Society for Immunotherapy of Cancer (SITC) recommendations on intratumoral immunotherapy clinical trials (IICT): from premalignant to metastatic disease.

BACKGROUND: Intratumorally delivered immunotherapies have the potential to favorably alter the local tumor microenvironment and may stimulate systemic host immunity, offering an alternative or adjunct to other local and systemic treatments. Despite their potential, these therapies have had limited success in late-phase trials for advanced cancer resulting in few formal approvals. The Society for Immunotherapy of Cancer (SITC) convened a panel of experts to determine how to design clinical trials with the greatest chance of demonstrating the benefits of intratumoral immunotherapy for patients with cancers across all stages of pathogenesis. METHODS: An Intratumoral Immunotherapy Clinical Trials Expert Panel composed of international key stakeholders from academia and industry was assembled. A multiple choice/free response survey was distributed to the panel, and the results of this survey were discussed during a half-day consensus meeting. Key discussion points are summarized in the following manuscript. RESULTS: The panel determined unique clinical trial designs tailored to different stages of cancer development-from premalignant to unresectable/metastatic-that can maximize the chance of capturing the effect of intratumoral immunotherapies. Design elements discussed included study type, patient stratification and exclusion criteria, indications of randomization, study arm determination, endpoints, biological sample collection, and response assessment with biomarkers and imaging. Populations to prioritize for the study of intratumoral immunotherapy, including stage, type of cancer and line of treatment, were also discussed along with common barriers to the development of these local treatments. CONCLUSIONS: The SITC Intratumoral Immunotherapy Clinical Trials Expert Panel has identified key considerations for the design and implementation of studies that have the greatest potential to capture the effect of intratumorally delivered immunotherapies. With more effective and standardized trial designs, the potential of intratumoral immunotherapy can be realized and lead to regulatory approvals that will extend the benefit of these local treatments to the patients who need them the most.

Evaluation of Differences in Patellar Height After Patellar Stabilization Procedures Not Intended to Address Patella Alta: A Multicenter Study.

Background: Recent studies have reported conflicting results as to whether isolated medial patellofemoral ligament reconstruction (MPFLr) leads to decreased patellar height. Purpose: To investigate if patellar stabilization surgery not intended to address patella alta influences patellar height. Study Design: Cohort study; Level of evidence, 3. Methods: A multicenter retrospective chart review was conducted, and patients who underwent MPFLr, medializing tibial tuberosity osteotomy (TTO), and/or trochleoplasty between 2016 and 2020 were included. The Caton-Deschamps index (CDI) was calculated from radiographs obtained preoperatively, 2 weeks postoperatively, and 3 months postoperatively. The preoperative CDI value was compared with the 2-week postoperative and 3-month postoperative values according to stabilization procedure (isolated MPFLr, isolated TTO, MPFLr + TTO, MPFLr + trochleoplasty, and MPFLr + trochleoplasty + TTO) using the paired t test. Analyses of the 1-bundle versus 2-bundle MPFLr technique and the presence of lateral retinacular release or lateral retinacular lengthening were conducted on the isolated MPFLr and combined MPFLr + TTO cohorts. Results: A total of 356 knees were included. Statistically significant pre- to postoperative decreases in CDI were seen in all stabilization procedures analyzed (P≤ .017 for all). Within the isolated MPFLr cohort, this significant decrease was seen at 2 weeks postoperatively with the 2-bundle technique (ΔCDI = -0.09; P < .001) but not with the 1-bundle technique (ΔCDI = -0.01; P = .621). Conclusion: The different surgical techniques analyzed in the current study affected patellar height, even when a distalizing TTO was not performed. The decrease was dependent on surgical technique, with a 2-bundle MPFLr leading to a statistically significant decrease and a 1-bundle MPFLr effecting no change.

High response rate with extended dosing of cemiplimab in advanced cutaneous squamous cell carcinoma.

