Management of Bone Disease with Concurrent Chimeric Antigen Receptor T-Cell Therapy for Multiple Myeloma.

In the intricate landscape of multiple myeloma, a hematologic malignancy of plasma cells, bone disease presents a pivotal and often debilitating complication. The emergence of Chimeric Antigen Receptor T-cell (CAR-T) therapy has marked a pivotal shift in the therapeutic landscape, offering novel avenues for the management of MM, particularly for those with relapsed or refractory disease. This innovative treatment modality not only targets malignant cells with precision but also influences the bone microenvironment, presenting both challenges and opportunities in patient care. In this comprehensive review, we aim to examine the multifaceted aspects of bone disease in patients with multiple myeloma and concurrent CAR-T therapy, highlighting its clinical ramifications and the latest advancements in diagnostic modalities and therapeutic interventions. The article aims to synthesize current understanding of the interplay between myeloma cells, CAR-T cells, and the bone microenvironment in the context of current treatment strategies in this challenging and unique patient population.

Imaging cholangiocarcinoma: CT and MRI techniques.

Cross-sectional imaging plays a crucial role in the detection, diagnosis, staging, and resectability assessment of intra- and extrahepatic cholangiocarcinoma. Despite this vital function, there is a lack of standardized CT and MRI protocol recommendations for imaging cholangiocarcinoma, with substantial differences in image acquisition across institutions and vendor platforms. In this review, we present standardized strategies for the optimal imaging assessment of cholangiocarcinoma including contrast media considerations, patient preparation recommendations, optimal contrast timing, and representative CT and MRI protocols with individual sequence optimization recommendations. Our recommendations are supported by expert opinion from members of the Society of Abdominal Radiology's Disease-Focused Panel (DFP) on Cholangiocarcinoma, encompassing a broad array of institutions and practice patterns.

E-cadherin expression and gene expression profiles in corticotroph pituitary neuroendocrine tumor subtypes.

Corticotroph adenomas/pituitary neuroendocrine tumors (PitNETs) are associated with significant morbidity and mortality. Predictors of tumor behavior have not shown high prognostic accuracy. For somatotroph adenomas/PitNETs, E-cadherin expression correlates strongly with prognosis. E-cadherin expression has not been investigated in other PitNETs. A retrospective chart review of adults with corticotroph adenomas/PitNETs was conducted to assess correlation between E-cadherin expression and tumor characteristics. In addition, gene expression microarray was performed in subset of tumors (n = 16). Seventy-seven patients were identified; 71% were female, with median age of cohort 45.2 years. Seventy-five percent had macroadenomas, of which 22% were hormonally active. Ninety-five percent of microadenomas were hormonally active. Adrenocorticotropic hormone granulation pattern by IHC identified 63% as densely granulated (DG) and 34% as sparsely granulated (SG). All microadenomas were DG (p < .001); 50% of macroadenomas were DG associated with increased tumor invasion compared to SG. E-cadherin IHC was positive in 80%, diminished in 17%, and absent in 20% and did not correlate with corticotroph PitNETs subtype, size, or prognosis. In contrast to the distinct transcriptomes of corticotroph PitNETs and normal pituitaries, a comparison of clinically active and silent corticotroph PitNETs demonstrated similar molecular signatures indicating their common origin, but with unique differences related to their secretory status.

ProstaMine: a bioinformatics tool for identifying subtype-specific co-alterations associated with aggressiveness in prostate cancer.

