September, 2024 Publications from the Department of Human Oncology

Ultrahigh-dose-rate therapy, also known as FLASH radiotherapy (RT), is an emerging technique that is garnering significant interest in cancer treatment due to its potential to revolutionize therapy. This method can achieve comparable tumor control to conventional-dose-rate RT while offering the enhanced protection of normal tissue through the FLASH-sparing effect. This innovative technique has demonstrated promising results in preclinical studies involving animals and cell lines. Particularly noteworthy is its potential application in treating head and neck (HN) cancers, especially in patients with challenging recurrent tumors and reirradiation cases, where the toxicity rates with conventional radiotherapy are high. Such applications aim to enhance tumor control while minimizing side effects and preserving patients' quality of life. In comparison to electron or photon FLASH modalities, proton therapy has demonstrated superior dosimetric and delivery characteristics and is a safe and effective FLASH treatment for human malignancies. Compared to the transmission proton FLASH, single-energy Bragg peak FLASH is a novel delivery method that allows highly conformal doses to targets and minimal radiation doses to crucial OARs. Proton Bragg peak FLASH for HN cancer has still not been well studied. This review highlights the significance of proton FLASH in enhancing cancer therapy by examining the advantages and challenges of using it for HN cancer reirradiation.

PMID:39409872 | PMC:PMC11482542 | DOI:10.3390/cancers16193249

PURPOSE: MR-guided Radiation Therapy (MRgRT) enables online adaptation to address intra- and inter-fractional changes. To address the need of high-fidelity synthetic CT (synCT) required for dose calculation, we developed a conditional generative adversarial network (cGAN) for synCT generation from low-field MRI in the brain.

METHODS AND MATERIALS: Simulation MR-CT pairs from twelve glioma patients imaged with a head and neck surface coil and treated on a 0.35T MR-linac were prospectively included to train the model consisting of a 9-block residual network generator and a PatchGAN discriminator. Four-fold cross validation was implemented. SynCT was quantitatively evaluated against real CT using mean absolute error (MAE), Peak Signal-to-Noise Ratio (PSNR) and Structural Similarity (SSIM). Dose was calculated on synCT applying original treatment plan. Dosimetric performance was evaluated by dose-volume histogram (DVH) metric comparison and local three-dimensional gamma analysis. To demonstrate utilization in treatment adaptation, longitudinal synCTs were generated for qualitative evaluation, and one offline adaptation case underwent two comparative plan evaluations. Secondary validation was conducted with 9 patients on a different MR-linac using a high-resolution brain coil.

RESULTS: Our model generated high-quality synCTs with MAE, PSNR and SSIM of 70.9±10.4 HU, 28.4±1.5 d.B. and 0.87±0.02 within the field-of-view, respectively. Underrepresented post-surgical anomalies challenged model performance. Nevertheless, excellent dosimetric agreement was observed with the mean difference between real and synCT DVH metrics of -0.07±0.29 Gy for target D95 and within [-0.14, 0.02] Gy for organs at risk. Significant differences were only observed in the right lens D0.01cc with negligible overall difference (<0.13 Gy). Mean gamma analysis pass rates were 92.2%±3.0%, 99.2%±0.7% and 99.9%±0.1% at 1%/1mm, 2%/2mm and 3%/3mm, respectively. Secondary validation yielded no significant differences in synCT performance for whole brain MAE, PSNR, and SSIM with comparable dosimetric results.

CONCLUSIONS: Our cGAN model generated high-fidelity brain synCTs from low-field MRI with excellent dosimetric performance. Secondary validation suggests great promise of implementing synCTs to facilitate robust dose calculation for online adaptive brain MRgRT.

