Integrated multi-omics profiling to dissect the spatiotemporal evolution of metastatic hepatocellular carcinoma.

Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased T cell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8+ T cells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis.

A novel CD47-blocking peptide fused to pro-apoptotic KLA repeat inhibits lung cancer growth in mice.

CD47 is highly expressed in many tumor tissues and induces immune evasion by interaction with SIRP-alpha (signal regulatory protein-alpha) expressed on tumor-associated macrophages. In this study, we identified a novel CD47-blocking peptide VK17 by phage display technique. A pro-apoptotic VK30 peptide was obtained after VK17 was fused to KLA amino acid repeat at C-termini. The VK30 was specifically bound to CD47 on lung cancer cells, and subsequently inducing lung cancer cell apoptosis. Meanwhile, the expression of Bax was increased, whereas the expression of Bcl-2 and Ki-67 were reduced in the VK30-treated lung cancer cells. In addition, VK30 effectively improved the phagocytic activity of macrophages against VK30-pretreated lung cancer cells. Combinational treatment of lung cancer cells with blocking antibody anti-CD47 and VK30 additively enhanced VK30 binding to CD47, subsequently increasing lung cancer cell apoptosis and macrophage phagocytosis. Intraperitoneal administration of 2 mg/kg VK30 induced effective trafficking of VK30 into tumor tissues, and suppressing lung cancer cell growth in mice, associated with increased tumor cell apoptosis, macrophage activation and phagocytosis in vivo. The expression of CD47 was reduced in the VK30-treated tumor tissues and the expression level was positively correlated to tumor size. In addition, VK30 reduced the infiltration of CD11b+Ly6G+ neutrophils and CD11b+Ly6C+Ly6G+ granulocytic myeloid-derived suppressor cells (Gr-MDSCs) in tumor tissues, associated with suppressed expression of tumorigenic IL-6 and TNF-alpha from these cell types. Thereby, VK30 exerted anti-tumor effects in mice through inducing tumor cell apoptosis and macrophage phagocytosis. VK30 would be a novel therapeutic peptide in lung cancer immunotherapy.

Percutaneous transforaminal endoscopic surgery (PTES) and mini-incision L5/S1 OLIF with a self-lock cage for the surgical treatment of L5 spondylolisthesis.

OBJECTIVES: We reported thirteen cases of percutaneous transforaminal endoscopic surgery (PTES) under local anesthesia and mini-incision L5/S1 OLIF (OLIF51) with a self-lock cage for the treatment of L5 spondylolisthesis. METHODS: From Jan 2019 to Feb 2020, the patients with L5 spondylolisthesis with nerve root symptoms undergoing PTES and OLIF51 were included in this study. PTES under local anesthesia was performed in a prone position, and OLIF51 with a self-lock cage and allograft was then undertaken through a left abdominal mini-incision and oblique retroperitoneal approach between bilateral iliac vessels with the external oblique, internal oblique and transverse abdominal muscles bluntly separated in turn for L5/S1 in a right oblique position under general anesthesia. Back and leg pain were preoperatively and postoperatively evaluated using the VAS, and the clinical outcomes were evaluated with the ODI before surgery and at the 2-year follow-up. The anterior and posterior intervertebral space height (AISH, PISH), lumbar lordotic, and surgical segmental lordotic angle (SLA) were measured on lumbar spine X-rays preoperatively and postoperatively. The fusion status was assessed according to Bridwell's fusion grades. RESULTS: Thirteen cases of L5 spondylolisthesis were included. The operation duration was 49.1 ± 5.6 min for PTES and 73.6 ± 8.2 min for OLIF. There was blood loss of 25 (15-45) ml. The incision length was 7.5 ± 1.1 mm for PTES and 46.8 ± 3.8 mm for OLIF. The hospital stay was 5 (4-6) days, and the follow-up duration was 29 (24-37) months. For the clinical evaluation, the VAS of back and leg pain significantly dropped after surgery (p < 0.001), and the ODI significantly decreased from 64.7 ± 7.8% to 12.9 ± 4.3% 2 years after surgery (p < 0.001). AISH, PISH and SLA significantly improved after surgery (p < 0.05). Fusion grades based on the Bridwell grading system at the 2-year follow-up were grade I in 9 segments (69.2%) and grade II in 4 segments (30.8%). No patients had any form of permanent iatrogenic nerve damage or major complications. No failure of instruments was observed. CONCLUSIONS: PTES and mini-incision OLIF51 with a self-lock cage is a viable option of minimally invasive surgery for L5 spondylolisthesis, which can achieve direct neurologic decompression, satisfactory fusion and hardly destroys the rectus abdominis and its sheath, paraspinal muscles and bone structures.

A novel microRNA-182/Interleukin-8 regulatory axis controls osteolytic bone metastasis of lung cancer.

