Citations

ABSTRACT Alterations in the tumor suppressor gene TP53 are common in human cancers and are associated with an aggressive nature. Approximately 8%–12% of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) harbor TP53 mutations ( TP53 mut ) and present immense challenges due to inherent chemoresistance and poor outcomes. As TP53 mut are more common in older individuals and those with secondary/therapy‐related myeloid neoplasms (MN), their incidence is expected to increase with an aging population and rising proportion of cancer survivors. Treatments used for other MN—intensive chemotherapy, hypomethylating agents, and the BCL‐2 inhibitor venetoclax—do not improve the survival of TP53 mut MN patients meaningfully. Additionally, further development of many promising agents has been discontinued, highlighting the challenges. Widespread acknowledgment of these problems led to the recognition of TP53 mut MN as a distinct entity in the 5th edition of the World Health Organization and International Consensus Classifications. However, critical discrepancies between the two classifications may lead to under‐ or overestimation of the prognostic risk. Here, we review recent advances in the biology, diagnosis, and treatment of TP53 mut MN. The development of TP53 mut MN is positioned at the intersection of age, hereditary predisposition, and anti‐cancer therapies. Precursor TP53 mut clones can be detected years prior to the eventual leukemic transformation—raising the possibility of early intervention. We discuss the two classification systems and the bearing of the discrepancies between the two on timely and effective management. We provide novel evidence in the areas of discrepancies. Finally, we review the current therapeutic landscape and the obvious limitations of the currently used therapies.

The 2024 Annual Congress of the International Liver Transplantation Society (ILTS) was from May 1–4 in Houston, Texas, USA, under the theme “Liver Disease and Transplantation: Breaking Barriers and Exploring New Frontiers.” In addition to a robust scientific program, the congress also hosted a hands-on cadaveric robotic liver surgery course, a machine perfusion workshop, and a transesophageal echocardiography course. In this report, the ILTS Vanguard and Basic Sciences Committees present a summary of the congress proceedings.

OBJECTIVE Management of locally invasive colorectal carcinoma at any stage currently involves surgical excision followed by chemoradiotherapy; however, the prognosis is poor, with a 5-year overall survival (OS) of only 5%. Failure to achieve gross-total resection is associated with poorer OS, and patients with residual tumor postresection (R1 or R2 resection) have a median OS of 7 months compared with 23 months in those who undergo resection with negative margins (R0 resection). For tumors that have invaded the sacrum, sacrectomy becomes necessary to achieve R0 resection. The objective of this study was to provide a descriptive multicenter account of resection for locally invasive colorectal carcinoma with sacral invasion, focusing on the association of tumor morphometry with surgical planning and perioperative outcomes. METHODS Demographic, comorbidity, clinical, tumor-specific, operative characteristic, and outcome data were collected on all patients who underwent resection of colorectal carcinoma with concurrent sacral resection between January 2005 and May 2022. Patients were grouped into those having undergone surgery for purely palliative intent, or those with resection with attempt at local control and dichotomized into level of osteotomy (either proximal or distal to the S2–3 level). RESULTS Twenty-two patients (median age 50.5 [IQR 43.3–60.0] years, 54.5% female) underwent sacrectomy for colorectal carcinoma. Operative records indicated intent for local control in 14 patients and palliative in the remaining 8 patients. Palliative surgical intent was based primarily on the presence of distant metastases. There was no significant difference in median local progression-free survival between patients undergoing osteotomy proximal to the S2–3 level and those undergoing osteotomy distal to the S2–3 level. CONCLUSIONS En bloc resection is believed to offer the best local control in patients with locally invasive colorectal carcinoma. The present descriptive series highlights outcomes of en bloc resection with partial or full sacrectomy in patients with tumors showing local extension into the sacrum. Complications are common, most often in the form of wound dehiscence or infection, and many patients require placement in a rehabilitation or intermediate-care facility upon discharge. However, for those with stage III (locally aggressive) disease, median OS exceeds 16 years, suggesting that such aggressive management with en bloc resection may be warranted in properly selected patients.

Abstract Purpose: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer. Previous studies demonstrated that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors. Patients and Methods: We conducted a phase I/II trial of pembrolizumab and binimetinib in patients with metastatic triple-negative breast cancer with ≤3 prior lines of therapy. There were two dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL −1. Results: The recommended phase II dose was the standard dose of pembrolizumab with binimetinib 30 mg twice daily. The objective response rate (ORR) was 30.4%, with a numerically higher ORR in patients without liver metastasis at 45.5%. Among patients who achieved objective responses, 80% had a duration of response >12 months and ongoing even after stopping treatment (5.4–69.0 months). Patients with PD-L1–positive tumors (modified proportion score ≥10) were more likely to respond with an ORR of 66.7%. However, clinical benefit was observed in 25% of patients with PD-L1–negative tumors. Consistent with preclinical studies, four of six patients with clinical benefit had either increased PD-L1 or decreased p-ERK expressions in serial circulating cancer-associated macrophage-like cells after starting binimetinib. Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination.