PMID:39357787 | DOI:10.1016/j.ijrobp.2024.09.046

Treatment plan quality is a crucial component for a successful outcome of radiation therapy treatments. As the complexity of radiation therapy planning and delivery techniques increases, the role of the medical physicist in assessing treatment plan quality becomes more critical. Integrating plan quality review throughout the treatment planning process allows improvements without delaying treatment or rushing to produce changes at the last minute. In this work, we aim to provide practical check items for physicists to reference when assessing treatment plan quality with a critical eye, asking questions such as "is this the best dose distribution feasible for this patient?," "could we change any planning parameters to improve plan quality?," and "could we change the planning strategy for this particular patient or for future patients?"; and to work with planners and physicians to create a multidisciplinary collaborative culture that achieves the best plan feasible for every patient. We tabulate the features that affect plan quality in each process step and check details for individual items. This report is aimed at medical physicists, planners, radiation oncologists, and other professionals who are involved in treatment planning.

PMID:39357772 | DOI:10.1016/j.prro.2024.08.008

Continuous chromosome missegregation over successive mitotic divisions, known as chromosomal instability (CIN), is common in cancer. Increasing CIN above a maximally tolerated threshold leads to cell death due to loss of essential chromosomes. Here, we show in two tissue contexts that otherwise isogenic cancer cells with higher levels of CIN are more sensitive to ionizing radiation, which itself induces CIN. CIN also sensitizes HPV-positive and HPV-negative head and neck cancer patient derived xenograft (PDX) tumors to radiation. Moreover, laryngeal cancers with higher CIN prior to treatment show improved response to radiation therapy. In addition, we reveal a novel mechanism of radiosensitization by docetaxel, a microtubule stabilizing drug commonly used in combination with radiation. Docetaxel causes cell death by inducing CIN due to abnormal multipolar spindles rather than causing mitotic arrest, as previously assumed. Docetaxel-induced CIN, rather than mitotic arrest, is responsible for the enhanced radiation sensitivity observed in vitro and in vivo, challenging the mechanistic dogma of the last 40 years. These results implicate CIN as a potential biomarker and inducer of radiation response, which could provide valuable cancer therapeutic opportunities.

STATEMENT OF SIGNIFICANCE: Cancer cells and laryngeal tumors with higher chromosome missegregation rates are more sensitive to radiation therapy, supporting chromosomal instability as a promising biomarker of radiation response.

PMID:39345631 | PMC:PMC11429890 | DOI:10.1101/2024.09.13.612942

In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. Employing a human-relevant ex vivo 'chip', AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via the multimerization of GABA(A) receptor-associated protein, GABARAP, the stabilization of mitochondrial receptor Nix, and the utilization of ubiquitin-binding protein p62. A high-affinity peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP-Nix multimerization axis that triggers autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity.

PMID:39335139 | PMC:PMC11430345 | DOI:10.3390/cancers16183167

Therapies against cell-surface targets (CSTs) represent an emerging treatment class in solid malignancies. However, high-throughput investigations of CST expression across cancer types have been reliant on data sets of mostly primary tumors, despite therapeutic use most commonly in metastatic disease. We identified a total of 818 clinical trials of CST therapies with 78 CSTs. We assembled a data set spanning RNA-seq and microarrays in 7,927 benign samples, 16,866 primary tumor samples, and 6,124 metastatic tumor samples. We also utilized single-cell RNA-seq data from 36 benign tissues and 558 primary and metastatic tumor samples, and matched RNA versus protein expression in 29 benign tissue samples, 1,075 tumor samples, and 942 cell lines. High RNA expression accurately predicted high protein expression across CST therapies in benign tissues, tumor samples, and cell lines. We compared metastatic versus primary tumor expression, identified potential opportunities for repositioning, and matched cell lines to tumor types based on CST and global RNA expression. We evaluated single-cell heterogeneity across tumors, and identified rare normal cell subpopulations that may contribute to toxicity. Finally, we identified combinations of CST therapies for which bispecific approaches could improve tumor specificity. This study helps better define the landscape of CST expression in metastatic and primary cancers.

