Enrichment of Wee1/CDC2 and NF-κB Signaling Pathway Constituents Mutually Contributes to CDDP Resistance in Human Osteosarcoma / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Osteosarcoma (OS) universally exhibits heterogeneity and cisplatin (CDDP) resistance. Although the Wee1/CDC2 and nuclear factor кB (NF-κB) pathways were reported to show abnormal activation in some tumor cells with CDDP resistance, whether there is any concrete connection is currently unclear. We explored it in human OS cells. @*Materials and Methods@#Multiple OS cell lines were exposed to a Wee1 inhibitor (AZD1775) and CDDP to assess the half-maximal inhibitory concentration values. Western blot, coimmunoprecipitation, confocal immunofluorescence, cell cycle, and Cell Counting Kit-8assays were performed to explore the connection between the Wee1/CDC2 and NF-κB pathways and their subsequent physiological contribution to CDDP resistance. Finally, CDDP-resistant PDX-OS xenograft models were established to confirm that AZD1775 restores the antitumor effects of CDDP. @*Results@#A sensitivity hierarchy of OS cells to CDDP and AZD1775 exists. In the highly CDDP-tolerant cell lines, Wee1 and RelA were physically crosslinked, which resulted in increased abundance of phosphorylated CDC2 (Y15) and RelA (S536) and consequent modulation of cell cycle progression, survival, and proliferation. Wee1 inhibition restored the effects of CDDP on these processes in CDDP-resistant OS cells. In addition, animal experiments with CDDP-resistant PDX-OS cells showed that AZD1775 combined with CDDP not only restored CDDP efficacy but also amplified AZD1775 in inhibiting tumor growth and prolonged the median survival of the mice. @*Conclusion@#Simultaneous enrichment of molecules in the Wee1/CDC2 and NF-κB pathways and their consequent coactivation is a new molecular mechanism of CDDP resistance in OS cells. OS with this molecular signature may respond well to Wee1 inhibition as an alternative treatment strategy.

Direct anterior approach combinedwithdirect posterior approach for the treatment of Pipkin Ⅳ fractures / 中华骨科杂志

Objective:To explore the efficacyof direct anterior approach (DAA) combined with direct posterior approach (DPA) for the treatment of Pipkin IV fracture.Methods:Data of 18 patients with Pipkin IV fracture treated through DAA combined with DPA from January 2016 to April 2019 was retrospectively analyzed. There were 13 males and 5 females, with an average age of 43.2 years (range,19-56 years). Fractures were caused by traffic accident in 15 and by falling in 3. The fracture lines of 13 cases were located below the fovea of the femoral head and 5 cases were located above the fovea. According to Letournel-Judet classification for acetabular fractures, there were 14 cases of posterior acetabular wall fractures, 2 cases of posterior wall fractures involving posterior column, and 2 transverse plus posterior wall fractures. The operation was performed through DAA approach to treat the femoral head fractures, and DPA approach was used to treat acetabular fractures. Radiographs and CT scans of the pelvis were reexamined after surgery, and fracture reduction, healing, and complications such as femoral head necrosis, sciatic nerve injury, superior gluteal neurovascular injury and heterotopic ossification were evaluated. Quality of acetabular reduction was evaluated according to the criteria proposed by Matta. Thompson-Epstein scoring system was used to evaluate hip function.Results:The average operation time was 133 min (range, 75-205 min). And the average blood loss was 371 ml (range, 240-600 ml). All 18 patients were followed up for 6 to 36 months, with an average period of 15.7 months. All fractures healed 10 to14 weeks after surgery. Three patients had symptoms of sciatic nerve injury after the injury, who recovered 6 to 12 weeks after the operation. All femoral head fractures were reduced. According to Matta criteria of reduction quality, anatomic reduction was gained in 13 cases, and satisfactory reduction was obtained in 3 cases, while unsatisfactory reduction was found in 2 cases, and the overall satisfactory rate was 88.9%(16/18). Two patients had Brooker I level heterotopic ossification. There was no iatrogenic vascular injury, avascular necrosis of femoral head, infection, internal fixation failure or other complications. According to the Thompson-Epstein scoring system at the latest follow-up, the functional results of the affected hip were excellent in 7 cases, good in 8, fair in 2 and poor in 1.Conclusion:Treatment of Pipkin IV fractures through DAA combined with DPA approach reduces surgical invasion. And it can directly reduce and fix the femoral head and posterior acetabular fracture, and protect the important structures such as the arteriae circumflexa femoris medialis, sciatic nerve and lateral femoral cutaneous nerve, and reduce the occurrence of complications such as femoral head necrosis and heterotopic ossification. Therefore, DAA combined with DPA is aneffective method for the treatment of Pipkin IV fractures.