Traumatic brain injury (TBI) is a leading cause of disability and death globally, presenting significant challenges for diagnosis, prognosis, and treatment. As healthcare technology advances, artificial intelligence (AI) has emerged as a promising tool in enhancing TBI rehabilitation outcomes. This literature review explores the current and potential applications of AI in TBI management, focusing on AI’s role in diagnostic tools, neuroimaging, prognostic modeling, and rehabilitation programs. AI-driven algorithms have demonstrated high accuracy in predicting mortality, functional outcomes, and personalized rehabilitation strategies based on patient data. AI models have been developed to predict in-hospital mortality of TBI patients up to an accuracy of 95.6%. Furthermore, AI enhances neuroimaging by detecting subtle abnormalities that may be missed by human radiologists, expediting diagnosis and treatment decisions. Despite these advances, ethical considerations, including biases in AI algorithms and data generalizability, pose challenges that must be addressed to optimize AI’s implementation in clinical settings. This review highlights key clinical trials and future research directions, emphasizing AI’s transformative potential in improving patient care, rehabilitation, and long-term outcomes for TBI patients.

BACKGROUND: A preservation system, the Organ Care System (OCS; TransMedics) uses normothermic pulsatile perfusion during organ transport for heart transplantation. This system has demonstrated favorable outcomes in hearts recovered from extended-criteria donors after brain death (DBD) and donors after circulatory death (DCD). METHODS: The OCS Heart Perfusion Registry collects data on US heart transplantations using the OCS, static cold storage (SCS), or thoracoabdominal normothermic regional perfusion (NRP) and donor hearts recovered from DBD or DCD donors. We analyzed donor and recipient characteristics and posttransplantation outcomes in patients transplanted with OCS donor hearts (either DBD or DCD) compared with SCS hearts, and with OCS hearts from DCD donors compared with those recovered with NRP followed by SCS. Propensity score matching was used in survival analyses to adjust for differences among recipient characteristics. RESULTS: Between 2021 and 2023, 3225 consecutive heart transplantations enrolled from 56 centers were analyzed in the Heart Perfusion Registry. The OCS was used in 854 of 3225 heart transplantations (26.4%), among which 340 (39.8%) were DBD and 514 (60.2%) were DCD donors, whereas 2174 DBD donors were recovered with SCS and another 197 DCD donors with NRP techniques. The OCS-DBD group experienced a greater number of organ offer refusals before final acceptance (13 versus 6; Wilcoxon rank sum, P <0.001) and a longer transport distance (667 miles versus 232 miles; Wilcoxon rank sum, P <0.001) compared with SCS-DBD. Survival at 12 months was similar between the 2 groups (89.9% for OCS-DBD versus 90.6% for SCS-DBD; marginal Cox model, P =0.54). Among the OCS-DCD and SCS-DBD groups, survival at 12 months was also similar (91.0% versus 92.5%, respectively; marginal Cox model, P =0.32). The OCS-DCD and NRP-DCD groups demonstrated similar survival (91.0% versus 91.7%, respectively; log rank, P =0.63), although the transport distance was longer in OCS-DCD compared with DCD with NRP followed by SCS (400 miles versus 223 miles; Wilcoxon rank sum, P <0.001). By 2023, 90% of all OCS donor management and recovery was performed with dedicated organ recovery teams. CONCLUSIONS: We demonstrate that real-world implementation of the OCS for DBD donors (using predominantly a dedicated recovery team) is associated with expanded donor criteria, longer transport distance, and excellent posttransplantation outcomes. In OCS-DCD donors, outcomes parallel those of donors recovered with NRP-DCD and compare favorably with DBD donor organs.

We describe the design and results from the BraTS 2023 Intracranial Meningioma Segmentation Challenge. The BraTS Meningioma Challenge differed from prior BraTS Glioma challenges in that it focused on meningiomas, which are typically benign extra-axial tumors with diverse radiologic and anatomical presentation and a propensity for multiplicity. Nine participating teams each developed deep-learning automated segmentation models using image data from the largest multi-institutional systematically expert annotated multilabel multi-sequence meningioma MRI dataset to date, which included 1000 training set cases, 141 validation set cases, and 283 hidden test set cases. Each case included T2, FLAIR, T1, and T1Gd brain MRI sequences with associated tumor compartment labels delineating enhancing tumor, non-enhancing tumor, and surrounding non-enhancing FLAIR hyperintensity. Participant automated segmentation models were evaluated and ranked based on a scoring system evaluating lesion-wise metrics including dice similarity coefficient (DSC) and 95% Hausdorff Distance. The top ranked team had a lesion-wise median dice similarity coefficient (DSC) of 0.976, 0.976, and 0.964 for enhancing tumor, tumor core, and whole tumor, respectively and a corresponding average DSC of 0.899, 0.904, and 0.871, respectively. These results serve as state-of-the-art benchmarks for future pre-operative meningioma automated segmentation algorithms. Additionally, we found that 1286 of 1424 cases (90.3%) had at least 1 compartment voxel abutting the edge of the skull-stripped image edge, which requires further investigation into optimal pre-processing face anonymization steps.

