Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial.

BACKGROUND: Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity. METHODS: KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50-1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41. FINDINGS: From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50-1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4-30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission. INTERPRETATION: Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing. FUNDING: Kura Oncology.

International medical graduates in orthopaedic surgery: An opportunity to improve diversity and inclusion?

Background/aims: Racial and ethnic minorities are under-represented in orthopaedic surgery despite efforts to promote diversity and inclusion in the specialty. The purpose of this study was to determine the proportion of international medical graduates (IMGs) in the surgical workforce and future residency pipeline. We further analyze IMG applicant qualifications relative to their US-based counterparts to assess the viability of recruiting IMG candidates as one strategy to advance diversity and inclusion in orthopaedic surgery. Methods: Physician workforce data from the American Medical Association and residency match data from the National Resident Match Program were analyzed for Orthopaedic Surgery. Trends in the proportion of IMG applicants were compared with those from other specialties. Qualifications of applicants were compared including board exam scores, number of abstracts/publications, and additional graduate degrees. Results: In 2020, orthopaedic surgery had the lowest percentage of IMGs relative to otolaryngology (5.8 %, p < 0.001), neurosurgery (12.1 %, p < 0.001), obstetrics & gynecology (14.0 %, p < 0.001), and general surgery (19.1 %, p < 0.001). From 1986 to 2021, IMG Graduates who matched into orthopaedic surgery increased from 1 (0.3 %) to 8 (0.9 %). Compared to other surgical specialties, orthopaedic surgery had among the lowest annual rates of incoming IMG residents. In 2021, most respondents to the orthopaedic surgery residency program directors survey reported never selecting IMG applicants for interview (74 % for non-US IMG applicants and 53 % for US IMG applicants). From 2020 to 2021, non-US IMG applicants (17 %) and US IMG applicants (26 %) had lower match rates than DO Senior (74 %) and MD Senior (80 %) applicants (p < 0.001). In 2020, matched non-US IMGs had similar board scores as matched US MD Senior applicants, but more abstracts/publications. Conclusion: The recruitment of IMGs into orthopaedic surgery residency remains limited and lower than other surgical specialties. IMGs have similar board scores and more abstracts/publications, thus representing a potential pipeline for workforce diversity. More research is needed to understand the special needs of IMGs in the orthopaedic surgery match.

All-soft tissue quadriceps tendon autograft and bone-patellar tendon-bone autograft demonstrate no significant ACL tunnel widening: An MRI comparison.

PURPOSE: This study sought to quantify the tunnel widening associated with quadriceps tendon (QT) autograft after anterior cruciate ligament reconstruction (ACLR) and compare it to bone-patellar tendon-bone (BTB) autografts. METHODS: A retrospective review of each ACLR performed at a single academic institution from 2011 to 2021 were reviewed. Subjects with repeat ipsilateral knee magnetic resonance imaging (MRI) studies performed after ACLR were included. Two reviewers independently measured the maximum diameter of the femoral and tibial tunnels 1 cm from the aperture. Tunnel widening was calculated as the difference between the initial drilled diameter and the measured diameters. RESULTS: Seventy-five patients (38 BTB and 37 QT autografts) were identified including 42 females and 33 males. With respect to graft type (QT vs. BTB), there was no statistically significant difference in median patient age (19.0 (16.0-31.5) years vs. 20.0 (16.8-30.0) years respectively; p = n.s.) or median time to MRI (12.0 [9.0-19.5] months vs. 13.0 [7.0-43.3] months respectively, p = n.s.). Mean tunnel diameter changes or widening was statistically significantly greater for QT autografts than BTB autografts at the tibial tunnel: (0.4 [±0.6] mm] vs. -0.4 [±1.1 mm; p < 0.001). Similarly, the mean tunnel diameter change was also significantly greater at the femoral tunnel for QT compared to BTB. (0.2 [±0.6] mm vs. -0.4 [±0.8] mm; p < 0.001) However, no patients with QT grafts demonstrated tibial or femoral tunnel diameters >12 mm. CONCLUSION: Although QT autografts had a statistically significant greater amount of tunnel widening compared to BTB autografts; the mean tibial and femoral net widening of 0.4 mm and 0.2 mm, respectively, does not meet previously reported clinically significant values. Thus, the tunnel widening presented in this study is unlikely to affect clinical outcomes and should not preclude the use of either graft. LEVEL OF EVIDENCE: Level III (Retrospective comparative study).

