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Importance Tumor-infiltrating lymphocytes (TILs) are a provocative biomarker in melanoma, influencing diagnosis, prognosis, and immunotherapy outcomes; however, traditional pathologist-read TIL assessment on hematoxylin and eosin–stained slides is prone to interobserver variability, leading to inconsistent clinical decisions. Therefore, development of newer TIL scoring approaches that produce more reliable and consistent readouts is important. Objective To evaluate the analytical and clinical validity of a machine learning algorithm for TIL quantification in melanoma compared with traditional pathologist-read methods. Design, Setting, and Participants This multioperator, global, multi-institutional prognostic study compared TIL scoring reproducibility between traditional pathologist-read methods and an artificial intelligence (AI)-driven approach. The study was conducted using retrospective cohorts of patients with melanoma between January 2022 and June 2023 across 45 institutions, with tissue evaluated by participants from academic, clinical, and research institutions. Participants were selected to ensure diverse expertise and professional backgrounds. Main Outcomes and Measures Intraclass correlation coefficient (ICC) values were calculated for the manual and AI-assisted arms using log-transformed data. Kendall W values were calculated for Clark scores (brisk = 3, nonbrisk = 2, and sparse = 1). Reliabilities of ICC and W values were classified as moderate (0.40-0.60), good (0.61-0.80), or excellent (>0.80). AI TIL measurements were dichotomized using the 16.6 and median cutoffs. Univariable and multivariable Cox regression analyses assessed the prognostic value of TIL scores adjusted for clinicopathologic variables. Results There were 111 patients with melanoma in the independent testing cohort (median [range] age at diagnosis, 61.0 [25.0-87.0] years; 56 [50.5%] male) who contributed melanoma whole tissue sections. A total of 98 participants evaluated TILs on 60 hematoxylin and eosin–stained melanoma tissue sections. All 40 participants in the manual arm were pathologists, while the AI-assisted arm included 11 pathologists and 47 nonpathologists (scientists). The AI algorithm demonstrated superior reproducibility, with ICCs higher than 0.90 for all machine learning TIL variables, significantly outperforming manual assessments (ICC, 0.61 for AI-derived stromal TILs vs Kendall W , 0.44 for manual Clark TIL scoring). AI-based TIL scores showed prognostic associations with patient outcomes (n = 111) using the median cutoff approach with a hazard ratio (HR) of 0.45 (95% CI, 0.26-0.80; P = .005), and using the cutoff of 16.6, with an HR of 0.56 (95% CI, 0.32-0.98; P = .04). Conclusions and Relevance In this prognostic study of TIL quantification in melanoma, the AI algorithm demonstrated superior reproducibility and prognostic associations compared with traditional methods. Although the retrospective nature of the cohorts limits demonstration of clinical utility, the publicly available dataset and open-source AI tool offer a foundation for future validation and integration into melanoma management.

Purpose To establish international expert consensus on surgical techniques, complications, and rehabilitation protocols for lateral extra‐articular procedures (LEAPs) performed adjunctively with anterior cruciate ligament reconstruction. Methods Fifty‐five knee surgeons from 17 countries on 5 continents completed a 3‐round modified Delphi process. In the final round, 16 statements on LEAP techniques and complications were scored on a 5‐point Likert scale; ≥75% “agree/strongly agree” constituted consensus. When appropriate, strength of recommendation was graded. Statements lacking support were revised until consensus or abandonment. Results Six statements achieved unanimous consensus (100%), 2 had strong consensus (90%‐99.9%), and 3 reached consensus (75%‐89.9%); 4 were removed. Key technical recommendations were as follows: (1) in iliotibial band procedures, the graft strip should pass beneath the lateral collateral ligament; (2) an anatomic technique is mandatory for anterolateral ligament reconstruction; and (3) no single LEAP is clinically superior to another. Unanimous agreement indicated that modern LEAPs do not increase lateral compartment osteoarthritis risk, carry a low complication rate, and do not necessitate changes to rehabilitation or return‐to‐play timelines. Conclusions Consensus defined core surgical principles and confirmed the safety of adding LEAPs to anterior cruciate ligament reconstruction. When an iliotibial band graft is used, it should be routed deep to the lateral collateral ligament and fixed between 0° and 60° of knee flexion under low tension. For anterolateral ligament reconstruction, femoral fixation should be in full extension at a posterior‐proximal point relative to the lateral epicondyle. Although no single LEAP proved superiority, adherence to these principles permits safe, effective surgery without altering standard rehabilitation or return‐to‐sport protocols and without increasing osteoarthritis risk. Level of Evidence Level V, expert opinion.

