Accelerating the speed of innovative anti-tumor drugs to first-in-human trials incorporating key de-risk strategies.

Pharmaceutical companies have recently focused on accelerating the timeline for initiating first-in-human (FIH) trials to allow quick assessment of biologic drugs. For example, a stable cell pool can be used to produce materials for the toxicology (Tox) study, reducing time to the clinic by 4-5 months. During the coronavirus disease 2019 (COVID-19) pandemic, the anti-COVID drugs timeline from DNA transfection to the clinical stage was decreased to 6 months using a stable pool to generate a clinical drug substrate (DS) with limited stability, virus clearance, and Tox study package. However, a lean chemistry, manufacturing, and controls (CMC) package raises safety and comparability risks and may leave extra work in the late-stage development and commercialization phase. In addition, whether these accelerated COVID-19 drug development strategies can be applied to non-COVID projects and established as a standard practice in biologics development is uncertain. Here, we present a case study of a novel anti-tumor drug in which application of "fast-to-FIH" approaches in combination with BeiGene's de-risk strategy achieved successful delivery of a complete CMC package within 10 months. A comprehensive comparability study demonstrated that the DS generated from a stable pool and a single-cell-derived master cell bank were highly comparable with regards to process performance, product quality, and potency. This accomplishment can be a blueprint for non-COVID drug programs that approach the pace of drug development during the pandemic, with no adverse impact on the safety, quality, and late-stage development of biologics.

Arthroscopic Rotator Cuff Repair In Patients With Parkinson's Disease: A Propensity Score Matching Study With Minimum 2-Year Follow-up.

BACKGROUND: Although the effectiveness of arthroscopic rotator cuff repair (ARCR) for structural and functional outcomes has been widespread proven, few researchers investigated the impact of ARCR on patients with Parkinson's Disease (PD), which may have previously been viewed as a relative contraindication to ARCR. METHODS: Data were collected retrospectively for all patients who underwent ARCR for small- to large-sized rotator cuff tears between September 2014 and May 2019. Patients were eligible for the study if they indicated that they diagnosed with rotator cuff repair and had minimum 2-year postoperative outcome scores for the range of motion (ROM), the Western Ontario Rotator Cuff Index (WORC), the Constant-Murley Score (CMS), the University of California, Los Angeles (UCLA), Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), and the visual analog scale (VAS) for pain. Propensity score matching (PSM), a statistical method, was used to screen a control group without PD matched 1:1 with similar age, sex, tear size, preoperative stiffness, and fatty infiltration, which have previously been identified as important factors influencing success rates. RESULTS: Three hundred and eighty-nine patients met all study criteria including required follow-up, of whom 31 and 358 with PD and without PD, respectively. After adjusting for confounders, the propensity score matched indicators were compared, patients with PD experienced significantly more pain (4.45 ± 2.43 vs. 0.52 ± 1.18; P<.001) and had lower WORC (49.10 ± 21.22 vs. 78.90 ± 17.54; P<.001), CMS (46.77 ± 22.24 vs. 79.45 ± 14.74; P<.001) and UCLA (21.11 ± 8.54 vs. 28.16 ± 6.16; P<.001) scores respectively than the matched control group. They also exhibited higher sleep disturbance (10.04 ± 5.36 vs. 5.19 ± 3.28; P<.001), as well as higher anxiety and depression psychological status at 24 months (P<.001; P<.001). Overall clinical outcomes from preoperatively to postoperatively were not improved significantly for patients with PD vs. without PD. CONCLUSION: Patients with PD experienced significantly more pain, resulted in worse shoulder functional outcomes, and reported persistently diminished mental and physical health status. Shoulder surgeons should be cognizant of PD as an outcome-modifying variable when treating patients with rotator cuff tears. This finding suggested that the need for ARCR in patients with PD should be carefully considered in the light of personalized needs and physical conditions.

