Citations

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

Kidney dysfunction after heart transplantation (HT) is associated with significant morbidity and mortality. Recipient and perioperative factors may all influence the risk of kidney injury. Furthermore, data suggest that the incidence of kidney dysfunction, both acute and chronic, is increasing after the implementation of the United States’ 2018 allocation system due to increasing use of temporary mechanical circulatory support and changing recipient characteristics. While data are robust regarding nephroprotective therapies such as renin-angiotensin-aldosterone system inhibition and SGLT2i (sodium-glucose cotransporter 2 inhibitors) to minimize the progression of chronic kidney disease in patients with heart failure, data in HT recipients are beginning to emerge. This state-of-the-art review will critically examine the existing literature regarding the epidemiology of kidney dysfunction after HT, mitigation strategies for acute kidney injury and chronic kidney disease, including pharmacotherapeutics, the need for kidney transplantation after HT, and practical next steps for the larger HT community.

Background/Objectives: Diagnostic evaluation and management of nontraumatic osteonecrosis of the femoral head (ONFH) vary substantially. This systematic review was conducted to inform development of the Association Research Circulation Osseous (ARCO) clinical practice guideline for diagnosis and treatment of ARCO stages I to III ONFH. Methods: We searched MEDLINE, EMBASE, Web of Science, SCOPUS, Global Index Medicus, and the Cochrane Library for studies evaluating imaging modalities and treatments for adult ONFH. We assessed risk of bias using the QUADAS-2, the ROB-2, and the ROBINS-I tools; conducted meta-analyses using random-effects regression; and evaluated certainty of evidence using GRADE methodology. Results: Among 36 included studies, 18 addressed diagnostic test accuracy and 18 addressed comparative effectiveness of treatments. Magnetic resonance imaging (MRI) demonstrated the highest pooled sensitivity (0.91; 95% confidence interval (CI), 0.87 to 0.94) and specificity (0.96; 95% CI, 0.87 to 0.99) for ONFH diagnosis. Bone marrow edema and grade 2+ joint effusion on MRI differentiated symptomatic versus asymptomatic disease. Computed tomography and MRI better detected subchondral fractures than plain radiography. Very low-grade evidence suggested lower rates of femoral head collapse with core decompression plus bone marrow concentrate compared with core decompression alone (pooled relative risk [RR], 0.55; 95% CI, 0.36 to 0.83), and with vascularized versus non-vascularized bone grafting (RR, 0.35; 95% CI, 0.14 to 0.84) over a ≤5-year follow-up. Based on three non-comparative case series, osteotomies might have a lower risk of collapse over a 10- to 20-year follow-up, but this needs to be evaluated in future comparative research. Inconsistent outcome reporting hindered treatment outcome pooling. There were no comparative studies that evaluated observation only versus intervention in asymptomatic disease or strategies for monitoring treatment response. Conclusions: Evidence supporting optimal imaging modalities and early joint-preserving interventions remains limited and predominantly observational, underscoring the need for high-quality comparative studies with consistently defined core outcomes to guide clinical decision-making.

According to the current WHO classification, noninvasive germ cell neoplasia of the testis comprises germ cell neoplasia in situ (GCNIS), specific forms of intratubular germ cell neoplasia, and gonadoblastoma. Because type II germ cell tumors (GCT, type II) arise from GCNIS, accurate detection of precursor lesions is diagnostically important. In preparation for the 2024 International Society of Urological Pathology (ISUP) Consensus Conference on genitourinary precursor lesions, which took place in Florence, Italy, an anonymous survey was distributed to ISUP members to assess current diagnostic practices regarding testicular precursor lesions. The literature and current WHO classification affirm the significance of precursor lesions in testicular tumours. Working Group 4—Precursor Lesions of the Testis—focused on their practical application by individual pathologists rather than establishing consensus from scientific data. There is strong agreement that GCNIS is the preferred and appropriate term for GCT precursor lesions and that its presence should be reported in cases of invasive GCT. Respondents also agree that “seminoma with intratubular nonseminoma” is the appropriate terminology for seminoma with an associated noninvasive nonseminomatous (embryonal carcinoma, yolk sac tumor, trophoblasts, or teratoma) component. Most pathologists prefer to use OCT3/4 as the primary immunohistochemical marker, and a panel was generally not considered necessary. No consensus is reached regarding the requirement for immunohistochemistry to confirm GCT precursor lesions in the testis. Three questions remain open: the value of subtyping intratubular lesions, the immunohistochemical approach to gonadoblastoma, and the criteria distinguishing Sertoli cell nodules from Sertoli cell tumors.

