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Introduction: Pembrolizumab Gemcitabine Vinorelbine and Liposomal Doxorubicin (P-GVD) has become a commonly employed regimen for the treatment of relapsed or refractory classical Hodgkin lymphoma (CHL), often preceding autologous stem cell transplant in patients with good response. The utilization of P-GVD is based on a 38-evaluable patient prospective trial (Moskowitz et al. JCO 2021). There remains minimal data regarding the efficacy of this regimen in a larger, real-world cohort. Methods:Patients with CHL who received P-GVD at 9 United States centers were retrospectively evaluated to estimate efficacy and safety, with a focus on the second line use of this regimen. Demographic and clinical data were extracted from medical records. Responses reflected Lugano criteria per local investigator assessment. Study objectives were overall response rates (ORR), complete response rates (CRR), progression free survival (PFS), overall survival (OS), and safety. PFS and OS were estimated by Kaplan-Meier. Results: Patients and Treatment: We identified 65 CHL patients who received P-GVD between July 2019 and June 2024, including 43 who were treated in the second line. Enrolled patients included a median age of 31 years (range 17-69 years), 36.9% (24) females, 75.4% (49) nodular sclerosing subtype, and 60% (39) stage III-IV at diagnosis. Patients included 64.6% (42) White and non-Hispanic, 15.4% (10) Hispanic or White and Hispanic, 10.8% (7) Black, 3.1% (2) Asian/Pacific Islander, 3.1% (2) other, and 3.1% (2) unknown. The median number of prior regimens was 1 (range 0-12); these included 3.1% (2) who had prior checkpoint inhibitor (CPI), 50.8% (33) who had prior brentuximab vedotin (BV), and 3.1% (2) who had prior transplant. Patients with primary refractory disease [no initial complete response (CR)] comprised 58.5% (38), and 35.4% (23) had relapse within 1 year of completing initial therapy. The median number of cycles received was 3 (range 1-5). Treatment in a community practice setting was noted for 21.5% (14) patients. Efficacy: At a median follow up of 17.7 months, ORR and CRR after P-GVD were 95% (62/65) and 74% (48/65), respectively. This increased to 95% ORR and 81% CRR when limited to 43 patients who were treated 2nd line. Responses by line included: 1st [n=1; 100% ORR and CRR]; 3rd [n=15; 100% ORR, 73.3% CRR], 4th [n=3; 100% ORR, 33.3% CRR], 5th [n=2; 100% ORR, 0% CRR], and 13th [n=1; SD]. CRR in BV- and CPI-exposed patients were 60.6% and 50%, respectively. Ninety one percent (39) of 2nd line treated patients proceeded to autologous transplant, as well as all 3 patients > age 60. Among 41 response-evaluable second-line patients, CR was achieved in 94% (30/32) who received 2 or 3 cycles of P-GVD, and 56% (5/9) who received 4 cycles of P-GVD. For the entire cohort at 12 and 24 months after starting P-GVD, PFS was 95% (95% CI: 89-100%), 91% (95% CI: 83-100%) and OS was 98% (95% CI: 94-100%), 94% (95% CI: 86-100%), respectively. Ninety five percent (41) of 2nd line transplanted patients remain alive and in remission at a median of 18.5 months (range 3.5-38.7 months). In the primary refractory subset, PFS and OS at 24 months were 91% and 97%, respectively. For the cohort with 2 or more prior lines of therapy, PFS and OS at 24 months were 91% and 94%, respectively. Safety: Immune-related adverse events (IRAEs) were reported in 20% (13) of patients, of which grade 3 IRAEs per NCCN criteria version 1.2024 comprised 38.5%; all others were grades 1-2. Non-IRAE grade 3-4 toxicities per CTCAE version 5.0 were reported in 22% (14) patients. Of 29 patients evaluable for treatment-related interruptions, 7% (2) had therapy discontinued, and 34% (10) had holds, dose reductions, and/or delays. No deaths were attributed to P-GVD treatment. Conclusions:This retrospective study confirms the utility of P-GVD in treating relapsed/refractory CHL in a real-world population. Though fewer CRs and higher rates of grade 3 adverse events were observed, the vast majority of patients were able to proceed to transplant, and outcomes to date are highly encouraging.

