Citations

Abstract Background Cyclin D has been shown to play an essential role in acute lymphoblastic leukemia (ALL) initiation and progression, providing rationale for targeting the CDK4/6‐cyclin D complex that regulates cell cycle progression. Procedure The Children's Oncology Group AINV18P1 phase 1 trial evaluated the CDK4/6 inhibitor, palbociclib, in combination with standard four‐drug re‐induction chemotherapy in children and young adults with relapsed/refractory B‐ and T‐cell lymphoblastic leukemia (ALL) and lymphoma. Palbociclib (50 mg/m 2 /dose) was administered orally once daily for 21 consecutive days, first as a single agent (Days 1–3) and subsequently combined with re‐induction chemotherapy. This two‐part study was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D), followed by an expansion pharmacokinetic cohort. Results Twelve heavily pretreated patients enrolled, all of whom were evaluable for toxicity. One dose‐limiting hematologic toxicity (DLT) occurred at the starting dose of 50 mg/m 2 /dose orally for 21 days. No additional DLTs were observed in the dose determination or pharmacokinetic expansion cohorts, and overall rates of grade 3/4 nonhematologic toxicities were comparable to those observed with the chemotherapy platform alone. Five complete responses were observed, two among four patients with T‐ALL and three among seven patients with B‐ALL. Pharmacokinetic studies showed similar profiles with both liquid and capsule formulations of palbociclib. Conclusions Palbociclib in combination with re‐induction chemotherapy was well tolerated with a RP2D of 50 mg/m 2 /day for 21 days. Complete responses were observed among heavily pretreated patients.

This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on considerations for the comprehensive care of AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.

ImportanceCurrent olfactory neuroblastoma (ONB) staging systems inadequately delineate locally advanced tumors, do not incorporate tumor grade, and poorly estimate survival and recurrence.ObjectiveThe primary aims of this study were to (1) examine the clinical covariates associated with survival and recurrence of ONB in a modern-era multicenter cohort and (2) incorporate Hyams tumor grade into existing staging systems to assess its ability to estimate survival and recurrence.Design, Setting, and ParticipantsThis retrospective, multicenter, case-control study included patients with ONB who underwent treatment between January 1, 2005, and December 31, 2021, at 9 North American academic medical centers.InterventionStandard-of-care ONB treatment.Main Outcome and MeasuresThe main outcomes were overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) as C statistics for model prediction.ResultsA total of 256 patients with ONB (mean [SD] age, 52.0 [15.6] years; 115 female [44.9%]; 141 male [55.1%]) were included. The 5-year rate for OS was 83.5% (95% CI, 78.3%-89.1%); for DFS, 70.8% (95% CI, 64.3%-78.0%); and for DSS, 94.1% (95% CI, 90.5%-97.8%). On multivariable analysis, age, American Joint Committee on Cancer (AJCC) stage, involvement of bilateral maxillary sinuses, and positive margins were associated with OS. Only AJCC stage was associated with DFS. Only N stage was associated with DSS. When assessing the ability of staging systems to estimate OS, the best-performing model was the novel modification of the Dulguerov system (C statistic, 0.66; 95% CI, 0.59-0.76), and the Kadish system performed most poorly (C statistic, 0.57; 95% CI, 0.50-0.63). Regarding estimation of DFS, the modified Kadish system performed most poorly (C statistic, 0.55; 95% CI, 0.51-0.66), while the novel modification of the AJCC system performed the best (C statistic, 0.70; 95% CI, 0.66-0.80). Regarding estimation of DSS, the modified Kadish system was the best-performing model (C statistic, 0.79; 95% CI, 0.70-0.94), and the unmodified Kadish performed the worst (C statistic, 0.56; 95% CI, 0.51-0.68). The ability for novel ONB staging systems to estimate disease progression across stages was also assessed. In the novel Kadish staging system, patients with stage VI disease were approximately 7 times as likely to experience disease progression as patients with stage I disease (hazard ratio [HR], 6.84; 95% CI, 1.60-29.20). Results were similar for the novel modified Kadish system (HR, 8.99; 95% CI, 1.62-49.85) and the novel Dulguerov system (HR, 6.86; 95% CI, 2.74-17.18).Conclusions and RelevanceThe study findings indicate that 5-year OS for ONB is favorable and that incorporation of Hyams grade into traditional ONB staging systems is associated with improved estimation of disease progression.

Ewing sarcoma is a rare and deadly pediatric bone cancer for which survival rates and treatment options have stagnated for decades. Ewing sarcoma has not benefited from immunotherapy due to poor understanding of how its immune landscape is regulated. We recently reported that ubiquitin-specific protease 6 (USP6) functions as a tumor suppressor in Ewing sarcoma, and identified it as the first cell-intrinsic factor to modulate the Ewing sarcoma immune tumor microenvironment (TME). USP6 induces intratumoral infiltration and activation of multiple innate immune lineages in xenografted nude mice. Here we report that natural killer (NK) cells are essential for its tumor-inhibitory functions, as NK cell depletion reverses USP6-mediated suppression of Ewing sarcoma xenograft growth. USP6 expression in Ewing sarcoma cells directly stimulates NK cell activation and degranulation in vitro, and functions by increasing surface levels of multiple NK cell-activating ligands. USP6 also induces surface upregulation of the receptor for the apoptosis-inducing ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), providing an additional route for enhanced sensitivity to NK cell killing. Furthermore, USP6-expressing Ewing sarcoma and NK cells participate in a paracrine immunostimulatory feedforward loop, wherein IFNγ secreted by activated NK cells feeds back on USP6/Ewing sarcoma cells to induce synergistic expression of chemokines CXCL9 and CXCL10. Remarkably, expression of USP6 in subcutaneous Ewing sarcoma xenografts induces systemic activation and maturation of NK cells, and induces an abscopal response in which growth of distal tumors is inhibited, coincident with increased infiltration and activation of NK cells. This work reveals how USP6 reprograms the Ewing sarcoma TME to enhance antitumor immunity, and may be exploited for future therapeutic benefit. Significance: This study provides novel insights into the immunomodulatory functions of USP6, the only cancer cell–intrinsic factor demonstrated to regulate the immune TME in Ewing sarcoma. We demonstrate that USP6-mediated suppression of Ewing sarcoma tumorigenesis is dependent on NK cells. USP6 directly activates NK cell cytolytic function, inducing both intratumoral and systemic activation of NK cells in an Ewing sarcoma xenograft model.