PMID:39315546 | PMC:PMC11457844 | DOI:10.1172/jci.insight.183674

Human papillomaviruses (HPV), most commonly HPV16, are associated with a subset of head and neck squamous cell carcinoma (HNSCC) tumors, primarily oropharyngeal carcinomas, with integration of viral genomes into host chromosomes associated with worse survival outcomes. We analyzed TCGA data and found that HPV+ HNSCC expressed higher transcript levels of the bromodomain and extra terminal domain (BET) family of transcriptional coregulators. The role of BET protein-mediated transcription of viral-cellular genes in the viral-HNSCC genomes needs to be better understood. Using a combination of TAME-Seq, qRT-PCR, and immunoblot analyses, we show that BET inhibition downregulates E6 and E7 significantly, with heterogeneity in the downregulation of viral transcription across different HPV+ HNSCC cell lines. Chemical BET inhibition was phenocopied with the knockdown of BRD4, mirroring the downregulation of viral E6 and E7 expression. We found that BET inhibition directly downregulated c-Myc and E2F expression and induced CDKN1A (p21) expression, leading to a G1-cell cycle arrest with apoptotic activity. Overall, our studies demonstrate that BET inhibition regulates both E6 and E7 viral and key cellular cell cycle regulator E2F gene expression and cellular gene expression in HPV-associated HNSCC and highlight the potential of BET inhibitors as a therapeutic strategy for this disease while also underscoring the importance of considering the heterogeneity in cellular responses to BET inhibition.

PMID:39301555 | PMC:PMC11410754 | DOI:10.3389/fonc.2024.1440836

Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors.

PMID:39292804 | PMC:PMC11522033 | DOI:10.1126/scitranslmed.adk0642

BACKGROUND: Although squamous cell carcinoma of the anus (SCCA) is a relatively uncommon malignancy in the United States, it continues to increase in incidence. Treatment for locoregional disease includes mitomycin and 5-fluorouracil with radiation. This combination is associated with significant toxicity, limiting its use in patients who are older or have certain comorbidities. Carboplatin and paclitaxel (C/P) is an accepted treatment regimen for metastatic SCCA. We aim to evaluate the efficacy and toxicity of weekly C/P given with radiation for patients unable to receive standard chemoradiation for SCCA.

METHODS: From our cancer registry, adult patients who received weekly intravenous C/P concurrent with standard-dose radiation for localized SCCA were included in this study. Clinical response was determined based on the evidence of disease on imaging and/or anoscopy. Toxicities were graded according to the CTCAE v5.

RESULTS: Ten patients were included; eight were female, and the median age was 75.5 years (54-87). Six had T2 disease, and four had T3 tumors. Four had node-positive disease. The majority (70%) of patients were dosed at standard C (AUC 2) and P (50 mg/m2), with a limited subset requiring dose reduction for baseline performance status. Patients completed a mean of 78.3% (40-100%) of the intended treatments. A total of 89% of the patients achieved a complete clinical response. With a median follow-up of 25.8 months (3.4-50.4 months), 67% of the patients are alive and without recurrence. Two patients have had local recurrence, and one patient had metastatic progression. The most common toxicities of any grade included leukopenia (100%), anemia (100%), radiation dermatitis (100%), diarrhea (100%), and fatigue (100%). Grade 3 or higher toxicities included neutropenic fever (20%), neutropenia (30%), and anemia (30%).

CONCLUSIONS: This study demonstrates promising tolerability and efficacy for weekly C/P chemoradiation for patients with anal cancer unable to receive mitomycin and 5-fluorouracil. This regimen merits further investigation in prospective clinical trials.

PMID:39272920 | PMC:PMC11394111 | DOI:10.3390/cancers16173062

PURPOSE: To determine if patient-specific IMRT quality assurance can be measured on any matched treatment delivery system (TDS) for patient treatment delivery on another.

