Citations

Abstract Purpose: Around 10% to 15% of prostate cancers harbor recurrent aberrations in the Forkhead Box A1 gene, FOXA1, whereby the alteration type and the effect on the forkhead (FKH) domain affect protein function. We developed a FOXA1 classification system to inform clinical management. Experimental Design: A total of 5,014 prostate cancer samples were examined using whole-exome and -transcriptome sequencing from the Caris Life Sciences database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain. These were in the first part of the FKH domain [class 1A: amino acids (AA) 168–246], within the Wing2 region of FKH (class 1B: AA 247–269), or outside FKH (class 1C: AA 1–167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1–269 and class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims. Results: FOXA1 alterations did not influence survival when considered in aggregate but had distinct prognostic effects when stratified by class. In primary prostate samples, class 1A alterations were associated with overall improved survival (HR, 0.57; P = 0.03); a similar trend was seen in metastatic biopsies with class 1B (HR, 0.84; P = 0.09). Conversely, in primary specimens, class 1C exhibited worse survival upon second-generation androgen receptor signaling inhibitor treatment (HR, 1.93; P < 0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR, 2.05; P < 0.001) and worse outcomes to first-line androgen-deprivation therapies (HR, 2.5; P < 0.001). Class 3A alterations indicated improved survival (HR, 0.70; P = 0.01), whereas class 3B alterations portended poor outcomes (HR, 1.50; P < 0.001). Amplifications (class 4) indicated poor outcomes in metastatic samples (HR, 1.48; P = 0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European Americans, African Americans had increased class 1C alterations, whereas Asian/Pacific Islander patients had increased class 1B alterations. Conclusions: FOXA1 alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision-making for patients with prostate cancer and uncovers important racial differences.

Indications for and implications of germline genetic testing (GGT) in patients with prostate cancer have expanded over the past decade, particularly related to precision therapies and management. GGT has become the standard of care for many cancers such as breast, ovarian, colorectal, pancreatic, and metastatic prostate cancer, and it is imperative that patients be offered timely and equitable access to testing as it can inform patient-physician shared decision making for management of the current cancer as well as anticipatory guidance for disease progression. Additionally, GGT guides screening for and prevention of secondary malignancies for the patient and cascade testing for at-risk family members. Here, we present data supporting the notion that clinicians should offer all patients with prostate cancer the opportunity to undergo comprehensive GGT for pathogenic germline variants known to be associated with familial cancer and/or known to have implications for treatment and management.

Abstract Struma ovarii (SO) is a rare subtype of ovarian teratoma composed of more than 50% thyroid tissue. Extraovarian spread of SO, called peritoneal strumosis, was previously considered benign given the lack of histological malignant features. However, the 2020 World Health Organization Classification of Female Genital Tumors reclassified peritoneal strumosis as highly differentiated follicular carcinoma of ovarian origin (HDFCO), highlighting its low-grade malignant potential. We present a 38-year-old woman with SO treated initially with right salpingo-oophorectomy, with recurrence 2 years later with multifocal metastatic lesions in the abdomen and pelvis that was successfully treated with surgical resection, total thyroidectomy, and 157 mCi of I-131. Tumor molecular testing revealed a pathogenic DICER1 variant (c.5428G>T, exon 25). A second variant (c.319delinsTGCTGGTTTGACA, exon 4) was of uncertain significance. Germline testing confirmed the second DICER1 variant and also identified an increased risk variant in the APC gene (c.3920T>A). This is a rare case of extensive HFDCO with DICER1 variants, which has been associated with thyroid cancer. Given the germline DICER1 variant, this may also represent the first reported instance of DICER1 syndrome manifesting as HDFCO. Further research into the prognostic factors and optimal treatment of HFDCO is needed.