Background/Objectives: Spinal astrocytomas (SA) represent 30–40% of all intramedullary spinal cord tumors (IMSCTs) and present significant clinical challenges due to their aggressive behavior and potential for recurrence. We aimed to pool the evidence on SA and investigate predictors of regrowth or recurrence after surgical resection. Methods: A systematic review and meta-analysis were conducted on peer-reviewed human studies from several databases covering the field of SA. Data were collected including sex, age, tumor location, extent of resection, histopathological diagnosis, and adjuvant therapy to identify predictors of SA recurrence. Recurrence was defined as failure of local tumor control or regrowth after treatment. Results: A total of 53 studies with 1365 patients were included in the meta-analysis. A postoperative deterioration in neurological outcomes, as assessed by the modified McCormick scale, was noted in most of the patients. The overall recurrence rate amounted to 41%. On meta-analysis, high-grade WHO tumors were associated with higher odds of recurrence (OR = 2.65; 95% CI: 1.87, 3.76; p = 0.001). Similarly, GTR was associated with lower odds of recurrence compared to STR (OR = 0.33; 95% CI: 0.18, 0.60; p = 0.0003). Sex (p = 0.5848) and tumor location (p = 0.3693) did not show any significant differences in the odds of recurrence. Intraoperative neurophysiological monitoring was described in 8 studies and adjuvant radiotherapy in 41 studies. Conclusions: The results highlight the significant importance of tumor grade and extent of resection in patient prognosis. The role of adjuvant radiotherapy remains unclear, with most studies suggesting no differences in outcomes, with limitations due to potential confounders.

Abstract Immune thrombotic thrombocytopenic purpura (iTTP) is a chronically relapsing disorder caused by autoantibody-mediated deficiency of ADAMTS13. Rituximab is frequently administered to prevent relapses, but whether the durability of rituximab effect is maintained with subsequent treatment courses has not been studied. Using the United States Thrombotic Microangiopathy Consortium (USTMA) retrospective iTTP registry, we evaluated clinical relapse-free survival (RFS) with subsequent courses of rituximab treatment in multiply relapsing patients. Separately, we evaluated overall RFS (composite of time to clinical relapse, ADAMTS13 relapse, or preemptive rituximab) in a prospective iTTP cohort from the Johns Hopkins University and the University of Minnesota. In the USTMA registry, median clinical RFS was shorter after the second or subsequent rituximab-treated episode than the first (2.1 vs 6.0 years; P = .04). White patients’ clinical relapse risk after the second and subsequent rituximab courses was not significantly different compared with the first (hazard ratio [HR], 1.86; 95% confidence interval [CI], 0.22-15.80; P = .57), whereas for Black patients, clinical relapse risk was significantly higher after the second or subsequent courses (HR, 2.82; 95% CI, 1.52-5.24; P = .001). In the prospective cohort, overall RFS progressively shortened after each episode of rituximab treatment with the first episode having the longest RFS (2.8 years; interquartile range, 2.0-6.0) and this loss of response durability was most pronounced in Black patients. The durability of rituximab’s effect declines with subsequent treatments, which is more pronounced in Black patients, who may benefit from closer monitoring and alternative immunomodulatory approaches such as maintenance rituximab and consideration of other agents.