BACKGROUND: Cemiplimab (Libtayo®), a human monoclonal immunoglobulin G4 antibody to the programmed cell death-1 receptor, is approved for the treatment of patients with advanced cutaneous squamous cell carcinoma (CSCC), who are not candidates for curative surgery or curative radiation, using an every-3-weeks (Q3W) dosing interval. Pharmacokinetic modeling indicated that Ctrough of extended intravenous dosing of 600 mg every 4 weeks (Q4W) would be comparable to the approved intravenous dosage of 350 mg Q3W. We examined the efficacy, pharmacokinetics, and safety of cemiplimab dosed Q4W. METHODS: In this open-label, phase II trial (ClinicalTrials.gov identifier NCT02760498), the cohort of patients ≥18 years old with advanced CSCC received cemiplimab 600 mg intravenously Q4W for up to 48 weeks. Tumor measurements were recorded every 8 weeks. The primary endpoint was objective response rate by independent central review. RESULTS: Sixty-three patients with advanced CSCC were treated with cemiplimab. The median duration of follow-up was 22.4 months (range: 1.0-39.8). An objective response was observed in 39 patients (62%; 95% CI: 48.8% to 73.9%), with 22% of patients (n=14) achieving complete response and 40% (n=25) achieving partial response. The most common treatment-emergent adverse events were diarrhea, pruritus, and fatigue. CONCLUSIONS: Extended dosing of cemiplimab 600 mg intravenously Q4W exhibited substantial antitumor activity, rapid and durable responses, and an acceptable safety profile in patients with advanced CSCC. These results confirm that cemiplimab is a highly active therapy for advanced CSCC. Additional data would help ascertain the benefit-risk profile for the 600 mg intravenous dosing regimen compared with the approved regimen.

Biomechanical Characteristics of Ulnar Collateral Ligament Injuries Treated With and Without Augmentation: A Network Meta-analysis of Controlled Laboratory Studies.

BACKGROUND: Treatment of ulnar collateral ligament (UCL) tears with suture tape augmentation has gained interest given preliminary reports of favorable biomechanical characteristics. No study to date has quantitatively assessed the biomechanical effects of multiple augmentation techniques relative to the native UCL. PURPOSE: To perform a systematic review and meta-analysis of controlled laboratory studies to assess and comparatively rank biomechanical effects of UCL repair or reconstruction with or without augmentation. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 4. METHODS: PubMed, OVID/Medline, and Cochrane databases were queried in January 2023. A frequentist network meta-analytic approach was used to perform mixed-treatment comparisons of UCL repair and reconstruction techniques with and without augmentation, with the native UCL as the reference condition. Pooled treatment estimates were quantified under the random-effects assumption. Competing treatments were ranked in the network meta-analysis by using point estimates and standard errors to calculate P scores (greater P score indicates superiority of treatment for given outcome). RESULTS: Ten studies involving 206 elbow specimens in which a distal UCL tear was simulated were included. UCL reconstruction with suture tape augmentation (AugRecon) restored load to failure to a statistically noninferior magnitude (mean difference [MD], -1.99 N·m; 95% CI, -10.2 to 6.2 N·m; P = .63) compared with the native UCL. UCL reconstruction (Recon) (MD, -12.7 N·m; P < .001) and UCL repair with suture tape augmentation (AugRepair) (MD, -14.8 N·m; P < .001) were both statistically inferior to the native UCL. The AugRecon condition conferred greater load to failure compared with Recon (P < .001) and AugRepair (P = .002) conditions. AugRecon conferred greater torsional stiffness relative to all other conditions and was not statistically different from the native UCL (MD, 0.32 N·m/deg; 95% CI, -0.30 to 0.95 N·m/deg; P = .31). Medial ulnohumeral gapping was not statistically different for the AugRepair (MD, 0.30 mm; 95% CI, -1.22 to 1.82 mm; P = .70), AugRecon (MD, 0.57 mm; 95% CI, -0.70 to 1.84 mm; P = .38), or Recon (MD, 1.02 mm; 95% CI, -0.02 to 2.05 mm; P = .055) conditions compared with the native UCL. P-score analysis indicated that AugRecon was the most effective treatment for increasing ultimate load to failure and torsional stiffness, whereas AugRepair was the most effective for minimizing medial gapping. CONCLUSION: AugRecon restored load to failure and torsional stiffness most similar to the parameters of the native UCL, whereas Recon and AugRepair did not restore the same advantageous properties at time zero. Medial ulnohumeral gapping during a valgus load was minimized by all 3 treatments. Based on network interactions, AugRecon was the superior treatment approach for restoring important biomechanical features of the UCL at time zero that are jeopardized during a complete distal tear.

