Supratubercle Anterior Closing Wedge Osteotomy: No Changes in Patellar Height and Significant Decreases in Anterior Tibial Translation at 6 Months Postoperatively.

BACKGROUND: Because of the increased prevalence of revision anterior cruciate ligament (ACL) reconstruction, there has been a desire to understand the role of posterior tibial slope on increased anterior tibial translation and increased ACL graft forces. One potential concern in supratubercle anterior closing wedge proximal tibial osteotomy (ACW-PTO) for decreasing the posterior tibial slope is the risk of altering the patellar height. PURPOSE: To radiographically assess changes in (1) patellar height, (2) anterior tibial translation, and (3) posterior tibial slope after supratubercle ACW-PTO. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Patients who underwent supratubercle ACW-PTO by a single surgeon between July 2019 and June 2023 were included. Standardized lateral knee weightbearing radiographs to assess patellar height (via the Caton-Deschamps index), anterior tibial translation of the lateral tibial plateau relative to the lateral femoral condyle, and posterior tibial slope were obtained at 4 time points (preoperatively and 1 day, 3 months, and 6 months postoperatively). Paired t test was used to compare differences between preoperative, 1-day, and 3- and 6-month values for patellar height as measured using the Caton-Deschamps index and for posterior tibial slope. Paired t test was also used to compare differences in the preoperative and 6-month postoperative values for anterior tibial translation. RESULTS: In 20 patients after ACW-PTO, the Caton-Deschamps index demonstrated a significant increase in patellar height on postoperative day 1 (P < .001) but no significant differences at 3 (P = .057) and 6 (P = .176) months postoperatively. Anterior tibial translation on standing lateral knee radiographs was significantly decreased by a mean of 8.9 mm from preoperatively to 6 months postoperatively (P < .001). Posterior tibial slope was significantly decreased by a mean of 11.2° from preoperatively to 6 months postoperatively (P < .001). CONCLUSION: Supratubercle ACW-PTO performed for ACL reconstruction failure in the setting of an increased posterior tibial slope did not induce significant changes in patellar height postoperatively. Furthermore, after ACW-PTO, there was a significant decrease in anterior tibial translation and posterior tibial slope.

The Functional Integrity of the Anterior Cruciate Ligament Can Be Objectively Assessed With the Use of Stress Radiographs: A Systematic Review.

Background: Stress radiography is a viable imaging modality that can also be used to assess the integrity of the anterior cruciate ligament (ACL) after primary or secondary injury. Because conventional radiography is relatively easy, affordable, and available worldwide, the diagnostic efficacy of ACL standing, lateral decubitus, and supine stress radiography should be evaluated. Purpose: To examine the existing literature regarding the application of stress radiography in evaluating the integrity of the ACL. Study Design: Systematic review; Level of evidence, 3. Methods: Using the PubMed and MEDLINE databases for relevant articles published between 1980 and the present, a systematic review was conducted to identify evidence related to the radiographic diagnosis or assessment of ACL tears. The literature search was conducted in September 2022. Results: Of 495 studies, 16 (1823 patients) were included. Four studies examined standing stress radiography, and 12 investigated lateral decubitus or supine stress radiography. Significant heterogeneity in imaging technique and recorded anterior tibial translation was identified. Anterior tibial translation for ACL-injured knees ranged from 1.2 to 10.6 mm for standing stress radiographs and 2.7 to 11.2 mm for supine stress radiographs, with high sensitivities and specificities for both. Conclusion: Stress radiography was a dependable diagnostic method for identifying ACL rupture. Further research is necessary to determine the ideal anatomic landmarks, optimal patient positioning, and appropriate applied stresses to establish a standardized protocol for both assessing ACL tears and evaluating the postoperative integrity of ACL reconstruction using stress radiography.

Editorial Commentary: Trends in Hip Arthroscopy Require Rapid Dissemination From Higher-Volume and Academic Surgeons to the Greater Orthopaedic Community.

