Citations

The translation of AI-generated brain metastases (BM) segmentation into clinical practice relies heavily on diverse, high-quality annotated medical imaging datasets. The BraTS-METS 2023 challenge has gained momentum for testing and benchmarking algorithms using rigorously annotated internationally compiled real-world datasets. This study presents the results of the segmentation challenge and characterizes the challenging cases that impacted the performance of the winning algorithms. Untreated brain metastases on standard anatomic MRI sequences (T1, T2, FLAIR, T1PG) from eight contributed international datasets were annotated in stepwise method: published UNET algorithms, student, neuroradiologist, final approver neuroradiologist. Segmentations were ranked based on lesion-wise Dice and Hausdorff distance (HD95) scores. False positives (FP) and false negatives (FN) were rigorously penalized, receiving a score of 0 for Dice and a fixed penalty of 374 for HD95. The mean scores for the teams were calculated. Eight datasets comprising 1303 studies were annotated, with 402 studies (3076 lesions) released on Synapse as publicly available datasets to challenge competitors. Additionally, 31 studies (139 lesions) were held out for validation, and 59 studies (218 lesions) were used for testing. Segmentation accuracy was measured as rank across subjects, with the winning team achieving a LesionWise mean score of 7.9. The Dice score for the winning team was 0.65 ± 0.25. Common errors among the leading teams included false negatives for small lesions and misregistration of masks in space. The Dice scores and lesion detection rates of all algorithms diminished with decreasing tumor size, particularly for tumors smaller than 100 mm3. In conclusion, algorithms for BM segmentation require further refinement to balance high sensitivity in lesion detection with the minimization of false positives and negatives. The BraTS-METS 2023 challenge successfully curated well- annotated, diverse datasets and identified common errors, facilitating the translation of BM segmentation across varied environments and providing the tools for future development of personalized volumetric reports to patients undergoing BM treatment.

INTRODUCTION: Many patients with chronic pouchitis and Crohn's-like disease of the pouch (CLDP) are treated with biologics; however, the comparative effectiveness of advanced therapies in this population has not been systematically evaluated. We sought to compare the effectiveness of antitumor necrosis factor α (anti-TNF) therapies and ustekinumab in patients with chronic inflammatory conditions of the pouch. METHODS: We conducted a prospective, multicenter, cohort study. We included patients with chronic pouchitis and CLDP initiating treatment with anti-TNF therapies or ustekinumab. The primary outcome was clinical remission at 6 months after induction. We also evaluated clinical remission at 6 months among patients with chronic pouchitis and CLDP separately. RESULTS: Among 132 patients, 106 (80%) had a diagnosis of CLDP and 82 (62%) initiated therapy with ustekinumab. A significantly higher proportion of patients with CLDP treated with ustekinumab were in clinical remission at 6 months as compared with patients treated with anti-TNF therapy (62% vs 40%, P = 0.027); however, there was no significant difference among patients with chronic pouchitis ( P = 0.946). There was no independent statistical significance in the odds of remission at 6 months among patients with CLDP among patients receiving ustekinumab compared with anti-TNF therapy (adjusted odds ratio 1.91, 95% confidence interval 0.69–5.30) after adjusting for presence of a fistula, number of preoperative advanced therapies, and number of advanced therapies after IPAA. DISCUSSION: These data suggest the potential benefit of ustekinumab in patients with CLDP and should prompt future novel effectiveness evaluations in this population.

AbstractBackgroundGastric cancer with synchronous peritoneal metastases is a debilitating disease with limited treatment options. This article describes an update of the 2018 Chicago Consensus guidelines addressing the management of gastric cancer with synchronous peritoneal metastases in line with the most recent evidence.MethodsA clinical management pathway was updated through two rounds of a Delphi consensus to assess agreement levels with pathway blocks. Supporting evidence underwent evaluation using a rapid literature review. Meta‐analyses were performed as appropriate.ResultsOverall, the level of evidence in this disease subset was low to moderate. Of 124 participants in the first round, 109 (88%) responded in the second round. Strong consensus (>90%) was achieved in six of eight blocks (75%) in rounds 1 and 2. A multidisciplinary preoperative assessment and diagnostic laparoscopy should be offered to all patients, whereas patients with a high burden of disease or progression should undergo nonsurgical management. Patients with stable/responsive disease and a low peritoneal carcinomatosis index should subsequently be offered treatment with regional therapeutic interventions and cytoreductive surgery. In patients who are cytology‐positive, systemic therapy can be used to convert them to cytology‐negative, with subsequent surgery offered according to the patient's goals of care. Meta‐analysis of observational and randomized control trials revealed a survival benefit with the addition of intraperitoneal chemotherapy to cytoreductive surgery (hazard ratio, 0.52).ConclusionsThe consensus‐driven clinical pathway for gastric cancer with synchronous peritoneal metastases offers vital clinical guidance for practitioners. There is a growing body of high‐quality evidence to support management strategies, and future clinical trials are eagerly awaited.