Neoadjuvant cemiplimab and surgery for stage II-IV cutaneous squamous-cell carcinoma: follow-up and survival outcomes of a single-arm, multicentre, phase 2 study.

BACKGROUND: We previously reported rates of pathological complete responses (51% [95% CI 39-62] per independent central review, the primary endpoint) and major pathological responses (13% per independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival. METHODS: This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II-IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing. FINDINGS: Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66-81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6-22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received adjuvant cemiplimab, and 17 (26%) received adjuvant radiotherapy. 11 (14%) of 79 patients had event-free survival events, with an estimated 12-month event-free survival of 89% (95% CI 79-94) for all patients. None of 40 patients who had a pathological complete response and one (10%) of ten patients with major pathological response had recurrence. Six (9%) of 70 patients who completed surgery had a disease-free survival event, with an estimated 12-month disease-free survival of 92% (95% CI 82-97). Nine (11%) of 79 patients died, with an estimated 12-month overall survival for all patients of 92% (95% CI 83-96). Four (25%) of 16 patients who received adjuvant cemiplimab treatment had grade 3 adverse events, including one (6%) who had increased blood potassium, one (6%) who had traumatic limb amputation, and two who had serious adverse events (one [6%] cardiomyopathy and one [6%] hypophysitis). There were no grade 4 adverse events or treatment-related deaths. INTERPRETATION: For patients with resectable stage II-IV cutaneous squamous cell carcinoma, neoadjuvant cemiplimab followed by surgery might be a potential treatment option, addressing a substantial unmet need. FUNDING: Regeneron Pharmaceuticals and Sanofi.

Rice-Body Synovitis, Foreign Body Reaction, and Rotator Cuff Failure After Subacromial Balloon Spacer Augmentation of a Rotator Cuff Repair: A Case Report.

CASE: A 66-year-old woman presented with shoulder pain and weakness 4 months after augmentation of a rotator cuff repair with a Stryker InSpace subacromial balloon spacer. A magnetic resonance imaging (MRI) demonstrated a failed rotator cuff repair, large effusion with rice bodies, synovitis, axillary lymphadenopathy, loose anchors, and erosive changes to the greater tuberosity. Arthroscopy revealed balloon fragmentation surrounded by diffusely hyperemic synovium without repairable cuff tissue. Final cultures proved negative for infection. Histologic evaluation revealed ulcerated synovium with diffuse chronic and focal acute inflammation. CONCLUSION: Despite promising early results, augmentation of a rotator cuff repair with a subacromial balloon spacer introduces a risk of inflammatory reaction that may mimic a deep infection and compromise rotator cuff healing.

Evaluation, Treatment, and Outcomes of Batter's Shoulder.

PURPOSE OF REVIEW: This article reviews the incidence of batter's shoulder, the relevant biomechanics that predispose the lead shoulder to a posterior instability event, the evaluation and workup of posterior labral injury, the surgical technique for arthroscopic posterior labral repair, the postoperative rehabilitation process, and the clinical outcomes and return to sport after treatment of batter's shoulder. RECENT FINDINGS: New epidemiological studies have demonstrated the relatively low incidence of batter's shoulder at the professional baseball level with 85% of the injured players successfully returning to the sport with nonoperative management. However, recent studies have reinforced the limited historical literature that players requiring surgery are able to return to their prior sport at a high level. Batter's shoulder is a subtype of posterior glenohumeral instability caused by the significant forces experienced by the lead shoulder during the baseball swing. Although an uncommon injury, batter's shoulder is a source of significant time away from competition. In patients who do not improve with nonoperative management, arthroscopic posterior labral repair can reliably return players to sport. Future research studies should consider opportunities for injury prevention.

Cancer cell-derived type I interferons instruct tumor monocyte polarization.