Bone metastasis is one of the main complications of lung cancer and most important factors that lead to poor life quality and low survival rate in lung cancer patients. However, the regulatory mechanisms underlying lung cancer bone metastasis are still poor understood. Here, we report that microRNA-182 (miR-182) plays a critical role in regulating osteoclastic metastasis of lung cancer cells. We found that miR-182 was significantly upregulated in both bone-metastatic human non-small cell lung cancer (NSCLC) cell line and tumor specimens. We further demonstrated that miR-182 markedly enhanced the ability of NSCLC cells for osteolytic bone metastasis in nude mice. Mechanistically, miR-182 promotes NSCLC cells to secrete Interleukin-8 (IL-8) and in turn facilitates osteoclastogenesis via activating STAT3 signaling in osteoclast progenitor cells. Importantly, systemically delivered IL-8 neutralizing antibody inhibits NSCLC bone metastasis in nude mice. Collectively, our findings identify the miR-182/IL-8/STAT3 axis as a key regulatory pathway in controlling lung cancer cell-induced osteolytic bone metastasis and suggest a promising therapeutic strategy that targets this regulatory axis to interrupt lung cancer bone metastasis.

Percutaneous Transforaminal Endoscopic Surgery (PTES) for Treatment of Lumbar Degenerative Disease in Patients with Underlying Diseases: A Retrospective Cohort Study of 196 Cases.

Objective: To evaluate the postoperative outcomes, safety and feasibility of percutaneous transforaminal endoscopic surgery (PTES) for the treatment of lumbar degenerative disease (LDD) in the patients with underlying diseases. Methods: From June 2017 to April 2019, PTES was performed to treat 226 patients of single-level LDD. According to clinical background, the patients were divided into two groups. A total of 102 patients with underlying diseases were included in group A. The other 124 LDD patients without underlying diseases were included in group B. The occurrence of postoperative complications was recorded. Leg pain was assessed before, immediately, 1 month, 2 months, 3 months, 6 months, 1 year, and 2 years after PTES using VAS, and ODI before PTES and 2 years after PTES were recorded. The therapeutic quality (Excellent, Good, Moderate or Poor) was defined according to MacNab grade at 2-year follow-up. Results: No aggravation of underlying diseases or serious complications was observed in all patients within 6 months after the operation. Altogether, 196 patients were followed up for more than 2 years, 89 patients in group A and 107 patients in group B. The VAS score of leg pain and ODI dropped significantly after surgery (P<0.001) in both groups. One case of group B received PTES again due to recurrence 52 months after surgery. According to MacNab, the excellent and good rate was 97.75% (87/89) in group A and 96.26% (103/107) in group B. In operative duration, frequency of intraoperative fluoroscopy, blood loss, incision length, hospital stay, VAS, ODI, and the excellent and good rate, there was no statistical difference between the two groups. Conclusion: PTES is safe, effective and feasible for the treatment of LDD with underlying diseases, which is comparable to PTES for LDD without underlying diseases. The entrance point of PTES (Gu's Point) is located at the corner of the flat back turning to the lateral side. PTES is not only a minimally invasive surgical technique but also includes a postoperative care system for preventing LDD recurrence.

Hybrid surgery of percutaneous transforaminal endoscopic surgery (PTES) combined with OLIF and anterolateral screws rod fixation for treatment of multi-level lumbar degenerative diseases with intervertebral instability.

BACKGROUND: Oblique lumbar interbody fusion (OLIF) has been used to treat lumbar intervertebral instability, which has some advantages including less trauma, less blood loss, faster recovery and bigger cage. However, it usually needs posterior screws fixation for biomechanical stability, and possible direct decompression for relieving neurologic symptoms. In this study, OLIF and anterolateral screws rod fixation through mini-incision were combined with percutaneous transforaminal endoscopic surgery (PTES) for the treatment of multi-level lumbar degenerative diseases (LDDs) with intervertebral instability. The purpose of study is to evaluate the feasibility, efficacy and safety of this hybrid surgery. METHODS: From July 2017 to May 2018, 38 cases of multi-level LDDs of disc herniation, foramen stenosis, lateral recess stenosis or central canal stenosis with intervertebral instability and neurologic symptoms undergoing one-stage PTES combined with OLIF and anterolateral screws rod fixation through mini-incision were recruited in this retrospective study. The culprit segment was predicted according to the position of patient's leg pain and PTES under local anesthesia was performed for the culprit segment in the prone position to enlarge the foramen, remove the flavum ligamentum and herniated disc for the lateral recess decompression and expose bilateral traversing nerve roots for the central spinal canal decompression through an unilateral incision. During the operation, communicate with the patients to confirm the efficacy using VAS. And then mini-incision OLIF using allograft, autograft bone harvested in PTES and anterolateral screws rod fixation were performed in the right lateral decubitus position under general anesthesia. Back and leg pain were preoperatively and postoperatively evaluated using VAS. And the clinical outcomes were evaluated with ODI at the 2-year follow-up. The fusion status was assessed according to Bridwell's fusion grades. RESULTS: There were 27 cases of 2-level, 9 cases of 3-level and 2 cases of 4-level LDDs with single-level instability on the X-ray, CT and MRI. Five cases of L3/4 instability and 33 cases of L4/5 instability were included. PTES was performed for 1 segment of 31 cases (25 cases of instability segment, 6 cases of no instability segment) and 2 segments including instability segment of 7 cases. Then, all instability segments were treated using mini-incision OLIF and anterolateral screws rod fixation. The average operation duration was 48.9 ± 7.3 min per level for PTES and 69.2 ± 11.6 min for OLIF and anterolateral screws rod fixation. The mean frequency of intraoperative fluoroscopy was 6 (5-9) times per level for PTES and 7 (5-10) times for OLIF. There was a mean blood loss of 30 (15-60) ml, and the incision length was 8.1 ± 1.1 mm for PTES and 40.0 ± 3.2 mm for OLIF. The mean hospital stay was 4 (3-6) days. The average follow-up duration was 31.1 ± 4.0 months. For the clinical evaluation, the VAS pain index and the ODI showed excellent outcomes. Fusion grades based on the Bridwell grading system at 2-year follow-up were grade I in 29 segments (76.3%) and grade II in 9 segments (23.7%). One patient encountered nerve root sleeves rupture during PTES and did not confront cerebrospinal fluid leakage or other abnormal clinical symptoms. There were two cases of hip flexion pain and weakness, which was relieved during 1 week after surgery. No patients had any form of permanent iatrogenic nerve damage and a major complication. No failure of instruments was observed. CONCLUSIONS: The hybrid surgery of PTES combined with OLIF and anterolateral screws rod fixation is a good choice of minimally invasive surgery for multi-level LDDs with intervertebral instability, which can get direct neurologic decompression, easy reduction, rigid fixation and solid fusion, and hardly destroy the paraspinal muscles and bone structures.

