Assessing tumor microstructure with time-dependent diffusion imaging: Considerations and feasibility on clinical MRI and MRI-Linac.

BACKGROUND: Quantitative imaging biomarkers (QIBs) can characterize tumor heterogeneity and provide information for biological guidance in radiotherapy (RT). Time-dependent diffusion MRI (TDD-MRI) derived parameters are promising QIBs, as they describe tissue microstructure with more specificity than traditional diffusion-weighted MRI (DW-MRI). Specifically, TDD-MRI can provide information about both restricted diffusion and diffusional exchange, which are the two time-dependent effects affecting diffusion in tissue, and relevant in tumors. However, exhaustive modeling of both effects can require long acquisitions and complex model fitting. Furthermore, several introduced TDD-MRI measurements can require high gradient strengths and/or complex gradient waveforms that are possibly not available in RT settings. PURPOSE: In this study, we investigated the feasibility of a simple analysis framework for the detection of restricted diffusion and diffusional exchange effects in the TDD-MRI signal. To promote the clinical applicability, we use standard gradient waveforms on a conventional 1.5 T MRI system with moderate gradient strength (Gmax = 45 mT/m), and on a hybrid 1.5 T MRI-Linac system with low gradient strength (Gmax = 15 mT/m). METHODS: Restricted diffusion and diffusional exchange were simulated in geometries mimicking tumor microstructure to investigate the DW-MRI signal behavior and to determine optimal experimental parameters. TDD-MRI was implemented using pulsed field gradient spin echo with the optimized parameters on a conventional MRI system and a MRI-Linac. Experiments in green asparagus and 10 patients with brain lesions were performed to evaluate the time-dependent diffusion (TDD) contrast in the source DW-images. RESULTS: Simulations demonstrated how the TDD contrast was able to differentiate only dominating diffusional exchange in smaller cells from dominating restricted diffusion in larger cells. The maximal TDD contrast in simulations with typical cancer cell sizes and in asparagus measurements exceeded 5% on the conventional MRI but remained below 5% on the MRI-Linac. In particular, the simulated TDD contrast in typical cancer cell sizes (r = 5-10 µm) remained below or around 2% with the MRI-Linac gradient strength. In patients measured with the conventional MRI, we found sub-regions reflecting either dominating restricted diffusion or dominating diffusional exchange in and around brain lesions compared to the noisy appearing white matter. CONCLUSIONS: On the conventional MRI system, the TDD contrast maps showed consistent tumor sub-regions indicating different dominating TDD effects, potentially providing information on the spatial tumor heterogeneity. On the MRI-Linac, the available TDD contrast measured in asparagus showed the same trends as with the conventional MRI but remained close to typical measurement noise levels when simulated in common cancer cell sizes. On conventional MRI systems with moderate gradient strengths, the TDD contrast could potentially be used as a tool to identify which time-dependent effects to include when choosing a biophysical model for more specific tumor characterization.

Ibrutinib as treatment for Bing-Neel syndrome reclassified as glioblastoma: a case report.

BACKGROUND: Glioblastoma is a highly malignant disease with limited treatment options. Ibrutinib, a covalent Bruton tyrosine kinase inhibitor, is an oral agent with manageable side effects used for hematological diseases including Waldenström macroglobulinemia. We present the case of a 69-year-old Caucasian male patient treated with ibrutinib for suspected Bing-Neel syndrome (BNS), which following a biopsy, was reclassified as glioblastoma. CASE PRESENTATION: In December 2018, a 69-year-old Caucasian male patient was diagnosed with Waldenström macroglobulinemia. As the patient was asymptomatic, without bone marrow failure or high M-component count, watchful waiting was initiated. Due to increasing neurological symptoms, the patient, based on magnetic resonance imaging, was diagnosed with Bing-Neel syndrome in May 2019. The patient received different treatments before starting ibrutinib monotherapy in August 2019 due to disease progression, both on magnetic resonance imaging and clinically. The patient remained clinically stable for 7 months. In March 2020, the patient developed headaches, and both magnetic resonance imaging and a biopsy revealed glioblastoma IDH-wildtype. Treatment was changed in line with the new diagnosis, but the patient died at the end of 2020. CONCLUSION: We present a case in which a patient with glioblastoma IDH-wildtype remained clinically stable for 7 months when treated with ibrutinib monotherapy, which is similar to what would be expected for the standard treatment for glioblastoma. To our knowledge, this is the first patient receiving ibrutinib for a glioblastoma IDH-wildtype with a meaningful clinical outcome. Our case may therefore support previous nonclinical findings, indicating a therapeutic value of ibrutinib in patients with glioblastoma and support for further investigation of ibrutinib as a possible treatment for glioblastoma.