Monocytes are highly plastic immune cells that modulate antitumor immunity. Therefore, identifying factors that regulate tumor monocyte functions is critical for developing effective immunotherapies. Here, we determine that endogenous cancer cell-derived type I interferons (IFNs) control monocyte functional polarization. Guided by single-cell transcriptomic profiling of human and mouse tumors, we devise a strategy to distinguish and separate immunostimulatory from immunosuppressive tumor monocytes by surface CD88 and Sca-1 expression. Leveraging this approach, we show that cGAS-STING-regulated cancer cell-derived IFNs polarize immunostimulatory monocytes associated with anti-PD-1 immunotherapy response in mice. We also demonstrate that immunosuppressive monocytes convert into immunostimulatory monocytes upon cancer cell-intrinsic cGAS-STING activation. Consistently, we find that human cancer cells can produce type I IFNs that polarize monocytes, and our immunostimulatory monocyte gene signature is enriched in patient tumors that respond to anti-PD-1 immunotherapy. Our work exposes a role for cancer cell-derived IFNs in licensing monocyte functions that influence immunotherapy outcomes.

Neoadjuvant Cemiplimab for Stage II to IV Cutaneous Squamous-Cell Carcinoma.

BACKGROUND: In a pilot study involving patients with cutaneous squamous-cell carcinoma, a high percentage of patients had a pathological complete response with the use of two doses of neoadjuvant cemiplimab before surgery. Data from a phase 2 study are needed to confirm these findings. METHODS: We conducted a phase 2, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab as neoadjuvant therapy in patients with resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma. Patients received cemiplimab, administered at a dose of 350 mg every 3 weeks for up to four doses, before undergoing surgery with curative intent. The primary end point was a pathological complete response (the absence of viable tumor cells in the surgical specimen) on independent review at a central laboratory, with a null hypothesis that a pathological complete response would be observed in 25% of patients. Key secondary end points included a pathological major response (the presence of viable tumor cells that constitute ≤10% of the surgical specimen) on independent review, a pathological complete response and a pathological major response on investigator assessment at a local laboratory, an objective response on imaging, and adverse events. RESULTS: A total of 79 patients were enrolled and received neoadjuvant cemiplimab. On independent review, a pathological complete response was observed in 40 patients (51%; 95% confidence interval [CI], 39 to 62) and a pathological major response in 10 patients (13%; 95% CI, 6 to 22). These results were consistent with the pathological responses determined on investigator assessment. An objective response on imaging was observed in 54 patients (68%; 95% CI, 57 to 78). Adverse events of any grade that occurred during the study period, regardless of whether they were attributed to the study treatment, were observed in 69 patients (87%). Grade 3 or higher adverse events that occurred during the study period were observed in 14 patients (18%). CONCLUSIONS: Neoadjuvant therapy with cemiplimab was associated with a pathological complete response in a high percentage of patients with resectable cutaneous squamous-cell carcinoma. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov number, NCT04154943.).

EMPOWER CERVICAL-1: Effects of cemiplimab versus chemotherapy on patient-reported quality of life, functioning and symptoms among women with recurrent cervical cancer.

BACKGROUND: In a phase III, randomised, active-controlled study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9; R2810-ONC-1676; NCT03257267) and cemiplimab significantly improved survival versus investigator's choice of chemotherapy among patients with recurrent cervical cancer who had progressed on platinum-based therapy. Here we report patient-reported outcomes in this pivotal study. METHODS: Patients were randomised 1:1 to open-label cemiplimab (350 mg intravenously every 3 weeks) or investigator's choice of chemotherapy in 6-week cycles. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 during cycles 1-16. Least-squares mean changes from baseline in global health status (GHS)/quality of life (QoL) and physical functioning (PF) were secondary end-points in the statistical hierarchy. RESULTS: Of 608 patients (304/arm), 77.8% patients had squamous cell carcinoma and 22.2% patients had adenocarcinoma. Questionnaire completion rates were ∼90% throughout. In the squamous cell carcinoma population, overall between-group differences statistically significantly favoured cemiplimab in GHS/QoL (8.49; 95% confidence interval [CI]: 3.77-13.21; P = 0.0003) and PF (8.35; 95% CI: 4.08-12.62; P < 0.0001). Treatment differences favoured cemiplimab in both histologic populations by cycle 2. Overall changes from baseline in most functioning and symptom scales favoured cemiplimab, with clinically meaningful treatment differences in role functioning, appetite loss and pain in both populations. The sensitivity analyses, responder analyses and time to definitive deterioration favoured cemiplimab in both populations. CONCLUSIONS: Cemiplimab conferred favourable differences in GHS/QoL and PF compared with chemotherapy among patients with recurrent cervical cancer, with benefits in PF by cycle 2, and clinically meaningful differences favouring cemiplimab in role functioning, appetite loss, and pain.