Trends in hip arthroscopy show that labral repair and preservation, capsular repair and preservation, and treatment of femoroacetabular impingement during hip arthroscopy are associated with superior short-term and mid- to longer-term outcomes. Hip arthroscopy, and in particular arthroscopic femoroacetabular impingement correction, is in its infancy compared with many other orthopaedic procedures. As we assimilate knowledge, data, and evidence-based research, it is critical to evaluate surgical trends and how they affect our management of these patients and pathologies. However, it is important to recognize that there is great variability with regards to surgical volume and awareness of impending evidence-based research for relatively newer procedures such as hip arthroscopy. This can lead to delays for incorporating newer evidence-based techniques. The gap is closing, but the time required to close this disparity in management trends between higher-volume/academic surgeons and the orthopaedic community as a whole could be shorter. Whether this delay for adapting evidence-based trends is consistent across the spectrum of orthopaedic surgery or specific to smaller subspecialty areas such as hip arthroscopy is unclear. Regardless, it is essential that those who are performing the larger volume of cases and research must raise our voices, turn up our loudspeakers, and publish, present, and use social media platforms to spread the word of the latest evidence-based trends quickly! It is equally critical for the greater orthopaedic community to listen for the benefit of patients. If all parties collaborate, we can get up to speed in a timelier manner and achieve the best-possible outcomes together.

BETA prime: a first-in-man phase 1 study of AdAPT-001, an armed oncolytic adenovirus for solid tumors.

AdAPT-001 is an oncolytic adenovirus (OAV) with a transforming growth factor beta (TGF-ß) trap, which neutralizes the immunosuppressive and profibrotic cytokine, TGF-ß. The aim or purpose of this phase 1 study was to assess the safety and tolerability and, secondarily, the efficacy of AdAPT-001 after single intratumoral injection (IT) (Part 1) and multidose IT injection (Part 2) in patients with superficially accessible, advanced refractory solid tumors. Part 1 enrolled 9 patients with a 3 + 3 single dose-escalation safety run-in involving 2.5 × 1011, 5.0 × 1011, 1.0 × 1012 viral particles (vps). No dose-limiting toxicities or treatment-related serious adverse events (SAEs) were seen. In Part 2, a dose-expansion phase, 19 patients received AdAPT-001 at 1.0 × 1012 vps until disease progression according to Response Evaluation Criteria in Solid Tumors or RECIST 1.1. The overall responses to treatment included confirmed partial responses (3), durable stable disease ≥ 6 months (5), and progressive disease (13). AdAPT-001 is well tolerated. Evidence of an anti-tumor effect was seen in both injected and uninjected lesions. The recommended Phase 2 dose was 1.0 × 1012 vp administered by intratumoral injection once every 2 weeks. Combination of AdAPT-001 with a checkpoint inhibition is enrolling.

Commentary on oncolytic viruses: past, present, and future.

Whither oncolytic viruses? From the peak of their popularity in the early 2000s, when the ONYX-015 adenovirus had just entered the clinic, and then again in 2015 when the Food and Drug Administration-approved talimogene laherparepvec (also known as OncoVEXGM-CSF), which briefly revived interest, oncolytic viruses (OVs) have mostly fallen out of favor despite the many pharmaceutical companies with OVs in development.This commentary enumerates and addresses the core conceptions, perceptions, and misconceptions that characterize the current 'trough of disillusionment' in which the field of anticancer virotherapy finds itself and suggests reasons for optimism.

Radiographic and Dynamic Assessment for Resection of Cam Lesions in Patients With Femoroacetabular Impingement.