Distinct risk profiles for short-term surgical complications and venous thromboembolism exist among extensor mechanism repair procedures.

PURPOSE: Extensor mechanism injuries, which comprise patella fractures, patella tendon tears and quadriceps tendon tears, are severely debilitating injuries and a common cause of traumatic knee pathology that requires surgical intervention. Risk factors for short-term surgical complications and venous thromboembolism (VTE) in this population have not been well characterised. The aim of this study was to identify perioperative risk factors associated with these short-term complications. METHODS: The National Surgical Quality Improvement Program database was used to identify patients who underwent an isolated, primary extensor mechanism repair from 2015 to 2020. Patients were stratified by injury type. Demographic data were collected and compared. A multivariate logistic regression was used to control for demographic and comorbid factors while assessing risk factors for developing short-term complications. RESULTS: A total of 8355 patients were identified for inclusion in this study. Overall, 3% of patients sustained short-term surgical complications and 1% were diagnosed with VTE within 30 days of surgery. Patella fracture fixation had a nearly twofold higher risk for surgical complications compared to quadriceps tendon repair (p = 0.004). Patella tendon repair had a twofold higher risk for VTE (p = 0.045), specifically deep vein thrombosis (p = 0.020), compared to patella fracture fixation. Increasing age, smoking and American Society of Anesthesiologists Classifications 3 and 4 were also found to be risk factors for surgical complications (p = 0.012, p = 0.004, p = 0.011 and p = 0.032, respectively). CONCLUSION: This study used a nationally representative, widely validated, peer-reviewed database to provide valuable insights into risk factors for short-term postoperative complications associated with extensor mechanism repair procedures, revealing notable differences in risk profiles among distinct surgical procedures. The results of this study will inform surgeons and patients in enhancing risk assessment, guiding procedure-specific decision-making, optimising preoperative care, improving postoperative monitoring and contributing to future research of extensor mechanism injuries. LEVEL OF EVIDENCE: Level III.

Most Publications Regarding Platelet-Rich Plasma Use in the Knee Are From Asia, Investigate Injection for Osteoarthritis, and Show Outcome Improvement: A Scoping Review.

PURPOSE: To evaluate and synthesize the available literature related to platelet-rich plasma (PRP) treatment of knee pathologies and to provide recommendations to inform future research in the field. METHODS: PubMed, CINAHL, and Scopus databases were queried on October 6, 2023. All identified citations were collated and uploaded into Covidence for screening and data extraction. Studies were included if they were human studies published in English with adult cohorts that received PRP as a procedural injection or surgical augmentation for knee pathologies with patient-reported outcome measures (PROMs) and level of evidence Levels I-IV. RESULTS: Our search yielded 2,615 studies, of which 155 studies from 2006 to 2023 met the inclusion criteria. Median follow-up was 9 months (±11.2 months). Most studies (75.5%) characterized the leukocyte content of PRP, although most studies (86%) did not use a comprehensive classification scheme. In addition, most studies were from Asia (50%) and Europe (32%) and were from a single center (96%). In terms of treatment, 74% of studies examined PRP as a procedural injection, whereas 26% examined PRP as an augmentation. Most studies (68%) examined treatment of knee osteoarthritis. Many studies (83%) documented significant improvements in PROMs, including 93% of Level III/IV evidence studies and 72% of Level I/II evidence studies, although most studies (70%) failed to include minimal clinically important difference values. The visual analog scale was the most-used PROM (58% of studies), whereas the Short Form Health Survey 36-item was the least-used PROM (5% of studies). CONCLUSIONS: Most published investigations of knee PRP are performed in Asia, investigate procedural injection for osteoarthritis, and show significant outcome improvements. In addition, this review highlights the need for better classification of PRP formulations. LEVEL OF EVIDENCE: Level IV, scoping Review of level I-IV studies.

Long-term, high-resolution in vivo calcium imaging in pigeons.