Anterior expansion of sacral foramen and decompression of sacral plexus via lateral-rectus approach for sacral fractures complicated with sacral plexus injury / 中华创伤骨科杂志

Objective:To evaluate the anterior expansion of sacral foramen and decompression of sacral plexus via the lateral-rectus approach (LRA) in the surgical treatment of sacral fractures complicated with sacral plexus injury.Methods:From January 2013 to June 2018, 11 patients were treated at Department of Orthopaedics, The Third Hospital Affiliated to Southern Medical University for obsolete sacral fractures complicated with sacral plexus injury. They were 8 males and 3 females, aged from 17 to 54 years (average, 38 years). According to the Denis classification, all the sacral fractures belonged to Denis Zone Ⅱ. According to British Medical Research Council (BMRC) grading system, the nerve injury was complete damage in 2 cases and partial damage in 9. The mean time from injury to surgery was 6 months (range, from 0.7 to 12.0 months). After the sacroiliac joint was exposed via the LRA, the lumbosacral trunk was exposed and released between iliac vessels and the iliopsoas. Next, the S1 foramen was expanded and the S1 nerve root was released after separation of the median sacral artery and the internal iliac artery. Reduction and fixation of the sacroiliac joint was carried out for patients with unstable sacral fracture. X-ray and CT examinations of the pelvis were performed to evaluate fracture healing and neurological function recovery postoperatively.Results:Of this cohort of 11 cases, operation succeeded in 10 but failed in one whose sacral fracture was found to have completely healed with the S1 foramina totally occluded. The surgical time averaged 110 min (range, from 70 to 220 min) and the blood loss 1, 100 mL (range, from 450 to 2, 800 mL). Postoperative X-ray and CT examinations showed that the sacral foramens were expanded significantly without any complications. The follow-up time averaged 18 months (range, from 12 months to 4 years). By the BMRC grading system at the last follow-up, the neural function was completely recovered in 5 cases, partially recovered in 4 cases and not recovered in one.Conclusion:Significant anterior expansion of sacral foramen and decompression of sacral plexus via the LRA is a viable and effective alternative for treatment of sacral fractures complicated with sacral plexus injury.

Treatment of Tile C pelvic nonunions and malunions via the lateral rectus approach combined with the modified Starr pelvic reduction frame / 中华骨科杂志

Objective:To explore the surgical technique and the clinical efficacy of the lateral-rectus approach with traction reduction by the modified Starr pelvic reduction frame for Tile C pelvic nonunions and malunions.Methods:Data of 7 patients with Tile C pelvic nonunions and malunions from June 2017 to June 2018 who were treated via the lateral-rectus approach combined with traction reduction by the modified Starr pelvic reduction frame were retrospectively analyzed. There were 5 males and 2 females, aged from 22 to 53 (mean, 40 years). The injury mechanism included 3 cases of car accident injury, 3 of falling injury and 1 of crushing injury. The reasons for retreatment were pain in 7 cases, inability to walk and sit in 3, unequal length of lower limbs and lameness in 3. According to Tile classification, there were 4 cases of C1 type, 2 of C2 type and 1 of C3 type. A complete pelvic model with equal size as the patient’s pelvis was 3D-printed out according to three-dimensional reconstruction CT. The osteotomy or release site was designed, and the preoperative plan was detailed. Expose and release via the lateral rectus approach combined with traction reduction was conducted using the modified Starr pelvic reduction frame. Operative time, intraoperative blood loss and postoperative complications were collected. Visual analogue scale (VAS) at 6 months after surgery were recorded. Majeed score was used to evaluate the clinical efficacy. The quality of fracture reduction was evaluated by the Mears-Velyvis radiological evaluation criterion at the latest follow-up.Results:The operation time was 140-280 min, with an average of 190 min. The intraoperative blood loss was 700-2,800 ml, with an average of 1,250 ml. In 6 cases, the final fixation was performed at one time, while 1 case of Tile C3 type was performed in two stages. All patients were followed up for 10-22 months, and all the fractures healed. The mean time of bony union was 8 weeks (range, 6-12 weeks). The VAS of the 7 patients was improved from an average of 6.4 points to an average of 0.7 points during 6 months postoperative follow-up. The Majeed clinical efficacy score of the latest follow-up was improved from the average 60 points preoperative to 85 points postoperative. According to the Mears-Velyvis radiological evaluation criterion, the satisfaction rate reached 85.7%(6/7). After operation, 1 case occurred obturator nerve injury who recovered within 3 months, and 1 case remained limb shortening deformity of 1 cm. There was no fixation failure.Conclusion:The anterior osteotomy via the lateral-rectus approach can fully cut off nonunions and malunions of the pelvis, effectively release the soft tissues around the osteotomy site, with minimal surgical trauma and low risks of neurovascular injuries. Combined the modified Starr pelvic reduction frame, it can effectively correct pelvic deformities, lower limb rotation and unequal length deformities to achieve the expected effect of surgery.