METHODS: Three VMAT plans of varying complexity were created for each available energy for head and neck, SBRT lung, and right chestwall anatomical sites. Each plan was delivered on three matched Varian TrueBeam TDSs to the same Scandidos Delta4 Phantom+ diode array with only energy-specific device calibrations. Dose distributions were corrected for TDS output and then compared to TPS calculations using gamma analysis. Round-robin comparisons between measurements from each TDS were also performed using point-by-point dose difference, median dose difference, and the percent of point dose differences within 2% of the mean metrics.

RESULTS: All plans had more than 95% of points passing a gamma analysis using 3%/3 mm criteria with global normalization and a 20% threshold when comparing measurements to calculations. The tightest gamma analysis criteria where a plan still passed > 95% were similar across delivery systems-within 0.5%/0.5 mm for all but three plan/energy combinations. Median dose deviations in measurement-to-measurement comparisons were within 0.7% and 1.0% for global and local normalization, respectively. More than 90% of the point differences were within 2%.

CONCLUSION: A set of plans spanning available energies and complexity levels were delivered by three matched TDSs. Comparisons to calculations and between measurements showed dose distributions delivered by each TDS using the same DICOM RT-plan file meet tolerances much smaller than typical clinical IMRT QA criteria. This demonstrates each TDS is modeled to a similar accuracy by a common class (shared) beam model. Additionally, it demonstrates that dose distributions from one TDS show small differences in median dose to the others. This is an important validation component of the common beam model approach, allowing for operational improvements in the clinic.

PMID:39250771 | PMC:PMC11466462 | DOI:10.1002/acm2.14492

Salivary gland dysfunction is a common side effect of cancer treatments. Salivary function plays key roles in critical daily activities. Consequently, changes in salivary function can profoundly impair quality of life for cancer patients. We discuss salivary gland anatomy and physiology to understand how anticancer therapies such as chemotherapy, bone marrow transplantation, immunotherapy, and radiation therapy impair salivary function. We discuss approaches to quantify xerostomia in the clinic, including the advantages and limitations of validated quality-of-life instruments and approaches to directly measuring salivary function. Current and emerging approaches to treat cancer therapy-induced dry mouth are presented using radiation-induced salivary dysfunction as a model. Limitations of current sialagogues and salivary analogues are presented. Emerging approaches, including cellular and gene therapy and novel pharmacologic approaches, are described.

PMID:39225092 | PMC:PMC11364403 | DOI:10.1172/JCI182661

PURPOSE: Human Papilloma Virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is a distinct disease from other head and neck tumors. This guideline provides evidence-based recommendations on the critical decisions in its curative treatment, including both definitive and postoperative radiation therapy (RT) management.

METHODS: ASTRO convened a task force to address 5 key questions on the use of RT for management of HPV-associated OPSCC. These questions included indications for definitive and postoperative RT and chemoradiation; dose-fractionation regimens and treatment volumes; preferred RT techniques and normal tissue considerations; and posttreatment management decisions. The task force did not address indications for primary surgery versus RT. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength.

RESULTS: Concurrent cisplatin is recommended for patients receiving definitive RT with T3-4 disease and/or 1 node >3 cm, or multiple nodes. For similar patients who are ineligible for cisplatin, concurrent cetuximab, carboplatin/5-fluorouracil, or taxane-based systemic therapy are conditionally recommended. In the postoperative setting, RT with concurrent cisplatin (either schedule) is recommended for positive surgical margins or extranodal extension. Postoperative RT alone is recommended for pT3-4 disease, >2 nodes, or a single node >3 cm. Observation is conditionally recommended for pT1-2 disease and a single node ≤3 cm without other risk factors. For patients treated with definitive RT with concurrent systemic therapy, 7000 cGy in 33 to 35 fractions is recommended, and for patients receiving postoperative RT without positive surgical margins and extranodal extension, 5600 to 6000 cGy is recommended. For all patients receiving RT, intensity modulated RT over 3-dimensional techniques with reduction in dose to critical organs at risk (including salivary and swallowing structures) is recommended. Reassessment with positron emission tomography-computed tomography is recommended approximately 3 months after definitive RT/chemoradiation, and neck dissection is recommended for convincing evidence of residual disease; for equivocal positron emission tomography-computed tomography findings, either neck dissection or repeat imaging is recommended.