Abstract IBC Clear: A decentralized multi-center MRD Registry for Inflammatory Breast CancerInflammatory breast cancer is an aggressive subtype of breast cancer with distinct clinical phenotypes, including early recurrence post-tri-modal care (neoadjuvant systemic therapy, surgery, adjuvant radiation). Preliminary data from MDACC have shown a high rate of baseline and serial MRD positivity in IBC patients (35-40% at 6-12 months post-surgery), suggesting that newly diagnosed IBC is an ideal population to test MRD as a standard of care and design adjuvant interventional trials. However, to date, our understanding of the optimal monitoring cadence and interventions following MRD positivity remains limited. IBC Clear is a decentralized protocol developed to collect real-world data from patients treated amongst our IBC Connect network of 19 US-based and three international institutions (7 of whom have expressed interest in participating). Patients who have had, or plan to have Signatera® ordered at the post-chemo/pre-surgery timepoint can self-enroll from the community by emailing IBCClear@mdanderson.org for information on the consent process. Study Design: Eligibility criteria include English-speaking patients > 18 years of age with a clinical diagnosis of IBC, with Signatera testing ordered or planned. The post-chemo/pre-surgery timepoint is the only study-mandated timepoint; however, any additional serial testing conducted before or after this timepoint will also be collected. Patients who have at least one Signatera test ordered and plan to have a pre-surgery/post-chemo collection as standard of care will be enrolled in a central REDCap database. Physicians enrolling patients may act on the results according to their clinical judgment, including imaging assessments and treatment changes. These interventions will be captured in the database. An electronic EORTC QLQ C30 survey will also be administered prior to and after receiving Signatera results to gather information about the impact of testing on the patient's quality of life. A total of 200 patients from all sites will be enrolled over a period of two years. Patients will be followed remotely for up to 2 years from the first Signatera test or until clinical recurrence, whichever comes first. Endpoints: Data collected will include the feasibility of decentralized data collection studies, as well as Signatera and recurrence information. The goals are to gather real-world data regarding the association of MRD positivity with pathologic response in IBC, patient-reported QOL for worry about recurrence, median lead time between the first MRD-positive result and clinical recurrence, and, if possible, whether the adjuvant therapies decrease the amount of MRD in IBC patients (pending optional longitudinal testing). Status of the study: The study was activated in June 2025. As of abstract submission, 2 patients have been enrolled at the lead site. Collaborating sites are being added. Sponsor: The University of Texas MD Anderson Cancer Center Clinicaltrials.gov Accession number: NCT06966050 Citation Format: A. Alexander, M. Kai, K. A. Abou-Hussein, S. Ali, C. Anderson, S. W. Bahadur, Y. C. Cheng, N. T. Ueno, X. Wang, A. Lucci, W. A. Woodward, S. Saleem, MDACC Inflammatory Breast Cancer Team. PS2-02-05: Ibc clear: a decentralized multi-center mrd registry for inflammatory breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-02-05.

