (IJMS, ISSN 1422-0067) [...].

Involvement of Autophagy in Rat Tail Static Compression-Induced Intervertebral Disc Degeneration and Notochordal Cell Disappearance.

The intervertebral disc is the largest avascular low-nutrient organ in the body. Thus, resident cells may utilize autophagy, a stress-response survival mechanism, by self-digesting and recycling damaged components. Our objective was to elucidate the involvement of autophagy in rat experimental disc degeneration. In vitro, the comparison between human and rat disc nucleus pulposus (NP) and annulus fibrosus (AF) cells found increased autophagic flux under serum deprivation rather in humans than in rats and in NP cells than in AF cells of rats (n = 6). In vivo, time-course Western blotting showed more distinct basal autophagy in rat tail disc NP tissues than in AF tissues; however, both decreased under sustained static compression (n = 24). Then, immunohistochemistry displayed abundant autophagy-related protein expression in large vacuolated disc NP notochordal cells of sham rats. Under temporary static compression (n = 18), multi-color immunofluorescence further identified rapidly decreased brachyury-positive notochordal cells with robust expression of autophagic microtubule-associated protein 1 light chain 3 (LC3) and transiently increased brachyury-negative non-notochordal cells with weaker LC3 expression. Notably, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic death was predominant in brachyury-negative non-notochordal cells. Based on the observed notochordal cell autophagy impairment and non-notochordal cell apoptosis induction under unphysiological mechanical loading, further investigation is warranted to clarify possible autophagy-induced protection against notochordal cell disappearance, the earliest sign of disc degeneration, through limiting apoptosis.

Inhibition of Autophagy at Different Stages by ATG5 Knockdown and Chloroquine Supplementation Enhances Consistent Human Disc Cellular Apoptosis and Senescence Induction rather than Extracellular Matrix Catabolism.

The intervertebral disc is the largest avascular organ. Autophagy is an important cell survival mechanism by self-digestion and recycling damaged components under stress, primarily nutrient deprivation. Resident cells would utilize autophagy to cope with the harsh disc environment. Our objective was to elucidate the roles of human disc cellular autophagy. In human disc cells, serum deprivation and pro-inflammatory interleukin-1ß (IL-1ß) stimulation increased autophagy marker microtubule-associated protein 1 light chain 3 (LC3)-II and decreased autophagy substrate p62/sequestosome 1 (p62/SQSTM1), indicating enhanced autophagy. Then, RNA interference (RNAi) of autophagy-related gene 5 (ATG5), essential for autophagy, showed decreases in ATG5 protein (26.8%-27.4%, p < 0.0001), which suppressed early-stage autophagy with decreased LC3-II and increased p62/SQSTM1. Cell viability was maintained by ATG5 RNAi in serum-supplemented media (95.5%, p = 0.28) but reduced in serum-free media (80.4%, p = 0.0013) with IL-1ß (69.9%, p = 0.0008). Moreover, ATG5 RNAi accelerated IL-1ß-induced changes in apoptosis and senescence. Meanwhile, ATG5 RNAi unaffected IL-1ß-induced catabolic matrix metalloproteinase release, down-regulated anabolic gene expression, and mitogen-activated protein kinase pathway activation. Lysosomotropic chloroquine supplementation presented late-stage autophagy inhibition with apoptosis and senescence induction, while catabolic enzyme production was modest. Disc-tissue analysis detected age-related changes in ATG5, LC3-II, and p62/SQSTM1. In summary, autophagy protects against human disc cellular apoptosis and senescence rather than extracellular matrix catabolism.

The factors related to the poor ADL in the patients with osteoporotic vertebral fracture after instrumentation surgery.