Contralateral bridge fixation of freehand minimally invasive pedicle screws combined with unilateral MIS-TLIF vs. open TLIF in the treatment of multi-segmental lumbar degenerative diseases: A five years retrospective study and finite element analysis.

Objective: To evaluate the efficacy, safety, feasibility and biomechanical stability of contralateral bridge fixation of freehand minimally invasive pedicle screws (Freehand MIPS) combined with unilateral minimally invasive surgery-transforaminal lumbar interbody fusion (MIS-TLIF) (smile-face surgery) and open TLIF for the treatment of multi-segmental lumbar degenerative diseases (LDDs). Methods: From January 2013 to January 2016, clinical data of multi-segmental (2- or 3-level) LDDs receiving smile-face surgery or open TLIF were retrospectively collected and analyzed. The back and leg pain VAS and ODI were used to assess clinical outcomes preoperatively and postoperatively. The MacNab criteria were used to evaluate the satisfaction of patient. The disc height (DH), lumbar lordosis (LL) and segmental lordosis angle (SLA) were measured before and after surgery. We used patient's CT data to establish the finite element model of smile-face surgery and open TLIF, and analyze biomechanical stability of two methods. Results: Smile-face surgery group showed shorter operation time, shorter incision, less blood loss, shorter hospital stay than open TLIF (P < 0.05). The back VAS in smile-face surgery group was significantly lower than that in open TLIF immediately and 3 months after surgery, and no significant difference was observed 1 year, 2 years and 5 years after surgery. There was no significant difference in the leg pain VAS and ODI between both groups after surgery. No significant difference was observed between two groups in the DH, LL and SLA. At 5-year follow-up, grade I or II fusion was achieved in 99.00% (100/101) segments of smile-face surgery group and 97.67% (84/86) segments of open TLIF group according to Bridwell system. The complication rate of open TLIF was higher than that of smile-face surgery (24.32% vs. 0%, P < 0.01). After verification, the established finite element model can accurately simulate the biological structure of lumbar spine and there was no significant difference in biomechanical stability between two methods. Conclusions: Smile-face surgery has some advantages over open TLIF including smaller aggression, less blood loss, and lower cost, indicating that it is a good choice of treatment for multi-segmental LDDs. Both methods can achieve good biomechanical stability.

One step excision combined with unilateral transforaminal intervertebral fusion via minimally invasive technique in the surgical treatment of spinal dumbbell-shaped tumors: A retrospective study with a minimum of 5 years' follow-up.

