Integrated epigenetic and transcriptional single-cell analysis of t(11;14) multiple myeloma and its BCL2 dependency.

ABSTRACT: The translocation t(11;14) occurs in 20% of patients with multiple myeloma (MM) and results in the upregulation of CCND1. Nearly two-thirds of t(11;14) MM cells are BCL2 primed and highly responsive to the oral BCL2 inhibitor venetoclax. Although it is evident that this unique sensitivity to venetoclax depends on the Bcl-2 homology domain 3- proapoptotic protein priming of BCL2, the biology underlying t(11;14) MM dependency on BCL2 is poorly defined. Importantly, the epigenetic regulation of t(11;14) transcriptomes and its impact on gene regulation and clinical response to venetoclax remain elusive. In this study, by integrating assay for transposase-accessible chromatin by sequencing (ATAC-seq) and RNA-seq at the single-cell level in primary MM samples, we have defined the epigenetic regulome and transcriptome associated with t(11;14) MM. A B-cell-like epigenetic signature was enriched in t(11;14) MM, confirming its phylogeny link to B-cell rather than plasma cell biology. Of note, a loss of a B-cell-like epigenetic signature with a gain of canonical plasma cell transcription factors was observed at the time of resistance to venetoclax. In addition, MCL1 and BCL2L1 copy number gains and structural rearrangements were linked to venetoclax resistance in patients with t(11;14) MM. To date, this is the first study in which both single-cell (sc) ATAC-seq and scRNA-seq analysis are integrated into primary MM cells to obtain a deeper resolution of the epigenetic regulome and transcriptome associated with t(11;14) MM biology and venetoclax resistance.

Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma.

B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.

The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients.

Bispecific T cell engagers (TCEs) have shown promise in the treatment of various cancers, but the immunological mechanism and molecular determinants of primary and acquired resistance to TCEs remain poorly understood. Here, we identify conserved behaviors of bone marrow-residing T cells in multiple myeloma patients undergoing BCMAxCD3 TCE therapy. We show that the immune repertoire reacts to TCE therapy with cell state-dependent clonal expansion and find evidence supporting the coupling of tumor recognition via major histocompatibility complex class I (MHC class I), exhaustion, and clinical response. We find the abundance of exhausted-like CD8+ T cell clones to be associated with clinical response failure, and we describe loss of target epitope and MHC class I as tumor-intrinsic adaptations to TCEs. These findings advance our understanding of the in vivo mechanism of TCE treatment in humans and provide the rationale for predictive immune-monitoring and conditioning of the immune repertoire to guide future immunotherapy in hematological malignancies.

Transarterial Yttrium-90 Glass Microsphere Radioembolization of Chemotherapy-Refractory Breast Cancer Liver Metastases: Results of a Single Institution Retrospective Study.

PURPOSE: Our purpose was to retrospectively evaluate the safety and efficacy of transarterial hepatic radioembolization (TARE) treatment with yttrium-90 labeled glass microspheres in patients with chemotherapy-refractory breast cancer with liver-dominant metastatic disease. METHODS AND MATERIALS: This retrospective single-institution study evaluated 31 female patients (mean age of 59.6 ± 13.2 years) who were treated with TARE. All patients received and progressed on systemic chemotherapy before TARE. Twenty-one patients also had extrahepatic metastases, including 13 patients who had metastases in bones only besides the liver. Survival data were analyzed by Kaplan-Meier method and compared using log-rank test. Imaging response to treatment was determined by Response Evaluation Criteria in Solid Tumors. RESULTS: Median overall survival (OS) from the TARE was 13 months (95% confidence interval, 9.1-16.9 months). The survival probability at 1, 2, and 3 years was 60.1%, 36.7%, and 24.5%, respectively. The median hepatic progression-free survival was 7 months (95% confidence interval, 6.1-7.9 months). There was no 30-day mortality and 3 patients (9.4%) had grade 3 toxicity. Estrogen receptor (ER) positive status predicted prolonged survival (14 months for ER+ vs 9 months for ER-; P = .028). Patients who had bone-only extrahepatic disease had higher OS than patients with extraosseous metastases (23 vs 8 months, P = .02). At the 3-month follow-up the radiographic objective response rate was 46.6% and disease control rate was 70%. CONCLUSIONS: The treatment of patients with liver-dominant chemotherapy-refractory breast cancer metastases with TARE using yttrium-90 labeled glass microspheres is safe and led to promising hepatic disease control and OS especially in patients with ER+ tumors and in patients without extrahepatic extraosseous metastases.

Pattern of changes in cross sectional area of arterial branches after jailing with pipeline embolization device: beyond parent neck artery patency.