PURPOSE: Osteoporotic vertebral fracture (OVF) with nonunion or neurological deficit may be a candidate for surgical treatment. However, some patients do not show improvement as expected. Therefore, we conducted a nationwide multicenter study to determine the predictors for postoperative poor activity of daily living (ADL) in patients with OVF. METHODS: We retrospectively reviewed the case histories of 309 patients with OVF who underwent surgery. To determine the factors predicting postoperative poor ADL, uni- and multivariate statistical analyses were performed. RESULTS: The frequency of poor ADL at final follow-up period was 9.1%. In univariate analysis, preoperative neurological deficit (OR, 4.1; 95% CI, 1.8-10.3; P < 0.001), perioperative complication (OR, 3.4; P = 0.006), absence of preoperative bone-modifying agent (BMA) administration (OR, 2.7; P = 0.03), and absence of postoperative recombinant human parathyroid hormone (rPTH) administration (OR, 3.9; P = 0.006) were significantly associated. In multivariate analysis, preoperative neurological deficit (OR, 4.6; P < 0.001), perioperative complication (OR, 3.4; P = 0.01), and absence of postoperative rPTH administration (OR, 3.9; P = 0.02) showed statistical significance. CONCLUSIONS: Preoperative neurological deficit, perioperative complication, and absence of postoperative rPTH administration were considered as predictors for postoperative poor ADL in patients with OVF. Neurological deficits and complications are often inevitable factors; therefore, rPTH is an important option for postoperative treatment for OVF. These slides can be retrieved under Electronic Supplementary Material.

Effect of bisphosphonates or teriparatide on mechanical complications after posterior instrumented fusion for osteoporotic vertebral fracture: a multi-center retrospective study.

BACKGROUND: The optimal treatment of osteoporosis after reconstruction surgery for osteoporotic vertebral fractures (OVF) remains unclear. In this multicentre retrospective study, we investigated the effects of typically used agents for osteoporosis, namely, bisphosphonates (BP) and teriparatide (TP), on surgical results in patients with osteoporotic vertebral fractures. METHODS: Retrospectively registered data were collected from 27 universities and affiliated hospitals in Japan. We compared the effects of BP vs TP on postoperative mechanical complication rates, implant-related reoperation rates, and clinical outcomes in patients who underwent posterior instrumented fusion for OVF. Data were analysed according to whether the osteoporosis was primary or glucocorticoid-induced. RESULTS: A total of 159 patients who underwent posterior instrumented fusion for OVF were included. The overall mechanical complication rate was significantly lower in the TP group than in the BP group (BP vs TP: 73.1% vs 58.2%, p = 0.045). The screw backout rate was significantly lower and the rates of new vertebral fractures and pseudoarthrosis tended to be lower in the TP group than in the BP group. However, there were no significant differences in lumbar functional scores and visual analogue scale pain scores or in implant-related reoperation rates between the two groups. The incidence of pseudoarthrosis was significantly higher in patients with glucocorticoid-induced osteoporosis (GIOP) than in those with primary osteoporosis; however, the pseudoarthrosis rate was reduced by using TP. The use of TP also tended to reduce the overall mechanical complication rate in both primary osteoporosis and GIOP. CONCLUSIONS: The overall mechanical complication rate was lower in patients who received TP than in those who received a BP postoperatively, regardless of type of osteoporosis. The incidence of pseudoarthrosis was significantly higher in patients with GIOP, but the use of TP reduced the rate of pseudoarthrosis in GIOP patients. The use of TP was effective to reduce postoperative complications for OVF patients treated with posterior fusion.

Serum and nutrient deprivation increase autophagic flux in intervertebral disc annulus fibrosus cells: an in vitro experimental study.