Introduction: Spinal dumbbell-shaped tumors are rare, usually benign tumors with intraspinal and paravertebral components connected through intervertebral foramen. Complete excision is often performed through traditional open surgery (TOS). The efficacy and long-term outcomes of minimally invasive surgery (MIS) have not been reported to date in resection of dumbbell-shaped spinal tumors. Purpose: The purpose was to evaluate the efficacy and long-term outcomes of minimally invasive resection combined with unilateral transforaminal intervertebral fusion (TIF) through comparing with TOS in the treatment of spinal dumbbell-shaped tumors. Methods: Fifteen patients underwent MIS and 18 patients underwent TOS. Thoracic dumbbell-shaped tumors were directly exposed after removal of costotransverse joints, adjacent rib components, unilateral hemilamina, and facet joints. Lumbar dumbbell-shaped tumors were completely exposed after removal of transverse processes, unilateral hemilamina, and facet joints. Whether for minimally invasive resection or traditional open removal, dumbbell-shaped tumors were completely excised and unilateral TIF was performed to guarantee spinal stability. All patients were followed up for 5 years at least. Results: The mean length of surgical incision for two groups was 3.47 ± 0.37 vs. 6.49 ± 0.39 cm (p < 0.05). The average duration of the operation was 131.67 ± 26.90 vs. 144.17 ± 23.59 min (p > 0.05). The mean blood loss was 172.00 ± 48.79 vs. 285.83 ± 99.31 ml (p < 0.05). No blood transfusions were required in the two groups. The median length of hospitalization was 6 vs. 10 days (range: 5-8 vs. 7-14 days). The patients of two groups were monitored for an average of 65.93 ± 3.88 vs. 65.78 ± 3.56 months. At 5-year follow-up, all patients presented with normal neurological function (American Spinal Injury Association scale E). The Oswestry Disability Index in the MIS group decreased significantly more than the TOS group. No spondylolisthesis or spinal instability were found in the follow-up period. There was no recurrence of any spinal tumor 5 years after surgery. Conclusions: Spinal dumbbell-shaped tumors can be safely and effectively treated with minimally invasive resection combined with unilateral TIF. Compared with TOS, MIS offers a reduced length of surgical incision, blood loss, hospital stay, and postoperative pain. This surgical protocol might provide an alternative for the treatment of spinal dumbbell-shaped tumors.

Regulatory roles of external cholesterol in human airway epithelial mitochondrial function through STARD3 signalling.

BACKGROUND: Hypercholesterolemia is found in patients with chronic lung inflammation, during which airway epithelial cells play important roles in maintenance of inflammatory responses to pathogens. The present study aims at molecular mechanisms by which cholesterol changes airway epithelial sensitivity in response to smoking. METHODS: Human bronchial epithelial cells (HBEs) were stimulated with cigarette smoke extract (CSE) and mice were exposed to CS/lipopolysaccharide (LPS) as models in vitro and in vivo. Severe COPD patients and healthy volunteers were also enrolled and the level of cholesterol in plasma was detected by metabolomics. Filipin III and elisa kits were used to stain free cholesterol. Mitochondrial function was detected by mitotracker green, mitotracker green, and Seahorse. Mitochondrial morphology was detected by high content screening and electron microscopy. The mRNA and protein levels of mitochondrial dynamics-related proteins were detected by RT-qPCR and Western blot,respectively. BODIPY 493/503 was used to stain lipid droplets. Lipidomics was used to detect intracellular lipid components. The mRNA level of interleukin (IL)-6 and IL-8 were detected by RT-qPCR. RESULTS: We found that the cholesterol overload was associated with chronic obstructive pulmonary disease (COPD) and airway epithelia-driven inflammation, evidenced by hypercholesterolemia in patients with COPD and preclinical models, alteration of lipid metabolism-associated genes in CSE-induced airway epithelia and production of ILs. External cholesterol altered airway epithelial sensitivity of inflammation in response to CSE, through the regulation of STARD3-MFN2 pathway, cholesterol re-distribution, altered transport and accumulation of cholesterol, activities of lipid transport regulators and disorder of mitochondrial function and dynamics. MFN2 down-regulation increased airway epithelial sensitivity and production of ILs after smoking, at least partially by injuring fatty acid oxidation and activating mTOR phosphorylation. CONCLUSIONS: Our data provide new insights for understanding molecular mechanisms of cholesterol-altered airway epithelial inflammation and for developing diagnostic biomarkers and therapeutic targets to improve patient outcomes.

One-stage freehand minimally invasive pedicle screw fixation combined with mini-access surgery through OLIF approach for the treatment of lumbar tuberculosis.

OBJECTIVE: To compare one-stage freehand minimally invasive pedicle screw fixation (freehand MIPS) combined with mini-access surgery through OLIF approach with posterior approach for treatment of lumbar tuberculosis (TB), and evaluate its feasibility, efficacy and safety in debridement, bone graft fusion and internal fixation. METHODS: 48 patients with single segment lumbar TB from June 2014 to June 2017 were included. Among them, 22 patients underwent one-stage freehand MIPS combined with mini-access surgery through OLIF approach (group 1), 26 patients were treated with posterior open surgery (group 2). Duration of operation, blood loss, and stay time in hospital were compared. Pre- and postoperative visual analog scale (VAS) pain scores, Oswestry disability index (ODI), erythrocyte sedimentation rate, complications and images were also recorded. RESULTS: Patients in group 1 showed significantly less blood loss (165 ± 73 ml vs 873 ± 318 ml, P < 0.001), shorter stay time in hospital (6/4-8 days vs 12/8-15 days, P < 0.001), while longer duration of operation (185 ± 14 min vs 171 ± 12 min, P < 0.001) than group 2 did. VAS scores significantly decreased after surgery in both groups, however, VAS scores of group 1 were significantly lower than that of group 2 immediately after surgery and during follow-ups (P < 0.001). ODI of group 1 was also significantly lower than that of group 2 at 12-month after surgery (P < 0.001). CONCLUSION: One-stage freehand MIPS combined with mini-access surgery through OLIF approach is a feasible, efficient and safe method in treating single segment lumbar TB. It shows advantages of less surgical trauma and faster postoperative recovery.

