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Background: Although advanced stage cHL typically has excellent disease outcomes, 20-30% of patients (pts) experience treatment failure. In addition, decision-making is challenging given varying treatment options and incomplete prognostic data across the disease course. Pre-treatment factors, such as those incorporated into the Advanced Stage Hodgkin Lymphoma International Prognostication Index (A-HIPI), predict 5 year (y) overall survival (OS) and progression-free survival (PFS) (Rodday JCO 2023). Other than interim PET (iPET) results, it is unknown what factors influence cHL disease states mid-therapy. Using multistate modeling (MSM) and individual pt data from the HoLISTIC Consortium, we refined prognostication across the cHL disease course, specifically assessing the relationships between A-HIPI, iPET and end of treatment (EOT) response, and whether the A-HIPI and iPET provide independent prognostic information. Methods: We analyzed 1240 pts aged 18-65y with newly diagnosed Stage IIB, III or IV cHL treated on 2 advanced stage PET-adapted trials (RATHL, SWOG0816). All pts first received 2 cycles of ABVD; those with a negative iPET (Deauville score (DS) ≤3) received ABVD or AVD, and those with a positive iPET (DS >3) received BEACOPP. In contrast to other methods, MSMs incorporate multiple disease states into one model, account for censoring and competing risks, and estimate transitions between disease states using different covariates. Our MSM had 6 states: diagnosis, negative iPET, positive iPET, EOT non-progression (e.g., DS ≤ 3), treatment failure, and death. Treatment failure included progression or relapse. All pts start at the diagnosis state and can transition to other states without return to prior states. Transition states with <5 events were excluded. The MSM was estimated using a multivariable Cox model with censoring at 5y. Covariates were the 5y PFS A-HIPI (comprised of stage and continuous age, lymphocyte count and albumin), which was included for all transitions, and iPET, which was included for transitions from EOT non-progression and from treatment failure. Higher scores on the 5y PFS A-HIPI indicate lower risk of progression or death; the A-HIPI was modeled for a 1 standard deviation (SD) increase. We calculated probabilities of 5y treatment failure for 4 sample pts based on low (70) and high (85) A-HIPI scores, positive and negative iPET, and EOT non-progression. Results: Median age was 33y (Q1=25, Q3=45), 56% were male, 23% were stage IIB, 40% III and 37% IV, and mean A-HIPI was 77 (SD=7). Median follow-up was 75 months (Q1=53, Q3=92). At iPET, 80% (95% CI 78%, 83%) were negative and 16% (95% CI 14%, 18%) were positive. At EOT, 90% (95% CI 89%, 92%) were in the non-progression state. At 5y, 75% (95% CI 73%, 78%) were in the non-progression state, 16% (95% CI 14%, 19%) had experienced treatment failure, and 9% (7%, 11%) had died. Better A-HIPI scores (per SD) were associated with lower rates of transitioning from diagnosis to positive iPET (HR=0.80, p<0.01) and from positive iPET to treatment failure (HR=0.58, p=0.04). Better A-HIPI scores (per SD) were also associated with lower rates of transitioning from EOT non-progression to treatment failure (HR=0.78, p<0.01) and from treatment failure to death (HR=0.64, p<0.01), adjusting for iPET. Positive iPET was associated with an increased rate of transitioning from EOT non-progression to treatment failure (HR=1.90, p<0.01), adjusting for A-HIPI. The probability of 5y treatment failure for 4 sample pts was: 25% for low A-HIPI and positive iPET; 20% for high A-HIPI and positive iPET; 13% for low A-HIPI and negative iPET; and 12% for high A-HIPI and negative iPET. Conclusions: We created a novel MSM that refines prognostication across the cHL disease course by incorporating pre- and post-treatment factors (e.g., iPET) to estimate transitions to future disease states. Although the A-HIPI was developed using pre-treatment factors to predict 5y OS and PFS, we found that it was also associated with transitions to interim disease states, including iPET and EOT response. The A-HIPI and iPET each provided independent prognostic information, supporting the use of both in estimating cHL outcomes. Future analyses will develop clinical prediction models using MSMs that also incorporate varying frontline and salvage treatments and treatment-specific late effects, with the goal of providing individualized information across the disease course.