Cam-type femoroacetabular impingement is characterized by a pathologic asphericity of the femoral head-neck junction, and arthroscopic femoral osteoplasty is indicated to correct the bony abnormality and restore normal hip mechanics when symptomatic. Residual femoroacetabular impingement deformity after arthroscopy is a leading cause of failure, and it is therefore critical to perform a thorough fluoroscopic and dynamic assessment when addressing cam deformities arthroscopically. The fluoroscopic assessment uses 6 anteroposterior views, including 3 in hip extension (30° internal rotation, neutral rotation, and 30° external rotation) and 3 in 50° flexion (neutral rotation, 40° external rotation, 60° of external rotation), performed before, during, and after the femoral resection. The dynamic assessment includes evaluation of impingement-free range of motion and "end feel" (a subjective description of the tactile feedback during assessment of hip motion), and should be performed before and after the femoral resection in 3 specific positions (extension/abduction, flexion/abduction, and flexion/internal rotation). Although the anterior aspect of the head-neck junction is readily accessed through standard arthroscopic portals with the hip in 30 to 50° of flexion, the posterolateral, posteromedial, and posterior extent of the femoral head-neck junction are challenging to address. The natural external rotation of the proximal femur during flexion and internal rotation during extension can be used to gain posterior lateral and medial access. Antero/posteromedial femoral access can be obtained with >50° of hip flexion with the burr in the anteromedial portal. Posterolateral femoral access is achieved with hip extension with the burr in the anterolateral portal, and further posterolateral access can be achieved with the addition of traction, allowing resection of posterolateral deformities extending beyond the lateral retinacular vessels while remaining proximal to the vessels. This comprehensive intraoperative fluoroscopic and dynamic assessment and surgical technique can lead to a predictable correction of most cam-type deformities.

Acetabular Rim Ossification Variants Are Found in Almost 20% of Patients Presenting With Hip Pain.

Purpose: To determine the prevalence of 4 different types of acetabular rim ossifications, including partial labral ossification or punctate calcification, true os acetabuli, acetabular rim stress fracture, and complete labral ossification, and to determine whether different types of periacetabular ossifications are linked to demographic or radiological factors. Methods: We retrospectively reviewed the medial records of patients presenting for hip-related complaints at 2 sports medicine practices from September 2007 to December 2009. An anteroposterior radiograph of both hips and a lateral radiograph of each hip was obtained for all patients and reviewed for findings of cam and pincer femoroacetabular impingement, degenerative changes (Tönnis grade), and periacetabular calcifications for both hips. These parameters were also evaluated with respect to symptoms, sex, and age. Results: Four hundred ninety-one consecutive patients (982 hips) presented to 2 orthopaedic surgeons at 2 centers for "hip"-related complaints. There were 223 males and 268 females (age 39 ± 14 years). The overall prevalence of periacetabular calcifications in hips was 17.6%, with 56.6% of calcifications in the symptomatic hip and 43.4% in the contralateral hip. Four basic patterns of calcification were identified: punctuate calcifications within the labrum (8.0% hips), large rounded calcifications (os acetabuli) (4.2% hip), large fragments with a vertical line of the superior-lateral acetabular rim, consistent with healed or non-healed stress fracture (2.0% hips), and complete ossification of the labrum (3.4% hips). Overall, male sex (P = .002), increased lateral center-edge angle (P = .046), and higher Tönnis grade (P < .001) statistically predicted the presence of periacetabular ossification. Punctate calcifications were more prevalent in males (P = .002). Higher Tönnis grade (P = .029) and increased alpha angle (P = .046) were more prevalent with os acetabuli. Younger age (P = .001), male sex (P = .048), increased alpha angle (P = .012), and increased lateral center-edge angle (P < .001) were more prevalent in acetabular rim fractures. No factors were statistically significant at predicting the presence of an ossified labrum. Conclusions: Periacetabular calcifications are not uncommon. Four particular patterns of calcification are identified: punctate labral calcifications (8%), larger rounded calcifications (i.e., os acetabuli) (4.2%), acetabular rim stress fractures (2%), and complete ossification of the labrum (3.4%) for a combined prevalence of 17.6% in patients presenting to an orthopaedic surgeon with "hip"-related complaints. Nearly half were in the asymptomatic hip. Male sex had a higher prevalence of periacetabular calcifications. An increased lateral center edge angle and higher Tönnis grade also had a higher prevalence of periacetabular calcifications. Younger male patients are more likely to have acetabular rim stress fractures. Patients with an increased alpha angle have a higher prevalence of os acetabuli and rim stress fractures. Clinical Relevance: This study aims to identify, quantify, and categorize periacetabular calcifications about the hip. Their clinical relationships and relevance have been discussed, but no study has distinctly categorized the various types and their prevalence. This study provides a framework for identification and categorization.