In vivo 2-photon calcium imaging has led to fundamental advances in our understanding of sensory circuits in mammalian species. In contrast, few studies have exploited this methodology in birds, with investigators primarily relying on histological and electrophysiological techniques. Here, we report the development of in vivo 2-photon calcium imaging in awake pigeons. We show that the genetically encoded calcium indicator GCaMP6s, delivered by the adeno-associated virus rAAV2/7, allows high-quality, stable, and long-term imaging of neuronal populations at single-cell and single-dendrite resolution in the pigeon forebrain. We demonstrate the utility of our setup by investigating the processing of colors in the visual Wulst, the avian homolog of the visual cortex. We report that neurons in the Wulst are color selective and display diverse response profiles to light of different wavelengths. This technology provides a powerful tool to decipher the operating principles that underlie sensory encoding in birds.

Novel high throughput screen reports that benzo(a)pyrene overrides mouse trophoblast stem cell multipotency, inducing SAPK activity, HAND1 and differentiated trophoblast giant cells.

INTRODUCTION: Cultured mouse trophoblast stem cells (mTSC) maintain proliferation/normal stemness (NS) under FGF4, which when removed, causes normal differentiation (ND). Hypoxic, or hyperosmotic stress forces trophoblast giant cells (TGC) differentiate. Hypoxic, hyperosmotic, and genotoxic benzo(a)pyrene (BaP), which is found in tobacco smoke, force down-regulation of inhibitor of differentiation (Id)2, enabling TGC differentiation. Hypoxic and hyperosmotic stress induce TGC by SAPK-dependent HAND1 increase. Here we test whether BaP forces mTSC-to-TGC while inducing SAPK and HAND1. METHODS: Hand1 and SAPK activity were assayed by immunoblot, mTSC-to-TGC growth and differentiation were assayed at Tfinal after 72hr exposure of BaP, NS, ND, Retinoic acid (RA), or sorbitol. Nuclear-stained cells were micrographed automatically by a live imager, and assayed by ImageJ/FIJI, Biotek Gen 5, AIVIA proprietary artificial intelligence (AI) software or open source, CellPose artificial intelligence/AI software. RESULTS: BaP (0.05-1µM) activated SAPK and HAND1 without diminishing growth. TSC-to-TGC differentiation was assayed with increasingly accuracy for 2-4 N cycling nuclei and >4 N differentiating TGC nuclei, using ImageJ/FIJI, Gen 5, AIVIA, or CellPose AI software. The AIVIA and Cellpose AI software matches human accuracy. The lowest BaP effects on SAPK activation/HAND1 increase are >10-fold more sensitive than similar effects for mESC. RA induces 44-47% 1st lineage TGC differentiation, but the same RA dose induces only 1% 1st lineage mESC differentiation. DISCUSSION: First, these pilot data suggest that mTSC can be used in high throughput screens (HTS) to predict toxicant exposures that force TGC differentiation. Second, mTSC differentiated more cells than mESC for similar stress exposures, Third, open source AI can replace human micrograph quantitation and enable a miscarriage-predicting HTS.

Tape-Reinforced Graft Suturing and Retensioning of Adjustable-Loop Cortical Buttons Improve Quadriceps Tendon Autograft Biomechanics in Anterior Cruciate Ligament Reconstruction: A Cadaveric Study.