Importance Neoadjuvant therapy (NT) is an increasingly used treatment strategy for patients with localized pancreatic ductal adenocarcinoma (PDAC). Little research has been conducted on cancer care delivery during NT, and the standards for optimal delivery of NT have not been defined. Objective To develop consensus best practices for delivering NT to patients with localized PDAC. Design, Setting, and Participants This study used a modified Delphi approach consisting of 2 rounds of voting, and a series of virtual conferences (from October to December 2023) to reach expert consensus on candidate best practice statements generated from a systematic review of the literature and expert opinion. An interdisciplinary panel was formed including 47 North American experts from surgical, medical, and radiation oncology, radiology, pathology, gastroenterology, integrative oncology, anesthesia, pharmacy, nursing, cancer care delivery research, and nutrition as well as patient and caregiver stakeholders. Main Outcome and Measures Statements that reached 75% agreement or greater were included in final consensus statements. Results Of the 47 participating panel members, 27 (57.64%) were male, and the mean (SD) age was 47.6 (8.2) years. Physicians reported completing training a mean (SD) 14.6 (8.6) years prior and seeing a mean (SD) 110.6 (38.4) patients with PDAC annually; 35 (77.7%) were in academic practice. Final consensus was reached on 82 best practices for delivering NT. Of these, 38 statements focused on pre-NT practices, including diagnosis and staging (n = 15), evaluation and optimization (n = 20), and decision-making (n = 3); 29 statements defined best practices during NT, including initiation (n = 3), delivery of therapy (n = 8), restaging practices (n = 12), and management of complications during NT (n = 6); and 15 best practices were identified to guide treatment post-NT, focusing on surgery (n = 7), pathology (n = 4), and follow-up (n = 3). Conclusions Using a modified Delphi consensus technique, best practice guidelines were developed focusing on the optimal standards for delivering NT to patients with localized PDAC. Given the prognostic importance of completing multimodality therapy, efforts to standardize and optimize the delivery of NT represent an immediate opportunity to decrease care variation and improve outcomes for patients with PDAC. Future research should focus on validating and implementing best practice standards into clinical practice.

ABSTRACTBackgroundCoccidioidomycosis is a fungal infection that poses a serious risk when transmitted through organ transplantation. We analyzed cases reported to the Organ Procurement and Transplantation Network ad hoc Disease Transmission Advisory Committee from 2013 to 2022.MethodsDonors and/or recipients who had positive Coccidioides immitis/posadasii serology, pathology, and/or culture were included in this study. Cases adjudicated as ‘proven’ or ‘probable’ were analyzed for donor infection risk factors, the timing of infection, transmission by organ type, clinical manifestations, and recipient outcomes. Patient and facility identifiers were removed prior to review.ResultsDuring this time period, 73 potential instances of Coccidioides donor disease transmission events were reported. Among them, infection was transmitted from seven deceased donors to eight recipients. All seven deceased donors had prior infection or exposure to regions where coccidioidomycosis is endemic. Of 20 individuals receiving organs from these donors, eight developed infection, resulting in a 40% transmission rate. The median time to diagnosis post‐transplant was 39 days. Disseminated disease occurred in six recipients, five of whom died from the infection. Notably, none of the recipients who received prophylactic antifungal treatment died from the infection.ConclusionDespite its rarity, donor‐derived Coccidioides infection is a serious concern, particularly due to the high mortality rate in the early post‐transplant period. To mitigate these risks, a thorough assessment of donor exposure history, coupled with donor serology and bronchoalveolar lavage cultures, can effectively guide post‐transplant antifungal prophylaxis. Prompt reporting is crucial to prevent Coccidioides infections among other recipients. image

Background: As machine learning becomes increasingly utilized in orthopaedic clinical research, the application of machine learning methodology to cohort data from the Multicenter ACL Revision Study (MARS) presents a valuable opportunity to translate data into patient-specific insights. Purpose: To apply novel machine learning methodology to MARS cohort data to determine a predictive model of revision anterior cruciate ligament reconstruction (rACLR) graft failure and features most predictive of failure. Study Design: Cohort study; Level of evidence, 3. Methods: The authors prospectively recruited patients undergoing rACLR from the MARS cohort and obtained preoperative radiographs, surgeon-reported intraoperative findings, and 2- and 6-year follow-up data on patient-reported outcomes, additional surgeries, and graft failure. Machine learning models including logistic regression (LR), XGBoost, gradient boosting (GB), random forest (RF), and a validated ensemble algorithm (AutoPrognosis) were built to predict graft failure by 6 years postoperatively. Validated performance metrics and feature importance measures were used to evaluate model performance. Results: The cohort included 960 patients who completed 6-year follow-up, with 5.7% (n = 55) experiencing graft failure. AutoPrognosis demonstrated the highest discriminative power (model area under the receiver operating characteristic curve: AutoPrognosis, 0.703; RF, 0.618; GB, 0.660; XGBoost, 0.680; LR, 0.592), with well-calibrated scores (model Brier score: AutoPrognosis, 0.053; RF, 0.054; GB, 0.057; XGBoost, 0.058; LR, 0.111). The most important features for AutoPrognosis model performance were prior compromised femoral and tibial tunnels (placement and size) and allograft graft type used in current rACLR. Conclusion: The present study demonstrated the ability of the novel AutoPrognosis machine learning model to best predict the risk of graft failure in patients undergoing rACLR at 6 years postoperatively with moderate predictive ability. Femoral and tibial tunnel size and position in prior ACLR and allograft use in current rACLR were all risk factors for rACLR failure in the context of the AutoPrognosis model. This study describes a unique model that can be externally validated with larger data sets and contribute toward the creation of a robust rACLR bedside risk calculator in future studies. Registration: NCT00625885 (ClinicalTrials.gov identifier).