Clinic and Home-Based Exercise with Blood Flow Restriction Resolves Thigh Muscle Atrophy after Anterior Cruciate Ligament Reconstruction with the Bone-Patellar Tendon-Bone Autograft: A Case Report.

Anterior cruciate ligament reconstruction (ACLR) results in thigh muscle atrophy. Of the various interventions proposed to mitigate thigh muscle atrophy, exercise with blood flow restriction (BFR) appears safe and effective. Some literature suggests daily exposure to exercise with BFR may be indicated during the early phase of ACLR rehabilitation; this case report outlines the methodology utilized to prescribe clinic- and home-based BFR within an outpatient rehabilitation program. A 15-year-old male soccer player suffered a left knee injury involving the anterior cruciate ligament and both menisci. He underwent ACLR and completed exercise with BFR as part of his clinic- and home-based rehabilitation program, which included practical blood flow restriction during home-based rehabilitation. After 16 weeks of rehabilitation, surgical limb thigh girth values were objectively larger than the non-surgical limb (surgical, 52.25 cm; non-surgical 50 cm), as well as the multi-frequency bioelectrical impedance analysis of his lower-extremity lean body mass (surgical limb, 10.37 kg; non-surgical limb, 10.02 kg). The findings of this case report suggest that the inclusion of clinic- and home-based BFR within an outpatient rehabilitation program may be indicated to resolve thigh muscle atrophy early after ACLR.

The Impact of Age on Clinical Outcomes of Acetabular Microfracture During FAI Surgery.

BACKGROUND: Full-thickness acetabular cartilage lesions are common findings during primary surgical treatment of femoroacetabular impingement (FAI). PURPOSE: To evaluate clinical outcomes after acetabular microfracture performed during FAI surgery in a prospective, multicenter cohort. STUDY DESIGN: Cohort Study; Level of evidence, 3. METHODS: Patients with FAI who had failed nonoperative management were prospectively enrolled in a multicenter cohort. Preoperative and postoperative (mean follow-up, 4.3 years) patient-reported outcome measures were obtained with a follow-up rate of 81.6% (621/761 hips), including 54 patients who underwent acetabular microfracture. Patient characteristics, radiographic parameters, intraoperative disease severity, and operative procedures were analyzed. Propensity matching using linear regression was used to match 54 hips with microfracture to 162 control hips (1:3) to control for confounding variables. Subanalyses of hips ≤35 and >35 years of age with propensity matching were also performed. RESULTS: Patients who underwent acetabular microfracture were more likely to be male (81.8% vs 40.9%; P < .001), be older in age (35.0 vs 29.9 years; P = .001), have a higher body mass index (27.2 vs 25.0; P = .001), and have a greater alpha angle (69.6° vs 62.3°; P < .001) compared with the nonmicrofracture cohort (n = 533). After propensity matching to control for covariates, patients treated with microfracture displayed no differences in the modified Harris Hip Score or Hip Disability and Osteoarthritis Outcome Score (P = .22-.95) but were more likely to undergo total hip arthroplasty (THA) (13% [7/54] compared with 4% [6/162] in the control group; P = .002), and age >35 years was associated with conversion to THA after microfracture. Microfracture performed at or before 35 years of age portended good outcomes with no significant risk of conversion to THA at the most recent follow-up. CONCLUSION: Microfracture of acetabular cartilage defects appears to be safe and associated with reliably improved short- to mid-term results in younger patients; modified expectations should be realized when full-thickness chondral lesions are identified in patients >35 years of age.

A Local and Abscopal Effect Observed with Liposomal Encapsulation of Intratumorally Injected Oncolytic Adenoviral Therapy.