PURPOSE: The loss of nutrient supply is a suspected contributor of intervertebral disc degeneration. However, the extent to which low nutrition affects disc annulus fibrosus (AF) cells is unknown as nutrient deprivation has mainly been investigated in disc nucleus pulposus cells. Hence, an experimental study was designed to clarify the effects of limited nutrients on disc AF cell fate, including autophagy, the process by which cells recycle their own damaged components. METHODS: Rabbit disc AF cells were cultured in different media with varying serum concentrations under 5% oxygen. Cellular responses to changes in serum and nutrient concentrations were determined by measuring proliferation and metabolic activity. Autophagic flux in AF cells was longitudinally monitored using imaging cytometry and Western blotting for LC3, HMGB1, and p62/SQSTM1. Apoptosis (TUNEL staining and cleaved caspase-3 immunodetection) and cellular senescence (senescence-associated ß-galactosidase assay and p16/INK4A immunodetection) were measured. RESULTS: Markers of apoptosis and senescence increased, while cell proliferation and metabolic activity decreased under the withdrawal of serum and of nutrients other than oxygen, confirming cellular stress. Time-dependent increases in autophagy markers, including LC3 puncta number per cell, LC3-II expression, and cytoplasmic HMGB1, were observed under conditions of reduced nutrition, while an autophagy substrate, p62/SQSTM1, decreased over time. Collectively, these findings suggest increased autophagic flux in disc AF cells under serum and nutrient deprivation. CONCLUSION: Disc AF cells exhibit distinct responses to serum and nutrient deprivation. Cellular responses include cell death and quiescence in addition to reduced proliferation and metabolic activity, as well as activation of autophagy under conditions of nutritional stress. These slides can be retrieved under Electronic Supplementary Material.

Surgical outcomes of spinal fusion for osteoporotic thoracolumbar vertebral fractures in patients with Parkinson's disease: what is the impact of Parkinson's disease on surgical outcome?

BACKGROUND: To date, there have been little published data on surgical outcomes for patients with PD with thoracolumbar OVF. We conducted a retrospective multicenter study of registry data to investigate the outcomes of fusion surgery for patients with Parkinson's disease (PD) with osteoporotic vertebral fracture (OVF) in the thoracolumbar junction. METHODS: Retrospectively registered data were collected from 27 universities and their affiliated hospitals in Japan. In total, 26 patients with PD (mean age, 76 years; 3 men and 23 women) with thoracolumbar OVF who underwent spinal fusion with a minimum of 2 years of follow-up were included (PD group). Surgical invasion, perioperative complications, radiographic sagittal alignment, mechanical failure (MF) related to instrumentation, and clinical outcomes were evaluated. A control group of 296 non-PD patients (non-PD group) matched for age, sex, distribution of surgical procedures, number of fused segments, and follow-up period were used for comparison. RESULTS: The PD group showed higher rates of perioperative complications (p < 0.01) and frequency of delirium than the non-PD group (p < 0.01). There were no significant differences in the degree of kyphosis correction, frequency of MF, visual analog scale of the symptoms, and improvement according to the Japanese Orthopaedic Association scoring system between the two groups. However, the PD group showed a higher proportion of non-ambulators and dependent ambulators with walkers at the final follow-up (p < 0.01). CONCLUSIONS: A similar surgical strategy can be applicable to patients with PD with OVF in the thoracolumbar junction. However, physicians should pay extra attention to intensive perioperative care to prevent various adverse events and implement a rehabilitation regimen to regain walking ability.

Surgical outcomes of spinal fusion for osteoporotic vertebral fracture in the thoracolumbar spine: Comprehensive evaluations of 5 typical surgical fusion techniques.

BACKGROUND: A consensus on the optimal surgical procedure for thoracolumbar OVF has yet to be reached due to the previous relatively small number of case series. The study was conducted to investigate surgical outcomes for osteoporotic vertebral fracture (OVF) in the thoracolumbar spine. METHODS: In total, 315 OVF patients (mean age, 74 years; 68 men and 247 women) with neurological symptoms who underwent spinal fusion with a minimum 2-year follow-up were included. The patients were divided into 5 groups by procedure: anterior spinal fusion alone (ASF group, n = 19), anterior/posterior combined fusion (APSF group, n = 27), posterior spinal fusion alone (PSF group, n = 40), PSF with 3-column osteotomy (3CO group, n = 92), and PSF with vertebroplasty (VP + PSF group, n = 137). RESULTS: Mean operation time was longer in the APSF group (p < 0.05), and intraoperative blood loss was lower in the VP + PSF group (p < 0.05). The amount of local kyphosis correction was greater in the APSF and 3CO groups (p < 0.05). Clinical outcomes were approximately equivalent among all groups. CONCLUSION: All 5 procedures resulted in acceptable neurological outcomes and functional improvement in walking ability. Moreover, they were similar with regard to complication rates, prevalence of mechanical failure related to the instrumentation, and subsequent vertebral fracture. Individual surgical techniques can be adapted to suit patient condition or severity of OVF.