Change in humeral anchor position significantly affects isometry in ulnar collateral ligament repair: a 3-dimensional computer modeling study.

BACKGROUND: Medial ulnar collateral ligament (UCL) repair utilization is increasing in recent years, bolstered by shorter rehabilitation and satisfactory clinical outcomes. Although previous literature has illustrated the importance of tunnel position on restoring graft isometry in reconstruction, there remains a paucity of literature guiding anchor placement in UCL repair. The purpose of this study is to design a 3-dimensional (3D) elbow model to understand the effect of anchor location on UCL repair isometry. METHODS: A 3D computer model of an elbow joint was created using computed tomographic and magnetic resonance imaging MRI scans from a single patient. The humeral and ulnar attachments of the UCL were plotted using 3 methodologies: (1) geometric cloud mapping and (2) quantitative measurements from the anatomic studies by Camp et al and (3) Frangiamore et al. A 3.5-mm-diameter clockface was placed on each attachment site, which allowed for simulation of 12 distinct 1.75-mm deviations in anchor position. The 3 models were ranged through 0°-120° at 10° increments, and the 3D distances were measured between the ligament centroids. The humeral and ulnar anchors were sequentially repositioned around the clockfaces, and construct lengths were again measured to evaluate changes in isometry. A paired Student t test was performed to determine if there was a significant difference in isometry between the humeral and ulnar anchor deviations. RESULTS: Using method 1, the UCL repair length at 90° of elbow flexion was 26.8 mm. This construct underwent 13.6 mm of total excursion for a 46.4% change in length throughout its arc of motion. Method 2 produced a 19.3-mm construct that underwent 0.8 mm of excursion for a 3.9% length change throughout the arc. Method 3 produced a 24.5-mm construct that underwent 2.3 mm of excursion for a 9.4% length change. Identifying ligament footprints using the quantitative anatomic measurements from Camp et al and Frangiamore et al improved construct isometry through 120° of flexion (length changes of 3.9% and 9.4%, respectively) when compared to using the geometric cloud technique alone (46.4% length change). Humeral anchor deviations produced a significant increase in repair construct excursion compared with ulnar anchor deviations (P < .001). CONCLUSION: When performing UCL repair, small deviations in humeral anchor position may significantly influence ligament repair isometry. Using quantitative anatomic data may help identify anchor positions with improved repair isometry. Particularly when addressing detachments of the humeral footprint, surgeons should be critical of the humeral anchor position in order to restore native anatomy and optimal biomechanics.

Hedgehog pathway inhibitor real-world treatment patterns in patients with basal cell carcinoma: a claims-based analysis.

Aims: To examine real-world treatment patterns for Hedgehog pathway inhibitors (HHIs) for the treatment of advanced basal cell carcinoma. Patients & methods: HHI initiators between January 2013 and June 2019 were identified from IBM MarketScan® claims data. Time to treatment discontinuation and reinitiation were estimated using Kaplan-Meier methods using a 60-day grace period. Results: Among 526 patients with basal cell carcinoma who initiated an HHI, median time to first discontinuation was 144 days, and risk of discontinuation by 12 months was 88.0%. Probability of reinitiation within 12 months was 19.7%, and median time to second discontinuation was 118 days. Conclusion: HHI discontinuation was common and reinitiation uncommon in clinical practice. Future research should evaluate persistence with recently approved therapies.