Intra-articular Pure Platelet-Rich Plasma Combined With Open-Wedge High Tibial Osteotomy Improves Clinical Outcomes and Minimal Joint Space Width Compared With High Tibial Osteotomy Alone in Knee Osteoarthritis: A Prospective Study.

PURPOSE: To compare the clinical efficacy of the patients with medial compartment knee osteoarthritis who underwent either opening-wedge high tibial osteotomy alone (HTO) or simultaneous HTO and pure platelet-rich plasma therapy (HTO+P-PRP). METHODS: Eighty patients were divided into 2 groups randomly, the HTO-alone group (n = 41) and the HTO+P-PRP group (n = 39). Patients were matched for preoperative age, sex, and body mass index. The outcomes studied included visual analogue scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Lysholm score. The minimum width of medial knee joint (MJSW), medial proximal tibial angle (MPTA), femoral tibial angle (FTA), and weightbearing line (WBL) were measured preoperatively, immediately postoperatively, and 1, 6, 12, and 24 months postoperatively. Paired t test and chi-squared test were used for statistical analysis. RESULTS: All patients were followed up at 1, 6, 12, and 24 months postoperatively. At 1, 6, and 12 months, pain and function scores in the HTO+P-PRP group were better than those in the HTO-alone group, especially at 6 months in Lysholm score (HTO alone, 72.5 ± 10.6; HTO+P-PRP, 83.1 ± 14.7; P = .003, 95% CI -14.13 to -10.42) and WOMAC (HTO alone, 90.3 ± 11.9; HTO+P-PRP, 75.6 ± 15.4; P < .001, 95% CI 13.36 to 20.11). For both groups, no difference was found preoperatively (HTO alone, varus 3.5 ± 3.9; HTO+P-PRP, varus 4.1 ± 4.0; P = .898) or postoperatively (HTO alone, valgus 6.7 ± 4.5; HTO+P-PRP, valgus 7.7 ± 2.3; P = .768) in FTA or WBL. The increase of the MJSW in the HTO+P-PRP group was significantly greater than that in the HTO-alone group during the first year, especially at 6 months (HTO alone, 3.8 ± 1.2 mm; HTO+P-PRP, 4.6 ± 1.1 mm; P = .001, 95% CI -1.27 to -0.35). CONCLUSIONS: Compared with HTO alone, HTO combined with intra-articular P-PRP improved the minimum medial knee joint space width during the first year postoperatively. Clinically, a higher proportion of patients in the HTO+P-PRP group exceeded the minimal clinically important difference (MCID) in the first year, especially at 6 months in Lysholm score (HTO alone, 65.9%; HTO+P-PRP, 97.4%) and WOMAC (HTO alone, 82.9%; HTO+P-PRP, 100.0%). LEVEL OF EVIDENCE: 2, prospective comparative study.

Fatigue Crack Growth and Fracture of Internal Fixation Materials in In Vivo Environments-A Review.

The development of crack patterns is a serious problem affecting the durability of orthopedic implants and the prognosis of patients. This issue has gained considerable attention in the medical community in recent years. This literature focuses on the five primary aspects relevant to the evaluation of the surface cracking patterns, i.e., inappropriate use, design flaws, inconsistent elastic modulus, allergic reaction, poor compatibility, and anti-corrosiveness. The hope is that increased understanding will open doors to optimize fabrication for biomedical applications. The latest technological issues and potential capabilities of implants that combine absorbable materials and shape memory alloys are also discussed. This article will act as a roadmap to be employed in the realm of orthopedic. Fatigue crack growth and the challenges associated with materials must be recognized to help make new implant technologies viable for wider clinical adoption. This review presents a summary of recent findings on the fatigue mechanisms and fracture of implant in the initial period after surgery. We propose solutions to common problems. The recognition of essential complications and technical problems related to various approaches and material choices while satisfying clinical requirements is crucial. Additional investigation will be needed to surmount these challenges and reduce the likelihood of fatigue crack growth after implantation.

