Efficacy of PD-1 Inhibitors Combined with Anti-Angiogenic Therapy in Driver Gene Mutation Negative Non-Small-Cell Lung Cancer with Brain Metastases.

OBJECTIVE: Anti-angiogenic therapy has proven effective in non-small-cell lung cancer (NSCLC) patients. The purpose of this study was to evaluate the efficacy of programmed cell death protein 1 (PD-1) inhibitors combined with anti-angiogenic therapy in patients with driver gene mutation negative NSCLC and brain metastases (BMs). METHODS: A retrospective analysis was performed on NSCLC BMs in patients without driver gene mutations who received PD-1 inhibitors. Two groups, receiving either PD-1 inhibitor monotherapy or PD-1 inhibitor plus anti-angiogenesis therapy, were identified. The primary endpoints were overall survival (OS) and intracranial progression-free survival (iPFS). The secondary endpoints were safety, intracranial objective response rate (iORR) and intracranial disease control rate (iDCR). RESULTS: 113 NSCLC patients were included, 51 (45.1%) in the PD-1 inhibitor monotherapy group and 62 (54.9%) in the PD-1 inhibitor plus anti-angiogenesis therapy group. The median follow-up time was 26.2 months. OS was higher in the combination therapy cohort than in the monotherapy cohort (OS: 21.4 vs. 11.8 months; p = 0.004), with no significant difference in iPFS (p = 0.088). Moreover, the PD-1 inhibitor + anti-angiogenic therapeutic regimen exhibited the preferred iDCR (p = 0.005) but not the iORR (p = 0.121). There was no significant difference in the incidence of grade 3-4 adverse events between the two groups. In multivariate Cox regression analysis, PD-1 inhibitor therapy combined with anti-angiogenic treatment (p = 0.003) was an independent prognostic indicator of OS. CONCLUSIONS: Combining PD-1 inhibitor therapy with anti-angiogenic treatment significantly improves the OS of driver gene mutation negative NSCLC patients with BMs.

Mid-Term Outcomes of Cemented Stem and Subtrochanteric Shortening Derotational Osteotomy in Total Hip Arthroplasty for Crowe IV Developmental Dysplasia.

OBJECTIVE: Performing subtrochanteric osteotomy with cemented components in patients with Crowe IV developmental dysplasia of the hip (DDH) is technically challenging and not widely reported. This study aimed to evaluate the mid-term outcomes of cemented stem total hip arthroplasty (THA) with subtrochanteric femoral shortening and transverse derotational osteotomy in patients with Crowe IV DDH. METHODS: Data collected from patients with Crowe IV DDH who underwent cemented stem THA with subtrochanteric femoral shortening and transverse derotational osteotomy between 2010 and 2018 were retrospectively evaluated. The cemented Lubinus SP II femoral component and the cementless CombiCup acetabular component were used together in all cases. These data, including Harris hip scores, limb length discrepancy (LLD), severity of limp, Trendelenburg test, bone union, length of the resected femur, limb lengthening, level of the osteotomy site, and length bridging the osteotomy site, as well as complications, were analyzed. A paired Student t-test was used to analyze continuous variables, categorical data were compared using Fisher's exact probability test, and correlation analysis was performed using Spearman's rank correlation coefficient. RESULTS: Among 14 included patients (10 females and four males), the mean age was 60.4 years (range, 47-73). The mean follow-up period was 49.1 months, and no patient was lost to follow-up. The mean Harris hip score improved from 40.7 to 87.7. The mean LLD decreased from 52 to 12.7 mm. The mean length of the excised femoral segment was 38.4 mm, and the mean length of limb lengthening was 27.1 mm. The mean distance between the osteotomy site and the lesser trochanter was 21.1 mm after surgery. The mean length of the femoral stem bridging the osteotomy site was 97.6 mm. Finally, the mean osteotomy union time was 10.6 months. No statistically significant correlation was found between the osteotomy union time and these factors. No neurological deficits were noted. Delayed union was observed in one patient, and postoperative dislocation was observed in two patients. Cement leakage into the osteotomy gap was observed in one patient, however, no revisions were required, and no signs of loosening or migration were observed. CONCLUSIONS: Cemented stem THA combined with subtrochanteric femoral shortening and transverse derotational osteotomy is safe and effective in treating patients with Crowe IV DDH. Rather than leading to nonunion, cement leakage may negatively affect bone healing.

Osimertinib combined with bevacizumab for leptomeningeal metastasis from EGFR-mutation non-small cell lung cancer: A phase II single-arm prospective clinical trial.