This study examined patterns of discontinuation and reinitiation of Hedgehog pathway inhibitors (HHIs) such as vismodegib or sonidegib for patients with basal cell carcinoma, the most common form of skin cancer. Initiation of HHI treatment was identified from prescriptions filled by patients with commercial insurance or Medicare who had basal cell carcinoma. Discontinuation was defined as a gap of more than 60 days without treatment, after drug supply had run out. Among the 526 patients identified, one-half had discontinued HHI treatment within about 5 months and 88% had discontinued treatment within 1 year. Fewer than 20% of patients restarted treatment. Discontinuations are common but restarting treatment is uncommon among patients with basal cell carcinoma treated with HHIs.

Real-World Treatment Patterns and Outcomes Among Patients with Basal Cell Carcinoma Following First-Line Hedgehog Inhibitor Discontinuation.

INTRODUCTION: Until recently, patients discontinuing first-line (1L) hedgehog inhibitors (HHIs) for basal cell carcinoma (BCC) had few subsequent treatment options. The objective of this study was to describe the treatment journey and prognosis of patients discontinuing 1L HHI for BCC. METHODS: This was a retrospective cohort study of patients with BCC who discontinued 1L HHI treatment in The US Oncology Network between 1 January 2012 and 1 January 2019 (with follow-up until 1 May 2020). Two cohorts were identified: patients who initiated a second-line (2L) treatment (2L initiators), and patients with 1L progression or toxicity without pathology-confirmed complete response who did not initiate 2L treatment (2L non-initiators). Patient demographics, treatment characteristics, and outcomes are reported for each cohort. RESULTS: Among 115 patients with BCC who received 1L HHI treatment, 63.5% (n = 73/115) discontinued 1L HHIs. Of those, 50.7% (n = 37/73) discontinued because of documented toxicity or progression, without evidence of a complete response. We identified 4 patients who initiated 2L systemic treatment (median age 68.7 years, 100.0% female) and 15 patients who were eligible for the 2L non-initiator cohort (median age 80.2 years, 20.0% female). Median 1L HHI duration was 6.8 months (range 1.9-20.6 months) for the 2L non-initiator cohort and 8.6 months (range 6.8-42.2 months) for 2L initiators. At the end of follow-up, among 2L non-initiators (median follow-up duration 9.7 months), 40.0% were lost to follow-up, 33.3% had died, 20.0% continued observation, and 6.7% transitioned to an academic medical center or hospital; among 2L initiators (median follow-up duration 6.3 months), 50.0% were lost to follow-up, 25.0% had died, and 25.0% continued observation. CONCLUSIONS: Following 1L HHI discontinuation, lack of standardized care and suboptimal outcomes were observed, including limited receipt of 2L treatment. Further studies are necessary to evaluate the impact of newer BCC treatment options.

Pharmacodynamic and therapeutic pilot studies of single-agent ribavirin in patients with human papillomavirus-related malignancies.

OBJECTIVES: Ribavirin inhibits eukaryotic translation initiation factor 4E (eIF4E), thereby decreasing cap-dependent translation. In this two-part study, we assessed the pharmacodynamic effects and therapeutic potential of ribavirin in human papillomavirus (HPV)-related malignancies. METHODS: In the pharmacodynamic study, ribavirin (400 mg BID for 14 days) was evaluated in 8 patients with HPV-positive localized oropharyngeal carcinoma with phosphorylated-eIF4E (p-eIF4E) ≥ 30%. In the therapeutic study, ribavirin (1400 mg BID in 28-day cycles, continuously dosed) was evaluated in 12 patients with recurrent and/or metastatic HPV-related cancer. Dose interruptions or reductions were allowed according to prespecified criteria. Toxicities were assessed in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events version 4; response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Patients remained on study until disease progression or unacceptable toxicity. RESULTS: Six patients were evaluable in the pharmacodynamic study: 4 had decreased p-eIF4E after 14 days of ribavirin. In the therapeutic study, 12 patients were evaluable for toxicity, and 9 were evaluable for response. Among these, median follow-up was 3.5 months, and best overall response was stable disease in 5 patients and progression of disease in 4 patients. Median progression-free survival was 1.8 months. The most common treatment-related adverse events (grade > 2) were anemia, dyspnea, and hyperbilirubinemia. All patients had anemia (grades 1-3), with 33% having at least 1 dose reduction. CONCLUSION: Oral ribavirin decreases p-eIF4E levels and is well-tolerated. However, a clear signal of efficacy in patients with recurrent and/or metastatic HPV-related cancers was not observed. (NCT02308241, NCT01268579).