OBJECTIVE: The Pipeline-Embolization-Device (PED) has been used increasingly for intracranial-aneurysms. Despite the high-patency-rate of jailed branches following PED deployment, little is known about changes in these vessels size. This study measured change in size after PED. METHODS: This retrospective-study screened a database of 183-consecutive-patients treated with PED (07/2011-07/2017) across inclusion criteria. We included patients in whom the ophthalmic artery (OA) and/or the posterior communicating artery (PComA) were jailed by the PED. MRA was used to calculate change in cross-sectional-area (CSA) of these vessels. 29 patients who had MRA before and after treatment were included in the study. The CSA was measured automatically using Syngo®.via-software at fixed points along the analyzed vessels. After exclusion of low-quality and software non-capturable MRA-images, 16 OA and 23 PComA were included in the final analysis. Statistical Package for Social Sciences was used for analysis. RESULTS: The mean CSA of PComA, P1-segement of posteriror-cerebral-artery (P1-PCA), and OA was 3.3 ± 1.3, 4.1 ± 1.2, and 3.2 ± 0.9 mm2 at baseline and 1.9 ± 1.4, 4.3 ± 1.2, and 3.1 ± 0.7 mm2 at follow-up, respectively. The average follow-up was approximately 26 months. While the decrease in CSA of PComA was statistically significant, the increase in P1-PCA CSA was not. The change in OA CSA was not statistically significant. CONCLUSION: Jailing PComA with a PED resulted in a statistically significant decrease in PComA CSA and a statistically non-significant increase in ipsilateral P1 CSA. No statistically significant change in the CSA of OA was noted. Changes might be due to a balance between flow demand through the jailed ostium and presence of collateral flow.

Partial splenic embolization treats recurrent left pleural effusions in a patient with portal venous system thrombosis.

A 56-year-old female with thrombocythemia complicated by portal venous system thrombosis presented with recurrent left pleural effusions after failed recanalization via mechanical thrombectomy and stenting at an outside center. With no other cause, splenic vein thrombosis and left-sided portal hypertension was suggested as a possible etiology. Partial splenic embolization was performed with immediate decrease in effusions and resolution by 8 weeks. Portal and splenic venous system thrombosis may cause recurrent pleural effusions from left-sided portal hypertension and fluid leakage across diaphragmatic defects. Upper pole partial splenic embolization may treat recurrent left pleural effusions and offer an alternative to splenectomy.

Magnetic resonance imaging (MRI) features of cataracts in pediatric and young adult patients.

BACKGROUND: The goal of this study is to systematically evaluate the magnetic resonance imaging (MRI) signal characteristics and size of cataracts that may be encountered in pediatric and young adult patients. METHODS: A retrospective analysis of the MRI features with cataracts in a series of cases, including characterization of signal intensity on T2-weighted and T1-weighted sequences, as well as measuring the thickness of the lens. RESULTS: Among nine cataracts in seven patients, three lenses were thickened and hyperintense on T2-weighted sequences, presumably related to osmotic effects. The rest of the lenses were either normal in size and signal characteristics, such as in the cases of neurofibromatosis type 2 or small in cases of microphthalmos, with signal characteristics related to calcifications. CONCLUSIONS: There are several different types of cataracts that can occur in pediatric and young adult patients, which may or may not be conspicuous on MRI. The findings in this study can serve as a guide for what abnormalities of the lens may be encountered on MRI.

Differential Change in Size of Human Papillomavirus-Positive Cystic Versus Solid Squamous Cell Carcinoma Lymph Node Metastases in Response to Induction Chemotherapy.

PURPOSE: According to certain cancer treatment protocols, the response to induction chemotherapy of lymph node metastases based on radiographic measurements guides further management. The aim of this study is to verify the observation that cystic metastatic lymph nodes tend not to shrink as rapidly as solid metastatic lymph nodes in response to induction chemotherapy in patients with human papillomavirus-related oropharyngeal squamous cell carcinoma. METHODS: The lymphadenopathy in a cohort of patients from a clinical trial with human papillomavirus-related oropharyngeal squamous cell carcinoma with both baseline and postinduction chemotherapy (carboplatin/paclitaxel/cetuximab) contrast-enhanced neck computed tomography was retrospectively reviewed. The appearance of the metastatic lymph nodes on computed tomography was characterized as cystic or solid. A cystic lymph node was defined as having a hypoattenuating component greater than 20% of the total volume. The rates of short-axis and volume changes of cystic and solid lymph nodes were compared using 1-tailed t test. RESULTS: A total of 46 patients were included in this study, comprising 39 solid and 45 cystic lymph nodes. The rate of short-axis decrease was significantly greater for solid (1.33% per day) than cystic (1.08% per day) lymph nodes (P = 0.036). Likewise, the rate of volume decrease was significantly greater for solid (2.13% per day) than cystic (1.87% per day) lymph nodes (P = 0.014). CONCLUSIONS: This study suggests that in patients with human papillomavirus-related oropharyngeal squamous cell carcinoma solid lymph node metastases generally decrease in size at a greater rate than cystic lymph nodes after induction chemotherapy.