PURPOSE: To investigate the biomechanical effects of tape-reinforced graft suturing and graft retensioning for all-soft tissue quadriceps tendon (ASTQT) anterior cruciate ligament reconstruction (ACLR) in a full-construct human cadaveric model. METHODS: Harvested cadaveric ASTQT grafts were assigned to either (1) double-suspensory adjustable-loop cortical button device (ALD) fixation in which both graft ends were fixed with a suspensory fixation device with (n = 5) or without (n = 5) tape-reinforced suturing or (2) single-suspensory distal tendon fixation in which only the patellar end was fixed with an ALD (n = 5) or fixed-loop cortical button device (FLD) (n = 5). All specimens were prepared using a No. 2 whipstitch technique, and tape-reinforced specimens had an integrated braided tape implant. Graft preparation time was recorded for double-suspensory constructs. Samples were tested on an electromechanical testing machine using a previously published protocol simulating rehabilitative kinematics and loading. RESULTS: Tape-reinforced graft suturing resulted in greater graft load retention after cycling (11.9% difference, P = .021), less total elongation (mean [95% confidence interval (CI)], 5.57 mm [3.50-7.65 mm] vs 32.14 mm [25.38-38.90 mm]; P < .001), greater ultimate failure stiffness (mean [95% CI], 171.9 N/mm [158.8-185.0 N/mm] vs 119.4 N/mm [108.7-130.0 N/mm]; P < .001), and less graft preparation time (36.4% difference, P < .001) when compared with unreinforced specimens. Retensioned ALD constructs had less cyclic elongation compared with FLD constructs (mean total elongation [95% CI], 7.04 mm [5.47-8.61 mm] vs 12.96 mm [8.67-17.26 mm]; P = .004). CONCLUSIONS: Tape-reinforced graft suturing improves time-zero ASTQT ACLR construct biomechanics in a cadaveric model with 83% less total elongation, 44% greater stiffness, and reduced preparation time compared with a whipstitched graft without tape reinforcement. ALD fixation improves construct mechanics when compared with FLD fixation as evidenced by 46% less total elongation. CLINICAL RELEVANCE: Tape-reinforced implants and graft retensioning using ALDs improve time-zero ACLR graft construct biomechanics in a time-zero biomechanical model. Clinical studies will be necessary to determine whether these implants improve clinical outcomes including knee laxity and the incidence of graft rupture.

Quadriceps tendon autograft has similar clinical outcomes when compared to hamstring tendon and bone-patellar tendon-bone autografts for revision ACL reconstruction: a systematic review and meta-analysis.

PURPOSE: Research regarding revision anterior cruciate ligament reconstruction (RACLR) with quadriceps tendon (QT) autografts is lacking. The purpose of this study was to perform a systematic review and meta-analysis of RACLR with QT and compare its patient outcomes to RACLR with hamstring tendon (HT) and bone-patellar tendon-bone (BTB) autografts. METHODS: Adhering to PRISMA guidelines, a search for studies using QT in RACLR was performed within PubMed, Scopus, and CINAHL from database date of inception through December 26, 2022. Primary outcomes sought included: failure rate, Lysholm scores, International Knee Documentation Committee (IKDC) scores, IKDC grades, arthrometric knee side-to-side differences (STSD), pivot shift grade, donor site morbidity, return to sport, visual analog scale (VAS) pain scores. RESULTS: Nine studies were included consisting of 606 RACLR: 349 QT, 169 HT, and 88 BTB. Overall failure rates were 7.6% QT, 13.3% HT, and 8.7% BTB. Mean weighted Lysholm scores were 85.8 ± 3.8 QT, 82.5 ± 3.8 HT and 86.6 ± 4.5 BTB. IKDC average scores were 82.3 ± 1.6 QT, 80.1 ± 1.7 HT, and 81.7 ± 5.5BTB. Combined rates of IKDC A/B grades were 88.4% and 80.0% for QT and HT, respectively. VAS average scores were 0.9 ± 1.1 QT, 1.4 ± 0.2 HT, and 0.7 ± 0.8 for BTB. Side-to-side difference was reported for QT and HT with average values of 1.7 ± 0.6 mm and 2.1 ± 0.5 mm, respectively. Grade 0 or 1 pivot shifts were reported in 96.2% of QT patients and 91.3% of HT. Donor site morbidity, only reported for QT and HT, was 14.6 ± 9.7% and 23.6 ± 14.1%, respectively. QT resulted in a mean Tegner score of 5.9 ± 1.5 versus HT 5.7 ± 1.5. Rate of return to pivoting sports was 38.0% QT, 48.6% HT, and 76.9% BTB. Across all outcomes, there was no significant difference when comparing QT to HT, QT to BTB, and QT compared to HT and BTB combined. CONCLUSIONS: RACLR with QT yields satisfactory patient reported outcomes, satisfactory improvement in knee laxity, expected return to sport rates, and has an overall 7.6% failure rate. Outcomes are comparative to those of HT and BTB making it an acceptable graft choice for RACLR. Surgeons should consider using QT autograft for RACLR, especially when other autografts are unavailable. LEVEL OF EVIDENCE: IV.

Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in PIK3CA- and HRAS-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity.

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility. SIGNIFICANCE: The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease. See related commentary by Lee et al., p. 3162.