Background: Prostate cancer is a leading cause of cancer-related deaths among men, marked by heterogeneous clinical and molecular characteristics. The complexity of the molecular landscape necessitates tools for identifying multi-gene co-alteration patterns that are associated with aggressive disease. The identification of such gene sets will allow for deeper characterization of the processes underlying prostate cancer progression and potentially lead to novel strategies for treatment. Methods: We developed ProstaMine to systematically identify co-alterations associated with aggressiveness in prostate cancer molecular subtypes defined by high-fidelity alterations in primary prostate cancer. ProstaMine integrates genomic, transcriptomic, and clinical data from five primary and one metastatic prostate cancer cohorts to prioritize co-alterations enriched in metastatic disease and associated with disease progression. Results: Integrated analysis of primary tumors defined a set of 17 prostate cancer alterations associated with aggressive characteristics. We applied ProstaMine to NKX3-1-loss and RB1-loss tumors and identified subtype-specific co-alterations associated with metastasis and biochemical relapse in these molecular subtypes. In NKX3-1-loss prostate cancer, ProstaMine identified novel subtype-specific co-alterations known to regulate prostate cancer signaling pathways including MAPK, NF-kB, p53, PI3K, and Sonic hedgehog. In RB1-loss prostate cancer, ProstaMine identified novel subtype-specific co-alterations involved in p53, STAT6, and MHC class I antigen presentation. Co-alterations impacting autophagy were noted in both molecular subtypes. Conclusion: ProstaMine is a method to systematically identify novel subtype-specific co-alterations associated with aggressive characteristics in prostate cancer. The results from ProstaMine provide insights into potential subtype-specific mechanisms of prostate cancer progression which can be formed into testable experimental hypotheses. ProstaMine is publicly available at: https://bioinformatics.cuanschutz.edu/prostamine.

Magnetic resonance imaging of tumor response to stroma-modifying pegvorhyaluronidase alpha (PEGPH20) therapy in early-phase clinical trials.

Pre-clinical and clinical studies have shown that PEGPH20 depletes intratumoral hyaluronic acid (HA), which is linked to high interstitial fluid pressures and poor distribution of chemotherapies. 29 patients with metastatic advanced solid tumors received quantitative magnetic resonance imaging (qMRI) in 3 prospective clinical trials of PEGPH20: HALO-109-101 (NCT00834704), HALO-109-102 (NCT01170897), and HALO-109-201 (NCT01453153). Apparent Diffusion Coefficient of water (ADC), T1, ktrans, vp, ve, and iAUC maps were computed from qMRI acquired at baseline and ≥ 1 time point post-PEGPH20. Tumor ADC and T1 decreased, while iAUC, ktrans, vp, and ve increased, on day 1 post-PEGPH20 relative to baseline values. This is consistent with HA depletion leading to a decrease in tumor extracellular water content and an increase in perfusion, permeability, extracellular matrix space, and vascularity. Baseline parameter values predictive of pharmacodynamic responses were: ADC > 1.46 × 10-3 mm2/s (Balanced Accuracy (BA) = 72%, p < 0.01), T1 > 0.54 s (BA = 82%, p < 0.01), iAUC < 9.2 mM-s (BA = 76%, p < 0.05), ktrans < 0.07 min-1 (BA = 72%, p = 0.2), ve < 0.17 (BA = 68%, p < 0.01), and vp < 0.02 (BA = 60%, p < 0.01). A low ve at baseline was moderately predictive of response in any parameter (BA = 65.6%, p < 0.01 averaged across patients). These qMRI biomarkers are potentially useful for guiding patient pre-selection and post-treatment follow-up in future clinical studies of PEGPH20 and other tumor stroma-modifying anti-cancer therapies.

The role of rectal magnetic resonance imaging in accurate localization and designation of colorectal cancer for optimal management: Case study.

Colorectal cancer, developing from malignant transformation of the distal gut epithelium, is the second leading cause of cancer death in the United States. We present a gentleman in his 60s who was diagnosed with colorectal cancer during a routine screening colonoscopy with no evidence of distant metastasis on subsequent staging with positron emission tomography and computed tomography (PET-CT). The outside rectal MR (magnetic resonance) imaging report localized a mass to the upper rectum. Review of the MRI at an institutional, Multidisciplinary Tumor Board designated the tumor as "rectosigmoid," straddling the rectosigmoid junction at the level of the "sigmoid take-off" (STO) or alternatively at the level of the last sigmoid artery take-off (SAT) at the origin of the superior rectal artery. The anatomic differentiation between upper rectal and lower sigmoid colon cancers carries clinical importance which is highlighted in this case report and brief literature review. Optimal anatomic localization of colorectal cancers helps direct the clinical team to tailor an individualized patient care plan.