The "birth of death": MRI step-by-step reveals the early appearance of a bone marrow infarct.

The magnetic resonance imaging (MRI) appearance of an "established" bone marrow infarct is well-known, consisting of an area of preserved bone marrow signal surrounded by a serpiginous line. We report the uncommon observation of the very early phases of appearance of a bone marrow infarct, showing its progressive de novo appearance on MR images paralleling clinical symptoms and high-dose systemic steroid administration in a young female patient, presenting with acute knee pain. The initial knee MR examination performed one week after pain onset showed no abnormality. One week later, a second examination showed subtle ill-defined dotted signal abnormalities of the bone marrow of uncertain significance, of high signal on PDFS sequences. A third MR study obtained again one week later showed more evident findings with confluence of the high signal "dots" into a serpiginous line with a geographical appearance of the lesion, corresponding to the typical MRI presentation of bone marrow infarcts. Follow-up MRI at seven weeks showed definitive stability of this bone marrow infarct. A whole-body MRI performed for whole skeleton screening revealed multiple bone marrow infarcts typical for systemic avascular necrosis. This case represents a novel observation of the "birth" of a bone marrow infarct, from early intriguing changes to its typical ring-shaped appearance on MR images. It also reminds of the key role of MRI for early diagnosis of bone marrow infarcts and illustrates the emerging role of whole-body MRI for the detection of multifocal, asymptomatic skeletal involvement by ischemic lesions in systemic osteonecrosis.

Whole-Body Magnetic Resonance Imaging in Rheumatic and Systemic Diseases: From Emerging to Validated Indications.

Whole-body magnetic resonance (MR) imaging techniques and protocols have been evolving continuously for the last 20 years, resulting in a powerful and mature tool for the detection, staging, and treatment monitoring of many oncologic and musculoskeletal disorders. The unique contrast resolution of MR imaging makes this imaging modality highly sensitive to pathologic alterations in bones, muscles, entheses, joints, and soft tissues, enabling this method to be expanded to the whole musculoskeletal system. Whole-body MR imaging is now used in numerous rheumatic, bone, and muscle disorders, and a full range of developing applications for this method have been emerging.

A Proposed Simple and Accurate Technique for Optimal Long-Term Hemodialysis Catheter Tip Placement.

We describe a simple ultrasound (US)-guided technique for accurate anatomical right atrium localization prior to permanent hemodialysis catheter insertion. It is used in patients for whom a permanent hemodialysis catheter will be inserted through an internal jugular vein access, in order to have the functional catheter tip located at the mid-level of the right atrium. In this technique, the right atrium is localized on US via left intercostal approach prior to catheter insertion under fluoroscopic guidance.

The Use of a Software-Assisted Method to Estimate Fetal Weight at and Near Term Using Magnetic Resonance Imaging.

OBJECTIVE: The aim of this study was to apply a semi-automated calculation method of fetal body volume and, thus, of magnetic resonance-estimated fetal weight (MR-EFW) prior to planned delivery and to evaluate whether the technique of measurement could be simplified while remaining accurate. METHODS: MR-EFW was calculated using a semi-automated method at 38.6 weeks of gestation in 36 patients and compared to the picture archiving and communication system (PACS). Per patient, 8 sequences were acquired with a slice thickness of 4-8 mm and an intersection gap of 0, 4, 8, 12, 16, or 20 mm. The median absolute relative errors for MR-EFW and the time of planimetric measurements were calculated for all 8 sequences and for each method (assisted vs. PACS), and the difference between the methods was calculated. RESULTS: The median delivery weight was 3,280 g. The overall median relative error for all 288 MR-EFW calculations was 2.4% using the semi-automated method and 2.2% for the PACS method. Measurements did not differ between the 8 sequences using the assisted method (p = 0.313) or the PACS (p = 0.118), while the time of planimetric measurement decreased significantly with a larger gap (p < 0.001) and in the assisted method compared to the PACS method (p < 0.01). CONCLUSION: Our simplified MR-EFW measurement showed a dramatic decrease in time of planimetric measurement without a decrease in the accuracy of weight estimates.