All-Inside Anterior Cruciate Ligament Reconstruction.

Anterior cruciate ligament (ACL) reconstruction is one of the most commonly performed knee operations. An "all-inside" technique creates bone sockets for ACL graft passage, as opposed to more traditional full bone tunnels, and typically incorporates suspensory fixation instead of screw fixation to secure the graft. This technique may be indicated for any ACL reconstruction surgery, where adequate bone stock exists to drill sockets and to use cortical fixation. The technique may be used with all soft tissue, as well as bone plug ACL grafts and autograft hamstring or quadriceps tendon; most allograft tendon options may be performed with an all-inside technique. Advantages include anatomic tunnel/socket placement, decreased postoperative pain and swelling, minimal hardware, appropriate graft tensioning and retensioning, and circumferential graft to bone healing. Tips for successful all-inside surgery include matching graft diameter to socket diameter, drilling appropriate length sockets based on individual graft length, so as not to "bottom out" the graft and confirming cortical button fixation intraoperatively. Potential complications include graft-socket mismatch, full-tunnel reaming, and loss of cortical fixation. Multiple studies have shown the all-inside technique to have similar or superior biomechanical properties and clinical outcomes compared to the more traditional full-tunnel ACL reconstruction techniques.

Infigratinib in Patients with Recurrent Gliomas and FGFR Alterations: A Multicenter Phase II Study.

PURPOSE: FGFR genomic alterations (amplification, mutations, and/or fusions) occur in ∼8% of gliomas, particularly FGFR1 and FGFR3. We conducted a multicenter open-label, single-arm, phase II study of a selective FGFR1-3 inhibitor, infigratinib (BGJ398), in patients with FGFR-altered recurrent gliomas. PATIENTS AND METHODS: Adults with recurrent/progressive gliomas harboring FGFR alterations received oral infigratinib 125 mg on days 1 to 21 of 28-day cycles. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by Response Assessment in Neuro-Oncology criteria. Comprehensive genomic profiling was performed on available pretreatment archival tissue to explore additional molecular correlations with efficacy. RESULTS: Among 26 patients, the 6-month PFS rate was 16.0% [95% confidence interval (CI), 5.0-32.5], median PFS was 1.7 months (95% CI, 1.1-2.8), and objective response rate was 3.8%. However, 4 patients had durable disease control lasting longer than 1 year. Among these, 3 had tumors harboring activating point mutations at analogous positions of FGFR1 (K656E; n = 2) or FGFR3 (K650E; n = 1) in pretreatment tissue; an FGFR3-TACC3 fusion was detected in the other. Hyperphosphatemia was the most frequently reported treatment-related adverse event (all-grade, 76.9%; grade 3, 3.8%) and is a known on-target toxicity of FGFR inhibitors. CONCLUSIONS: FGFR inhibitor monotherapy with infigratinib had limited efficacy in a population of patients with recurrent gliomas and different FGFR genetic alterations, but durable disease control lasting more than 1 year was observed in patients with tumors harboring FGFR1 or FGFR3 point mutations or FGFR3-TACC3 fusions. A follow-up study with refined biomarker inclusion criteria and centralized FGFR testing is warranted.

Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Treatment options are sparse for patients with advanced cholangiocarcinoma after progression on first-line gemcitabine-based therapy. FGFR2 fusions or rearrangements occur in 10-16% of patients with intrahepatic cholangiocarcinoma. Infigratinib is a selective, ATP-competitive inhibitor of fibroblast growth factor receptors. We aimed to evaluate the antitumour activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, FGFR2 alterations, and previous gemcitabine-based treatment. METHODS: This multicentre, open-label, single-arm, phase 2 study recruited patients from 18 academic centres and hospitals in the USA, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. Eligible participants were aged 18 years or older, had histologically or cytologically confirmed, locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements, and were previously treated with at least one gemcitabine-containing regimen. Patients received 125 mg of oral infigratinib once daily for 21 days of 28-day cycles until disease progression, intolerance, withdrawal of consent, or death. Radiological tumour evaluation was done at baseline and every 8 weeks until disease progression via CT or MRI of the chest, abdomen, and pelvis. The primary endpoint was objective response rate, defined as the proportion of patients with a best overall response of a confirmed complete or partial response, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors, version 1.1. The primary outcome and safety were analysed in the full analysis set, which comprised all patients who received at least one dose of infigratinib. This trial is registered with ClinicalTrials.gov, NCT02150967, and is ongoing. FINDINGS: Between June 23, 2014, and March 31, 2020, 122 patients were enrolled into our study, of whom 108 with FGFR2 fusions or rearrangements received at least one dose of infigratinib and comprised the full analysis set. After a median follow-up of 10·6 months (IQR 6·2-15·6), the BICR-assessed objective response rate was 23·1% (95% CI 15·6-32·2; 25 of 108 patients), with one confirmed complete response in a patient who only had non-target lesions identified at baseline and 24 partial responses. The most common treatment-emergent adverse events of any grade were hyperphosphataemia (n=83), stomatitis (n=59), fatigue (n=43), and alopecia (n=41). The most common ocular toxicity was dry eyes (n=37). Central serous retinopathy-like and retinal pigment epithelial detachment-like events occurred in 18 (17%) patients, of which ten (9%) were grade 1, seven (6%) were grade 2, and one (1%) was grade 3. There were no treatment-related deaths. INTERPRETATION: Infigratinib has promising clinical activity and a manageable adverse event profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 gene fusions or rearrangements, and so represents a potential new therapeutic option in this setting. FUNDING: QED Therapeutics and Novartis.

Resident Level Involvement Affects Operative Time and Surgical Complications in Lower Extremity Fracture Care.

OBJECTIVE: The purpose of this study is to evaluate the effect of resident participation on operative time and surgical complications in isolated lower extremity fracture care. SETTING: Patients who were treated at teaching hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program database. PARTICIPANTS: A total of 2,488 patients who underwent surgical fixation of isolated hip fractures, femoral or tibial shaft fractures, and ankle fractures. DESIGN: Patients were stratified by surgical procedure and post-graduate year (PGY) of the resident involved. Total operative time and surgical complications were analyzed with respect to resident participation and seniority. Multivariable logistic regression analyses were used to adjust for potential confounders including case complexity, wound class, and patient comorbidity burden. RESULTS: As PGY level increased, operative time increased for each procedure. The odds for a deep surgical site infection decreased as resident seniority increased, but the odds for wound dehiscence increased as resident seniority increased. We found no difference in the incidences of superficial infections or return to the OR with respect to PGY level. Academic quarter within the academic year did not correlate with any of the surgical complications. Furthermore, when cases performed with residents were compared to those performed without residents, there was no increased risk of superficial infections, deep infections, or return to the OR. CONCLUSIONS: This nationally representative dataset demonstrates that operative times for lower extremity orthopedic trauma increased as resident seniority increased. Additionally, senior resident participation was associated with increased wound dehiscence, whereas junior resident participation was associated with an increased risk of deep surgical site infections. However, there was no associated "July effect" for residents at any level of training and there was no increased risk for surgical site infections or return to the OR in cases involving resident participation.

Revision Anterior Cruciate Ligament Reconstruction with the All-Soft Tissue Quadriceps Tendon Autograft Has Acceptable Early and Intermediate-Term Outcomes.