Respiratory viral infection promotes the awakening and outgrowth of dormant metastatic breast cancer cells in lungs.

Breast cancer is the second most common cancer globally. Most deaths from breast cancer are due to metastatic disease which often follows long periods of clinical dormancy1. Understanding the mechanisms that disrupt the quiescence of dormant disseminated cancer cells (DCC) is crucial for addressing metastatic progression. Infection with respiratory viruses (e.g. influenza or SARS-CoV-2) is common and triggers an inflammatory response locally and systemically2,3. Here we show that influenza virus infection leads to loss of the pro-dormancy mesenchymal phenotype in breast DCC in the lung, causing DCC proliferation within days of infection, and a greater than 100-fold expansion of carcinoma cells into metastatic lesions within two weeks. Such DCC phenotypic change and expansion is interleukin-6 (IL-6)-dependent. We further show that CD4 T cells are required for the maintenance of pulmonary metastatic burden post-influenza virus infection, in part through attenuation of CD8 cell responses in the lungs. Single-cell RNA-seq analyses reveal DCC-dependent impairment of T-cell activation in the lungs of infected mice. SARS-CoV-2 infected mice also showed increased breast DCC expansion in lungs post-infection. Expanding our findings to human observational data, we observed that cancer survivors contracting a SARS-CoV-2 infection have substantially increased risks of lung metastatic progression and cancer-related death compared to cancer survivors who did not. These discoveries underscore the significant impact of respiratory viral infections on the resurgence of metastatic cancer, offering novel insights into the interconnection between infectious diseases and cancer metastasis.

Habitat escalated adaptive therapy (HEAT): a phase 2 trial utilizing radiomic habitat-directed and genomic-adjusted radiation dose (GARD) optimization for high-grade soft tissue sarcoma.

BACKGROUND: Soft tissue sarcomas (STS), have significant inter- and intra-tumoral heterogeneity, with poor response to standard neoadjuvant radiotherapy (RT). Achieving a favorable pathologic response (FPR ≥ 95%) from RT is associated with improved patient outcome. Genomic adjusted radiation dose (GARD), a radiation-specific metric that quantifies the expected RT treatment effect as a function of tumor dose and genomics, proposed that STS is significantly underdosed. STS have significant radiomic heterogeneity, where radiomic habitats can delineate regions of intra-tumoral hypoxia and radioresistance. We designed a novel clinical trial, Habitat Escalated Adaptive Therapy (HEAT), utilizing radiomic habitats to identify areas of radioresistance within the tumor and targeting them with GARD-optimized doses, to improve FPR in high-grade STS. METHODS: Phase 2 non-randomized single-arm clinical trial includes non-metastatic, resectable high-grade STS patients. Pre-treatment multiparametric MRIs (mpMRI) delineate three distinct intra-tumoral habitats based on apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) sequences. GARD estimates that simultaneous integrated boost (SIB) doses of 70 and 60 Gy in 25 fractions to the highest and intermediate radioresistant habitats, while the remaining volume receives standard 50 Gy, would lead to a > 3 fold FPR increase to 24%. Pre-treatment CT guided biopsies of each habitat along with clip placement will be performed for pathologic evaluation, future genomic studies, and response assessment. An mpMRI taken between weeks two and three of treatment will be used for biological plan adaptation to account for tumor response, in addition to an mpMRI after the completion of radiotherapy in addition to pathologic response, toxicity, radiomic response, disease control, and survival will be evaluated as secondary endpoints. Furthermore, liquid biopsy will be performed with mpMRI for future ancillary studies. DISCUSSION: This is the first clinical trial to test a novel genomic-based RT dose optimization (GARD) and to utilize radiomic habitats to identify and target radioresistance regions, as a strategy to improve the outcome of RT-treated STS patients. Its success could usher in a new phase in radiation oncology, integrating genomic and radiomic insights into clinical practice and trial designs, and may reveal new radiomic and genomic biomarkers, refining personalized treatment strategies for STS. TRIAL REGISTRATION: NCT05301283. TRIAL STATUS: The trial started recruitment on March 17, 2022.