BACKGROUND: Leptomeningeal metastasis (LM) is associated with poor prognosis in non-small cell lung cancer (NSCLC). The aim of this study was to investigate the efficacy and safety of osimertinib combined with bevacizumab for LM from epidermal growth factor receptor mutation (EGFRm) NSCLC. METHODS: We conducted a phase II single-arm prospective clinical trial of EGFRm NSCLC with LM treated with osimertinib combined with bevacizumab. LM response assessment was based on the modified RANO LM radiological criteria; CNS and extra-CNS response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary end points included LM progression-free survival (PFS) and objective response rate (ORR); the secondary end points included safety and LM overall survival (OS). RESULTS: A total of 14 patients were included in the study, with a median age of 61 years, and they were predominantly female (64%). EGFR mutations were reported in exons 19 del (n = 7) and 21 L858R (n = 7). When LM was diagnosed, 12 (85.7%) patients had clinical symptoms, 71.4% (10/14) of patients were diagnosed with LM by cytology, and five (35.7%) patients had a performance status (PS) score > 2. The median LM PFS was 9.3 months (95% CI: 8.2-10.4), and the LM ORR was 50%. The safety findings in the present study were consistent with the known profile of osimertinib with bevacizumab; the median LM OS was 12.6 months, and the one-year survival rate was 35.7%. CONCLUSIONS: Osimertinib combined with bevacizumab is an appropriate treatment option for patients with LM from EGFRm NSCLC. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: To date, there is no prospective clinical study on the treatment of osimertinib combined with bevacizumab in EGFRm NSCLC with LM. WHAT THIS STUDY ADDS: The median LM PFS was 9.3 months (95% CI: 8.2-10.4), and the LM ORR was 50%, the median LM OS was 12.6 months, and the one-year survival rate was 35.7%. Osimertinib combined with bevacizumab is an appropriate treatment option for patients with LM from EGFRm NSCLC.

Approximating the maximum tibial coverage in total knee arthroplasty does not necessarily result in implant malrotation.

Traditionally, the practice of the tibial component placement in total knee arthroplasty has focused on achieving maximum coverage without malrotation. However, the concept of maximizing coverage has not been well defined or researched and yet biased results are often produced. This study aimed to evaluate the effect of a prioritizing maximum coverage positioning strategy on the rotational alignment by using a strict computer algorithm. Computed tomographic scans of 103 tibial specimens were used to reconstruct three-dimensional tibia models. A virtual surgery was performed to generate the resection plane with a posterior slope of 7° on the proximal tibia. Symmetrical and anatomical tibial components were placed and analyzed with an automated program designed for approximating the maximum coverage based on the coherent point drift algorithm. We found that the average tibial coverage achieved across all specimens and implants was 85.62 ± 3.65%, ranging from 83.64 ± 4.10% to 86.69 ± 3.07%. When placed for maximal tibial coverage, the mean degree of rotation related to the Insall line was - 0.73° ± 4.53° for all subjects, 23% of the tibial components were malrotated. The average percentage position of the baseplate anteroposterior axis over the patellar tendon was 26.95 ± 14.71% from the medial edge. These results suggest that with specific design and proper placement of the component, approximating the maximum tibial coverage in total knee arthroplasty does not necessarily result in implant malrotation. The current tibial baseplates have shown good performance on the coverage when aligned parallel to the Insall line with the anteroposterior axis positioned between the medial 1/3 and medial 1/6 of the patella tendon.

Optimal location of subtrochanteric osteotomy in total hip arthroplasty for crowe type IV developmental dysplasia of hip.

BACKGROUND: When reconstructing a hip with developmental dysplasia and high dislocation, sub-trochanteric shortening osteotomy is typically needed for placing the acetabular component in the appropriate anatomical position. However, the procedure can result in complications such as non-union of the osteotomy. We evaluated the contact area and the coincidence rate between the proximal and distal fragments at different femoral osteotomy levels and lengths. We then determined the optimal location of subtrochanteric femoral shortening transverse osteotomy in patients with unilateral Crowe type IV developmental dysplasia of the hip (DDH). The consistency between the proximal and distal segments was assessed as a possible predictive indicator of the union at the osteotomy site. METHODS: We retrospectively reviewed 57 patients with unilateral Crowe type IV DDH who underwent X-ray imaging of both hip joints. We labelled the inner and outer diameters of the circular ring as N (mm) and M (mm), respectively. We defined the overlapped area between the proximal and distal ring as contact area S (mm2), and the ratio of contact area to distal ring area as coincidence rate R. RESULTS: N varied from 9.8-15.2 mm and M varied from 20.7-24 mm, both demonstrated a decreasing trend in the proximal to distal direction. At osteotomy lengths ranging from 0.5-2 cm, there were no differences in S between the different levels of osteotomy in each group. At osteotomy lengths ≤2.5 cm, a significant higher coincidence rate was noted from 2 cm below the lesser trochanter to other positions below the level. At osteotomy lengths from 3 to 5.5 cm, a significantly higher coincidence rate was observed from the level of 1.5 cm below the lesser trochanter to other positions below the level. CONCLUSIONS: Our findings suggest that femoral shortening transverse osteotomy at the optimal subtrochanteric level can predictably increase the contact area and coincidence rate, which may contribute to the union at the osteotomy site. Considering the stability of the prostheses, it appears appropriate that osteotomy location should be shifted slightly distally. TRIAL REGISTRATION: Retrospectively registered.