Quality of life and cost-utility of surgical treatment for patients with spinal metastases: prospective cohort study.

PURPOSE: Palliative surgery for patients with spinal metastasis provides good clinical outcomes. However, there have been few studies on quality of life (QOL) and cost-utility of this surgery. We aimed to elucidate QOL and cost-utility of surgical treatment for spinal metastasis. METHODS: We prospectively analyzed 47 patients with spinal metastasis from 2010 to 2014 who had a surgical indication. Thirty-one patients who desired surgery underwent spinal surgery (surgery group). Sixteen patients who did not want to undergo spinal surgery (non-surgery group). The EuroQol 5D (EQ-5D) and relevant costs were measured at one, three, six, and 12 months after study enrollment. Health state values were obtained by Japanese EQ-5D scoring and quality-adjusted life years (QALY) gained were calculated for each group. Cost-utility was expressed as the incremental cost-utility ratio (ICUR). RESULTS: Health state values improved from 0.036 at study enrollment to 0.448 at 12 months in the surgery group, but deteriorated from 0.056 to 0.019 in the non-surgery group, with a significant difference between groups (P < 0.05). The mean QALY gained at 12 months were 0.433 in the surgery group and 0.024 in the non-surgery group. The mean total cost per patient in the surgery group was $25,770 compared with $8615 in the non-surgery group. The ICUR using oneyear follow-up data was $42,003/QALY gained. CONCLUSIONS: Surgical treatment for spinal metastases is associated with significant improvement in health state value. In orthopaedic surgery, an ICUR less than $50,000/QALY gained is considered acceptable cost-effectiveness. Our results indicate that surgical treatment could be cost-effective.

Surgical debridement with retention of spinal instrumentation and long-term antimicrobial therapy for multidrug-resistant surgical site infections after spinal surgery: a case series.

PURPOSE: Post-operative surgical site infection (SSI) is one of the most significant complications after instrumented spinal surgery. However, implant retention feasibility for early-onset multidrug-resistant SSI is still controversial. We aimed to verify our therapeutic strategy, surgical debridement with implant retention and long-term antimicrobial therapy for post-operative early-onset multidrug-resistant SSI. METHODS: We retrospectively analyzed the clinical course of 11 cases [eight men and three women, with a mean age of 70.4 (54-82) years] with early-onset multidrug-resistant SSI out of 409 consecutive cases of spinal instrumentation surgery performed between 2007 and 2013 at our institution. RESULTS: The median duration of follow-up was 868 (178-1,922) days. All SSIs were controlled, without recurrence during follow-up. The microbial pathogens were methicillin-resistant Staphylococcus aureus (seven cases), multidrug-resistant Corynebacterium (two cases), methicillin-resistant Staphylococcus epidermidis (one case), and methicillin-resistant coagulase-negative Staphylococcus aureus (one case). The mean duration from SSI diagnosis to surgery was 2.9 (1-6) days. Ten patients underwent surgical debridement with implant retention. No patients required multiple operations. All patients were given antimicrobial treatments. Mean duration of intravenous antimicrobials (vancomycin, vancomycin+ piperacillin/tazobactam, or gentamicin) was 66.5 (12-352) days and 336 (89-1,673) days for oral antimicrobials (rifampicin + sulfamethoxazole/trimethoprim, sulfamethoxazole/trimethoprim, or minomycin). The mean duration of clinical signs and symptom recovery was 31.0 (7-73) days, and the mean time for normalization of C-reactive protein was 54.5 (7-105) days. CONCLUSIONS: Early-onset multidrug-resistant SSI was successfully treated by surgical debridement with implant retention and long-term antimicrobial therapy.