Study Design This study is part of the AO Spine Metastatic Tumor Research and Outcomes Network [MTRON], an international multicenter prospective observational registry including patients with spinal metastases. Objectives This study aims to elucidate the incidence of surgical complications, their risk factors and consequent effects on survival outcomes, hospital length of stay, and overall health-related quality of life (HRQOL) parameters in a large cohort of patients affected by spinal metastases who were surgically treated. Methods Available data from February 2017 to July 2023 were analyzed. The primary outcome of this study was the evaluation of the incidence of intraoperative and postoperative adverse events (AEs). The secondary outcomes included the assessment of risk factors for surgery-related AEs and the impact of AEs on survival, length of hospital stay and quality of life. Results Among the 1267 patients analyzed, 6.9% experienced intraoperative AEs and 19.3% experienced at least 1 postoperative AE. Several factors resulted to be associated to the occurrence of postoperative AEs: age, smoking habit, poor Eastern Cooperative Oncology Group (ECOG) Performance status, previous radiation therapy at the index target, duration of surgery, number of instrumented levels, simultaneous anterior and posterior approach, presence of metastases at other sites, multiple spinal metastases. Postoperative AEs were associated with reduced survival rates, increased hospital length of stay and poorer HRQOL outcomes, particularly in domains such as neurological function and mental health. In general, surgery substantially improves HRQOL across multiple domains, with these benefits persisting over time despite the occurrence of AEs. However, patients with preoperative risk factors, including comorbidities, smoking, neurological impairment, and prior radiation therapy, experienced less improvement. Conclusions The negative impact of AEs on overall survival and HRQOL could be associated with the presence of some preoperative parameters of frailty that are detected as risk factors for AEs occurrence. This finding emphasizes the need for personalized preoperative assessments and optimized perioperative care strategies.