Double-Row Repair With Platelet-Rich Plasma Optimizes Retear Rates After Small to Medium Full-Thickness Rotator Cuff Repair: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials.

PURPOSE: To compare the different interventions described in the literature for the surgical treatment of small and medium complete rotator cuff tears. METHODS: A systematic review of randomized controlled trials of small-medium, full-thickness rotator cuff tears published since 2000 was performed. Clinical characteristics, re-tear rates, range of motion (ROM), and patient-reported outcomes (PRO) data were collected. Interventions were compared via arm-based Bayesian network meta-analysis in a random-effects model. Interventions were ranked for each domain (re-tear risk, pain, ROM, and PROs) via surface under the cumulative ranking curves. RESULTS: A total of 18 studies comprising 2046 shoulders (47% females, mean age 61 ± 3 years, mean follow-up 21 ± 5 months) were included. Interventions that ranked highest for minimizing re-tear risk included arthroscopic single-row repair (A+SR) or double-row repair (A+DR) with or without platelet-rich plasma (PRP). Open repair and A+SR repair with acromioplasty (ACP) ranked highest for pain relief. Interventions that ranked highest for ROM improvement included open repair, PT, and A+DR with or without ACP. Interventions that ranked highest for PROs included arthroscopic footprint microfracture with or without SR, open repair, and A+SR with or without ACP. CONCLUSIONS: Based on a network meta-analysis of level 1 studies, arthroscopic rotator cuff repair with a SR or DR construct demonstrates similar retear rates, PROs, and clinical outcomes. The highest-ranking treatment for minimizing retears was arthroscopic repair with DR constructs and PRP augmentation, although open repair and arthroscopic SR remain reliable options with excellent clinical outcomes. Addition of PRP to DR constructs trended toward a 56% decreased risk of retear as compared to DR repair alone. Although no single treatment emerged superior, several interventions offered excellent clinical improvements in pain, ROM, and PROs that exceeded minimal clinically important difference thresholds. LEVEL OF EVIDENCE: I, systematic review and meta-analysis of level I studies.

Survival with Cemiplimab in Recurrent Cervical Cancer.

BACKGROUND: Patients with recurrent cervical cancer have a poor prognosis. Cemiplimab, the fully human programmed cell death 1 (PD-1)-blocking antibody approved to treat lung and skin cancers, has been shown to have preliminary clinical activity in this population. METHODS: In this phase 3 trial, we enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of their programmed cell death ligand 1 (PD-L1) status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator's choice of single-agent chemotherapy. The primary end point was overall survival. Progression-free survival and safety were also assessed. RESULTS: A total of 608 women were enrolled (304 in each group). In the overall trial population, median overall survival was longer in the cemiplimab group than in the chemotherapy group (12.0 months vs. 8.5 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.84; two-sided P<0.001). The overall survival benefit was consistent in both histologic subgroups (squamous-cell carcinoma and adenocarcinoma [including adenosquamous carcinoma]). Progression-free survival was also longer in the cemiplimab group than in the chemotherapy group in the overall population (hazard ratio for disease progression or death, 0.75; 95% CI, 0.63 to 0.89; two-sided P<0.001). In the overall population, an objective response occurred in 16.4% (95% CI, 12.5 to 21.1) of the patients in the cemiplimab group, as compared with 6.3% (95% CI, 3.8 to 9.6) in the chemotherapy group. An objective response occurred in 18% (95% CI, 11 to 28) of the cemiplimab-treated patients with PD-L1 expression greater than or equal to 1% and in 11% (95% CI, 4 to 25) of those with PD-L1 expression of less than 1%. Overall, grade 3 or higher adverse events occurred in 45.0% of the patients who received cemiplimab and in 53.4% of those who received chemotherapy. CONCLUSIONS: Survival was significantly longer with cemiplimab than with single-agent chemotherapy among patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. (Funded by Regeneron Pharmaceuticals and Sanofi; EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 ClinicalTrials.gov number, NCT03257267.).