AbstractCurrent US clinical practice guidelines for advanced prostate cancer management contain recommendations based on high‐level evidence from randomized controlled trials; however, these guidelines do not address the nuanced clinical questions that are unanswered by prospective trials but nonetheless encountered in day‐to‐day practice. To address these practical questions, the 2024 US Prostate Cancer Conference (USPCC 2024) was created to generate US‐focused expert clinical decision‐making guidance for circumstances in which level 1 evidence is lacking. At the second annual USPCC meeting (USPCC 2024), a multidisciplinary panel of experts convened to discuss ongoing clinical challenges related to 5 topic areas: biochemical recurrence; metastatic, castration‐sensitive prostate cancer; poly [ADP‐ribose] polymerase inhibitors; prostate‐specific membrane antigen radioligand therapy; and metastatic, castration‐resistant prostate cancer. Through a modified Delphi process, 34 consensus recommendations were developed and are intended to provide clinicians who manage prostate cancer with guidance related to the implementation of novel treatments and technologies. In this report, the authors review the areas of consensus identified by the USPCC 2024 experts and evaluate ongoing unmet needs regarding translational application of the current clinical evidence.

Aims Cutibacterium acnes ( C. acnes ; previously known as Propionibacterium acnes or P. acnes ) periprosthetic hip and knee infections are under-reported. While culture contamination with C. acnes occurs, true infections are important to recognize and treat. We sought to describe the demographics and treatment outcomes of patients with C. acnes periprosthetic joint infections (PJIs) of the hip and knee. Methods Patients with C. acnes PJI between January 2005 and December 2018 were retrospectively reviewed utilizing the institutional total joint registry. Patients with monomicrobial PJI and two or more positive cultures were considered to have true C. acnes PJI. Patients with polymicrobial infection or with only one positive culture were excluded. This resulted in 35 PJIs (21 hips and 14 knees); the patients’ mean age was 63 years (35 to 84) and 15 (43%) were female. Mean follow-up was five years (1 to 14). Results The median time to positive culture was five days (IQR 5 to 6) and median synovial fluid cell count was 22,583 cells (IQR 15,200 to 53,231). The median ESR was 25 mm/hr (IQR 7 to 37), and CRP was 15 mg/l (IQR 3 to 29). Of the 35 PJIs, 18 (51%) were treated with chronic antibiotic suppression without surgical intervention, and the remainder were treated with two-stage exchange arthroplasty. The two-year survival free of any revision was 94%. Four patients failed treatment due to symptomatic infection, with three treated with two-stage exchange and one treated with irrigation and debridement with modular component exchange for a survival rate of 89% and 83% at two and five years, respectively. Conclusion Laboratory evidence of C. acnes PJI in this cohort was typical compared to more conventional organisms. Cultures grew more quickly than previously thought in patients with C. acnes PJI. Treatment with two-stage exchange or chronic antibiotic suppression alone both had few treatment failures at mid-term follow-up. Cite this article: Bone Joint J 2024;106-B(12):1426–1430.

Abstract Purpose This study examined occupational histories in neuropathologically confirmed cases of multiple system atrophy to identify environmental associations of potential relevance to disease causation. Methods 270 neuropathologically confirmed cases of multiple system atrophy obtained from the Mayo Clinic brain bank for neurodegenerative disorders in Jacksonville, Florida, were included in this case-control study. Demographic and disease information was collected from medical records. Information regarding occupational history was collected retrospectively from medical records and published obituaries. Proportions of employment by occupational sector were compared to United States census data. Results The most common prior occupations in patients were healthcare (15.2%), education (15.2%), administration (14.8%), clerical (10.7%), petroleum industry (8.9%), business ownership (8.5%), and metal industry (7.8%). When comparing patients to United States census data, significant differences were identified for electrical (5.6% vs. 0.4%, P < 0.001), education (15.2% vs. 2.3%, P < 0.001), real estate (4.4% vs. 0.7%, P < 0.001), metal industry (7.8% vs. 3.0%, P < 0.001), information technology (4.1% vs. 1.8%, P = 0.011), clerical (10.7% vs. 5.5%, P = 0.001), and petroleum industry (8.9% vs. 5.6%, P = 0.024). Conclusions Electrical engineers and electricians, educators, real estate agents, workers in the metal industry, information technologists, clerical staff, and workers in the petroleum industry were significantly overrepresented in our series of multiple system atrophy patients as compared to population data. We hypothesize that these occupational associations may signify environmental exposures increasing disease risk in genetically susceptible individuals. We cannot exclude a potential selection bias in patients willing to donate their brains to an academic center in order to contribute to scientific knowledge.