Abstract Introduction and rationale: There is a wide-spread urgent need for an objective reproducible diagnostic tool capable of precisely classifying atypical mammary lesions into cancer vs. benign. Current diagnostic methods in pathology rely on routine and highly subjective histomorphologic and immunophenotypic features. Some authors report a 35% error rate in pathologic interpretation of atypical lesions of the breast (Elmore, 2015). Diagnostic variability can drop to the flip-of-the-coin 50%, even amongst expert breast pathologists (Tozbekian, 2017; Samples, 2017) and is largely attributed to the lack of innovative tools to adequately distinguish biologic differences (Allison, 2016), resulting in diagnoses that are described as “murky” and “arbitrary” (Khoury, 2022). Genomic imprinting, a vital epigenetic regulatory mechanism, is critical in mammalian development and tumorigenesis (Barlow, 2014, Murrell, 2006). Typically, imprinted genes exhibit parent-specific allele silencing through differential methylation. However, in cancer, this regulation often breaks down, resulting in the aberrant activation of the typically silenced allele—a phenomenon known as loss of imprinting (LOI) (Jelinic, 2016). LOI is considered one of the earliest molecular changes in cancer development, occurs early in tumorigenesis, making it ideal for identifying precursor lesions. Objectives: We hypothesize loss of imprinting (LOI) can be developed as a diagnostic, predictive and prognostic novel epigenetic marker (Quantitative Chromogenic Imprinted Gene In-Situ Hybridization, QCIGISH) for breast precancerous lesions and cancer detection. Our objective is to initiate a proof of concept for atypical breast lesions with QCIGISH and develop a diagnostic model. Methods: We retrospectively identified benign, atypical, and carcinoma core needle specimens from year 2023 in the Department of Pathology at Mayo Clinic Florida. Inclusion criteria included female patients, ages 18-99, with archived breast material obtained through standard of care (n=20). All diagnoses were ascertained by a breast pathologist (MKK). Following a thorough literature review, we processed the material for in situ hybridization, and pretreated with RNA scope preparation procedure using probes targeting noncoding intronic regions of nascent RNAs (QCIGISH). Based on high Area Under the Receiver Operating Characteristics Curve (AUROC), 2 genes - HM13 and GRB10 were identified as the most promising candidates for classification with QCIGISH. Upon test completion, the detected gene-expression site appeared as a distinct red dot on the slide under the common bright-field microscope. Next, the gene expression signals were counted and further classified as bi-allelic (BAE), multi-allelic (MAE) and total expression (TE). Results: A decision tree model based on BAE, MAE, and TE metrics showed differential signal expression. High MAE was a strong predictor for malignancy. We achieved 100% sensitivity and specificity with the ground truth, thereby initiating proof of concept. Furthermore, one histomorphologically challenging atypical lesion, for which the positive LOI finding accurately classified as ductal carcinoma in situ (DCIS), was confirmed indeed DCIS by ground truth validation on the excision specimen. Conclusion: We have demonstrated a breakthrough molecular biomarker that is fully objective, reproducible, and practical. First of its kind, the innovative QCIGISH has superior performance than the current standard of care in breast cancer diagnostics allowing for single-cell resolution of epigenetic changes. Next, we seek to undergo full model validation. Citation Format: M. Abdollahi Neisani, R. Guo, T. Cheng, M. K. Komforti. Epigenetic Imprinting as a Novel Precision Biomarker for Early Breast Cancer and Precancer Diagnosis and Detection [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-07-09.

Background The use of 3D imaging with navigation bronchoscopy has increased with the introduction of mobile cone-beam CT (mCBCT). Shape-sensing robotic-assisted bronchoscopy (ssRAB) integrated with mCBCT has been introduced to correct for CT to body divergence (CT-BD) during the biopsy of peripheral pulmonary nodules (PPNs). Methods Prospective observational multicentre study, enrolling patients with a PPN of ≤20 mm suspicious for malignancy, assessing tool-in-lesion (TIL), diagnostic yield, sensitivity for malignancy and incidence of pneumothorax or airway bleeding. Non-malignant index biopsies were followed for 12 months. Descriptive statistics are reported for all variables along with 95% CI for primary endpoints. Results 155 consecutive patients were enrolled at six centres. Median nodule size was 14.0 mm (IQR 11.0–17.0), with 54.8% of nodules (85/155) in the upper lobes, 25.8% (40/155) with CT bronchus sign present and median distance to the nearest pleural surface of 8.2 mm (IQR 1.8–20.0). TIL was achieved in 154/155 (99.4%, 95% CI 96.5 to 100.0) procedures. A median of two (IQR 1–3) mCBCT spins were performed, with median dose area product of 25.7 Gy · cm 2 (IQR 11.0–46.7). Diagnostic yield per the American Thoracic Society/American College of Chest Physicians (ATC/ACCP) definition was 89.0% (n=138/155; 95% CI 83.0 to 93.5) and sensitivity for malignancy was 91.5% (95% CI 86.4 to 96.5). No pneumothorax (0%, 95% CI 0.0 to 2.4) and two Nashville Grade three bleeding events were reported (1.3%, 95% CI 0.2 to 4.6). Interpretation The first prospective multicentre study of integrated ssRAB and mCBCT for small peripheral nodules resulted in diagnostic outcomes similar to those reported for transthoracic biopsy with a more favourable safety profile. Trial registration number ClinicalTrials.gov ID: NCT05562895 .