BRCA1 protects cardiac microvascular endothelial cells against irradiation by regulating p21-mediated cell cycle arrest.

AIMS: Microvascular endothelial cell dysfunction is a leading cause of radiation-induced heart disease (RIHD). BRCA1 plays an important role in DNA damage repair. The study aims to explore the effect of BRCA1 in endothelial cells involved in RIHD. MATERIALS AND METHODS: BRCA1 and p21 expression were detected in human umbilical vein endothelial cells (HUVECs) and in mouse heart tissue after irradiation exposure. The effects of BRCA1 on cell proliferation, cell cycle and radiosensitivity were determined in HUVECs with overexpression and knockdown of BRCA1. A mouse model of RIHD was established. Heart damage was detected in C57BL/6J mice and endothelial cell specific knockout BRCA1 mice (EC-BRCA1-/-). KEY FINDINGS: BRCA1 and p21 expression was significantly increased both in vitro and vivo response to irradiation. BRCA1 overexpression in endothelial cells enhanced cell growth and G1/S phase arrest, and the opposite results were observed in BRCA1 knockdown endothelial cells. BRCA1 downregulated endothelial cell cycle-related genes cyclin A, cyclin D1, cyclin E and p-Rb through increasing p21 expression, and HUVECs with BRCA1 gene knockdown were more sensitive to radiation. In vivo, a decrease in cardiac microvascular density, as well as cardiomyocyte hypoxia and apoptosis were observed in a time-dependent manner. EC-BRCA1-/- mice were more prone to severe RIHD than EC-BRCA1+/- mice after 16Gy radiation exposure due to endothelial dysfunction caused by loss of BRCA1, and p21 was declined in EC-BRCA1-/- mice heart. SIGNIFICANCE: These findings indicate that BRCA1 plays a protective role in RIHD by regulating endothelial cell cycle arrest mediated by p21 signal.

Positive association between heart dosimetry parameters and a novel cardiac biomarker, solubleST-2, in thoracic cancer chest radiation.

BACKGROUND: Early screening and diagnosis of radiation-induced heart disease (RIHD) is difficult in patients with chest radiation exposure. sST-2 is involved in myocardial stress or injury. We evaluated the relationship between heart dose parameters and sST-2 changes in chest malignant tumor patients who received chest radiation. METHODS: We prospectively collected thoracic malignancy cancer patients who had received chest radiotherapy. Heart dosimetry parameters were extracted from the treatment planning system. sST-2 was measured at baseline, the middle stage, and after radiotherapy (recorded as pre-ST-2, mid-ST-2, and post-ST-2). sST-2 change rate was calculated. Scatter plots showed the relationship between cardiac dose parameters and ST-2 change rate. Multiple regression was used to analyze the relationship between cardiac dose parameters and ST-2 change rate. RESULTS: Totally, 60 patients were enrolled. The mean V5 , V10 , V20 , V30 , V40 , and MHD was 60.93 ± 27.79%, 51.43 ± 25.44%, 39.17 ± 21.75%, 28.07 ± 17.15%,18.66 ± 12.18%, and 18.60 ± 8.63 Gy, respectively. The median M-LAD was 11.31 (IQR 3.33-18.76) Gy. The mean pre-ST-2, mid-ST-2, and post-ST-2 was 5.1 ± 3.8, 6.4 ± 3.9, and 7.6 ± 4.4, respectively. sST-2 was elevated with thoracic irradiation (P < .001). Multivariate linear regression analyses showed that V5 , V10 , V20 , and MHD were independently and positively associated with ST-2 change rate (ß = .04, .04, .04, and .10, respectively, all P < .05). CONCLUSION: Serum sST-2 levels were elevated over time during radiotherapy. V5 , V10 , V20 and MHD were independently and positively associated with the elevated ST-2 change rate.