Purpose To define expert consensus on whether and how lateral extra‐articular procedures (LEAPs) should accompany anterior cruciate ligament (ACL) reconstruction to optimize outcomes in ACL‐deficient knees. Methods Fifty‐five knee surgeons from 17 countries on 5 continents completed a 3‐round modified Delphi process. Twenty‐one statements on patient selection for combined ACL reconstruction (ACLR) + LEAPs were graded on 5‐point Likert scales; ≥75% “agree/strongly agree” signified consensus. Strength of recommendation was ranked, and statements failing the threshold were revised or discarded after discussion. Results One statement achieved unanimous agreement (100%): it is strongly recommended to add a LEAP for active patients ≤25 years receiving hamstring‐autograft ACLR to reduce graft failure. Strong consensus (≥90%) supported LEAPs in primary ACLR when grade 3 pivot shift (97.9%), knee hyperextension (97.9%), skeletally immature status (79.5%), revision ACLR (91.5%), return to pivoting sports (93.2%), active patients ≤25 years using nonhamstring grafts (90.7%), grade 3 Lachman test (90%), and when multiple relative risk factors coexist (statement 36, 97.1%). Consensus (75%‐89.9%) favored LEAPs for chronic symptomatic ACL deficiency (86.1%), posterior tibial slope >12° (85.7%), and a history of contralateral ACL injury (88.9%). Eight statements did not reach consensus regarding small‐diameter autografts, female athletes, imaging signs of anterolateral injury (e.g., Segond fracture, lateral femoral‐notch sign), and concomitant meniscal procedures. One statement on LEAPs with primary ACL repair was withdrawn because the project focused on reconstruction. Conclusions International experts strongly recommend adding a LEAP in young active patients undergoing hamstring‐autograft ACLR and in cases of high‐grade rotational or anterior laxity, knee hyperextension, revision surgery, or returning to pivoting sports. Unresolved issues include small graft size, female athletes, imaging findings of rotational instability, and concurrent meniscal procedures, highlighting priorities for future research. Level of Evidence Level V, expert opinion.

Abstract Objective This study was undertaken to evaluate the response to second treatments for infantile epileptic spasms syndrome (IESS). Methods Infants aged 2–24 months with IESS were prospectively enrolled in the National Infantile Spasms Cohort study at 21 pediatric epilepsy centers in the United States from 2012 to 2018. We analyzed data from infants who initially received standard treatment (hormonal therapy [adrenocorticotropic hormone, high‐dose prednisolone] or vigabatrin), had continued or recurring epileptic spasms, and received a second treatment. We excluded those with tuberous sclerosis. Treatment groups included hormonal therapy followed by vigabatrin (reference), hormonal‐to‐hormonal, hormonal‐to‐nonstandard, vigabatrin‐to‐hormonal, and vigabatrin‐to‐nonstandard. Nonstandard treatments included other antiseizure medications and dietary therapy. Treatment groups were tested for differences in 3‐month clinical remission using a binary logistic regression to estimate odds ratios (ORs). Results There were 153 infants with IESS who received second treatments. The highest rates of 3‐month remission were among infants in the hormonal‐to‐vigabatrin (22/65, 34%) and vigabatrin‐to‐hormonal (9/26, 35%) groups, followed by vigabatrin‐to‐nonstandard (3/10, 30%), hormonal‐to‐hormonal (4/22, 18%), and hormonal‐to‐nonstandard (1/30, 3.3%). Compared to the hormonal‐to‐vigabatrin group (reference), fewer infants had remission in the hormonal‐to‐nonstandard group (OR = .07, 95% confidence interval [CI] = .01–.53), and there was a trend toward fewer infants in the hormonal‐to‐hormonal group (OR = .43, 95% CI = .13–1.4, p = .17). Following initial hormonal treatment, the number needed to treat was three infants for one additional infant to have remission when treated with vigabatrin compared to nonstandard therapy as the second treatment. Significance This updated analysis with an expanded sample size provided power for additional subgroup analysis. Overall response rates were low, and at best only one third had remission after second treatment. Results support a clinical strategy of switching mechanism of action when selecting a second medication for epileptic spasms (i.e., use vigabatrin after hormonal therapy, or hormonal therapy after vigabatrin). Our findings also support the use of standard over nonstandard therapies.

Background: Periarticular local infiltration analgesia has become an important mainstay of multimodal analgesia after elective total hip arthroplasty (THA). However, the role of novel motor-sparing fascial plane blocks—with or without periarticular local infiltration analgesia—has not been fully elucidated for patients undergoing THA. The authors conducted a network meta-analysis evaluating the relative analgesic effectiveness of motor-sparing fascial plane blocks (quadratus lumborum, erector spinae, and pericapsular nerve group blocks) and periarticular local infiltration analgesia for adult patients undergoing THA. Methods: Randomized trials examining single-injection quadratus lumborum, erector spinae, or pericapsular nerve group blocks, or periarticular local infiltration analgesia, for THA were sought. The primary outcome was area under the curve (AUC) rest pain scores during the period from 0 to 24 h. Secondary outcomes included rest pain scores at 0, 6, 12, and 24 h; postoperative function at 6, 12, and 24 h; analgesic consumption at 0 to 24 h; incidence of opioid-related side effects; and incidence of block-related complications. Network meta-analysis was performed using a frequentist approach. Results: A total of 44 trials (3,579 patients) evaluating the quadratus lumborum block, erector spinae block, pericapsular nerve group block, or periarticular local infiltration analgesia for THA were considered. Network meta-analysis was used to derive the probability of each intervention being the most effective as compared to the others (P score). For AUC 0 to 24 h rest pain, periarticular local infiltration analgesia was the most effective intervention, as demonstrated by a P score of 89%. For postoperative analgesic consumption, the quadratus lumborum block was the most effective intervention, with a P score of 88%. This was followed by the pericapsular nerve group block (74%), the erector spinae block (38%), and periarticular local infiltration analgesia (42%). Conclusions: Periarticular local infiltration analgesia alone provides the most consistent improvements in postoperative rest pain, analgesic consumption, and functional recovery after THA. The addition of a quadratus lumborum block or pericapsular nerve group block to periarticular local infiltration may further improve analgesic outcomes.