Support Through Remote Observation and Nutrition Guidance (STRONG), a digital health intervention to reduce malnutrition among pancreatic cancer patients: A study protocol for a pilot randomized controlled trial.

Background: Malnutrition is a common and distressing condition among pancreatic cancer patients. Fewer than a quarter of pancreatic cancer patients receive medical nutrition therapy (MNT), important for improving nutritional status, weight maintenance, quality of life and survival. System, provider, and patient level barriers limit access to MNT. We propose to examine the feasibility of a 12-week multi-level, digital health intervention designed to expand MNT access among pancreatic cancer patients. Methods: Individuals with advanced pancreatic cancer starting chemotherapy (N = 80) will be 1:1 randomized to the intervention or usual care. The Support Through Remote Observation and Nutrition Guidance (STRONG) intervention includes system-level (e.g., routine malnutrition and screening), provider-level (e.g., dietitian training and web-based dashboard), and patient-level strategies (e.g., individualized nutrition plan, self-monitoring of dietary intake via Fitbit, ongoing goal monitoring and feedback). Individuals receiving usual care will be referred to dietitians based on their oncologists' discretion. Study assessments will be completed at baseline, 4-, 8-, 12-, and 16-weeks. Results: Primary outcomes will be feasibility (e.g., recruitment, retention, assessment completion) and acceptability. We will collect additional implementation outcomes, such as intervention adherence, perceived usability, and feedback on intervention quality via an exit interview. We will collect preliminary data on outcomes that may be associated with the intervention including malnutrition, quality of life, treatment outcomes, and survival. Conclusion: This study will advance our knowledge on the feasibility of a digital health intervention to reduce malnutrition among individuals with advanced pancreatic cancer. Trial registration: NCT05675059, registered on December 9, 2022.

NPEPPS Is a Druggable Driver of Platinum Resistance.

There is an unmet need to improve the efficacy of platinum-based cancer chemotherapy, which is used in primary and metastatic settings in many cancer types. In bladder cancer, platinum-based chemotherapy leads to better outcomes in a subset of patients when used in the neoadjuvant setting or in combination with immunotherapy for advanced disease. Despite such promising results, extending the benefits of platinum drugs to a greater number of patients is highly desirable. Using the multiomic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified puromycin-sensitive aminopeptidase (NPEPPS) as a driver of cisplatin resistance. NPEPPS depletion sensitized resistant bladder cancer cells to cisplatin in vitro and in vivo. Conversely, overexpression of NPEPPS in sensitive cells increased cisplatin resistance. NPEPPS affected treatment response by regulating intracellular cisplatin concentrations. Patient-derived organoids (PDO) generated from bladder cancer samples before and after cisplatin-based treatment, and from patients who did not receive cisplatin, were evaluated for sensitivity to cisplatin, which was concordant with clinical response. In the PDOs, depletion or pharmacologic inhibition of NPEPPS increased cisplatin sensitivity, while NPEPPS overexpression conferred resistance. Our data present NPEPPS as a druggable driver of cisplatin resistance by regulating intracellular cisplatin concentrations. SIGNIFICANCE: Targeting NPEPPS, which induces cisplatin resistance by controlling intracellular drug concentrations, is a potential strategy to improve patient responses to platinum-based therapies and lower treatment-associated toxicities.

Pancreatic Cyst Size Measurement on Magnetic Resonance Imaging Compared to Pathology.