A clinical study of shoulder arthroscopic rotator cuff repair on the psychological function of patients after operation.

BACKGROUND: Recently, psychological function in patients who underwent rotator cuff repair has been emphasized. However, the relationship of psychological function and clinical outcomes after rotator cuff repair is still poorly understood. This study aims to investigate the impact of arthroscopic rotator cuff repair on psychological status. METHODS: Clinical data were collected retrospectively from 60 patients with rotator cuff tears treated at the First Affiliated Hospital of Soochow University from January 2013 to June 2016. Preoperative and postoperative parameters were calculated and analyzed, including the Visual Analog Scale (VAS) pain score, the University of California, Los Angeles Scale (UCLA), the American Shoulder and Elbow Surgeons scale (ASES), the Simple Shoulder Test (SST), and the Short Form 36 Health Survey (SF-36) scores. RESULTS: Compared with preoperative scores, the VAS score decreased significantly 1 year postoperatively (P<0.05). In contrast, the UCLA, ASES and SST scores improved significantly (P<0.05). The results of the Short Form 36 Physical Component Summary score (SF-36 PCS) and the Short Form 36 Mental Component Summary score (SF-36 MCS) were also improved, which had significant differences before and after arthroscopy surgery (P<0.05). CONCLUSIONS: Arthroscopic rotator cuff repair can significantly improve the psychological function of patients, promote their rapid recovery, and achieve satisfactory results.

Hundreds of rice bodies in the subacromial-subdeltoid bursa: report of two cases and literature review.

BACKGROUND: Multiple rice bodies (RB) in the shoulder joint is a rare disorder of unknown etiology that requires percutaneous drainage or surgical operation. CASE PRESENTATION: We reported arthroscopic removal of hundreds of RB in the subacromial-subdeltoid bursa in two cases by our "chopsticks technique". One was associated with seropositive rheumatoid arthritis and the other was a rare synovial origin possibly due to microinfarction and ischemia after the radiotherapy. Radical debridement of necrotic tissue, "red tissue" and synovitis by arthroscopic radiofrequency ablation was essential for eliminating the cause of RB. A favorable clinical evolution was observed for both patients. CONCLUSIONS: We highlight the importance of patient-specific differential diagnosis and the clinical course of RB to help us further understand the pathogenesis of this uncommon disorder. Meanwhile, evacuation of RB and "red tissue" ablation by arthroscopy showed good results.

Relationship between the lateral acromion angle and postoperative persistent pain of distal clavicle fracture treated with clavicle hook plate.

BACKGROUND: The clavicular hook plate is an accepted surgical procedure for distal clavicle fractures. The relationship of the characteristics of the hook plate, acromioclavicular joint and acromion morphology, and clinical outcome has remained poorly understood. We reviewed the clinical records of patients who had distal clavicle fractures with different lateral acromion angles treated using a clavicle hook plate and evaluated their clinical outcomes with respect to shoulder pain and acromial morphology. METHODS: We retrospectively reviewed 102 patients with distal clavicle fractures treated with hook plates at our institution from 2010 to 2017. They were divided into four groups according to lateral acromion angle on shoulder AP view X-rays. The angle was defined as the incline angle between the superior surface of distal clavicle and the inferior facet of acromion on coronal plane. We reviewed their clinical features, including Neer's impingement sign, MRI findings, and outcomes using Japanese Orthopaedic Association Scores. The mean follow-up was 25.5 months (range, 24 to 28 months). RESULTS: All patients in group D (large lateral acromion angle (α) > 40°, acromion coronal angle (ß) < 60°) complained of postoperative symptoms. Compared to those with common lateral acromion angle, the incidence of postoperative impingement in group D was undoubtedly much higher (100%). Japanese Orthopaedic Association (JOA) scores in group D were worse at 3 months post-surgery, 3 months post plate removal, and at the last follow-up despite a slightly earlier removal in this group. CONCLUSION: Lateral acromion angle appears to be an important factor in the development of postoperative pain and worse outcomes (JOA scores) in patients treated with the hook plate. The incidence of subacromial impingement and rotator cuff lesion (RCL) increased with the α angle. Early limited mobility and removal of the implant may improve the prognosis and resolve the postoperative shoulder pain. STUDY DESIGN: Retrospective review, level of evidence IV.