Background: Antithrombotic regimens play a pivotal role in averting complications and ischemic incidents post-percutaneous coronary intervention (PCI) in MI (myocardial infarction) patients. Bivalirudin stands as a viable alternative to unfractionated heparin in this cohort, demonstrating the efficacy and safety profiles. Aim: We aimed to compare the efficacy and safety of bivalirudin versus unfractionated heparin in post-percutaneous coronary intervention (PCI) in MI (myocardial infarction) patients. Research Question : What is the efficacy and safety of Bivalirudin compared to unfractionated heparin in patients with MI undergoing PCI, specifically in terms of major bleeding, cardiovascular mortality, and other major adverse cardiovascular events? Methods: We systematically searched PubMed, including MEDLINE, Embase, Cochrane Library, Google Scholar, ClinicalTrials.gov, and EBSCOhost/CINAHL, from January 1, 2000, through May 29, 2024, for randomized controlled trials (RCTs) that evaluated Bivalirudin versus unfractionated heparin and with a study population of patients with MI undergoing PCI. Data extraction was done using a spreadsheet, and data analysis was done using RevMan 5.4.1 for meta-analysis. The primary efficacy and safety endpoints were major bleeding, major cardiovascular events, cardiovascular mortality, all-cause mortality, myocardial infarction, stent thrombosis, and stroke. Results: Our analysis included 11 RCTs, encompassing a total of 40,919 participants. When compared with unfractionated heparin, bivalirudin was associated with a significant reduction in major bleeding events (RR 0.66 [0.55 to 0.80]; p < 0.0001) and cardiovascular mortality (RR 0.79 [0.67 to 0.92]; p < 0.003). However, there were no significant differences between Bivalirudin and unfractionated heparin in terms of major adverse cardiovascular events (RR 1.02 [0.91 to 1.13]; p = 0.76), all-cause mortality (RR 0.89 [0.78 to 1.01]; p = 0.08), MI (RR 0.99 [0.85 to 1.15]; p = 0.90), stent thrombosis (RR 1.12 [0.53 to 2.40]; p = 0.76), or stroke (RR 0.96 [0.73 to 1.26]; p = 0.75). Conclusion: Our meta-analysis indicates that in patients with MI undergoing PCI, Bivalirudin is associated with lower rates of major bleeding and cardiovascular mortality compared to unfractionated heparin. However, there were no significant differences observed in major adverse cardiovascular events, all-cause mortality, MI, stroke, or stent thrombosis between the two treatment groups.