BACKGROUND: While multiple cyst features are evaluated for stratifying pancreatic intraductal papillary mucinous neoplasms (IPMN), cyst size is an important factor that can influence treatment strategies. When magnetic resonance imaging (MRI) is used to evaluate IPMNs, no universally accepted sequence provides optimal size measurements. T2-weighted coronal/axial have been suggested as primary measurement sequences; however, it remains unknown how well these and maximum all-sequence diameter measurements correlate with pathology size. This study aims to compare agreement and bias between IPMN long-axis measurements on seven commonly obtained MRI sequences with pathologic size measurements. METHODS: This retrospective cohort included surgically resected IPMN cases with preoperative MRI exams. Long-axis diameter tumor measurements and the presence of worrisome features and/orhigh-risk stigmata were noted on all seven MRI sequences. MRI size and pathology agreement and MRI inter-observer agreement involved concordance correlation coefficient (CCC) and intraclass correlation coefficient (ICC), respectively. The presence of worrisome features and high-risk stigmata were compared to the tumor grade using kappa analysis. The Bland-Altman analysis assessed the systematic bias between MRI-size and pathology. RESULTS: In 52 patients (age 68 ± 13 years, 22 males), MRI sequences produced mean long-axis tumor measurements from 2.45-2.65 cm. The maximum MRI lesion size had a strong agreement with pathology (CCC = 0.82 (95% CI: 0.71-0.89)). The maximum IPMN size was typically observed on the axial T1 arterial post-contrast and MRCP coronal series and overestimated size versus pathology with bias +0.34 cm. The radiologist interobserver agreement reached ICCs 0.74 to 0.91 on the MRI sequences. CONCLUSION: The maximum MRI IPMN size strongly correlated with but tended to overestimate the length compared to the pathology, potentially related to formalin tissue shrinkage during tissue processing.

Stereotactic body radiotherapy plus rucosopasem in locally advanced or borderline resectable pancreatic cancer: GRECO-2 phase II study design.

Ablative doses of stereotactic body radiotherapy (SBRT) may improve pancreatic cancer outcomes but may carry greater potential for gastrointestinal toxicity. Rucosopasem, an investigational selective dismutase mimetic that converts superoxide to hydrogen peroxide, can potentially increase tumor control of SBRT without compromising safety. GRECO-2 is a phase II, multicenter, randomized, double-blind, placebo-controlled trial of rucosopasem in combination with SBRT in locally advanced or borderline resectable pancreatic cancer. Patients will be randomized to rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT fraction (5 × 10 Gy). The primary end point is overall survival. Secondary end points include progression-free survival, locoregional control, time to metastasis, surgical resection rate, best overall response, in-field local response and acute and long-term toxicity.

The use of high doses of radiation delivered directly to tumors (stereotactic body radiation therapy [SBRT]) may improve survival compared with lower doses of radiation in patients with pancreatic cancer, but it may increase side effects. Rucosopasem, an investigational new drug being developed, can potentially improve the ability of SBRT to treat tumors without decreasing safety. In a previous study, median overall survival was improved when patients were treated with SBRT plus avasopasem, a drug that works the same way as rucosopasem. GRECO-2 is a clinical trial of rucosopasem used in combination with SBRT for treatment of localized pancreatic cancer. Patients will be randomly selected to receive either rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT treatment. The main result being studied is overall survival. Additional results include amount of time before tumors start to grow, how often patients get tumors surgically removed, best overall response and long-term safety. Clinical Trial Registration: NCT04698915 (ClinicalTrials.gov).

Accurate, repeatable, and geometrically precise diffusion-weighted imaging on a 0.35 T magnetic resonance imaging-guided linear accelerator.