Artificial intelligence for MRI stroke detection: a systematic review and meta-analysis.

OBJECTIVES: This systematic review and meta-analysis aimed to assess the stroke detection performance of artificial intelligence (AI) in magnetic resonance imaging (MRI), and additionally to identify reporting insufficiencies. METHODS: PRISMA guidelines were followed. MEDLINE, Embase, Cochrane Central, and IEEE Xplore were searched for studies utilising MRI and AI for stroke detection. The protocol was prospectively registered with PROSPERO (CRD42021289748). Sensitivity, specificity, accuracy, and area under the receiver operating characteristic (ROC) curve were the primary outcomes. Only studies using MRI in adults were included. The intervention was AI for stroke detection with ischaemic and haemorrhagic stroke in separate categories. Any manual labelling was used as a comparator. A modified QUADAS-2 tool was used for bias assessment. The minimum information about clinical artificial intelligence modelling (MI-CLAIM) checklist was used to assess reporting insufficiencies. Meta-analyses were performed for sensitivity, specificity, and hierarchical summary ROC (HSROC) on low risk of bias studies. RESULTS: Thirty-three studies were eligible for inclusion. Fifteen studies had a low risk of bias. Low-risk studies were better for reporting MI-CLAIM items. Only one study examined a CE-approved AI algorithm. Forest plots revealed detection sensitivity and specificity of 93% and 93% with identical performance in the HSROC analysis and positive and negative likelihood ratios of 12.6 and 0.079. CONCLUSION: Current AI technology can detect ischaemic stroke in MRI. There is a need for further validation of haemorrhagic detection. The clinical usability of AI stroke detection in MRI is yet to be investigated. CRITICAL RELEVANCE STATEMENT: This first meta-analysis concludes that AI, utilising diffusion-weighted MRI sequences, can accurately aid the detection of ischaemic brain lesions and its clinical utility is ready to be uncovered in clinical trials. KEY POINTS: There is a growing interest in AI solutions for detection aid. The performance is unknown for MRI stroke assessment. AI detection sensitivity and specificity were 93% and 93% for ischaemic lesions. There is limited evidence for the detection of patients with haemorrhagic lesions. AI can accurately detect patients with ischaemic stroke in MRI.

Response Monitoring in Metastatic Breast Cancer: A Prospective Study Comparing 18F-FDG PET/CT with Conventional CT.

This study aimed to compare contrast-enhanced CT (CE-CT) and 18F-FDG PET/CT for response monitoring in metastatic breast cancer using the standardized response evaluation criteria RECIST 1.1 and PERCIST. The objective was to examine whether progressive disease was detected systematically earlier by one of the modalities. Methods: Women with biopsy-verified metastatic breast cancer were enrolled prospectively and monitored using combined CE-CT and 18F-FDG PET/CT every 9-12 wk to evaluate response to first-line treatment. CE-CT scans and RECIST 1.1 were used for clinical decision-making without accessing the 18F-FDG PET/CT scans. At study completion, 18F-FDG PET/CT scans were unmasked and assessed according to PERCIST. Visual assessment was used if response criteria could not be applied. The modality-specific time to progression was defined as the time from the baseline scan until the first scan demonstrating progression. Paired comparative analyses for CE-CT versus 18F-FDG PET/CT were applied, and the primary endpoint was earlier detection of progression by one modality. Secondary endpoints were time to detection of progression, response categorization, visualization of changes in response over time, and measurable disease according to RECIST and PERCIST. Results: In total, 87 women were evaluable, with a median of 6 (1-11) follow-up scans. Progression was detected first by 18F-FDG PET/CT in 43 (49.4%) of 87 patients and first by CE-CT in 1 (1.15%) of 87 patients (P < 0.0001). Excluding patients without progression (n = 32), progression was seen first on 18F-FDG PET/CT in 78.2% (43/55) of patients. The median time from detection of progression by 18F-FDG PET/CT to that of CE-CT was 6 mo (95% CI, 4.3-6.4 mo). At baseline, 76 (87.4%) of 87 patients had measurable disease according to PERCIST and 51 (58.6%) of 87 patients had measurable disease according to RECIST 1.1. Moreover, 18F-FDG PET/CT provided improved visualization of changes in response over time, as seen in the graphical abstract. Conclusion: Disease progression was detected earlier by 18F-FDG PET/CT than by CE-CT in most patients, with a potentially clinically relevant median 6-mo delay for CE-CT. More patients had measurable disease according to PERCIST than according to RECIST 1.1. The magnitude of the final benefit for patients is a perspective for future research.