Evaluation of the Characteristics of Asthma in Severe and Extremely Severe COPD.

Background: Biotherapy for asthma may be useful in patients suffering from chronic obstructive pulmonary disease (COPD) with asthma characteristics. Therefore, the evaluation and close monitoring of asthma characteristics in severe and extremely severe COPD can guide treatment decisions to improve prognosis. Methods: Stable patients suffering from COPD and having a forced expiratory volume in 1 s (FEV1%) of ≤50% (GOLD 3-4) in the First Affiliated Hospital of Sun Yat-Sen University from December 2014 to June 2018 were retrospectively enrolled in this study and evaluated in terms of their asthma characteristics (blood eosinophil counts, fractional exhaled NO [FeNO] values, and reversibility). Results: A total of 178 patients with an average age of 65.62±9.28 years were enrolled in this study. A total of 85 patients had an improvement of ≥12% in FEV1%, and 61 of these patients had an absolute increase of >200 mL. Of 122 patients, 68 had blood eosinophil counts of ≥150 cells/µl, whereas 27 showed blood eosinophil counts ≥300 cells/µl. The blood eosinophil of ≥2% was found in 66/122 (54.10%) patients, whereas ≥3% was found in 51/122 (41.80%) patients. A total of 46 of 58 patients had an increased serum IgE level of ≥30 IU/mL, and 32 patients had an IgE of ≥100 IU/mL. The FeNO value of ≥25 ACO (ppb) was found in 51/155 (32.90%) patients. Furthermore, 43 patients had asthma-COPD overlap (ACO), and the FeNO values in the ACO group was 26.13±14.91 ppb, which was significantly higher than that in the COPD alone group (20.99±9.16 ppb; P=0.016). A total of 12 patients with ACO had a negative response after bronchodilation. In the COPD alone group, 34 patients had an absolute increase of >200 mL, whereas 55 of the 95 patients had blood eosinophil counts of ≥150 cells/µl. The blood eosinophilia of ≥2% was found in 54/95 (56.84%) patients. A total of 36 of 45 patients had an increased serum IgE level of ≥30 IU/mL. The FeNO value of 34/123 (27.64%) patients was ≥25 ppb. Conclusion: The characteristics of asthma are common findings in patients with severe and extremely severe COPD. Biomarkers should be actively used to evaluate the characteristics of asthma in these patients. If the characteristics of asthma exist, then anti-IgE or anti-IL-5 therapy should be considered to reduce exacerbation.

[Fixed-bearing unicompartmental knee arthroplasty for medial compartmental knee osteoarthritis].

OBJECTIVE: To evaluate short-term clinical results of fixed-bearing unicompartmental knee arthroplasty (UKA) for patients with medial compartmental knee osteoarthritis. METHODS: From January 2015 to December 2017, 62 patients with medial compartmental knee osteoarthritis were treated by fixed-bearing UKA. Among them, including 19 males and 43 females, aged from 47 to 83 years old with an average of (65.3±8.2) years old. The courses of disease ranged from 5 to 72 months with an average of(19.4±14.3) months. Postoperative complications were observed, VAS score was used to observe degree of pain relief, Hospital for Special Surgery(HSS) score was used to evaluate clinical effects. RESULTS: All patients were followed up from 4 to 40 months with an average of(19.9 ±10.2) months. The incision healed well without blood transfusion, hospital stays ranged from 2 to 10 days with an average of (3.5±1.6) days. No deep infection, dislocation, loosing or per prosthetic fracture occurred after operation, while 1 patient suffered from posterior tibial vein thrombosis. HSS score improved from 69.9±7.2 before operation to 90.1±7.4 at final following-up, and 51 patients obtained excellent results, 9 patients good and 2 moderate. VAS score decreased from 3.8±0.9 before operation to 1.1±0.9 at final following-up. CONCLUSIONS: Fixed-bearing UKA for medial compartmental knee osteoarthritis could obtain short-term clinical results for shorter hospital stay, less complications. with fewer complication and fast recovery.

[Clinical outcome of enhanced recovery after surgery for hemiarthroplasty for the treatment of femoral neck fractures in elderly patients].