Background: Osteochondritis dissecans (OCD) of the knee is a focal idiopathic alteration of subchondral bone and/or its precursor with risk for instability and disruption of adjacent cartilage. Treatment options focused on preventing premature osteoarthritis vary depending on multiple patient and lesion characteristics, including lesion mobility. Purpose: To differentiate lesion mobility before arthroscopy using a multivariable model that includes patient demographic characteristics and physical examination findings. Study Design: Cohort study (Diagnosis); Level of evidence, 2. Methods: Demographic, preoperative physical examination, and radiographic data were collected from a multicenter national prospective cohort of patients with OCD of the knee. Inclusion criteria included patients <19 years of age and patients with arthroscopically confirmed mobility status based on the Research on Osteochondritis Dissecans of the Knee arthroscopy classification. Multivariable logistic regression analysis using stepwise model selection was used to determine factors associated with the likelihood of a mobile versus an immobile lesion. A 75% partition of the data was used for model training, and 25% was used as a validation cohort. Quantitative model fit statistics were computed using the holdout data, including sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC), along with the corresponding 95% CI. Results: A total of 407 patients in the prospective cohort met inclusion criteria, and 62% were male. The mean ± SD age was 13.7 ± 2.2 years, height 161.8 ± 5.3 cm, and weight 59.2 ± 42.2 kg. Arthroscopic evaluation yielded 235 immobile and 172 mobile lesions. Multivariable analysis determined that the best model to predict lesion mobility included chronologic age ≥14 years ( P < .001), effusion on physical examination ( P < .001), and any loss of range of motion on physical examination ( P = .07), while controlling for male sex ( P = .38) and weight >54.4 kg ( P = .12). In the 25% holdout validation sample (n = 102), a sensitivity of 83%, a specificity of 82%, and an AUC of 0.89 (95% CI, 0.82-0.95) were achieved with these predictive factors. Conclusion: Age, effusion, and loss of motion can predict knee OCD lesion mobility at the time of arthroscopy. Education about lesion mobility can help with surgical planning and patient and family counseling.

Abstract Background In BRAF-mutated high-risk melanoma, targeted therapy (BRAF/MEK inhibitors) and checkpoint inhibitor (CPI) immunotherapy have durable benefits as first-line (1L) adjuvant therapy. Based on differing action mechanisms of BRAF/MEK inhibitors and CPI immunotherapies, there is interest in evaluating the activity of 2L adjuvant targeted therapy in decreasing the risk of subsequent recurrence after repeat resection following relapse on/after 1L adjuvant CPI. Patients and methods This was a retrospective review of BRAF V600-mutated resected stage III/IV melanoma patients in the United States, Australia, and The Netherlands who received 1L adjuvant CPI immunotherapy, relapsed locoregionally/distantly, were again resected to no evidence of disease, and received dabrafenib/trametinib (dab/tram) as 2L adjuvant therapy. The primary endpoint was relapse-free survival (RFS) from initiation of 2L adjuvant dab/tram (RFS-2), analyzed via Kaplan-Meier methods. Results Thirty-eight patients were included (median age 50 years, 63% male, 87% stage III, median follow-up 19 months from 2L dab/tram initiation). Median dab/tram duration was 10.1 months (range: 1 day–22.7 months), with half discontinuing due to progression or adverse events. Median (95% CI) RFS-2 was 18.9 (14.9–28.1) months, with 91%, 81%, and 58% remaining relapse-free at 6, 12, and 18 months, respectively. Most patients remained distant metastasis-free at 6, 12, and 18 months (97%, 85%, and 71%, respectively). Two patients were deceased at the last follow-up, with 97% alive at 18 months. Conclusions Over 80% of patients remained relapse- and metastasis-free at 12 months after 2L dab/tram initiation, with only 2 deaths observed. Dab/tram appears to have activity in the 2L adjuvant setting, although more follow-up is required.