Introduction Genomic alterations are common in multiple myeloma precursor stages, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, commonly used stratification systems do not include somatic alterations that play a role in the disease. To address this clinical need, we generated a comprehensive genomic map of MM and precursors by harmonizing and analyzing mostly WGS data from 1,030 patients. We used these data to define a simple MM-like score, that is able to discriminate which premalignant patients are at risk to progress. Methods We collected, enriched, and performed WGS of tumor plasma cells and matched normals from 138 participants with MGUS or SMM, including those in low, intermediate, and high-risk groups. We combined our precursor dataset with genomic profiles from MM (n=20) and external sources of 872 individuals with MGUS (n=18), SMM (n=62), and MM (n=792) for a cohort of 1,030 individuals with MM or a precursor condition. In 16 patients, we could perform WGS serially from the bone marrow or circulating tumor cells (n=39) and reassess the presence of mutations. Results To develop a simple score that reflects the similarity of precursor genomes to full-blown multiple myeloma disease, we searched among the 107 common driver events (occurring in >1% of patients) and initiating translocations for ones that are differently altered in precursor conditions versus MM. We found 26 differentially altered events: only MAF and MAFB translocations were enriched in MGUS/SMM whereas 24 events were enriched in MM, including known drivers MYC, KRAS, FAM46C, del(1p) and gain(1q). We then defined a simple “MM-like” score for each tumor as the number of MM-enriched drivers minus the number of MGUS-enriched drivers. As expected, the MM-like score in our cohort increased throughout MM development (MM-like score median of 1 in MGUS, 2 in SMM, and 3 in MM). Even among SMM patients, we found a gradual increase of the MM-like score from low- (median=1), to intermediate (median=2), to high-risk (median=3) groups that match the overall medians in MGUS, SMM and MM (p=2e-5). We tested whether the MM-like score can be used to estimate risk of progression. Among untreated SMM patients characterized with WGS, an MM-like score greater than 2 was associated with a higher likelihood of progression (HR=5.3, P=0.03). Using an independent dataset of 87 patients with SMM, we were able to validate that a MM-like score greater than 2 was indeed associated with a higher risk of progression (HR=3.3, P=5x10-5). 11 patients who did not progress and for whom we performed longitudinal WGS, has stable MM-like scores over time, while three patients clinically progressed and their MM-like score increased at the time of progression (due to newly detected mutations in KRAS and NRAS). For the two remaining patients, their MM-like score increased, and we observed growth of the subclone that acquired the additional MM-like driver. In the first patient with MGUS/low-risk SMM, a novel hyperdiploid clone was detected in addition to a TP53 bi-allelic hit and t(11;14) translocation and was shown to increase in clonal fraction with tumor burden (light chains +104% within three years). In the second non-progressor with an increasing MM-like score, a novel del(1p) was detected, and other subclones in the phylogenetic tree either shrank or were stable over three years. Finally, because the MM-like score can place tumors on a gradual axis of evolution towards a more genomically-mature tumor, we tested whether the MM-like score was also predictive of survival in patients treated with a newly diagnosed MM. To do so, we calculated the MM-like score in patients from the publicly available CoMMpass database. We found that an increased score significantly correlated with shorter progression-free survival (median PFS1: 3 years in high score, versus 5 years in low/intermediate score; p=1e-3) and overall survival (median OS: 4.5 years in high score, versus not reached in low/intermediate score; p=1e-5). Conclusion Overall, we demonstrate that it is possible to stratify precursor stages of MM by discovering drivers, detecting those that are associated with the stage of the disease, and defining a genomically-based score that can be used to assess risk of progression and is easy to implement in the clinic.