2-[18F]FDG-PET/CT is a better predictor of survival than conventional CT: a prospective study of response monitoring in metastatic breast cancer.

This study aimed to compare CE-CT and 2-[18F]FDG-PET/CT for response monitoring metastatic breast cancer (MBC). The primary objective was to predict progression-free and disease-specific survival for responders vs. non-responders on CE-CT and 2-[18F]FDG-PET/CT. The secondary objective was to assess agreement between response categorization for the two modalities. Treatment response in women with MBC was monitored prospectively by simultaneous CE-CT and 2-[18F]FDG-PET/CT, allowing participants to serve as their own controls. The standardized response evaluation criteria in solid tumors (RECIST 1.1) and PET response criteria in solid tumors (PERCIST) were used for response categorization. For prediction of progression-free and disease-specific survival, treatment response was dichotomized into responders (partial and complete response) and non-responders (stable and progressive disease) at the first follow-up scan. Progression-free survival was defined as the time from baseline until disease progression or death from any cause. Disease-specific survival was defined as the time from baseline until breast cancer-specific death. Agreement between response categorization for both modalities was analyzed for all response categories and responders vs. non-responders. At the first follow-up, tumor response was reported more often by 2-[18F]FDG-PET/CT than CE-CT, with only fair agreement on response categorization between the two modalities (weighted Kappa 0.28). Two-year progression-free survival for responders vs. non-responders by CE-CT was 54.2% vs. 46.0%, compared with 59.1% vs. 14.3% by 2-[18F]FDG-PET/CT. Correspondingly, 2-year disease-specific survival were 83.3% vs. 77.8% for CE-CT and 84.6% vs. 61.9% for 2-[18F]FDG-PET/CT. Tumor response on 2-[18F]FDG-PET/CT was significantly associated with progression-free (HR: 3.49, P < 0.001) and disease-specific survival (HR 2.35, P = 0.008), while no association was found for tumor response on CE-CT. In conclusion, 2-[18F]FDG-PET/CT appears a better predictor of progression-free and disease-specific survival than CE-CT when used to monitor metastatic breast cancer. In addition, we found low concordance between response categorization between the two modalities. TRIAL REGISTRATION: Clinical. TRIALS: gov. NCT03358589. Registered 30/11/2017-Retrospectively registered, http://www. CLINICALTRIALS: gov.

Association Between Statin Use and Intracerebral Hemorrhage Location: A Nested Case-Control Registry Study.

BACKGROUND AND OBJECTIVES: A causal relationship between statin use and intracerebral hemorrhage (ICH) is uncertain. We hypothesized that an association between long-term statin exposure and ICH risk might vary for different ICH locations. METHODS: We conducted this analysis using linked Danish nationwide registries. Within the Southern Denmark Region (population 1.2 million), we identified all first-ever cases of ICH between 2009 and 2018 in persons aged ≥55 years. Patients with medical record-verified diagnoses were classified as having a lobar or nonlobar ICH and matched for age, sex, and calendar year to general population controls. We used a nationwide prescription registry to ascertain prior statin and other medication use that we classified for recency, duration, and intensity. Using conditional logistic regression adjusted for potential confounders, we calculated adjusted ORs (aORs) and corresponding 95% CIs for the risk of lobar and nonlobar ICH. RESULTS: We identified 989 patients with lobar ICH (52.2% women, mean age 76.3 years) who we matched to 39,500 controls and 1,175 patients with nonlobar ICH (46.5% women, mean age 75.1 years) who we matched to 46,755 controls. Current statin use was associated with a lower risk of lobar (aOR 0.83; 95% CI, 0.70-0.98) and nonlobar ICH (aOR 0.84; 95% CI, 0.72-0.98). Longer duration of statin use was also associated with a lower risk of lobar (<1 year: aOR 0.89; 95% CI, 0.69-1.14; ≥1 year to <5 years aOR 0.89; 95% CI 0.73-1.09; ≥5 years aOR 0.67; 95% CI, 0.51-0.87; p for trend 0.040) and nonlobar ICH (<1 year: aOR 1.00; 95% CI, 0.80-1.25; ≥1 year to <5 years aOR 0.88; 95% CI 0.73-1.06; ≥5 years aOR 0.62; 95% CI, 0.48-0.80; p for trend <0.001). Estimates stratified by statin intensity were similar to the main estimates for low-medium intensity therapy (lobar aOR 0.82; nonlobar aOR 0.84); the association with high-intensity therapy was neutral. DISCUSSION: We found that statin use was associated with a lower risk of ICH, particularly with longer treatment duration. This association did not vary by hematoma location.