CONCLUSIONS: The role and practice of RT continues to evolve for HPV-associated OPSCC, and these guidelines inform best clinical practice based on the available evidence.

PMID:39078350 | DOI:10.1016/j.prro.2024.05.007

BACKGROUND: The dynamic collimation system (DCS) provides energy layer-specific collimation for pencil beam scanning (PBS) proton therapy using two pairs of orthogonal nickel trimmer blades. While excellent measurement-to-calculation agreement has been demonstrated for simple cube-shaped DCS-trimmed dose distributions, no comparison of measurement and dose calculation has been made for patient-specific treatment plans.

PURPOSE: To validate a patient-specific quality assurance (PSQA) process for DCS-trimmed PBS treatment plans and evaluate the agreement between measured and calculated dose distributions.

METHODS: Three intracranial patient cases were considered. Standard uncollimated PBS and DCS-collimated treatment plans were generated for each patient using the Astroid treatment planning system (TPS). Plans were recalculated in a water phantom and delivered at the Miami Cancer Institute (MCI) using an Ion Beam Applications (IBA) dedicated nozzle system and prototype DCS. Planar dose measurements were acquired at two depths within low-gradient regions of the target volume using an IBA MatriXX ion chamber array.

RESULTS: Measured and calculated dose distributions were compared using 2D gamma analysis with 3%/3 mm criteria and low dose threshold of 10% of the maximum dose. Median gamma pass rates across all plans and measurement depths were 99.0% (PBS) and 98.3% (DCS), with a minimum gamma pass rate of 88.5% (PBS) and 91.2% (DCS).

CONCLUSIONS: The PSQA process has been validated and experimentally verified for DCS-collimated PBS. Dosimetric agreement between the measured and calculated doses was demonstrated to be similar for DCS-collimated PBS to that achievable with noncollimated PBS.

PMID:38977285 | PMC:PMC11781041 | DOI:10.1002/mp.17295

BACKGROUND: Mutation or amplification of the mesenchymal-epithelial transition (MET) tyrosine kinase receptor causes dysregulation of receptor function and stimulates tumor growth in non-small cell lung cancer (NSCLC) with the most common mutation being MET exon 14 (METex14). We sought to compare the genomic and immune landscape of MET-altered NSCLC with MET wild-type NSCLC.

METHODS: 18,047 NSCLC tumors were sequenced with Tempus xT assay. Tumors were categorized based on MET exon 14 (METex14) mutations; low MET amplification defined as a copy number gain (CNG) 6-9, high MET amplification defined as CNG ≥ 10, and MET other type mutations. Immuno-oncology (IO) biomarkers and the frequency of other somatic gene alterations were compared across MET-altered and MET wild-type groups.

RESULTS: 276 (1.53%) METex14, 138 (0.76%) high METamp, 63 (0.35%) low METamp, 27 (0.15%) MET other, and 17,543 (97%) MET wild-type were identified. Patients with any MET mutation including METex14 were older, while patients with METex14 were more frequently female and nonsmokers. MET gene expression was highest in METamp tumors. PD-L1 positivity rates were higher in MET-altered groups than MET wild-type. METex14 exhibited the lowest tumor mutational burden (TMB) and lowest neoantigen tumor burden (NTB). METamp exhibited the lowest proportion of CD4 T cells and the highest proportion of NK cells. There were significant differences in co-alterations between METamp and METex14.

CONCLUSIONS: METex14 tumors exhibited differences in IO biomarkers and the somatic landscape compared to non-METex14 NSCLC tumors. Variations in immune profiles can affect immunotherapy selection in MET-altered NSCLC and require further exploration.