Background Data on the safety profiles and clinical outcomes of patients with solid tumors and cardiac metastasis treated with immune checkpoint inhibitors (ICIs) are limited. Methods This is an international multicenter retrospective study of patients with cancer and cardiac metastasis at baseline. Patients who had received ≥1 dose of ICI were included. Treatment-related adverse events (trAEs) were graded per Common Terminology Criteria for Adverse Event V.5.0. Objective response rates (ORR) were evaluated by Response Evaluation Criteria in Solid Tumors V.1.1 when available. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Results Among 110 pts, median age at ICI initiation was 65 (IQR: 59–75). Median follow-up time since ICI initiation was 36 (95% CI: 26 to 51) months. Melanoma (38%, n=42) and non-small cell lung cancer (24%, n=26) were the most common. 68 (62%) patients received ICIs as first-line, and 29 (26%) patients were treated with combination anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen 4. The most common location of cardiac metastasis was in the atria (37%, n=41) and ventricles (35%, n=39). 15 patients (13.6%) had bilateral cardiac/pericardial metastasis, 44 (40%) had left-sided, and 43 (39.8%) had right-sided. At ICI initiation, 21% (n=23) had a cardiac thrombus. Cardiology referrals and cardiac MRIs at the time of cancer diagnosis were completed on 58 (53%) and 52 (47%) patients, respectively. Cardiac events occurred in 40 (36%) patients, including arrhythmias (n=14, 13%), arterial/venous emboli (n=4, 3.6%), and cardiac tamponade (n=3, 2.7%). 53 (47%) patients developed trAEs; most common were colitis/diarrhea (n=16, 15%), dermatitis (n=13, 12%), and hepatitis (n=9, 8.2%). ICI-related major cardiac trAEs occurred in 2 (1.8%) patients. 22 patients (20%) developed grade ≥3 trAE. Patients with multiple cardiac metastases had significantly lower responses to ICI-based regimens compared with patients with single cardiac metastasis (11% vs 63%, p=0.02). For melanoma, ORR, median PFS, and median OS were 38%, 9.0 months, and 28.9 months, respectively. 83% of patients with melanoma had concordant responses in overall disease burden and cardiac disease. 91 patients discontinued ICIs, and the main reason was progression or death in 55 (49%) patients. Conclusions Among patients with pre-existing cardiac metastasis, ICIs demonstrated meaningful clinical efficacy with no increase in safety signals. Most patients had concordant responses in the overall disease burden and cardiac mass. Multidisciplinary teams are crucial for the appropriate management of patients with cardiac metastasis.

Objectives While extracorporeal shockwave therapy (ESWT) may be an efficacious adjunctive treatment option for musculoskeletal injuries, current research is limited by significant heterogeneity within treatment protocols. This study aims to establish international expert consensus recommendations on ESWT terminology, parameters, procedural considerations, contraindications and side effects in the application of ESWT to sports injuries. Methods A systematic literature search was performed on the use of ESWT for musculoskeletal and sports medicine injuries to identify potential panellists, followed by the development of a steering committee-led questionnaire. A three-stage, modified Delphi questionnaire was provided to a panel of 41 international clinical and research experts across 13 countries. Panellists had the opportunity to suggest edits to existing statements or recommend additional statements in Round 1. Consensus was defined as≥75% agreement. Results All 41 panellists completed Rounds 1, 2 and 3. Consensus was reached on 69/118 statements (58.5%), including recommendations on terminology and fundamental concepts, indications for use, procedural aspects for tendinopathy and bone pathologies, treatment correlations with imaging, periprocedural and postprocedural considerations, absolute and relative contraindications and potential side effects. Of the 49 statements that did not reach consensus, 17/49 (34.7%) were related to procedural aspects of bone pathology. Conclusion This international panel presents recommendations on ESWT terminology, indications and treatment considerations to guide ESWT use and decision-making by sports medicine clinicians. While our panel supported the use of ESWT in the treatment of bone pathologies, certain procedural aspects of ESWT specific to these injuries did not reach consensus and require further investigation.