This study evaluated the in vivo therapeutic efficacy of oncolytic serotype 5 adenovirus TAV255 in CAR-deficient tumors. In vitro experiments were performed with cell lines that expressed different levels of CAR (HEK293, A549, CT26, 4T1, and MCF-7). Low CAR cells, such as CT26, were poorly transduced by Ad in vitro unless the adenovirus was encapsulated in liposomes. However, the CT26 tumor in an immune-competent mouse model responded to the unencapsulated TAV255; 33% of the tumors were induced into complete remission, and mice with complete remission rejected the rechallenge with cancer cell injection. Encapsulation of TAV255 improves its therapeutic efficacy by transducing more CT26 cells, as expected from in vitro results. In a bilateral tumor model, nonencapsulated TAV255 reduced the growth rate of the locally treated tumors but had no effect on the growth rate of the distant tumor site. Conversely, encapsulated TAV255-infected CT26 induced a delayed growth rate of both the primary injected tumor and the distant tumor, consistent with a robust immune response. In vivo, intratumorally injected unencapsulated adenoviruses infect CAR-negative cells with only limited efficiency. However, unencapsulated adenoviruses robustly inhibit the growth of CAR-deficient tumors, an effect that constitutes an 'in situ vaccination' by stimulating cytotoxic T cells.

Graft-Specific Surgical and Rehabilitation Considerations for Anterior Cruciate Ligament Reconstruction with the Quadriceps Tendon Autograft.

Anterior cruciate ligament reconstruction (ACLR) with a bone-patellar tendon-bone (BPTB) or hamstring tendon (HT) autograft has traditionally been the preferred surgical treatment for patients returning to Level 1 sports. More recently, international utilization of the quadriceps tendon (QT) autograft for primary and revision ACLR has increased in popularity. Recent literature suggests that ACLR with the QT may yield less donor site morbidity than the BPTB and better patient-reported outcomes than the HT. Additionally, anatomic and biomechanical studies have highlighted the robust properties of the QT itself, with superior levels of collagen density, length, size, and load-to-failure strength compared to the BPTB. Although previous literature has described rehabilitation considerations for the BPTB and HT autografts, there is less published with respect to the QT. Given the known impact of the various ACLR surgical techniques on postoperative rehabilitation, the purpose of this clinical commentary is to present the procedure-specific surgical and rehabilitation considerations for ACLR with the QT, as well as further highlight the need for procedure-specific rehabilitation strategies after ACLR by comparing the QT to the BPTB and HT autografts. Level of Evidence: Level 5.

Editorial Commentary: Minimizing Traction Force and Time as Well as Application of Specific Technical Pearls Might Trump the Importance of Choosing Between Post or Postless Hip Arthroscopy With Regards to Complications.

Recently, there has been a trend toward performing hip arthroscopy without a post (postless) in an effort to decrease perineal post-related complications. Previous studies have revealed a variable risk of pudendal nerve neuralgia and perineal soft-tissue injury when using a post. There is emerging evidence that arthroscopic hip procedures can be done without the use of a post, with less traction force on the perineal region, and with adequate exposure to safely accomplish a well-done femoroacetabular impingement corrective procedure. Prospective comparative studies with conclusive evidence of the superiority of either technique, however, are lacking. Complications with a post are likely associated with high traction forces, prolonged traction times, and potentially suboptimal technique and patient positioning. In addition, postless traction is in its infancy and new adverse events/outcomes are likely to emerge. There are likely specific situations and patient populations in which one technique might be superior to the other. We are the carpenters of medicine and rather than blaming our tools and throwing out a technique that has served us well for decades, we should better understand some important pearls and pitfalls that might allow either method to be safely performed.

The Use of Biologics in NFL Athletes: An Expert Consensus of NFL Team Physicians.