PMID:38852006 | PMC:PMC12121485 | DOI:10.1016/j.cllc.2024.05.001

BACKGROUND: MRI-guided radiation therapy (MRgRT) requires unique quality assurance equipment to address MR-compatibility needs, minimize electron return effect, handle complex dose distributions, and evaluate real-time dosimetry for gating. Plastic scintillation detectors (PSDs) are an attractive option to address these needs.

PURPOSE: To perform a comprehensive characterization of a multi-probe PSD system in a low-field 0.35 T MR-linac, including detector response assessment and gating performance.

METHODS: A four-channel PSD system (HYPERSCINT RP-200) was assembled. A single channel was used to evaluate repeatability, percent depth dose (PDD), detector response as a function of orientation with respect to the magnetic field, and intersession variability. All four channels were used to evaluate repeatability, linearity, and output factors. The four PSDs were integrated into an MR-compatible motion phantom at isocenter and in gradient regions. Experiments were conducted to evaluate gating performance and tracking efficacy.

RESULTS: For repeatability, the maximum standard deviation of repeated measurements was 0.13% (single PSD). Comparing the PSD to reference data, PDD had a maximum difference of 1.12% (10 cm depth, 6.64 × 6.64 cm2). Percent differences for rotated detector setups were negligible (< 0.3%). All four PSDs demonstrated linear response over 10-1000 MU delivered and the maximum percent difference between the baseline and measured output factors was 0.78% (2.49 × 2.49 cm2). Gating experiments had 400 cGy delivered to isocenter with < 0.8 cGy variation for central axis measures and < 0.7 cGy for the gradient sampled region. Real-time dosimetry measurements captured spurious beam-on incidents that correlated to tracking algorithm inaccuracies and highlighted gating parameter impact on delivery efficiency.

CONCLUSIONS: Characterization of the multi-point PSD dosimetry system in a 0.35 T MR-linac demonstrated reliability in a low-field MR-Linac setting, with high repeatability, linearity, small intersession variability, and similarity to baseline data for PDD and output factors. Time-resolved, multi-point dosimetry also showed considerable promise for gated MR-Linac applications.

PMID:38843532 | PMC:PMC11489030 | DOI:10.1002/mp.17192

PURPOSE: T1 mapping is a widely used quantitative MRI technique, but its tissue-specific values remain inconsistent across protocols, sites, and vendors. The ISMRM Reproducible Research and Quantitative MR study groups jointly launched a challenge to assess the reproducibility of a well-established inversion-recovery T1 mapping technique, using acquisition details from a seminal T1 mapping paper on a standardized phantom and in human brains.

METHODS: The challenge used the acquisition protocol from Barral et al. (2010). Researchers collected T1 mapping data on the ISMRM/NIST phantom and/or in human brains. Data submission, pipeline development, and analysis were conducted using open-source platforms. Intersubmission and intrasubmission comparisons were performed.

RESULTS: Eighteen submissions (39 phantom and 56 human datasets) on scanners by three MRI vendors were collected at 3 T (except one, at 0.35 T). The mean coefficient of variation was 6.1% for intersubmission phantom measurements, and 2.9% for intrasubmission measurements. For humans, the intersubmission/intrasubmission coefficient of variation was 5.9/3.2% in the genu and 16/6.9% in the cortex. An interactive dashboard for data visualization was also developed: https://rrsg2020.dashboards.neurolibre.org.

CONCLUSION: The T1 intersubmission variability was twice as high as the intrasubmission variability in both phantoms and human brains, indicating that the acquisition details in the original paper were insufficient to reproduce a quantitative MRI protocol. This study reports the inherent uncertainty in T1 measures across independent research groups, bringing us one step closer to a practical clinical baseline of T1 variations in vivo.

PMID:38730562 | DOI:10.1002/mrm.30111