Efficacy and safety of anterior cervical discectomy and fusion (ACDF) through mini-incision and posterior laminoplasty (LAMP) for treatment of long-level cervical spondylosis: a retrospective cohort study.

BACKGROUND: The efficacy and safety of anterior cervical discectomy and fusion (ACDF) through mini-incision and posterior laminoplasty for long-level cervical spondylosis were investigated. METHOD: From January 2018 to September 2019, clinical patients data with 3-4 segments (C3-7) cervical spondylotic radiculopathy, cervical spondylotic myelopathy, or mixed cervical spondylosis who received ACDF (42 cases) throughwith mini-incision or LAMP (36 cases) treatment were retrospectively collected and analyzed. The operative time, bleeding volume, incisive length, and hospital stay were recorded. Moreover, the intervertebral height, functional segment height, cervical lordosis, cervical hyperextension and hyperflexion range-of-motion (ROM) and ROM in all directions of the cervical spine before and after the operation were measured. Additionally, all relevant postoperative complications were also recorded. Then, the therapeutic effects of both surgical methods were investigated. RESULTS: Patients in the ACDF group had less bleeding, shorter incision, and fewer hospitalization days than the LAMP group. There was no significant difference in JOA, VAS score of the upper limb, NDI score after surgery between two groups. Postoperative intervertebral height and functional segment height in the ACDF group were significantly higher than those before the operation, and postoperative functional segment height of the ACDF group was significantly higher than that of the LAMP group. Moreover, the postoperative cervical lordosis angle in the ACDF group was significantly larger than the LAMP group. There was no significant difference between preoperative and postoperative ROM in all directions of the cervical spine for the two groups. CONCLUSIONS: Both ACDF through mini-incision and LAMP are effective treatments for long-level cervical spondylosis. However, ACDF through mini-incision shows minor trauma, less bleeding, fast recovery, and it is beneficial for cervical lordosis reconstruction.

Efficacy and safety of percutaneous transforaminal endoscopic surgery (PTES) compared with MIS-TLIF for surgical treatment of lumbar degenerative disease in elderly patients: A retrospective cohort study.

Objectives: To evaluate the efficacy and safety of PTES for surgical treatment of lumbar degenerative disease (LDD) including lumbar disc herniation, lateral recess stenosis, intervertebral foraminal stenosis and central spinal canal stenosis in elderly patients compared with MIS-TLIF. Methods: From November 2016 to December 2018, 84 elderly patients (>70 years old) of single-level LDD with neurologic symptoms underwent the surgical treatment. 45 patients were treated using PTES under local anesthesia in group 1 and 39 patients treated using MIS-TLIF in group 2. Preoperative, postoperative back and leg pain were evaluated using Visual analog scale (VAS) and the results were determined with Oswestry disability index (ODI) at 2-year follow-up. All complications were recorded. Results: PTES group shows significantly less operation time (55.6 ± 9.7 min vs. 97.2 ± 14.3 min, P < 0.001), less blood loss [11(2-32) ml vs. 70(35-300) ml, P < 0.001], shorter incision length (8.4 ± 1.4 mm vs. 40.6 ± 2.7 mm, P < 0.001), less fluoroscopy frequency [5(5-10) times vs. 7(6-11) times, P < 0.001] and shorter hospital stay[3(2-4) days vs. 7(5-18) days, P < 0.001] than MIS-TLIF group does. Although there was no statistical difference of leg VAS scores between two groups, back VAS scores in PTES group were significantly lower than those in MIS-TLIF group during follow-ups after surgery (P < 0.001). ODI of PTES group was also significantly lower than that of MIS-TLIF group at 2-year follow-up (12.3 ± 3.6% vs. 15.7 ± 4.8%, P < 0.001). Conclusion: Both PTES and MIS-TLIF show favorable clinical outcomes for LDD in elderly patients. Compared with MIS-TLIF, PTES has the advantages including less damage of paraspinal muscle and bone, less blood loss, faster recovery, lower complication rate, which can be performed under local anesthesia.

Percutaneous transforaminal endoscopic surgery combined with mini-incision OLIF and anterolateral screws rod fixation vs. MIS-TLIF for surgical treatment of single-level lumbar spondylolisthesis.