Background: Persistent atrial fibrillation (AF) presents a significant management challenge, particularly in patients with concurrent heart failure. The effectiveness of catheter ablation compared to medical therapy for these patients remains under debate. Aim: This meta-analysis aims to evaluate the outcomes of catheter ablation versus medical therapy for managing persistent AF. Research Question: How does catheter ablation compare to medical therapy in managing persistent AF considering outcomes like arrhythmia recurrence, hospitalizations, cardiac function, exercise capacity, and mortality? Methods: We performed a meta-analysis of randomized controlled trials (RCTs) comparing catheter ablation with medical therapy in patients with persistent AF. Data sources included PubMed, Embase, Cochrane Library, Clinicaltrial.gov, Google Scholar, and CINAHL/EBSCOHOST, with studies selected based on predefined inclusion criteria. Primary outcomes assessed were recurrence of atrial arrhythmias, hospitalizations, changes in left ventricular ejection fraction (LVEF), changes in 6-minute walk test (6MWT) distance, and all-cause mortality. The data extraction was done using a spreadsheet, and the data analysis was done using RevMan 5.4.1: for meta-analysis Results: A total of 10 RCTs involving 1812 patients were included in the analysis. Compared to medical therapy, catheter ablation significantly reduced the recurrence of atrial arrhythmias (risk ratio [RR] = 0.43, 95% confidence interval [CI]: 0.29-0.63, P < 0.0001). Hospitalization rates due to heart failure were also lower in the ablation group (RR = 0.57, 95% CI: 0.44-0.73, P < 0.001). Improvements in LVEF were observed with a mean difference (MD) of 5.98% (95% CI: 3.81% to 8.15%, P < 0.00001). The performance on the 6MWT was better in the catheter ablation group, with an MD of 28.83 meters (95% CI: 8.61 to 49.05 meters, P = 0.005). Additionally, catheter ablation was associated with a reduction in all-cause mortality (RR = 0.60, 95% CI: 0.45-0.80, P = 0.00006). Conclusion: This meta-analysis demonstrates that catheter ablation is superior to medical therapy in managing persistent atrial fibrillation. Catheter ablation offers significant benefits in reducing atrial arrhythmia recurrence, lowering hospitalization rates, improving cardiac function and exercise capacity, and reducing mortality. These findings support the consideration of catheter ablation as a preferred treatment strategy for patients with persistent AF.

AbstractPurposeTo systematically review the literature regarding machine learning in leg length discrepancy (LLD) and to provide insight into the most relevant manuscripts on this topic in order to highlight the importance and future clinical implications of machine learning in the diagnosis and treatment of LLD.MethodsA systematic electronic search was conducted using PubMed, OVID/Medline and Cochrane libraries in accordance with Preferred Reporting Items for Systematic Review and Meta‐Analysis guidelines. Two observers independently screened the abstracts and titles of potential articles.ResultsA total of six studies were identified in the search. All measurements were calculated using standardized anterior‐posterior long‐leg radiographs. Five (83.3%) of the studies used measurements of the femoral length, tibial length and leg length to assess LLD, whereas one (16.6%) study used the iliac crest height difference to quantify LLD. The deep learning models showed excellent reliability in predicting all length measurements with intraclass correlation coefficients ranging from 0.98 to 1.0 and mean absolute error (MAE) values ranging from 0.11 to 0.45 cm. Three studies reported measurements of LLD, and the convolutional neural network model showed the lowest MAE of 0.13 cm in predicting LLD.ConclusionsMachine learning models are effective and efficient in determining LLD. Implementation of these models may reduce cost, improve efficiency and lead to better overall patient outcomes.Clinical RelevanceThis review highlights the potential of deep learning (DL) algorithms for accurate and reliable measurement of lower limb length and leg length discrepancy (LLD) on long‐leg radiographs. The reported mean absolute error and intraclass correlation coefficient values indicate that the performance of the DL models was comparable to that of radiologists, suggesting that DL‐based assessments could potentially be used to automate the measurement of lower limb length and LLD in clinical practice.Level of EvidenceLevel IV.

Abstract Background Malignant peripheral nerve sheath tumors (MPNSTs) can arise from atypical neurofibromas (ANF). Loss of the polycomb repressor complex 2 (PRC2) is a common event. Previous studies on PRC2-regulated genes in MPNST used genetic add-back experiments in highly aneuploid MPNST cell lines which may miss PRC2-regulated genes in NF1-mutant ANF-like precursor cells. A set of PRC2-regulated genes in human Schwann cells (SCs) has not been defined. We hypothesized that PRC2 loss has direct and indirect effects on gene expression resulting in MPNST, so we sought to identify PRC2-regulated genes in immortalized human Schwann cells (iHSCs). Methods We engineered NF1-deficient iHSCs with loss of function SUZ12 or EED mutations. RNA sequencing revealed 1327 differentially expressed genes to define PRC2-regulated genes. To investigate MPNST pathogenesis, we compared genes in iHSCs to consistent gene expression differences between ANF and MPNSTs. Chromatin immunoprecipitation sequencing was used to further define targets. Methylome and proteomic analyses were performed to further identify enriched pathways. Results We identified potential PRC2-regulated drivers of MPNST progression. Pathway analysis indicates many upregulated cancer-related pathways. We found transcriptional evidence for activated Notch and Sonic Hedgehog (SHH) signaling in PRC2-deficient iHSCs. Functional studies confirm that Notch signaling is active in MPNST cell lines, patient-derived xenografts, and transient cell models of PRC2 deficiency. A combination of MEK and γ-secretase inhibition shows synergy in MPNST cell lines. Conclusions We identified PRC2-regulated genes and potential drivers of MPNSTs. Our findings support the Notch pathway as a druggable target in MPNSTs. Our identification of PRC2-regulated genes and pathways could result in more novel therapeutic approaches.