Treatment of vertical shear pelvic fracture combined with lumbosacral plexus injury through the lateral-rectus approach / 中华创伤骨科杂志

Objective:To investigate the clinical efficacy of lateral-rectus approach(LRA) for vertical shear fracture of pelvis combined with lumbosacral plexus nerve injury.Methods:A retrospective study was conducted of the 37 patients who had been treated at Department of Orthopaedics, The Third Affiliated Hospital to Southern Medical University for vertical shear pelvic fracture combined with lumbosacral plexus nerve injury from August 2010 to August 2018. They were 25 males and 12 females, aged from 18 to 61 years (mean, 36.2 years). By the Tile classification, there were 31 cases of type C1.3, 5 cases of type C2 and one of type C3. LRA was used in all the patients to explore and release the lumbosacral plexus nerve and to reduce the sacral fracture. The posterior ring was fixated with an anterior iliac plate or sacral screws before fixation of the anterior ring and treatment of the acetabular fracture. The operation time, intraoperative bleeding volume, quality of fracture reduction, fracture union time and recovery of nerve and muscle strength were recorded.Results:For this cohort, the operation time ranged from 105 to 228 minutes (mean, 155.0 minutes) and the intraoperative bleeding volume from 680 to 2, 440 mL (mean, 1, 070 mL). Thefollow-up time ranged from 1 to 8 years (average, 2 years). According to the Matta criteria, the quality of fracture reduction was evaluated as excellent in 21 cases, as good in 12 cases and as fair in 4 cases, giving an excellent and good rate of 89.2%. Follow-ups revealed reduction loss in 4 patients, nonunion and reduction loss in one patient and bony union in the other 32 patients after 8 to 12 weeks (mean, 10.1 weeks). According to the criteria by the Nerve Injuries Committee of the British Medical Research Council (BMRC), the recovery of nerve and muscle strength achieved M5 (full recovery of neurological symptoms) in 22 cases, M4 (fine recovery of neurological symptoms) in 7 cases, M1, M2 and M3 (partial recovery of neurological symptoms) in 5 cases, and M0 (no recovery of neurological symptoms) in 3 cases.Conclusion:LRA is an ideal surgical approach for treatment of pelvic vertical shear fractures complicated with lumbosacral plexus nerve injury, because it can well expose the medial pelvic joint from the sacroiliac joint to the symphysis pubis, allow direct release of the lumbosacral plexus nerve compressed and stretched, and, together with traction of the lower limbs, lead to satisfactory fracture reduction.

Direct posterior approach for the treatment of posterior acetabular fractures / 中华骨科杂志