ABSTRACT Background Atherothrombosis, the main event leading to acute coronary syndrome (ACS), is strongly linked to disturbed blood flow (d-flow) regions. Although the involvement of the Hippo pathway and its kinases Large Tumor Suppressor Kinase 1and 2 (LATS 1 and 2) in mechanical stress responses is known, the mechanisms by which d-flow simultaneously induces senescence, proliferation, and atherothrombosis remain unclear. Methods The role of endothelial cells (EC)-specific LATS1/2 was examined using EC specific knock-out (EKO) mice in a partial left carotid ligation (PLCL) model. Plaque spatial multi-omics analysis was performed by integrating imaging mass cytometry, sequential immunofluorescence (COMET™), and spatial metabolomics at the single-cell level in human and mouse atherosclerotic plaques. Results In tamoxifen-inducible Lats1 homo( -/- ) / Lats2 homo( -/- ) EC-specific knockout (EKO) mice, deletion of LATS1/2 induced by tamoxifen led to fatal outcomes, characterized by severe systemic edema and markedly increased vascular permeability. In contrast, Lats1 het(+ /- ) / Lats2 homo( -/- ) -EKO mice survived and developed atherothrombotic plaques exhibiting neovascularization even without further additional dietary or genetic intervention. Spatial proteomics analysis revealed that LATS1/2 depletion in ECs triggered a senescence-associated stemness (SAS) phenotype, primarily driven by CD38 upregulation. Complementary spatial metabolomics profiling demonstrated a significant increase in sulfite and taurine within LATS1/2-deficient plaques, indicating lowered sulfite oxidase (SUOX) activity. Mechanistically, CD38 upregulation was found to suppress SUOX expression, induce the reverse mode of mitochondrial complex V, and increase succinate dehydrogenase (SDH) activity along with ATP consumption. Paradoxically, despite ATP depletion, this metabolic disturbance enhanced glutamate metabolism and the tricarboxylic acid (TCA) cycle, sustaining EC proliferation under energetically stressed conditions. The combined effect of LATS1/2 deletion and CD38 activation established a unique EC phenotype defined by increased SAS, leading to proliferation, senescence, and eventual cell death. These pathological processes culminated in the formation of atherothrombotic plaques, which were attenuated by inhibition of CD38. Notably, a similar phenotype—marked by metabolically active ECs—was observed in human atherothrombotic plaques, suggesting translational relevance. Conclusion Loss of LATS1/2 in ECs induces SAS state that promotes excessive EC proliferation, senescent cell accumulation, and the development of structurally fragile, leaky neo vessels—hallmarks of atherothrombotic lesions. CD38-mediated SUOX deficiency further amplifies this pathological process by inducing mitochondrial dysfunction, depleting ATP, and triggering compensatory upregulation of glutamate and TCA cycle metabolism. These findings identify a novel LATS1/2–CD38–SUOX axis in ECs that orchestrates SAS-driven atherothrombosis. Targeting CD38 may represent a promising therapeutic strategy to mitigate vascular dysfunction and plaque instability in high-risk ACS patients. Graphical abstract Under normal physiological conditions, LATS1/2 and Lamin A work together to suppress CD38 expression. Lamin A binds directly to the CD38 promoter to repress transcription, and LATS1/2 interact with Lamin A to reinforce this suppression. This collaboration helps maintain low CD38 activity and preserves cellular NAD⁺ levels. However, under disturbed flow (d-flow), both LATS1/2 and Lamin A are downregulated. The loss of this dual repression leads to increased CD38 NADase expression. Elevated CD38 accelerates NAD⁺ consumption, causing NAD⁺ depletion—a hallmark of cellular senescence. Reduced NAD⁺ disrupts key metabolic and stress-response pathways, contributing to the onset of the senescent state. At the same time, CD38 suppresses sulfite oxidase (SUOX), leading to sulfite accumulation and mitochondrial redox imbalance. This shift activates the reverse mode of mitochondrial Complex V, which decreases ATP production and increases mitochondrial ROS, intensifying metabolic and oxidative stress in endothelial cells (ECs). In response, ECs compensate by upregulating succinate dehydrogenase (SDH), enhancing TCA cycle activity and glutamate metabolism. This metabolic adaptation provides the biosynthetic building blocks needed for cell growth and proliferation. As a result, ECs adopt a paradoxical phenotype: they show classical features of stress-induced senescence (such as NAD⁺ depletion, oxidative stress, and cell cycle arrest signals), while simultaneously undergoing metabolic activation and proliferation, also mediated by YAP. This defines a non-canonical endothelial program known as senescence-associated stemness (SAS), characterized by the formation of abnormal, proliferative, yet fragile neovessels. These dysfunctional vessels contribute to atherothrombosis, setting this process apart from the more stable lesions typical of conventional atherosclerosis.

OBJECTIVE Spinal stereotactic radiosurgery (SSRS) is an established treatment modality for spinal metastatic disease. A common complication of SSRS is postradiation pathologic fracture. The authors evaluated the risk of pathologic fracture in sacral SSRS. METHODS All patients receiving SSRS in 1 to 5 fractions to 1 or more sacral levels between 2011 and 2020 at participating institutions were included. Demographic, histological, anatomical, and outcome data were obtained from electronic medical records. Data were analyzed using SPSS version 28. RESULTS Of 67 total patients, 50 (74.6%) were men and 17 (25.4%) were women. The most common tumor histologies were prostate adenocarcinoma (n = 16 [23.9%]) and renal cell carcinoma (n = 12 [17.9%]). Median (range) age at treatment was 63 (8–87) years. The mean ± SD (range) number of levels treated was 1.5 ± 0.7 (1–4) levels. Mean ± SD (range) bone density at S1 was 208.0 ± 74.4 (−3.0 to 443.3) Hounsfield units (HUs). Median (range) follow-up was 16.6 (1.5–132) months, median ± SD (range) overall survival was 24 ± 21.0 (1.7–83.3) months, and the 1-year local control rate was 83.6%. Fourteen patients (20.9%) experienced fracture within the radiation field. There was no association between fracture and patient sex (p = 0.32), age (p = 0.40), S1 HU (p = 0.28), tumor location according to Denis classification (p = 0.87), presence of pain (p = 0.66), single versus multifraction radiation (p = 0.44), or number of levels treated (p = 0.52). Patients experiencing in-field progression were more likely to experience fracture (61.5% vs 10.2%, p < 0.001), and patients experiencing fracture had a higher average Spine Instability Neoplastic Score than patients without fracture (5.7 vs 4.3, p = 0.049). Only local control remained as a factor associated with sacral fracture in the multivariate analysis. Of the patients experiencing fracture, 10 (71.4%) were symptomatic and 3 of those (30.0%) underwent post-SSRS surgical intervention. CONCLUSIONS Pathologic fracture may occur after sacral SSRS in a significant number of patients and is significantly associated with failure of local control.