Background: Two National Cancer Institute-funded pharmacovigilance programs have identified 49 serious hematology-related ADRs since 1998. The programs, called RADAR (Research on Adverse Drug events and Reports) and then SONAR (Southern Network on Adverse Reactions) involve > 50 institutions and > 75 co-investigators worldwide. The work builds on three prior studies evaluating “Davids and Goliaths” in medical oncology and in cardiology (PLOS One, eClinicalMedicine, and Journal of Scientific and Professional Integrity). Here we review the hematology focused safety investigations of RADAR/SONAR. Methods: Data were based on initial safety signals being identified by a RADAR/SONAR co-investigator. Then, case-series were derived. Collaborations with basic scientists allowed for basic science correlative studies. Results were disseminated primarily as Brief Report in the literature and Black Box warnings on the related drug. In some instances, studies identified hematologic toxicities that prevent FDA from approving a submitted drug application. Results: sADRs were frequently identified based on very small case series, including ticlopidine-and clopidogrel associated thrombotic thrombocytopenic purpura (22 and 10 patients, respectively), thalidomide- and lenalidomide-associated venous thromboembolism (9 and 5 patients, respectively), rituximab-associated progressive multi-focal leukoencephalopathy (22 patients), peginesatide-associated fatal anaphylaxis (5 patients), and COVID-19 vaccine associated immune thrombocytopenia (1 patient). Meta-analyses provided data for epoetin- and darbepoetin-associated mortality among cancer patients and lenalidomide- and thalidomide-associated venous thromboembolism. Following the onset of the COVID-19 pandemic, RADAR/SONAR investigated social media and pre-prints (COVID-19 vaccine associated cerebral vein thrombosis and immune thrombocytopenia). Time from FDA approval to sADR discovery was a median of 5 years (range, 0 months (thalidomide-associated venous thromboembolism) to 34 years (ciprofloxacin-associated neuropsychiatric toxicity). Basic science correlative studies identified ADAMTS13 autoantibodies (ticlopidine), leachates that developed in a multi-dose vial (peginesatide), anti-red blood cell antibodies (epoetin-associated pure red cell aplasia), and high-risk genes (fluoroquinolones and rituximab). Overall, RADAR/SONAR studies are estimated to have saved over 1 million lives and also resulted in overall payments to the Department of Justice of $1.5 billion (related to marketing of unsafe drugs). Discussion: RADAR/SONAR has proven to be a very important adjunct to FDA and pharmaceutical manufacturer-led safety investigations for hematology, paralleling the success in medical oncology and in cardiology. Going forward, independent centers of excellence for safety-focused investigations such as the CERSI network and the SENTINEL network (both are NIH funded) should be broadened to include a hematology-focused safety center.