PURPOSE: The purposes were to (1) examine early to intermediate-term clinical outcomes and complications of revision anterior cruciate ligament reconstruction (ACLR) using all-soft tissue quadriceps tendon (QT) autografts, and (2) compare quadriceps strength between patients who had hamstring versus patella tendon autografts in their previous reconstruction. METHODS: One hundred patients (52 males/48 females; 22.6 ± 8.0 years) undergoing revision ACLR with all-soft tissue QT autografts were prospectively followed. All revision procedures were performed by a single surgeon, using a minimally invasive graft harvest technique and suspensory fixation. Subjective assessment of knee function was obtained before and after surgery with the International Knee Documentation Committee (IKDC) survey. Postoperative knee laxity and isokinetic quadriceps strength were collected at regular intervals. Strength was reported as limb symmetry index (LSI; surgical side divided by nonsurgical side). Complications including hematomas, postoperative loss of knee extension, and graft failures were recorded. To determine clinical significance (P ≤ .05), outcomes were compared using analysis of variance or paired samples t-tests. RESULTS: The mean IKDC scores significantly improved (54.3 ± 13.0 vs 82.8 ± 13.8), with an average follow-up of 42.2 ± 21.2 months. There were no significant changes in knee laxity side-to-side differences: 6 weeks (1.2 ± 1.5 mm), 3 months (1.2 ± 1.8 mm), 6 months (1.4 ± 1.6 mm). Quadriceps LSIs significantly improved from 71.6% ± 19.3% at 6 months to 81.5% ± 19.3% at 12 months for 60°/s isokinetic testing and 76.6% ± 16.4% at 6 months to 83.9% ± 16.9% at 12 months for 180°/s testing. Graft harvest site hematomas developed in 2 patients, postoperative loss of knee extension in 4 patients, and graft failure in 11 patients. No significant differences in quadriceps or hamstrings LSIs were noted between patients with previous hamstring versus patella tendon autografts (P > .050). CONCLUSION: Revision ACLR with all-soft tissue QT autografts has acceptable early and intermediate-term outcomes with reasonable complication rates (11/80 patients with follow-up). Secondary insult to the extensor mechanism via QT autograft harvest does not adversely affect strength after prior patellar tendon versus hamstring autograft. LEVEL OF EVIDENCE: Level IV, cases series subgroup analysis.

Elevated BMI increases concurrent pathology and operative time in adolescent ACL reconstruction.

PURPOSE: The purpose of this study was to (1) report on the incidence of concurrent surgical pathology at the time of adolescent ACL reconstruction, (2) evaluate patient risk factors for concurrent pathology, and (3) measure the effect of BMI on operating room (OR) time. METHODS: A retrospective analysis of the NSQIP database for the years 2005-2017 was conducted. Nine-hundred and seventeen patients 18 years of age and younger who underwent ACL reconstruction (ACLR) were identified using CPT code 29888 and patients undergoing surgery for multi-ligamentous knee injuries were excluded. The mean patient age was 17.6 years (range 14-18, standard deviation 0.52) and consisted of 546 males (59.5%) and 371 females (40.5%). Logistic regression was used to assess the relationship between BMI and additional CPT codes for internal derangement at the time of surgery. Internal derangement was defined as any procedure for the treatment of a meniscal tear, chondral lesion, or loose body removal. Linear regression analysis was then performed to evaluate the effect of BMI on operative time. RESULTS: 43.7% of patients undergoing ACLR required an associated procedure for internal derangement. Additionally, the risk of requiring additional procedures for internal derangement increased by 3.1% per BMI point. BMI was also predictive of operative time, independent of the number of additional procedures. Specifically, the operative time increased by nearly one minute for every point increase in BMI (58.0 s). CONCLUSIONS: Adolescent patients with an elevated BMI were much more likely to require additional surgical procedures for internal derangement at the time of ACL reconstruction. Additionally, BMI was a significant predictor for longer operative times. LEVEL OF EVIDENCE: Level III.

Combined Oral Contraceptive Use Increases the Risk of Venous Thromboembolism After Knee Arthroscopy and Anterior Cruciate Ligament Reconstruction: An Analysis of 64,165 Patients in the Truven Database.

PURPOSE: To use the Truven MarketScan database to (1) report the incidence of venous thromboembolism (VTE), including deep vein thromboses (DVTs) and pulmonary embolism (PE), in patients undergoing simple knee arthroscopy and anterior cruciate ligament (ACL) reconstruction, and (2) evaluate combined oral contraceptive (COCP) use as a potential risk factor for VTE in patients undergoing knee arthroscopy. METHODS: All female patients between the ages of 16 and 40 years undergoing knee arthroscopy and ACL reconstruction between 2010 and 2015 were identified in the MarketScan database. Patients were stratified by whether they had a documented pharmaceutical claim for COCP therapy, and the primary outcome was the risk of DVT and or PE within 90 postoperative days. RESULTS: In total, 64,165 patients were identified for inclusion. While the overall incidence of VTE was low, patients taking COCPs had an increased risk of a DVT or PE compared with those not on COCPs (odds ratio [OR] 2.1, P < .001). When patients were analyzed by procedural subgroup (ACL reconstruction and simple knee arthroscopy), similar results held true. Furthermore, smoking and obesity had a synergistic effect when combined with COCPs use on the risk of VTE. Specifically, 3.1% of patients with obesity on COCPs (OR 3.1, P < .001) and 4.0% of smokers on COCPs (OR 4.3, P < .001) developed a postoperative VTE. CONCLUSIONS: This study demonstrates that COCP use is associated with an increased risk for a symptomatic DVT or PE (1.70% and 0.27%, respectively) after knee arthroscopy and an increased risk for DVT, but not PE (1.80% and 0.23%, respectively), after ACL reconstruction. In addition, patients with multiple risk factors present such as tobacco use, obesity, and COCP use had odds ratios greater than the sum of the individual risk factors alone. LEVEL OF EVIDENCE: level III prognostic cohort study.