Objective To explore surgical technique and clinical results of the direct posterior approach (DPA) for ace?tabular fractures involving posterior column, posterior wall, or posterior column and wall. Methods From January 2016 to June 2017, data of 10 cases (7 males, 3 females, an average age of 37 years, ranging from 17 to 54 years) with posterior acetabular frac?tures treated by the DPA were retrospectively analyzed. Fractures were caused by traffic accident in 6 cases and by falling in 4 cas?es. According to Letournel?Judet classification of acetabular fractures, there were 6 cases of posterior acetabular wall fractures, 4 cases of posterior wall fractures involving posterior column. A straight skin incision was made from the middle of the line between the posterior margin of the tip of the femoral greater trochanter and the posterior superior iliac spine, to the posterior margin of the femoral greater trochanter. The gluteus maximus muscle was cleaved longitudinally. A view of the area from hip capsule to the su?perior margin of the greater sciatic foramen was obtained by entering along the interspace of the gluteus medius and pyriformis muscle, and the superior gluteal neurovascular bundle was protected. Acetabular posterior column and posterior wall fractures were reduced and fixed under direct vision. The fracture reduction, fracture healing, femoral head necrosis, sciatic nerve injury, su?perior gluteal neurovascular injury and heterotopic ossification were evaluated by the postoperative X?ray and CT examination. The function of hip joint was assessed by the Merle d’Aubigné?Posteal score modified by Matta. Results The average operative incision length was 9.6 cm (range, 8-11 cm). The average operation time was 50 min (range, 35-80 min). The average blood loss was 310 ml (range, 200-440 ml). The time of follow?up was 12-30 months. All the patients were healed within 8-12 weeks with?out any complications such as superior gluteal nerve injury, superior gluteal vessel injury, or sciatic nerve injury. One case of ace? tabular posterior wall and posterior column fracture with posterior dislocation of hip joint, suffered from femoral head necrosis at the 9th months after surgery, which was treated by total hip arthroplasty and was recovered one year after surgery. In one case of actebular posterior wall and posterior column fracture, heterotopic ossification occurred 3 month after operation, without any spe?cial treatment and the hip joint activity was not affected at the follow?up of 15 months after surgery. During the 12?month follow?up after surgery, the Merle d’Aubigné?Postel score modified by Matta was 13-18, among which there were excellent in 6 cases, good in 2, acceptable in 2, with an overall excellent and good rate of 80% (8/10). Conclusion The direct posterior approach for poste?rior acetabular fractures can obtain satisfactory clinical results. The advantages of the DPA include decreasing trauma, shortening operation time, reduing blood loss and decreasing risks of iatrogenic injury to the gluteus medius muscle, the external rotators, the arteriae circumflexa femoris medialis and sciatic nerves as well as reducing and fixing the fractures under direct vision. Thus, the DPA is a relatively safe surgical approach for acetabular posterior wall/column fracture.

Direct posterior approach for the treatment of posterior acetabular fractures / 中华骨科杂志

Objective@#To explore surgical technique and clinical results of the direct posterior approach (DPA) for acetabular fractures involving posterior column, posterior wall, or posterior column and wall.@*Methods@#From January 2016 to June 2017, data of 10 cases (7 males, 3 females, an average age of 37 years, ranging from 17 to 54 years) with posterior acetabular fractures treated by the DPA were retrospectively analyzed. Fractures were caused by traffic accident in 6 cases and by falling in 4 cases. According to Letournel-Judet classification of acetabular fractures, there were 6 cases of posterior acetabular wall fractures, 4 cases of posterior wall fractures involving posterior column. A straight skin incision was made from the middle of the line between the posterior margin of the tip of the femoral greater trochanter and the posterior superior iliac spine, to the posterior margin of the femoral greater trochanter. The gluteus maximus muscle was cleaved longitudinally. A view of the area from hip capsule to the superior margin of the greater sciatic foramen was obtained by entering along the interspace of the gluteus medius and pyriformis muscle, and the superior gluteal neurovascular bundle was protected. Acetabular posterior column and posterior wall fractures were reduced and fixed under direct vision. The fracture reduction, fracture healing, femoral head necrosis, sciatic nerve injury, superior gluteal neurovascular injury and heterotopic ossification were evaluated by the postoperative X-ray and CT examination. The function of hip joint was assessed by the Merle d’Aubigné-Posteal score modified by Matta.@*Results@#The average operative incision length was 9.6 cm (range, 8-11 cm). The average operation time was 50 min (range, 35-80 min). The average blood loss was 310 ml (range, 200-440 ml). The time of follow-up was 12-30 months. All the patients were healed within 8-12 weeks without any complications such as superior gluteal nerve injury, superior gluteal vessel injury, or sciatic nerve injury. One case of acetabular posterior wall and posterior column fracture with posterior dislocation of hip joint, suffered from femoral head necrosis at the 9th months after surgery, which was treated by total hip arthroplasty and was recovered one year after surgery. In one case of actebular posterior wall and posterior column fracture, heterotopic ossification occurred 3 month after operation, without any special treatment and the hip joint activity was not affected at the follow-up of 15 months after surgery. During the 12-month follow-up after surgery, the Merle d’Aubigné-Postel score modified by Matta was 13-18, among which there were excellent in 6 cases, good in 2, acceptable in 2, with an overall excellent and good rate of 80% (8/10).@*Conclusion@#The direct posterior approach for posterior acetabular fractures can obtain satisfactory clinical results. The advantages of the DPA include decreasing trauma, shortening operation time, reduing blood loss and decreasing risks of iatrogenic injury to the gluteus medius muscle, the external rotators, the arteriae circumflexa femoris medialis and sciatic nerves as well as reducing and fixing the fractures under direct vision. Thus, the DPA is a relatively safe surgical approach for acetabular posterior wall/column fracture.