Comparison of clinical and patient-reported outcomes of three procedures for recurrent anterior shoulder instability: arthroscopic Bankart repair, capsular shift, and open Latarjet.

BACKGROUND: Best surgical of recurrent anterior shoulder instability remained controversial. We knew little about the superiority and choice between traditional open and modern arthroscopic techniques. We hypothesized that outcomes of all patients will be similar regardless of surgical technique. METHODS: A retrospective case-cohort analysis of 168 patients who had recurrent anterior shoulder instability was conducted from September 2010 to December 2013. All cases (mean age 30.8 [range 18-50] years) were performed with arthroscopic Bankart repair (33 males/20 females), open Latarjet (34 males/18 females), and capsular shift (31 males/14 females). The average follow-up was 67.6 months (range 60-72). The shoulder instability index score (ISIS) was more than 3 with an average of 6.4. RESULTS: All treatments proved to be effective in improving shoulder functional status and reducing symptoms, while Latarjet had an advantage over subjective perception. The Rowe scores in arthroscopic Bankart, open Latarjet, and capsular shift group were 92.3 ± 1.5, 96.2 ± 2.1, and 93.2 ± 2.3, respectively, with significant difference. There was no significant difference in other functional outcomes. However, the Latarjet group in subjective results (subjective shoulder value (SSV) and subjective shoulder value for sport practice (SSV Sport)) was superior to the others (P < 0.05). There were two relapsed cases in arthroscopic Bankart and capsular shift group, respectively, and no recurrence in open Latarjet group. CONCLUSION: Arthroscopic Bankart repair has the advantage of mini-invasion and rapid recovery. Capsular shift offers stabilizing of inferior or multidirectional type, especially for little bone defect. Latarjet was more effective in reducing recurrence with higher stability. LEVEL OF EVIDENCE: Therapeutic level III.

Review of Percutaneous Kyphoplasty in China.

STUDY DESIGN: Review article. OBJECTIVE: The article mainly reviewed the development and current situation of percutaneous kyphoplasty (PKP) in China, aiming to introduce native efforts and progress for PKP procedure on the exploring road. SUMMARY OF BACKGROUND DATA: Since PKP was first reported in China in 2002, Chinese orthopedic researchers have performed lots of clinical applications and studies on the treatment of osteoporotic vertebral compression fracture, spinal metastatic tumor, hemangioma, myeloma, vertebral nonunion, and so on. METHODS: We reviewed the papers on PKP published by native researchers in English and Chinese via Pubmed, EMBASE, the Scopus database, and a series of Chinese databases including Wanfang Data, China National Knowledge Infrastructure (CNKI), and the China Science and Technology Journal Database. The large sample capacity researches, convictive systematic analysis, and overviews were mainly elected as convictive evidence to describe the overall situation of clinical outcomes, complications, and the various technical aspects used to improve conventional surgical management and clinical applications of PKP in China. RESULTS: Until October 2015, 211 articles in English and 2352 studies in Chinese about PKP were reported by 1443 Chinese institutions from 22 provinces around China. More than 50976 patients reported through published articles have received the treatment of PKP. With the technique gradually improved, including puncture, bone cement infusion, vertebral expander instruments, diagnosis, and treatment of special type of vertebral fractures, PKP is performed with the better efficacy and less complication. CONCLUSION: With the progression of minimally invasive spinal surgery around the world, PKP in China has been performed with a trend towards a rapid, safe, and effective treatment. Digital, real-time and artificial intelligence are the directions of future development of PKP. LEVEL OF EVIDENCE: 4.