Shoulder Position During Magnetic Resonance Arthrogram Significantly Affects Capsular Measurements.

PURPOSE: To determine whether change in shoulder position between internal rotation (IR) and external rotation (ER) during magnetic resonance arthrography (MRA) affects previously defined capsular measurements and to determine the utility of rotation in the diagnosis of instability. METHODS: A retrospective study was conducted of patients who received a shoulder MRA with humeral IR and ER views. Patients with an arthroscopically confirmed diagnosis of instability and those with clinically stable shoulders, no history of instability, and no MRA findings of instability were identified and compared. Humeral rotation, glenoid retroversion, humeral head subluxation, capsular length, and capsular area using axial sequences of IR and ER views were recorded. Analysis compared IR, ER, and Δ capsular measurements between groups using independent t tests and univariate and multivariate regression. RESULTS: Thirty-one subjects who were diagnosed with instability were included, along with 28 control subjects. Capsular length, capsular area, and humeral subluxations were significantly greater with ER compared with IR views (P < .001, P < .001, P < .001). Patients with instability displayed greater ER capsular length (P = .0006) and ER capsular area (P = .005) relative to controls. Multivariate logistic regression identified age, weight, sex, ER capsular length, and retroversion to be significant predictors of instability. ER capsular length independently predicts instability with 86% sensitivity and 84% specificity. Interobserver reliability using the intraclass correlation coefficient was rated good or excellent on all measurements. CONCLUSION: Variance in humeral rotation during shoulder MRA significantly affects capsular measurements. Rotational views increase the utility of capsular measurements when assessing for instability, particularly capsular length and capsular area. The implementation of ER positioning enhances the ability to examine capsular changes of the shoulder joint and can assist in the diagnosis of instability. LEVEL OF EVIDENCE: III, retrospective comparative study.

Risk Factors for Infection Following Total Wrist Arthroplasty and Arthrodesis: An Analysis of 6641 Patients.

Background: Infection following wrist arthroplasty (WA) or wrist fusion (WF) is an uncommon but difficult complication often resulting in explantation and prolonged courses of antibiotics. The purposes of this study are to: (1) characterize the demographic trends of individuals undergoing WA and WF; (2) determine the incidence of postoperative infection; and (3) identify risk factors for postoperative infection. Methods: The PearlDiver database was used to query 100% Medicare Standard Analytic files from 2005 to 2014. Patients undergoing WA or radiocarpal WF were identified using Current Procedural Terminology (CPT) codes. Diagnosis for infection within 1 year of operative intervention was assessed by International Classification of Diseases, Ninth Revision codes or CPT codes related to infection. Multivariable logistic regression analyses were performed to evaluate the risk factors for postoperative infection. Results: Of the 6641 patients included, 1137 (17.1%) underwent arthroplasty and 5504 (82.9%) underwent arthrodesis. Within 1 year of the index procedure, 3.5% had a diagnosis of, or procedure for, postoperative infection (WA: n = 40 of 1137; WF: n = 192 of 5504). Risk factors for infection following WA include age >85, tobacco use, depression, diabetes mellitus, and chronic kidney disease. Risk factors following radiocarpal WF include male sex, age >85, body mass index <19 kg/m2, depression, diabetes mellitus, and chronic kidney disease. Posttraumatic origin of wrist arthritis was a risk factor for infection following both WA and WF. Conclusions: Infection following WA and WF is relatively uncommon in a nationally representative Medicare database cohort. Risk factors common to both WA and WF include age >85, depression, diabetes mellitus, chronic kidney disease, and posttraumatic arthritis.