Return to Play and Player Performance After Meniscal Tear Among Elite-Level European Soccer Players: A Matched Cohort Analysis of Injuries From 2006 to 2016.

BACKGROUND: Meniscal injuries are extremely common in soccer athletes, and little is known about postrecovery performance. PURPOSE: To (1) identify characteristics associated with return to play (RTP) to the same league level and (2) evaluate long-term effects that injury and management approach may have on player performance. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Using publicly available records, we identified athletes who sustained meniscal tears across the 5 major European soccer leagues (English Premier League, Bundesliga, La Liga, Ligue 1, and Serie A) between 2006 and 2016. Injured athletes were matched to controls 1:2 by demographics and performance. Investigations included rate of RTP to the same league level, reinjury, player characteristics associated with RTP within 2 seasons, long-term availability, field time, and performance metrics standardized to 90 minutes of play during the next 4 seasons. RESULTS: A total of 250 players sustaining meniscal tears were included, of which 106 (42%) received surgical management. Median absence was 57.5 days (interquartile range [IQR], 35-92) or 7 games (IQR, 4-12). Rate of RTP was 70%, and the reinjury rate 5% if a player could RTP. Age greater than 30 years was a negative predictor for RTP (odds ratio [OR], 0.62; P = .002), whereas higher preinjury goals per game (OR, 2.80; P = .04) and surgical management (OR, 1.38; P = .002) were positive predictors for RTP. Surgical management was associated with higher long-term availability (P < .01). As compared with the control, there were no significant differences in field time or performance metrics after RTP, either overall or by player position. As compared with nonoperative management, defenders undergoing surgery demonstrated decreased field time. Attackers and midfielders demonstrated similar field time and performance regardless of management. CONCLUSION: RTP of elite soccer athletes sustaining meniscal tear is contingent on age, preinjury performance, and management approach. Those who RTP to the same league level can be expected to demonstrate equivalent field time, performance, and long-term availability as noninjured athletes.

Outpatient Shoulder Arthroplasty Patient Selection, Patient Experience, and Cost Analyses: A Systematic Review.

BACKGROUND: The utilization of outpatient shoulder arthroplasty has been increasing. With increasing pressure to reduce costs, further underscored by the coronavirus (COVID-19) pandemic, many health-care organizations will move toward outpatient interventions to conserve inpatient resources. Although abundant literature has shown the advantages of outpatient total hip arthroplasty (THA) and total knee arthroplasty (TKA), there is a relative paucity describing outpatient shoulder arthroplasty. Thus, the purpose of this study was to summarize the peer-reviewed literature of outpatient shoulder arthroplasty with particular attention to patient selection, patient outcomes, and cost benefits. METHODS: The PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Embase databases were queried according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All articles on outpatient shoulder arthroplasty were included. Data on patient selection, patient outcomes, and cost analyses were recorded. Patient outcomes, including complications, reoperations, and readmissions, were analyzed by weighted average. RESULTS: Twenty-three articles were included for analysis. There were 3 review articles and 20 studies with Level-III or IV evidence as assessed per The Journal of Bone & Joint Surgery Level of Evidence criteria. Patient selection was most often predicated on age <70 years, body mass index (BMI) <35 kg/m2, absence of active cardiopulmonary comorbidities, and presence of home support. Complications and readmissions were not common and either improved or were equivalent to those of inpatient shoulder arthroplasty. Patient satisfaction was high in studies of short-term and intermediate-term follow-up. The proposed cost benefit ranged from $747 to $53,202 with outpatient shoulder arthroplasty. CONCLUSIONS: The published literature to date supports outpatient shoulder arthroplasty as an effective, safe, and cost-reducing intervention with proper patient selection. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.