Background: There is a lack of published information outlining the use of biologics in National Football League (NFL) athletes and limited data to guide biologic treatment strategies. Purpose: To develop a consensus on the use of biologics among NFL team physicians. Study Design: Consensus statement. Methods: A working group of 6 experts convened a consensus process involving NFL team physicians using validated Delphi methodology. Physicians from 32 NFL teams as well as NFL London were invited to take part. This iterative process was used to define statements on the use of biologics in NFL athletes. A recent scoping review exploring biologics in professional athletes was used to inform the first of 3 rounds of surveys, with statements considered under 7 headings: biologics in general, challenges of treating NFL athletes, terminology/nomenclature, autologous blood products, cell-based therapies, guidance for NFL team physicians, and biologic research in the NFL. In addition to rating agreement, experts were encouraged to propose further items or modifications. Predefined criteria were used to refine item lists after each survey. For a consensus within the final round, defined a priori, items were included in the final information set if a minimum of 75% of respondents agreed and fewer than 10% disagreed. Results: Physicians from 26 NFL teams and NFL London responded to the initial invitation to participate in the Delphi process; 88.9% of participating team physicians completed the round 1 survey, with response rates of 87.5% in round 2 and 95.2% in round 3. After 3 rounds, 47 statements reached a consensus. A consensus was achieved that platelet-rich plasma has a positive impact on patellar tendinopathy and on symptoms in early osteoarthritis but not for other indications. NFL team physicians agreed that while cell therapies have the potential to improve symptoms, the misrepresentation of uncharacterized preparations as "stem cells" has contributed to the widespread use of unproven therapies. Conclusion: This study established an expert consensus on 47 statements relating to the use of biologics in NFL athletes. In addition to providing clinical guidance for the use of biologics in NFL athletes, this study identified key areas for future focus including the development of athlete education materials.

Outcomes of Arthroscopic Decompression of the Anterior Inferior Iliac Spine: A Systematic Review and Meta-analysis.

BACKGROUND: Anterior inferior iliac spine (AIIS) impingement has been increasingly recognized as a source of extra-articular impingement and hip pain. However, no aggregate data analysis of patient outcomes after AIIS decompression has been performed. PURPOSE: To evaluate outcomes after arthroscopic AIIS decompression. STUDY DESIGN: Meta-analysis; Level of evidence, 4. METHODS: A systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were queried for all English-language studies reporting outcomes of arthroscopic AIIS decompression performed in isolation or in conjunction with hip impingement correction surgery. After screening, 10 articles were included. The indications for AIIS decompression were recorded, and weighted mean improvements in patient-reported outcome (PRO) scores, complication rates, and revision rates were calculated. RESULTS: A total of 547 patients (311 women; 57%) were identified, with a total of 620 operative hips. The mean age was 28.42 ± 5.6 years, and the mean follow-up was 25.22 ± 11.1 months. A total of 529 hips (85%) underwent AIIS decompression, 530 hips (85%) underwent femoral osteochondroplasty, and 458 hips (74%) underwent labral repair. Of the patients, 13% underwent bilateral AIIS decompression. The mean modified Harris Hip Score improved from 61.3 ± 6.9 to 88.7 ± 4.7 postoperatively (change, 27.4 ± 5.7 points; P < .001), the Hip Outcome Score-Activities of Daily Living improved from 67.2 ± 10.6 to 91.1 ± 3.2 postoperatively (change, 24.0 ± 8.0 points; P = .001), and the Hip Outcome Score-Sports Specific Subscale improved from 36.8 ± 19.2 to 82.8 ± 3.8 postoperatively (change, 46.0 ± 18.2 points; P = .002). The pooled risk of postoperative complications was 1.1% (95% CI, 0.1%-2.1%), and the pooled risk of needing revision surgery was 1.0% (95% CI, 0.1%-2.0%). No complication was directly attributed to the AIIS decompression portion of the procedure. CONCLUSION: PROs improved significantly after hip arthroscopy with AIIS decompression, with a low risk of postoperative complications and subsequent revision surgeries. Failure to identify extra-articular sources of hip pain in outcomes of femoroacetabular impingement syndrome, including from the AIIS, could lead to poorer outcomes and future revision surgery.

Bidirectional Ventricular Tachycardia in a Young Female: A Case of Andersen-Tawil Syndrome.