PURPOSE The nodal burden of patients with residual isolated tumor cells (ITCs) in the sentinel lymph nodes (SLNs) after neoadjuvant chemotherapy (NAC) (ypN0i+) is unknown, and axillary management is not standardized. We investigated rates of additional positive lymph nodes (LNs) at axillary lymph node dissection (ALND) and oncologic outcomes in patients with ypN0i+ treated with and without ALND. METHODS The Oncoplastic Breast Consortium-05/ICARO cohort study (ClinicalTrials.gov identifier: NCT06464341 ) retrospectively analyzed data from patients with stage I to III breast cancer with ITCs in SLNs after NAC from 62 centers in 18 countries. The primary end point was the 3-year rate of any axillary recurrence. The rate of any invasive recurrence was the secondary end point. RESULTS In total, 583 patients were included, of whom 182 (31%) had completion ALND and 401 (69%) did not. The median age was 48 years. Most patients (74%) were clinically node-positive at diagnosis and 41% had hormone receptor–positive/human epidermal growth factor receptor 2–negative tumors. The mean number of SLNs with ITCs was 1.2. Patients treated with ALND were more likely to present with cN2/3 disease (17% v 7%, P < .001), have ITCs detected on frozen section (62% v 8%, P < .001), have lymphovascular invasion (38% v 24%, P < .001), and receive adjuvant chest wall (89% v 78%, P = .024) and nodal radiation (82% v 75%, P = .038). Additional positive nodes were found at ALND in 30% of patients, but only 5% had macrometastases. The 3-year rates of any axillary and any invasive recurrence were 2% (95% CI, 0.95 to 3.6) and 11% (95% CI, 8 to 14), respectively, with no statistical difference by type of axillary surgery. CONCLUSION The nodal burden in patients with ypN0(i+) was low, and axillary recurrence after ALND omission was rare in patients selected for this approach. These results do not support routine ALND in all patients with ypN0(i+).

Background: Revision anterior cruciate ligament (ACL) reconstruction has been documented to have inferior outcomes compared with primary ACL reconstruction. The reasons why remain unknown. Purpose: To determine whether surgical factors performed at the time of revision ACL reconstruction can influence a patient’s outcome at 6-year follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Patients who underwent revision ACL reconstruction were identified and prospectively enrolled between 2006 and 2011. Data collected included baseline patient characteristics, surgical technique and pathology, and a series of validated patient-reported outcome instruments: Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) subjective form, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx activity rating score. Patients were followed up for 6 years and asked to complete the identical set of outcome instruments. Regression analysis was used to control for baseline patient characteristics and surgical variables to assess the surgical risk factors for clinical outcomes 6 years after surgery. Results: A total of 1234 patients were enrolled (716 men, 58%; median age, 26 years), and 6-year follow-up was obtained on 79% of patients (980/1234). Using an interference screw for femoral fixation compared with a cross-pin resulted in significantly better outcomes in 6-year IKDC scores (odds ratio [OR], 2.2; 95% CI, 1.2-3.9; P = .008) and KOOS sports/recreation and quality of life subscale scores (OR range, 2.2-2.7; 95% CI, 1.2-4.8; P < .01). Use of an interference screw compared with a cross-pin resulted in a 2.6 times less likely chance of having a subsequent surgery within 6 years. Use of an interference screw for tibial fixation compared with any combination of tibial fixation techniques resulted in significantly improved scores for IKDC (OR, 1.96; 95% CI, 1.3-2.9; P = .001); KOOS pain, activities of daily living, and sports/recreation subscales (OR range, 1.5-1.6; 95% CI, 1.0-2.4; P < .05); and WOMAC pain and activities of daily living subscales (OR range, 1.5-1.8; 95% CI, 1.0-2.7; P < .05). Use of a transtibial surgical approach compared with an anteromedial portal approach resulted in significantly improved KOOS pain and quality of life subscale scores at 6 years (OR, 1.5; 95% CI, 1.02-2.2; P≤ .04). Conclusion: There are surgical variables at the time of ACL revision that can modify clinical outcomes at 6 years. Opting for a transtibial surgical approach and choosing an interference screw for femoral and tibial fixation improved patients’ odds of having a significantly better 6-year clinical outcome in this cohort.