Background: A retear after anterior cruciate ligament (ACL) reconstruction remains a common and devastating complication. Knee bone morphology is associated with the risk of ACL injuries, ACL retears, and osteoarthritis, and a combination of tools that derive bone shape from clinical imaging, such as magnetic resonance imaging (MRI) and statistical shape modeling, could identify patients at risk of developing these joint conditions. Purpose: To identify bone shape features before primary ACL reconstruction in patients with an eventual retear compared to those with a known intact ACL graft. Study Design: Case-control study; Level of evidence, 3. Methods: Bone was automatically segmented on 2-dimensional proton density–weighted MRI of the knee in patients at the time of the initial ACL injury using deep convolutional neural networks. Patients with a subsequent retear after reconstruction within 3 years (22 femurs, 19 tibias) were compared with those with an intact ACL graft at 3 years (20 femurs, 22 tibias) using statistical shape modeling to identify preoperative bone shape features predictive of a retear after ACL reconstruction. Results: Statistical shape modeling revealed 2 specific bone shape features (modes) in the femur and 1 mode in the tibia that demonstrated significant differences at the time of the initial injury in patients with subsequent retears. In the femur, a narrower intercondylar notch width, a widened medial condylar width, an increased femoral condylar offset ratio, increased surface area along the lateral femoral condyle relative to the medial condyle, and a more prominent trochlear sulcus at the time of the initial injury were associated with retears after ACL reconstruction. In the tibia, a diminished ACL facet prominence, a squared lateral and medial tibial plateaus, and a broader and flattened tibial spine at the time of the initial injury were associated with retears after ACL reconstruction. Conclusion: Using the automatic bone segmentation pipeline on preoperative MRI, the authors identified bone shape features associated with a retear after ACL reconstruction. The use of this pipeline enables large-scale studies of bone shape on MRI and could predict patients at risk of ACL retears to alter treatment decisions.

Background A multidisciplinary approach improves guideline‐directed medical therapy in systolic heart failure (HF), but its efficacy in patients with HF due to cardiac sarcoidosis is unreported. Methods and Results In a retrospective cohort study, we reviewed 848 patients from our institutional cardiac sarcoidosis clinics, identifying those with a cardiac sarcoidosis diagnosis, HF (left ventricular ejection fraction <50%) at index evaluation, and echocardiograms within 90 days and 11 to 36 months. Patients were stratified by participation in a pharmacist‐led medication therapy management (MTM) program for guideline‐directed medical therapy optimization (MTM versus non‐MTM [NMTM]) without randomization. Demographics, left ventricular ejection fraction, guideline‐directed medical therapy (quantified by Kansas City Medical Optimization score), and immunosuppressive therapy were assessed. Primary outcomes included changes in Kansas City Medical Optimization score, left ventricular ejection fraction, and cardiovascular event–free survival (unplanned HF hospitalization, left ventricular assist device /heart transplant, or death). The final cohort included 111 patients (median age, 57 years; 34% women; 64% New York Heart Association class I–II); 43 (39%) were MTM and 68 (61%) were NMTM. Mean Kansas City Medical Optimization score was similar at index evaluation (MTM, 23.2; NMTM, 29.6; P =0.83). At follow‐up (median, 16 months), the Kansas City Medical Optimization score increased significantly in both groups (MTM, 23.2 to 74.8; P <0.001; NMTM, 29.6 to 58.7; P <0.001) but was higher in MTM ( P =0.001). Mean left ventricular ejection fraction trended toward higher values in MTM (44.4% versus 40.0%, P =0.05). The primary clinical outcome occurred in 1 MTM (2.3%) and 16 NMTM (23.5%) patients, with higher risk in NMTM (hazard ratio, 11.97 [95% CI, 1.58–90.54]; P =0.002). Conclusions In this retrospective cohort study, a pharmacist‐led MTM program was associated with favorable guideline‐directed medical therapy optimization and lower risk of adverse cardiovascular outcomes in patients with cardiac sarcoidosis with HF.