Bidirectional ventricular tachycardia (VT) is a rare ventricular dysrhythmia with a limited differential diagnosis that includes digitalis toxicity, catecholaminergic polymorphic VT, aconite poisoning, and genetic channelopathy syndromes, specifically, Andersen-Tawil syndrome (ATS). We present a case of a young female with palpitations found to have bidirectional VT on cardiac event monitor and strong family history of cardiac dysrhythmias. Her physical examination findings included minor dysmorphic features of mandibular hypoplasia, hypertelorism, and clinodactyly. The patient was clinically diagnosed with ATS and started on a beta-blocker for control of ectopy. A second Holter review demonstrated markedly decreased burden of ventricular ectopy compared to the initial monitoring. She was referred for genetic testing, which revealed a KCNJ2 mutation. Bidirectional VT is an uncommon ventricular dysrhythmia that has a limited differential diagnosis, one of which is ATS-a rare genetic disorder that results from mutations in the KCNJ2 gene. The condition is frequently associated with developmental, skeletal, and cardiac abnormalities. Although there are no strong recommendations that exist for treatment of ventricular dysrhythmias associated with this genetic disorder, we demonstrate a case of clinical improvement in a patient with ATS by using the beta-blocker metoprolol succinate. Furthermore, we propose that ATS patients may not need exercise restrictions as overall ventricular ectopy burden decreased with exercise and there was no prolongation of the QT interval. This patient will continue to follow up in our clinic to reassess symptom burden and for continued monitoring for the development of any new features.

A Review of Persistent Post-COVID Syndrome (PPCS).

Persistent post-COVID syndrome, also referred to as long COVID, is a pathologic entity, which involves persistent physical, medical, and cognitive sequelae following COVID-19, including persistent immunosuppression as well as pulmonary, cardiac, and vascular fibrosis. Pathologic fibrosis of organs and vasculature leads to increased mortality and severely worsened quality of life. Inhibiting transforming growth factor beta (TGF-ß), an immuno- and a fibrosis modulator, may attenuate these post-COVID sequelae. Current preclinical and clinical efforts are centered on the mechanisms and manifestations of COVID-19 and its presymptomatic and prodromal periods; by comparison, the postdrome, which occurs in the aftermath of COVID-19, which we refer to as persistent post-COVID-syndrome, has received little attention. Potential long-term effects from post-COVID syndrome will assume increasing importance as a surge of treated patients are discharged from the hospital, placing a burden on healthcare systems, patients' families, and society in general to care for these medically devastated COVID-19 survivors. This review explores underlying mechanisms and possible manifestations of persistent post-COVID syndrome, and presents a framework of strategies for the diagnosis and management of patients with suspected or confirmed persistent post-COVID syndrome.

ROCKET: Phase II Randomized, Active-controlled, Multicenter Trial to Assess the Safety and Efficacy of RRx-001 + Irinotecan vs. Single-agent Regorafenib in Third/Fourth Line Colorectal Cancer.

INTRODUCTION: RRx-001 is a novel cysteine-targeted alkylating agent that releases nitric oxide (NO). The primary biological activities of this hybrid molecule include macrophage repolarizing and vascular normalization. The purpose of this clinical trial (ROCKET) (NCT02096354) was to compare the safety and efficacy of the combination therapy RRx-001 + irinotecan vs. regorafenib in third/fourth line colorectal cancer that previously received treatment with irinotecan. PATIENTS AND METHODS: A total of 34 patients were randomized (24 to RRx-001 + irinotecan (RxI) and 10 to single-agent regorafenib (RegI)) and were the basis for the intention-to-treat analysis (ITT, comprising all 34 patients). RRx-001 treatment was administered as an up-to-2-month "primer" followed by irinotecan for patients randomized to the RRx-001 arm (24). The efficacy and safety data are presented for the 34 patients in the (ITT) efficacy analysis. Therapy consisted of intravenous administration of RRx-001 at 4 mg once weekly for up to 2 months, at which point RRx-001 was discontinued, followed by intravenous infusion of irinotecan at 180 mg/m2 on day 1 in a 21-day cycle vs. 160 mg oral regorafenib daily for 3/4 weeks followed at progression, if applicable, by irinotecan 180 mg/m2 on day 1 in a 21-day cycle. There were 3 patients (3/24 = 12.5%) with prior single agent irinotecan on the RRx-001 randomized arm and 2 (2/10 = 20%) on the regorafenib randomized arm. Numerous patients had irinotecan combination therapies prior to randomized treatment. There were 15 patients on RRx-001 arm that received irinotecan post-RRx-001 in the randomized trial. There were 5 PRs on RRx-001 plus irinotecan leading to an overall response of 20.8% (5/24). There were 37.5% (9/24) of RRx-001 randomized patients with KRAS mutant type while 60% (6/10) regorafenib randomized patients were of KRAS type mutant. There were only 4 patients with available QOL and Edmonton Symptom Assessment System, an insufficient sample size to allow for any meaningful analysis. RESULTS: Median patient follow-up was approximately 14.5 months (SD 4.5 months). Median overall survival was 8.6 months for RxI and 4.7 months for RegI. Median progression free survival was 6.1 months for RxI vs. 1.7 months for RegI (a statistically significant result, 2-sided log-rank test, P = .0030). The toxicity profile of RxI was substantially improved compared with RegI. CONCLUSION: The results of this trial demonstrate improved efficacy of RxI compared with RegI in patients with metastatic colorectal cancer after previous treatment with irinotecan, and late-stage clinical development in this indication is planned on the strength of the observed "signal" accompanied by a sufficient safety profile.