Objective: Oblique lumbar interbody fusion (OLIF) has been used to treat lumbar spine spondylolisthesis. However, it usually needs posterior pedicle screws fixation for biomechanical stability and possible posterior direct decompression for relieving neurologic symptoms. We use percutaneous transforaminal endoscopic surgery (PTES) combined with mini-incision OLIF and anterolateral screws rod fixation for surgical treatment of lumbar spondylolisthesis. The purpose of study is to evaluate the feasibility, efficacy, and safety of this method compared with minimally invasive surgery-transforaminal lumbar interbody fusion (MIS-TLIF). Methods: From July 2016 to May 2018, 65 patients of lumbar spondylolisthesis (L2-4) with neurologic symptoms were treated using PTES combined with mini-incision OLIF and anterolateral screws rod fixation (31 cases, group A) or MIS-TLIF (34 cases, group B) in this study. Operative duration, blood loss, incision length, fluoroscopy frequency, and hospital stay are compared. Preoperative and postoperative visual analog scale (VAS) pain scores of back and legs, Oswestry disability index (ODI), intervertebral space height, lumbar lordotic angle, operative segmental lordotic angle, and complications are recorded. The fusion status is assessed according to Bridwell's fusion grades. Results: The VAS score of back and leg pain and ODI significantly dropped after surgery in both groups (p < 0.001). There was no statistical difference of back and leg VAS score and ODI between two groups except that back VAS scores in group A were significantly lower than that of group B immediately after surgery (p = 0.000). Group A had significantly more intervertebral space height and operative segmental lordotic angle than group B postoperatively (p = 0.022, p = 0.002). Twenty-three segments (74.2%) were grade I and 8 segments (25.8%) were grade II in group A; 20 segments (58.8%) were grade I and 14 segments (41.2%) were grade II in group B at a 2-year follow-up (p = 0.194). No difference was observed in the complication rate between the two groups (6.5% vs. 5.9%, p = 0.924). Conclusion: The long-term clinical efficacy and complication rates of both groups are comparable. PTES combined with mini-incision OLIF and anterolateral screws rod fixation is a good choice of minimally invasive surgery for lumbar spondylolisthesis, which hardly destroys the paraspinal muscles and bone structures.

How to predict the culprit segment in percutaneous transforaminal endoscopic surgery under local anesthesia for surgical treatment of lumbar degenerative diseases? Radiologic images or clinical symptoms.

Objective: Percutaneous transforaminal endoscopic surgery (PTES) is a novel, minimally invasive technique used to treat lumbar degenerative diseases (LDDs). PTES under local anesthesia was performed to treat the culprit segment of LDDs predicted by radiologic images or clinical symptoms, and the efficacy, security, and feasibility were evaluated. Methods: Eighty-seven cases of LDDs with nerve root symptoms, which were not consistent with lumbar degenerative levels and degrees on MRI and CT, were treated with PTES under local anesthesia in a day surgery ward from January 2015 to December 2019. Forty-two patients, whose culprit segments were predicted by radiologic images, were included in group A. The other 45 patients, whose culprit segments were predicted by clinical symptoms, were included in group B. Leg pain VAS and ODI scores before and after PTES were recorded. The outcome was defined according to the MacNab grade at the 2-year follow-up. Postoperative complications were recorded. Results: In group A, 2 patients underwent PTES for one segment, 37 patients underwent PTES for two segments, and 3 patients underwent PTES for three segments. One of the one-segment PTES patients had no relief from symptoms and underwent another PTES for other culprit segments 3 months after surgery. In group B, 44 of 45 patients were treated using PTES for one segment and 1 patient was treated for two segments. Group B showed significantly less operative duration, less blood loss, and less fluoroscopy frequency than group A (p < 0.001). The leg pain VAS score and the ODI score significantly decreased after the operation in both groups (p < 0.001), and the excellent and good rates were 97.6% (41/42) in group A and 100% (45/45) in group B at the 2-year follow-up. The leg pain VAS score of group B was significantly lower than that of group A immediately and 1 week, 1 month, 2 months, and 3 months after surgery (p < 0.001). There was no statistical difference in ODI scores and the excellent and good rates between the two groups. No complications, such as wound infection or permanent nerve injury, were observed. Conclusion: It is much more accurate to predict the culprit segment according to clinical symptoms than radiologic images in PTES under local anesthesia for surgical treatment of LDDs.

Freehand Minimally Invasive Pedicle Screw Fixation and Minimally Invasive Decompression for a Thoracic or Lumbar Vertebral Metastatic Tumor From Hepatocellular Carcinoma.