LBA1 Background: Standard adjuvant chemotherapy of stage III colon cancer consists of a fluoropyrimidine plus oxaliplatin. In patients (pts) with stage III colon cancer and deficient mismatch repair (dMMR), the benefit of an immune checkpoint inhibitor combined with adjuvant chemotherapy is unknown. The phase III ATOMIC trial (NCT02912559) was conducted to determine whether atezolizumab (atezo), an anti-PD-L1 antibody, can improve pt outcomes when added to adjuvant 5-fluorouracil, leucovorin plus oxaliplatin (mFOLFOX6) in pts with stage III dMMR tumors. Methods: We conducted an NCI-sponsored, multicenter and randomized phase III trial in pts with surgically resected stage III dMMR colon adenocarcinoma (any T, N 1,2 M 0 ). Pts, age > 12 years (yr), were accrued at NCTN sites and the German AIO. Tumor dMMR was determined by local immunohistochemistry and centrally verified. Pts were randomized 1:1 to mFOLFOX6 plus atezo (840 mg IV q2 weeks) for 12 cycles (6 months)[mo] followed by atezo monotherapy for 13 cycles (12 mo total) versus mFOLFOX6 alone for 12 cycles. Randomization stratification factors were N-stage (N 1 /N 1c vs N 2 ), T-stage (T 1 -T 3 vs T 4 ) and site (proximal vs distal). The primary endpoint was disease-free survival (DFS); secondary endpoints were overall survival and adverse event (AE) profile (CTCAE, PRO-CTCAE). Primary efficacy analysis was done in the intent-to-treat population; DFS was compared by arm (stratified log-rank test). Hazard ratio (HR) and 95% confidence interval (CI) were calculated using a stratified Cox model; 3-yr DFS was determined by Kaplan-Meier method. Among 700 pts., 165 DFS events with two interim analyses (50% , 75% of events) yielded 90% power to detect HR 0.6 (3-yr DFS 75% vs. 84.2%) assuming exponential survival and 1-sided alpha (0.025). Results: From 9/2017 to 1/2023, 712 pts were randomized (1 pediatric) to either atezo plus mFOLFOX6 (n= 355; atezo arm) or mFOLFOX6 (n= 357). Median pt age was 64 yr. 55.1% were female. Among tumors, 83.8% were proximal, 46.1% were clinical low risk (T 1-3 N 1 ) and 53.9% high risk (T 4 and/or N 2 ). At the second interim analysis, median pt follow-up was 37.2 mo (interquartile range, 24.2 to 55.5) and 124 DFS events were observed. Three-year DFS was 86.4 % (95% CI, 81.8 to 89.9) in the atezo arm and 76.6 % (95% CI, 71.3 to 81.0) in the mFOLFOX6 arm (HR, 0.50; 95% CI, 0.35 to 0.72). Stratified log-rank p-value was <0.0001, crossing the pre-specified efficacy boundary of 0.009. Efficacy for the atezo arm was consistent across subgroups, including pts >70 yr and low- and high-risk groups. Treatment-related > grade 3 AEs occurred in 71.7 % of pts in the atezo arm vs 62.1 % in the mFOLFOX6 arm. Conclusion: The addition of atezolizumab to mFOLFOX6 significantly improved DFS and should be considered the new adjuvant standard of care for patients with dMMR stage III colon cancer. Support: U10CA180821, U10CA180882, U24CA196171; Genentech, a member of the Roche group; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02912559 .

Crohn's disease (CD) is an idiopathic inflammatory disorder of unknown etiology with genetic, immunologic, and environmental influences. The incidence of CD has steadily increased over the past several decades. The diagnosis and treatment of patients with CD has evolved since the last practice guideline was published. These guidelines represent the official practice recommendations of the American College of Gastroenterology and were developed under the auspices of the Practice Parameters Committee for the management of adult patients with CD. These guidelines are established for clinical practice with the intent of suggesting preferable approaches to medical problems as established by interpretation and collation of scientifically valid research, derived from extensive review of published literature. When exercising clinical judgment, health care providers should incorporate this guideline along with patient's needs, desires, and their values to care for patients fully and appropriately with CD. Shared decision-making with the patient is advocated. This guideline is intended to be flexible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are inflexible and rarely violated. To evaluate the level of evidence and strength of recommendations, we used the Grading of Recommendations Assessment, Development, and Evaluation system. The Committee reviews guidelines in depth, with participation from experienced clinicians and others in related fields. The final recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientific developments later.