OBJECTIVE: To analyze and evaluate the clinical outcomes of enhanced recovery after surgery(ERAS) for hemiarthroplasty for the treatment of femoral neck fractures in elderly patients. METHODS: From January 2015 to December 2016, 466 patients with femoral neck fractures were admitted in our department. Among them, 154 patients were more than 80 years old, with an average age of (83.9±3.2) years old (ranged, 80 to 96 years old), including 27 males and 127 females. According to Garden classification system, 68 cases were type III and others were type IV. ERAS for hemiarthroplasty were performed for all the patients. The time before operation, blood transfusion rate, complications rate, lenth of stay and Harris score system were evaluated. RESULTS: Among 154 patients, 142 patients were followed up, with an average duration of 24.6 months(ranged, 14 to 38 months). Thirty-two patients (20.8%) completed the operation within 48 hours after admission, 67 patients(43.5%) completed the operation within 72 hours after admission, 76 patients(49.4%) discharged within 48 hours after operation, and the blood transfusion rate was 15.9%. One patient was re-hospitalized because of prosthetic dislocation. The re-hospitalization rate was 0.6%. No other patients were re-hospitalized because of superficial or deep infection or periprosthetic fracture. At the latest follow-up, the Harris hip score was 90.2±7.1, 106 patients got an excellent result, 23 good and 9 fair. CONCLUSIONS: ERAS for hemiarthroplasty can effectively shorten hospitalization time, relieve pain, reduce blood transfusion rate, reduce postoperative complications, and do not increase the readmission rate of elderly patients with femoral neck fracture, which can achieve good clinical efficacy.

[Evaluation of early clinical results of two stage hip replacement after failed internal fixation for femoral neck fractures].

OBJECTIVE: To evaluate the early clinical results of two stage hip replacement after failed internal fixation for femoral neck fractures in young patients. METHODS: From June 2008 to June 2010,24 patients with femoral head necrosis caused by failed internal fixation were treated with hip arthroplasty. Among them, 12 patients were male and 12 patients were female, with an average age of 42.9 years old (ranged, 18 to 58). According to Harris score and X-ray examination, the clinical result was evaluated. RESULTS: Twenty-three cases were followed up with an average age of 34.4 months (ranged, 25 to 48). After operation, 1 case complicated with the dislocation of hip joint. No deep infection of hip joint, prosthetic loosing or peripheral fracture was found. The mean Harris score was 90.9 +/- 4.3, and 18 obtained excellent results, 4 good and 1 fair. CONCLUSION: Although treatment of femoral head necrosis with two stage hip replacement after failed internal fixation is difficult during operation, its early result is satisfactory.

Biomechanical analysis of four different fixations for the posterolateral shearing tibial plateau fracture.

The posterolateral shearing tibial plateau fracture is uncommon in the literature, however with the increased usage of computer tomography (CT), the incidence of these fractures is no longer as low as previously thought. Few studies have concentrated on this fracture, least of all using a biomechanical model. The purpose of this study was to compare and analyse the biomechanical characteristics of four different types of internal fixation to stabilise the posterolateral shearing tibial plateau fracture. Forty synthetic tibiae (Synbone, right) simulated the posterolateral shearing fracture models and these were randomly assigned into four groups; Group A was fixed with two anterolateral lag screws, Group B with an anteromedial Limited Contact Dynamic Compression Plate (LC-DCP), Group C with a lateral locking plate, and Group D with a posterolateral buttress plate. Vertical displacement of the posterolateral fragment was measured using three different strengths of axial loading force, and finally loaded until fixation failure. It was concluded that the posterolateral buttress plate is biomechanically the strongest fixation method for the posterolateral shearing tibial plateau fracture.

Biomechanical analysis of posteromedial tibial plateau split fracture fixation.

The purpose of this study was to compare the biomechanical strength of four different fixation methods for a posteromedial tibial plateau split fracture. Twenty-eight tibial plateau fractures were simulated using right-sided synthetic tibiae models. Each fracture model was randomly instrumented with one of the four following constructs, anteroposterior lag-screws, an anteromedial limited contact dynamic compression plate (LC-DCP), a lateral locking plate, or a posterior T-shaped buttress plate. Vertical subsidence of the posteromedial fragment was measured from 500 N to 1500 N during biomechanical testing, the maximum load to failure was also determined. It was found that the posterior T-shaped buttress plate allowed the least subsidence of the posteromedial fragment and produced the highest mean failure load than each of the other three constructs (P=0.00). There was no statistical significant difference between using lag screws or an anteromedial LC-DCP construct for the vertical subsidence at a 1500 N load and the load to failure (P>0.05). This study showed that a posterior-based buttress technique is biomechanically the most stable in-vitro fixation method for posteromedial split tibial plateau fractures, with AP screws and anteromedial-based LC-DCP are not as stable for this type of fracture.