Background and purpose: Diffusion weighted imaging (DWI) allows for the interrogation of tissue cellularity, which is a surrogate for cellular proliferation. Previous attempts to incorporate DWI into the workflow of a 0.35 T MR-linac (MRL) have lacked quantitative accuracy. In this study, accuracy, repeatability, and geometric precision of apparent diffusion coefficient (ADC) maps produced using an echo planar imaging (EPI)-based DWI protocol on the MRL system is illustrated, and in vivo potential for longitudinal patient imaging is demonstrated. Materials and methods: Accuracy and repeatability were assessed by measuring ADC values in a diffusion phantom at three timepoints and comparing to reference ADC values. System-dependent geometric distortion was quantified by measuring the distance between 93 pairs of phantom features on ADC maps acquired on a 0.35 T MRL and a 3.0 T diagnostic scanner and comparing to spatially precise CT images. Additionally, for five sarcoma patients receiving radiotherapy on the MRL, same-day in vivo ADC maps were acquired on both systems, one of which at multiple timepoints. Results: Phantom ADC quantification was accurate on the 0.35 T MRL with significant discrepancies only seen at high ADC. Average geometric distortions were 0.35 (±0.02) mm and 0.85 (±0.02) mm in the central slice and 0.66 (±0.04) mm and 2.14 (±0.07) mm at 5.4 cm off-center for the MRL and diagnostic system, respectively. In the sarcoma patients, a mean pretreatment ADC of 910x10-6 (±100x10-6) mm2/s was measured on the MRL. Conclusions: The acquisition of accurate, repeatable, and geometrically precise ADC maps is possible at 0.35 T with an EPI approach.

Stereotactic body radiotherapy with or without selective dismutase mimetic in pancreatic adenocarcinoma: an adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has the potential to ablate localised pancreatic ductal adenocarcinoma. Selective dismutase mimetics sensitise tumours while reducing normal tissue toxicity. This trial was designed to establish the efficacy and toxicity afforded by the selective dismutase mimetic avasopasem manganese when combined with ablative SBRT for localised pancreatic ductal adenocarcinoma. METHODS: In this adaptive, randomised, double-blind, placebo-controlled, phase 1b/2 trial, patients aged 18 years or older with borderline resectable or locally advanced pancreatic cancer who had received at least 3 months of chemotherapy and had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at six academic sites in the USA. Eligible patients were randomly assigned (1:1), with block randomisation (block sizes of 6-12) with a maximum of 24 patients per group, to receive daily avasopasem (90 mg) or placebo intravenously directly before (ie, within 180 min) SBRT (50, 55, or 60 Gy in five fractions, adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy). Patients and physicians were masked to treatment group allocation, but not to SBRT dose. The primary objective was to find the optimal dose of SBRT with avasopasem or placebo as determined by the late onset EffTox method. All analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT03340974, and is complete. FINDINGS: Between Jan 25, 2018, and April 29, 2020, 47 patients were screened, of whom 42 were enrolled (median age was 71 years [IQR 63-75], 23 [55%] were male, 19 [45%] were female, 37 [88%] were White, three [7%] were Black, and one [2%] each were unknown or other races) and randomly assigned to avasopasem (n=24) or placebo (n=18); the placebo group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff (June 28, 2021), the avasopasem group satisfied boundaries for both efficacy and toxicity. Late onset EffTox efficacy response was observed in 16 (89%) of 18 patients at 50 Gy and six (100%) of six patients at 55 Gy in the avasopasem group, and was observed in three (50%) of six patients at 50 Gy and nine (75%) of 12 patients at 55 Gy in the placebo group, and the Bayesian model recommended 50 Gy or 55 Gy in five fractions with avasopasem for further study. Serious adverse events of any cause were reported in three (17%) of 18 patients in the placebo group and six (25%) of 24 in the avasopasem group. In the placebo group, grade 3 adverse events within 90 days of SBRT were abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase (one [6%] each); no grade 4 events occurred. In the avasopasem group, grade 3-4 adverse events within 90 days of SBRT were acute kidney injury, increased blood alkaline phosphatase, haematoma, colitis, gastric obstruction, lung infection, abdominal abscess, post-surgical atrial fibrillation, and pneumonia leading to respiratory failure (one [4%] each).There were no treatment-related deaths but one late death in the avasopasem group due to sepsis in the setting of duodenal obstruction after off-study treatment was reported as potentially related to SBRT. INTERPRETATION: SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localised pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase 2 trial (GRECO-2, NCT04698915) is underway to validate these results. FUNDING: Galera Therapeutics.

Tumor Response to Stroma-Modifying Therapy: Magnetic Resonance Imaging Findings in Early-Phase Clinical Trials of Pegvorhyaluronidase alpha (PEGPH20).