Editorial Commentary: Restoration of Hip Capsular Tension Is More Important Than Repair Construct Configuration.

The debate regarding optimal capsular management during hip arthroscopy has been evolving for over 20 years. Femoroacetabular impingement emerged in the arthroscopic world in the early 2000s. However, the ability to address osseous deformities and decompress and/or reshape them was limited by the hip capsular structures and small capsulotomies. Some surgeons attempted to arthroscopically manage these deformities with limited capsulotomies, with not surprisingly limited success. Others made larger capsular windows (capsulectomies) to more accurately manage these deformities but potentially left some patients with varying degrees of iatrogenic microinstability or macroinstability. Over time, an increasing awareness of post-arthroscopy instability in the form of case reports, case series, and backroom chatter among the hip arthroscopy thought leaders brought the idea of routine capsular closure to the forefront. Biomechanical studies defined the role of the hip capsular ligaments, the deficits created with various capsulotomies during surgery, and the ability to restore stability after capsular repair. Clinical studies revealed better outcomes and lower revision rates after capsular repair for subtle osseous and soft-tissue instability, revision cases, and athletes compared with unrepaired capsulotomies. Various capsular repair constructs (side-to-side repairs, capsular shifts, and various suture configurations and suture materials) have been proposed, without evidence to support a superior technique or suture material. In the end, capsular management is an evolving art that takes into account various patient-specific factors (i.e., individual activity requirements, soft-tissue and osseous parameters, and intraoperative impressions) with the end goal of achieving a stable, impingement-free joint. There might be various capsular management roads to travel, but the destination remains the same.

Development of Adenovirus Containing Liposomes Produced by Extrusion vs. Homogenization: A Comparison for Scale-Up Purposes.

Adenovirus (Ad) is a widely studied viral vector for cancer therapy as it can be engineered to cause selective lysis of cancer cells. However, Ad delivery is limited in treating cancers that do not have coxsackievirus and adenovirus receptors (CAR). To overcome this challenge, Ad-encapsulated liposomes were developed that enhance the delivery of Ads and increase therapeutic efficacy. Cationic empty liposomes were manufactured first, to which an anionic Ad were added, which resulted in encapsulated Ad liposomes through charge interaction. Optimization of the liposome formula was carried out with series of formulation variables experiments using an extrusion process, which is ideal for laboratory-scale small batches. Later, the optimized formulation was manufactured with a homogenization technique-A high shear rotor-stator blending, that is ideal for large-scale manufacturing and is in compliance with Good Manufacturing Practices (GMP). Comparative in vitro transduction, physicochemical characterization, long-term storage stability at different temperature conditions, and in vivo animal studies were performed. Ad encapsulated liposomes transduced CAR deficient cells 100-fold more efficiently than the unencapsulated Ad (p ≤ 0.0001) in vitro, and 4-fold higher in tumors injected in nude mice in vivo. Both extrusion and homogenization performed similarly-with equivalent in vitro and in vivo transduction efficiencies, physicochemical characterization, and long-term storage stability. Thus, two Ad encapsulated liposomes preparation methods used herein, i.e., extrusion vs. homogenization were equivalent in terms of enhanced Ad performance and long-term storage stability; this will, hopefully, facilitate translation to the clinic.