Background: Erdheim-Chester disease (ECD) manifests as multi-organ infiltration of clonal histiocytes with mutations primarily in the mitogen-activated protein kinase (MAPK) pathway. The revised classification of histiocytosis (2016) categorizes ECD with typical bilateral, symmetric osteosclerosis of the lower extremity long bones as classical (C) and as non-classical (NC) if otherwise. The clinical and biological significance of this classification is unclear. This study compared the clinical and genotypic findings of the 2 subtypes within a large cohort of ECD patients. Methods: We included patients seen at our institution since 1990 meeting the following criteria: A) had an ECD diagnosis based on the revised criteria by Haroche J, et al. (Blood 2020;135:1311-1318); B) completed whole-body imaging studies including long bones of the legs. Classification as C-ECD required symmetric osteosclerosis of the distal femur and/or proximal tibia/fibula. Results: A total of 145 patients were enrolled, comprising a male-to-female ratio of 2:1 (66.2% male). C-ECD was diagnosed in 77.2% of cases, and NC-ECD in 22.8%. The median age at diagnosis was similar with 58.5 years (range, 18-82) in C-ECD and 55 years (range, 20-81) in NC-ECD, (p=0.65). The most frequently affected systems included skeletal (81.4%), renal (60.0%), vascular (45.5%), cardiac (40.0%), central nervous (38.6%), sinus (37.2%), pulmonary (36.6%), and adrenal (32.4%). The numbers of organs involved were significantly higher in C-ECD compared to NC-ECD (median 5 vs 3, p<0.01). Higher rates of skeletal (100% vs. 18.2%, p<0.01), adrenal gland (37.5% vs. 15.2%, p=0.02), and sinus (44.6% vs. 12.1%, p<0.01) involvement were observed in C-ECD. Arginine vasopressin deficiency (AVP-D) was exclusively observed in C-ECD (20.7% vs. 0%, p<0.01). NC-ECD had a higher rate of cardiac involvement (69.7% vs. 31.3%, p<0.01). No significant differences were found in other systems. The overall median time between onset of the first symptoms/signs to diagnosis was 15 months with no significant difference between C-ECD and NC-ECD (17.5 vs. 12 months, p=0.18). The median time to diagnosis of ECD in patients with AVP-D was 38.5 months, compared to 12 months without AVP-D (p=0.09). Genetic testing was conducted in 86.2% of patients and B-Raf proto-oncogene (BRAF) alterations were identified in 59.2% of the tested cases. BRAFV600E was more prevalent in C-ECD (61.3% vs. 21.9%, p<0.01), whereas non-V600 mutations were more commonly found in NC-ECD (12.5% vs. 1.1%, p<0.01). There was no significant difference in the frequency of BRAF fusions. NC-ECD patients exhibited a higher rate of MAP2K1 mutations (25.0% vs. 5.4%, p<0.01). Other frequently mutated genes included KRAS (4.0%), NRAS (2.4%), and CSF1R (2.4%), although no significant difference was observed in their frequency between C-ECD and NC-ECD. Testicular involvement appeared to be more common in patients with MAP2K1 mutations (23.1% vs. 8%, p=0.08). Two patients with pathogenic CSF1R mutations both had central nervous system (CNS) involvement. Among C-ECD patients, BRAFV600E conferred a higher rate of CNS involvement (50.9% vs. 25%, p=0.01). No significant difference was observed in NC-ECD patients (71.4% vs 36%, p=0.09). Among NC-ECD cases, MAP2K1 mutations conferred a reduced risk of cardiac involvement (37.5% vs. 79.2%, p=0.03) and no such difference was observed in patients with C-ECD (40% vs 34.1%, p=0.79). The median numbers of organs involved in patients with BRAF, MAP2K1, and KRAS/NRAS mutations were 5, 3, and 3, respectively, with no significant difference. Conclusions: C-ECD affects more organs and more frequently involves bones, adrenal glands, and sinuses. AVP-D was exclusively observed in C-ECD. Conversely, NC-ECD showed a higher prevalence of cardiac involvement. BRAFV600E was more commonly identified in C-ECD, whereas non-V600 mutations and MAP2K1 mutations were more prevalent in NC-ECD. Among C-ECD patients, BRAFV600E was correlated with a greater likelihood of CNS involvement. Conversely, NC-ECD patients with MAP2K1 mutations had a reduced risk of cardiac involvement. This study highlights the distinct clinical and molecular features of C-ECD and NC-ECD, underscoring the importance of subclassifying ECD into classical and non-classical forms. Further studies are needed to explore differences in the clinical outcomes between the 2 forms.