Abstract Cardiac sarcoidosis (CS), with either extracardiac involvement or in isolation, is increasingly recognized. Complications from cardiac involvement are the leading cause of death in patients with sarcoidosis, rendering early detection extremely important given the significant therapeutic and prognostic implications. However, the diagnosis of CS remains challenging due to the lack of a reliable gold standard, largely due to the low sensitivity of traditional endomyocardial biopsy and patchy myocardial involvement. Recent advances in cardiac imaging with [18F] fluoro-deoxyglucose positron emission tomography-computed tomography ([18F]FDG PET/CT) and cardiac magnetic resonance (CMR) have provided unprecedented information on the prevalence of CS and have revolutionized the diagnosis and management of CS patients. Abnormal PET/CMR findings are now major criteria in societal guidelines to establish a probabilistic diagnosis of CS. This review provides a brief introduction to CS and a summary of current diagnostic criteria, followed by a review on the current use and strengths of PET/CT and CMR for diagnosis, risk stratification and treatment response evaluation. CMR is the most robust technique to assess left ventricular function, to detect myocardial fibrosis and differentiate CS from other cardiomyopathies and has an excellent negative predictive value. On the other hand, [18F]FDG PET/CT is the modality of choice to assess active myocardial inflammation which may be amenable to immunosuppressive treatment as well as to detect extracardiac involvement, to identify potential biopsy sites and to monitor treatment efficacy. Understanding the complementary value of both techniques is crucial to the optimal utilization of advanced imaging in patients with CS. Lastly, some gaps are identified for future research.

Objective: To define benchmark values for adult-to-adult living-donor liver transplantation (LDLT). Background: LDLT utilizes living-donor hemiliver grafts to expand the donor pool and reduce waitlist mortality. Although references have been established for donor hepatectomy, no such information exists for recipients to enable conclusive quality and comparative assessments. Methods: Patients undergoing LDLT were analyzed in 15 high-volume centers (≥10 cases/year) from 3 continents over 5 years (2016–2020), with a minimum follow-up of 1 year. Benchmark criteria included a Model for End-stage Liver Disease ≤20, no portal vein thrombosis, no previous major abdominal surgery, no renal replacement therapy, no acute liver failure, and no intensive care unit admission. Benchmark cutoffs were derived from the 75th percentile of all centers’ medians. Results: Of 3636 patients, 1864 (51%) qualified as benchmark cases. Benchmark cutoffs, including posttransplant dialysis (≤4%), primary nonfunction (≤0.9%), nonanastomotic strictures (≤0.2%), graft loss (≤7.7%), and redo-liver transplantation (LT) (≤3.6%), at 1-year were below the deceased donor LT benchmarks. Bile leak (≤12.4%), hepatic artery thrombosis (≤5.1%), and Comprehensive Complication Index (CCI ® ) (≤56) were above the deceased donor LT benchmarks, whereas mortality (≤9.1%) was comparable. The right hemiliver graft, compared with the left, was associated with a lower CCI ® score (34 vs 21, P < 0.001). Preservation of the middle hepatic vein with the right hemiliver graft had no impact neither on the recipient nor on the donor outcome. Asian centers outperformed other centers with CCI ® score (21 vs 47, P < 0.001), graft loss (3.0% vs 6.5%, P = 0.002), and redo-LT rates (1.0% vs 2.5%, P = 0.029). In contrast, non-benchmark low-volume centers displayed inferior outcomes, such as bile leak (15.2%), hepatic artery thrombosis (15.2%), or redo-LT (6.5%). Conclusions: Benchmark LDLT offers a valuable alternative to reduce waitlist mortality. Exchange of expertise, public awareness, and centralization policy are, however, mandatory to achieve benchmark outcomes worldwide.

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

Abstract Objectives To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well‐characterized individuals with BD in North America, Europe, and Australia. Methods Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta‐analyses with generalized linear mixed methods were conducted to identify prescription patterns. Results This study included 10,351 individuals from North America ( n = 3985), Europe ( n = 3822), and Australia ( n = 2544). Overall, participants were predominantly female (60%) with BD‐I (60%; vs. BD‐II = 33%). Cross‐sectionally, mood‐stabilizing anticonvulsants (44%), second‐generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First‐generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD‐II (47%) compared to BD‐I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort. Conclusions Mood‐stabilizing anticonvulsants, second‐generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first‐generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence‐based guidelines to help improve treatment practices in BD.