Clinical Features and Therapeutic Process of Sacral Fatigue Fractures in Adolescents.

BACKGROUND: Sacral fatigue fractures are a rare injury but should be considered as a differential diagnosis for low back and buttock pain in young adults. Collective reports are limited, most of which have focused on long-distance runners. PURPOSE: To investigate the characteristics of sacral fatigue fractures in adolescents. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We analyzed patient background characteristics, physical examination and imaging findings, and treatment courses of those diagnosed with sacral fatigue fractures using magnetic resonance imaging. RESULTS: Among 34 patients with sacral fatigue fractures, 15 and 19 were male and female patients, respectively, with an age range of 11 to 19 years (mean age, 15.0 years). Almost all patients were athletes, and 29 patients performed their sport ≥5 times a week. Long-distance runners were the most commonly affected, comprising 7 patients, and participants in other common sports such as baseball (6 patients), basketball (4 patients), and soccer (3 patients) were also affected. Physical examination revealed tension sign (Lasègue test) on the affected side in 6 patients and tight hamstrings in 24 patients. Imaging findings included 18 patients with right-side involvement, 12 with left-side involvement, and 4 with involvement on both sides. In 11 patients, spina bifida occulta was observed at S1 and 8 patients had a history of lumbar spondylolysis with 4 patients having concurrent sacral fatigue fractures. Physical therapy was performed concurrently with the cessation of exercise, and return to exercise was permitted if the pain had been relieved after 1 month. All patients returned to sports at a median of 48 days (range, 20-226 days) after symptom onset. However, 2 patients experienced recurrence (1 patient on the ipsilateral side and 1 patient on the contralateral side). CONCLUSION: Sacral stress fractures are not limited to long-distance runners in this population and can manifest as lower back pain or buttock pain in athletes participating in a variety of sports. Although the course of treatment was generally good, the possibility of recurrence must always be considered.

Rapamycin mitigates inflammation-mediated disc matrix homeostatic imbalance by inhibiting mTORC1 and inducing autophagy through Akt activation.

Background: Low back pain is a global health problem that originated mainly from intervertebral disc degeneration (IDD). Autophagy, negatively regulated by the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, prevents metabolic and degenerative diseases by removing and recycling damaged cellular components. Despite growing evidence that autophagy occurs in the intervertebral disc, the regulation of disc cellular autophagy is still poorly understood. Methods: Annulus fibrosus (rAF) cell cultures derived from healthy female rabbit discs were used to test the effect of autophagy inhibition or activation on disc cell fate and matrix homeostasis. Specifically, different chemical inhibitors including rapamycin, 3-methyladenine, MK-2206, and PP242 were used to modulate activities of different proteins in the PI3K/Akt/mTOR signaling pathway to assess IL-1ß-induced cellular senescence, apoptosis, and matrix homeostasis in rAF cells grown under nutrient-poor culture condition. Results: Rapamycin, an inhibitor of mTOR complex 1 (mTORC1), reduced the phosphorylation of mTOR and its effector p70/S6K in rAF cell cultures. Rapamycin also induced autophagic flux as measured by increased expression of key autophagy markers, including LC3 puncta number, LC3-II expression, and cytoplasmic HMGB1 intensity and decreased p62/SQSTM1 expression. As expected, IL-1ß stimulation promoted rAF cellular senescence, apoptosis, and matrix homeostatic imbalance with enhanced aggrecanolysis and MMP-3 and MMP-13 expression. Rapamycin treatment effectively mitigated IL-1ß-mediated inflammatory stress changes, but these alleviating effects of rapamycin were abrogated by chemical inhibition of Akt and mTOR complex 2 (mTORC2). Conclusions: These findings suggest that rapamycin blunts adverse effects of inflammation on disc cells by inhibiting mTORC1 to induce autophagy through the PI3K/Akt/mTOR pathway that is dependent on Akt and mTORC2 activities. Hence, our findings identify autophagy, rapamycin, and PI3K/Akt/mTOR signaling as potential therapeutic targets for IDD treatment.