Introduction: Heparin induced-thrombocytopenia (HIT) is a severe autoimmune reaction to heparin that increases patients' risk of developing venous thrombosis, leading to fatal conditions such as pulmonary embolism. The clinical 4T scoring system guides need for further testing, based on noting fall in platelet counts, the timing of platelet counts falling in conjunction with heparin exposure, the presence of new thromboses, and ruling out other causes of thrombocytopenia. In patients in whom 4T scoring indicates a higher protest probability for HIT, screening is then performed. The Enzyme-Linked Immunosorbent Assay (ELISA) detects antibodies against platelet factor 4 (PF4)-heparin complexes. In order to confirm the diagnosis of HIT, the serotonin release assay testing is required, which refers to measuring the serotonin levels produced during platelet activation using radio-labeling techniques. Since the start of the COVID-19 Pandemic in 2020, there has been ongoing discussion regarding whether incidence of HIT diagnosis has increased. Herein we report on a retrospective observational study of a cohort of patients seen at a community hospital in Georgia between March 2017 to December 2022 to determine the changes in frequency of HIT and SRA testing, and to assess its association with the COVID-19 pandemic. Methods: We included patients aged >18 years, hospitalized at a community hospital in Georgia during the study duration and de-identified data was collected from electronic medical records. Text-based data analysis was performed to identify those patients who received HIT testing, SRA testing, and ultimately a final diagnosis of HIT (HIT positive and SRA positive). The overall rates of 4T scoring documentation and assessment in the hospital were also assessed. Several multivariable logistic regression models were constructed to examine factors associated with HIT testing and SRA testing, and their association since the start of the the COVID-19 pandemic (March 2020). Results: A total of 244,457 patients were included in the study population. Of them, 2,375 (0.97% of total) patients were tested with the HIT-ELISA, and only 468 (0.19% of total) patients were tested with SRA. In further subgroup analysis, evaluating the temporal associations of HIT and SRA testing, it was observed that the rate of HIT-ELISA testing increased since the onset of the COVID-19 pandemic, as did the rate of SRA testing (p < 0.000). Notably, of the 2,375 patients who received the HIT-ELISA testing, only 193 (8% of HIT-tested patients) had documentation of clinical suspicion of HIT with the 4T score. Discussion: An increase in HIT and SRA testing has been observed since the start of COVID-19 pandemic, with a notable lack of 4T score data in the study population preceding this testing. This study emphasizes the importance of clinician education regarding the process of accurate HIT diagnosis, which would start with clinical 4T scoring, followed by ELISA testing for screening, and finally confirmed by SRA testing. Further research is warranted to understand the barriers that may exist in providing guideline-directed evaluation of HIT so that targeted interventions can be implemented to ensure high-quality care is delivered to patients.

Abstract Senescent cells drive tissue dysfunction through the senescence-associated secretory phenotype (SASP). We uncovered a central role for mitochondria in the epigenetic regulation of the SASP, where mitochondrial-derived metabolites, specifically citrate and acetyl-CoA, fuel histone acetylation at SASP gene loci, promoting their expression. We identified the mitochondrial citrate carrier (SLC25A1) and ATP-citrate lyase (ACLY) as critical for this process. Inhibiting these pathways selectively suppresses SASP without affecting cell cycle arrest, highlighting their potential as therapeutic targets for age-related inflammation. Notably, SLC25A1 inhibition reduces systemic inflammation and extends healthspan in aged mice, establishing mitochondrial metabolism as pivotal to the epigenetic control of aging.

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.

Background: Traumatic carotid artery pseudoaneurysms (PSAs) represent a vascular anomaly with potential for serious complications, including stroke. Traditional treatments involve endovascular stenting, which may not be ideally suited to otherwise healthy vessels that have the potential to remodel. Given the limitations of smaller animal models in replicating human vasculature and the need for improved treatment modalities, this study introduces a novel swine model for the creation and evaluation of carotid PSAs. Methods: The PSAs were created from bovine dura and anastomosed in an end-to-side fashion to bilateral carotid arteries. The PSAs were radiologically followed up post-operatively and were harvested at 3 and 10 days for histological analysis. Results: Pseudoaneurysms were successfully created in both animals without intra-operative or immediate post-operative complications. Radiological analysis showed well-perfused PSAs with intra-aneurysmal turbulence, hemodynamically mimicking human carotid artery PSAs. There was no evidence of thrombus or arterial stenosis. Histological examinations revealed thrombus maturation and tight anastomosis of the PSA sac with the native artery. Conclusions: This PSA swine model offers a replicable, cost-effective, and easily implemented tool with the potential to advance carotid PSA management and educational efforts in vascular surgery. Clinical Impact The model presented in this methodology paper allows for a standardized PSA animal model allowing for the standardization of a clinical entity which is frequently heterogenenous in morphology. This can allow for the development of new therapies or provide a ground truth for computer modelling for further in silico study.