PURPOSE Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+HER2–) patients from five IO arms. METHODS A total of 204 HR+HER2– (MammaPrint high-risk) patients from five IO arms (anti–PD-1, anti–PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti–PD-1/toll-like receptor 9 dual-IO combination, and anti–PD-1 ± lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint+ (likely sensitive) versus ImPrint– (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%). RESULTS Overall, the pCR rate across the five IO arms was 33%. 26% of HR+HER2– patients were ImPrint+, and pCR rates with IO were 75% in ImPrint+ versus 17% in ImPrint–, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint–. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR = 14.5). CONCLUSION Using an accurate selection strategy, HR+HER2– patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR+HER2– patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.

Although innovation in cancer treatment has improved cure rates and survival, the costs have escalated beyond societies' ability to pay. Cancer care costs in the United States are expected to rise to 245 billion by 2030. In this health policy session, we focused on three cost-containment strategies, and their potential impact on cancer care delivery. Site Neutrality: Curbing the Cost of Cancer Care, but at What Risk? , explores legislation that would introduce payment parity across differing sites of care: elimination of facility fees in hospital owned practices and shift of billing for oncology infusions away from hospital owned practices. Unintended consequences could reduce access to care for vulnerable populations, shift costs to patients, and reduce safety. Post-Pandemic Digital Health Reimbursement: Impact on Access to Care , explores how the emergency waivers, licensure flexibilities, and parity reimbursement necessitated by COVID-19 shepherded innovation that outpaced the regulatory framework needed for long-term sustainability. Today, telehealth services, hospital at home, remote patient monitoring, and decentralized clinical trial enrollment face reintroduction of regulatory and payment barriers. Will we live to see efficacy-based pricing for cancer drugs? Learning from international models , explores how lack of drug price negotiation has led to higher prices in the United States compared with Canada and Europe. Comparative clinical effectiveness pricing systems compare the value of each drug to standard treatments. Comparative cost-effectiveness programs look at the incremental cost per additional unit of health gained above the standard of care. The United States could learn from these approaches used in comparable countries.

Background/Objectives: Adjuvant radiation for gynecologic malignancies often exposes organs at risk (OARs), such as the bone marrow, bowel, rectum, and bladder, to radiation, leading to toxicities that impact treatment tolerance and patient quality of life. Scanning proton beam therapy, particularly with Individual Field Simultaneous Optimization (IFSO), may offer dosimetric and biological advantages over volumetric modulated arc therapy (VMAT). This study evaluates the clinical impact of IFSO-based proton planning in post-operative gynecologic cancer patients. Materials and Methods: Fourteen patients receiving adjuvant proton therapy to 45 Gy in 25 fractions were retrospectively analyzed. Comparison VMAT plans were generated on the same datasets. Dose–volume metrics for key OARs and normal tissue complication probabilities (NTCPs) were compared using paired statistical tests. Robustness evaluations accounted for setup and range uncertainties. Results: Proton plans significantly reduced dose to bone marrow (V10Gy: 58% vs. 86%, p < 0.00001; V20Gy: 47% vs. 58%, p < 0.00001), small bowel (V20Gy: 21% vs. 56%, p < 0.00001), and femoral heads (left femoral head mean: 11Gy vs. 13Gy, p = 0.032; right femoral head mean: 11Gy vs. 13Gy, p = 0.022). NTCP modeling predicted significantly lower rates of bowel urgency (9.4% vs. 3.3%, p < 0.001) and hematologic toxicity (10.2% vs. 4.9%, p < 0.001) with proton therapy. Plans remained robust across uncertainty scenarios. Conclusions: IFSO-based scanning proton therapy provides clinically meaningful sparing of bone marrow and bowel, with the potential to reduce hematologic and gastrointestinal toxicities. These findings support its use in patients receiving adjuvant pelvic radiotherapy, particularly those undergoing extended field treatment or chemotherapy.