Pre-clinical and clinical studies have shown that PEGPH20 depletes intratumoral hyaluronic acid (HA), which is linked to high interstitial fluid pressures and poor distribution of chemotherapies. 29 patients with metastatic advanced solid tumors received quantitative magnetic resonance imaging (qMRI) in 3 prospective clinical trials of PEGPH20, HALO-109-101 (NCT00834704), HALO-109-102 (NCT01170897), and HALO-109-201 (NCT01453153). Apparent Diffusion Coefficient of water (ADC), T1, ktrans, vp, ve, and iAUC maps were computed from qMRI acquired at baseline and ≥ 1 time point post-PEGPH20. Tumor ADC and T1 decreased, while iAUC, ktrans, vp, and ve increased, on day 1 post-PEGPH20 relative to baseline values. This is consistent with HA depletion leading to a decrease in tumor water content and an increase in perfusion, permeability, extracellular matrix space, and vascularity. Baseline parameter values that were predictive of pharmacodynamic responses were: ADC > 1.46×10-3 mm2/s (Balanced Accuracy (BA) = 72%, p < 0.01), T1 > 0.54s (BA = 82%, p < 0.01), iAUC < 9.2 mM-s (BA = 76%, p < 0.05), ktrans<0.07min-1 (BA = 72%, p = 0.2), ve<0.17 (BA = 68%, p < 0.01), and vp<0.02 (BA = 60%, p < 0.01). Further, ve<0.39 at baseline was moderately predictive of response in any parameter (BA = 65.6%, p < 0.01 averaged across patients). These qMRI biomarkers are potentially useful for guiding patient pre-selection and post-treatment follow-up in future clinical studies of PEGPH20 and other tumor stroma-modifying anti-cancer therapies.

Down syndrome is associated with altered frequency and functioning of tracheal multiciliated cells, and response to influenza virus infection.

Individuals with Down syndrome (DS) clinically manifest severe respiratory illnesses; however, there is a paucity of data on how DS influences homeostatic physiology of lung airway, and its reactive responses to pulmonary pathogens. We generated well-differentiated ciliated airway epithelia using tracheas from wild-type and Dp(16)1/Yey mice in vitro, and discovered that Dp(16)1/Yey epithelia have significantly lower abundance of ciliated cells, an altered ciliary beating profile, and reduced mucociliary transport. Interestingly, both sets of differentiated epithelia released similar quantities of viral particles after infection with influenza A virus (IAV). However, RNA-sequencing and proteomic analyses revealed an immune hyperreactive phenotype particularly for monocyte-recruiting chemokines in Dp(16)1/Yey epithelia. Importantly, when we challenged mice in vivo with IAV, we observed immune hyper-responsiveness in Dp(16)1/Yey mice, evidenced by higher quantities of lung airway infiltrated monocytes, and elevated levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid. Our findings illuminate mechanisms underlying DS-mediated pathophysiological changes in airway epithelium.

SIX1 and EWS/FLI1 co-regulate an anti-metastatic gene network in Ewing Sarcoma.

Ewing sarcoma (ES), which is characterized by the presence of oncogenic fusion proteins such as EWS/FLI1, is an aggressive pediatric malignancy with a high rate of early dissemination and poor outcome after distant spread. Here we demonstrate that the SIX1 homeoprotein, which enhances metastasis in most tumor types, suppresses ES metastasis by co-regulating EWS/FLI1 target genes. Like EWS/FLI1, SIX1 promotes cell growth/transformation, yet dramatically inhibits migration and invasion, as well as metastasis in vivo. We show that EWS/FLI1 promotes SIX1 protein expression, and that the two proteins share genome-wide binding profiles and transcriptional regulatory targets, including many metastasis-associated genes such as integrins, which they co-regulate. We further show that SIX1 downregulation of integrins is critical to its ability to inhibit invasion, a key characteristic of metastatic cells. These data demonstrate an unexpected anti-metastatic function for SIX1, through coordinate gene regulation with the key oncoprotein in ES, EWS/FLI1.