Objective: To compare freehand minimally invasive pedicle screw fixation (freehand MIPS) combined with percutaneous vertebroplasty (PVP), minimally invasive decompression, and partial tumor resection with open surgery for treatment of thoracic or lumbar vertebral metastasis of hepatocellular carcinoma (HCC) with symptoms of neurologic compression, and evaluate its feasibility, efficacy, and safety. Methods: Forty-seven patients with 1-level HCC metastatic thoracolumbar tumor and neurologic symptoms were included between February 2015 and April 2017. Among them, 21 patients underwent freehand MIPS combined with PVP, minimally invasive decompression, and partial tumor resection (group 1), while 26 patients were treated with open surgery (group 2). Duration of operation, blood loss, times of fluoroscopy, incision length, and stay in hospital were compared between the two groups. Pre- and postoperative visual analog scale (VAS) pain score, Oswestry Disability Index (ODI), American Spinal Injury Association (ASIA) grade, ambulatory status, and urinary continence were also recorded. The Cobb angle and central and anterior vertebral body height were measured on lateral radiographs before surgery and during follow-ups. Results: Patients in group 1 showed significantly less blood loss (195.5 ± 169.1 ml vs. 873.1 ± 317.9 ml, P = 0.000), shorter incision length (3.4 ± 0.3 vs. 13.6 ± 1.8 cm, P = 0.000), shorter median stay in hospital (4-8/6 vs. 8-17/12 days, P = 0.000), more median times of fluoroscopy (5-11/6 vs. 4-7/5 times, P = 0.000), and longer duration of operation (204.8 ± 12.1 vs. 171.0 ± 12.0 min, P = 0.000) than group 2. Though VAS significantly decreased after surgery in both groups, VAS of group 1 was significantly lower than that of group 2 immediately after surgery and during follow-ups (P < 0.05). Similar results were found in ODI. No differences in the neurological improvement and spinal stability were observed between the two groups. Conclusion: Freehand MIPS combined with PVP, minimally invasive decompression, and partial tumor resection is a safe, effective, and minimally invasive method for treating thoracolumbar metastatic tumors of HCC, with less blood loss, better pain relief, and shorter length of midline incision and stay in hospital.

Application of Oblique Lateral Interbody Fusion in Treatment of Lumbar Spinal Tuberculosis in Adults.

OBJECTIVE: The purpose of the present paper was to evaluate the safety and clinical efficacy of mini-open retroperitoneal oblique lumbar interbody fusion (OLIF) for the treatment of lumbar spinal tuberculosis. METHODS: A total of 115 patients who suffered from lumbar spinal tuberculosis from June 2014 to December 2017 were included in this research. A total of 59 patients underwent OLIF and percutaneous pedicle screw fixation (OLIF group) and 56 patients underwent the anterior-only approach (anterior-only group). All patients were followed up for at least 24 months. Operation time, blood loss, and rate of complications were used to assess the safety of these two techniques. The visual analog scale (VAS) and the Oswestry disability index (ODI) were used to evaluate the relief of neurological and functional symptoms. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured to investigate the activity and recurrence of spinal tuberculosis. The Cobb angle, the sagittal vertical axis of the spine (SVA), the pelvic tilt (PT), the sacral slope (SS), the pelvic incidence (PI), and postoperative Frankel classification were also used to assess the efficiency of the spine deformity correction and the recovery of long-term neurological function. RESULTS: Most patients were successfully treated with OLIF and the anterior-only technique and attained satisfactory clinical efficiency during the 24-month follow-up period. In the perioperative period, the mean operative time (154.68 ± 23.64 min, P < 0.001), the mean blood loss (110.57 ± 87.67 mL, P < 0.001), and the mean hospital stay (9.55 ± 3.62 days, P < 0.001) of the OLIF group were all significantly lower than in the anterior-only group (172.49 ± 25.67 min, 458.56 ± 114.89 mL, and 14.89 ± 3.89 days, respectively). A total of 10 patients (16.95%) experienced complications in the OLIF group, including neurological injury, segmental artery and iliac vein lacerations, peritoneal injury, instrument failure, and infection of incisions; this rate of complications was lower than in the anterior-only group (37.50%, P = 0.013). Regard to spinal deformity correction, the Cobb angle (9.42° ± 1.72°, P = 0.032), the SVA (2.23 ± 1.07 cm, P = 0.041), the PT (14.26° ± 2.37°, P = 0.037), and the SS (39.49° ± 2.17°, P = 0.042) of the OLIF group at last follow-up were all significantly different when compared to the anterior-only group (14.75° ± 2.13°, 3.48 ± 0.76 cm, 18.58° ± 1.45°, and 36.78° ± 1.96°, respectively). The VAS and the ODI of the OLIF group at 1 week postoperatively (3.15 ± 0.48, 21.85 ± 3.78, P = 0.032, 0.037) and at the last follow-up (2.12 ± 0.35, 16.70 ± 5.25, P = 0.043, 0.035) were both lower than for the anterior-only group (5.18 ± 0.56, 29.83 ± 5.42 and 3.67 ± 0.62, 20.68 ± 6.23). The Frankel classification was improved for both OLIF and anterior-only patients; however, there were 35 cases (59.32%) classified as Frankel grade E in the OLIF group and 22 cases (39.29%, P = 0.021) in the anterior-only group CONCLUSION: The OLIF surgical technique for single lumbar (L2 -L5 ) spinal tuberculosis is less invasive, has lower complication rates, and is more efficient than the anterior-only approach. However, the long-term effects of this surgical technique still need to be explored.

Bone marrow mesenchymal stem cell-derived extracellular vesicles containing miR-497-5p inhibit RSPO2 and accelerate OPLL.