A harmonized resource of integrated prostate cancer clinical, -omic, and signature features.

Genomic and transcriptomic data have been generated across a wide range of prostate cancer (PCa) study cohorts. These data can be used to better characterize the molecular features associated with clinical outcomes and to test hypotheses across multiple, independent patient cohorts. In addition, derived features, such as estimates of cell composition, risk scores, and androgen receptor (AR) scores, can be used to develop novel hypotheses leveraging existing multi-omic datasets. The full potential of such data is yet to be realized as independent datasets exist in different repositories, have been processed using different pipelines, and derived and clinical features are often not provided or  not standardized. Here, we present the curatedPCaData R package, a harmonized data resource representing >2900 primary tumor, >200 normal tissue, and >500 metastatic PCa samples across 19 datasets processed using standardized pipelines with updated gene annotations. We show that meta-analysis across harmonized studies has great potential for robust and clinically meaningful insights. curatedPCaData is an open and accessible community resource with code made available for reproducibility.

Non-muscle-invasive bladder cancer molecular subtypes predict differential response to intravesical Bacillus Calmette-Guérin.

The recommended treatment for patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guérin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. If progression to advanced disease occurs, then patients must undergo a radical cystectomy with risks of substantial morbidity and poor clinical outcome. Identifying tumors unlikely to respond to BCG can translate into alternative treatments, such as early radical cystectomy, targeted therapies, or immunotherapies. Here, we conducted molecular profiling of 132 patients with BCG-naive HR-NMIBC and 44 patients with recurrences after BCG (34 matched), which uncovered three distinct BCG response subtypes (BRS1, 2 and BRS3). Patients with BRS3 tumors had a reduced recurrence-free and progression-free survival compared with BRS1/2. BRS3 tumors expressed high epithelial-to-mesenchymal transition and basal markers and had an immunosuppressive profile, which was confirmed with spatial proteomics. Tumors that recurred after BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive patients with HR-NMIBC, and the molecular subtypes outperformed guideline-recommended risk stratification based on clinicopathological variables. For clinical application, we confirmed that a commercially approved assay was able to predict BRS3 tumors with an area under the curve of 0.87. These BCG response subtypes will allow for improved identification of patients with HR-NMIBC at the highest risk of progression and have the potential to be used to select more appropriate treatments for patients unlikely to respond to BCG.

A primer on rectal MRI in patients on watch-and-wait treatment for rectal cancer.

Total neoadjuvant treatment (TNT) for rectal cancer is becoming an accepted treatment paradigm and is changing the landscape of this disease, wherein up to 50% of patients who undergo TNT are able to avoid surgery. This places new demands on the radiologist in terms of interpreting degrees of response to treatment. This primer summarizes the Watch-and-Wait approach and the role of imaging, with illustrative "atlas-like" examples as an educational guide for radiologists. We present a brief literature summary of the evolution of rectal cancer treatment, with a focus on magnetic resonance imaging (MRI) assessment of response. We also discuss recommended guidelines and standards. We outline the common TNT approach entering mainstream practice. A heuristic and algorithmic approach to MRI interpretation is also offered. To illustrate management and common scenarios, we arranged the illustrative figures as follows: (I) Clinical complete response (cCR) achieved at the immediate post-TNT "decision point" scan time; (II) cCR achieved at some point during surveillance, later than the first post-TNT MRI; (III) near clinical complete response (nCR); (IV) incomplete clinical response (iCR); (V) discordant findings between MRI and endoscopy where MRI is falsely positive, even at follow-up; (VI) discordant cases where MRI seems to be falsely positive but is proven truly positive on follow-up endoscopy; (VII) cases where MRI is falsely negative; (VIII) regrowth of tumor in the primary tumor bed; (IX) regrowth outside the primary tumor bed; and (X) challenging scenarios, i.e., mucinous cases. This primer is offered to achieve its intended goal of educating radiologists on how to interpret MRI in patients with rectal cancer undergoing treatment using a TNT-type treatment paradigm and a Watch-and-Wait approach.