AIMS: Muscle and adipose tissue-derived mesenchymal stem cells presented high osteogenic potentials, which modulate osteoblast function through releasing extracellular vesicles (EVs) containing miRNAs. Herein, this study evaluated the function of bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) delivering miR-497-5p in ossification of the posterior longitudinal ligament (OPLL). MAIN METHODS: The expression level of miR-497-5p was validated in ossified posterior longitudinal ligament (PLL) tissues and BMSC-EVs. The uptake of BMSC-EVs by ligament fibroblasts was observed by immunofluorescence. miR-497-5p was overexpressed or downregulated to assess its role in osteogenic differentiation of ligament fibroblasts. Further, an OPLL rat model was established to substantiate the effect of BMSC-EVs enriched with miR-497-5p on OPLL. KEY FINDINGS: Ossified PLL tissues presented with high miR-497-5p expression. PLL fibroblasts were identified to endocytose BMSC-EVs. BMSC-EVs could upregulate miR-497-5p and shuttle it to ligament fibroblasts to accelerate the osteogenic differentiation. miR-497-5p targeted and inversely regulated RSPO2. Then, RSPO2 overexpression activated Wnt/ß-catenin pathway and repressed the osteogenic differentiation of ligament fibroblasts. In vivo experiments further showed that miR-497-5p-containing BMSC-EVs enhanced OPLL through diminishing RSPO2 and inactivating Wnt/ß-catenin pathway. SIGNIFICANCE: BMSC-EVs could deliver miR-497-5p to ligament fibroblasts and modulate RSPO2-mediated Wnt/ß-catenin pathway, thereby accelerating OPLL.

Evaluation of efficacy and safety of percutaneous transforaminal endoscopic surgery (PTES) for surgical treatment of calcified lumbar disc herniation: a retrospective cohort study of 101 patients.

BACKGROUND: Percutaneous transforaminal endoscopy has been widely used to treat lumbar disc herniation (LDH), but the steep learning curve and difficulties in removing the calcified disc hinders the application of conventional endoscopy in treating calcified lumbar disc herniation (CLDH). In 2017, we first reported Percutaneous Transforaminal Endoscopic Surgery (PTES) as an easy-to-learn posterolateral transforaminal endoscopic technique to decompress the nerve root for LDH. We used our PTES technique to remove the calcified LDH and the purpose of this study is to evaluate the safety and efficacy of this technique. METHODS: Forty-six patients with CLDH and fifty-five patients with uncalcified lumbar disc herniation (ULDH) underwent PTES to decompress the nerve root. Visual analogue scale was collected before the surgery, immediately, one week, one month, two months, three months, six months, 12 months and 24 months after surgery. The outcomes of MacNab classification were collected 24 months after surgery. Intra- and Post-operative complications were also recorded. RESULTS: For CLDH patients, the VAS score was 9 (5-10) before operation, and then dropped to 2 (1-4) after surgery. VAS score continually decreased to 0 (0-3) at 24 months after surgery. 95.65% of CLDH patients showed excellent or good outcomes. ULDH group showed similar MacNab classification (94.55%) and VAS changing curve. The therapeutic effect of PTES in treating CLDH was as good as that in treating uncalcified patients. CONCLUSIONS: PTES is an effective and safe method to treat calcified lumbar disc herniation.

AZD3463, an IGF-1R inhibitor, suppresses breast cancer metastasis to bone via modulation of the PI3K-Akt pathway.

BACKGROUND: The bone-derived insulin-like growth factor I (IGF-1) and its receptor IGF-1R play a crucial role in promoting the survival and proliferation of cancer cells, and have thus been considered as prime targets for the development of novel antitumor therapeutics. METHODS: By using the MDA-MB-231BO cell line, which is the osteotropic metastatic variant of the human breast adenocarcinoma cell line MDA-MB-231, and an in vivo model of breast cancer metastasis to bone, the current study evaluated the effect of AZD3463, an IGF-1R inhibitor, used alone or in combination with zoledronic acid (ZA), on the regulation of IGF-1R associated signal pathway and treatment of bone metastases (BM). Cell proliferation and invasion were measured by methyl thiazolyl tetrazolium (MTT) and Transwell assay respectively. Apoptotic cell number was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL). RESULTS: AZD3463 was shown to alleviate IGF-1R phosphorylation promoted by IGF-1 treatment in MDA-MB-231BO cells in a dose-dependent manner. In both the cells and the mouse model, 5 nM of AZD3463 stimulated cell apoptosis and suppressed proliferation on a level similar to that of 100 µM of ZA. Remarkably, the combined use of AZD3463 and ZA exhibited a synergistic effect and greater antitumor activity compared to when they were employed individually. Mechanistic investigations indicated that the apoptosis-inducing activity of AZD3463 could be associated to its role in the activation of the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway. CONCLUSIONS: These findings suggested that AZD3463 could serve as a promising therapeutic molecule for treating BM in breast cancer patients, particularly when applied in conjunction with ZA or other antitumor agents.