Magnetic Resonance Elastography in Intracranial Neoplasms: A Scoping Review.

BACKGROUND: Magnetic resonance elastography (MRE) allows noninvasive assessment of intracranial tumor mechanics and may thus be predictive of intraoperative conditions. Variations in the use of technical terms complicate reading of current literature, and there is need of a review using consolidated nomenclature. OBJECTIVES: We present an overview of current literature on MRE relating to human intracranial neoplasms using standardized nomenclature suggested by the MRE guidelines committee. We then discuss the implications of the findings, and suggest approaches for future research. METHOD: We performed a systematic literature search in PubMed, Embase, and Web of Science; the articles were screened for relevance and then subjected to full text review. Technical terms were consolidated. RESULTS: We identified 12 studies on MRE in patients with intracranial tumors, including meningiomas, glial tumors including glioblastomas, vestibular schwannomas, hemangiopericytoma, central nervous system lymphoma, pituitary macroadenomas, and brain metastases. The studies had varying objectives that included prediction of intraoperative consistency, histological separation, prediction of adhesiveness, and exploration of the mechanobiology of tumor invasiveness and malignancy. The technical terms were translated using standardized nomenclature. The literature was highly heterogeneous in terms of image acquisition techniques, post-processing, and study design and was generally limited by small and variable cohorts. CONCLUSIONS: MRE shows potential in predicting tumor consistency, adhesion, and mechanical homogeneity. Furthermore, MRE provides insight into malignant tumor behavior and its relation to tissue mechanics. MRE is still at a preclinical stage, but technical advances, improved understanding of soft tissue rheological impact, and larger samples are likely to enable future clinical introduction.

[Magnetic resonance elastography of the brain].

Magnetic resonance elastography (MRE) is a novel imaging modality allowing quantification of tissue consistency. Multiple trials have focused on the use of MRE to describe meningioma consistency prior to surgery and on improving diagnostic accuracy of normal pressure hydrocephalus and other dementias. MRE shows promising results, but still lacks direct clinical translational value. Within neurosurgery and neurosciences MRE could contribute and improve decision-making, diagnosis and treatment. Furthermore, the use of MRE will improve the basic understanding of neuroanatomy, physiology and pathology.

Validity of Simple Algorithms to Identify Recurrence of Intracerebral Hemorrhage in Two Danish Nationwide Registries.

PURPOSE: Danish registries could be an attractive resource for studies of recurrent intracerebral hemorrhage (re-ICH). We developed and validated algorithms to identify re-ICH in the Danish Stroke Registry (DSR) and the Danish National Patient Registry (DNPR). PATIENTS AND METHODS: Using multiple sources, we followed-up an inception cohort with verified first-ever spontaneous ICH (n = 2528) for their first re-ICH in 2009-2018 (study period). We used verified cases of re-ICH (n = 124) as the gold standard to assess the performance of register-based algorithms for identifying re-ICH. For each cohort member, we traced events of re-ICH (ICD-10-code I61) in the study period according to DSR and DNPR, respectively. For each registry, we tested algorithms with a blanking period (BP) - ie, a period immediately following the index ICH during which outcome events were ignored - of varying length (7 days-360 days). The algorithm with the shortest BP that returned a positive predictive value (PPV) of ≥80% was considered optimal. We also calculated negative predictive value (NPV), sensitivity, and specificity of each algorithm and [95% confidence intervals] for all proportions. RESULTS: The optimal algorithm for DSR (BP 30 days) had a PPV of 89.5% [82.2-94.0], NPV 98.8% [98.2-99.1], sensitivity 75.8% [67.6-82.5], and specificity 99.5% [99.2-99.7]. The optimal algorithm for DNPR (BP 120 days) had a PPV of 80.6% [71.7-87.2], NPV 98.1% [97.5-98.6], sensitivity 63.7% [55.0-71.6], and specificity 99.2% [98.8-99.5]. CONCLUSION: Simple algorithms accurately identified re-ICH in DSR and DNPR. Compared with DNPR, DSR achieved higher PPV and sensitivity with a shorter BP. The proposed algorithms could facilitate valid use of DSR and DNPR for studies of re-ICH.

Evolution of the gross tumour volume extent during radiotherapy for glioblastomas.

BACKGROUND AND PURPOSE: Tumour growth during radiotherapy may lead to geographical misses of the target volume. This study investigates the evolution of the tumour extent and evaluates the need for plan adaptation to ensure dose coverage of the target in glioblastoma patients. MATERIALS AND METHODS: The prospective study included 29 patients referred for 59.4 Gy in 33 fractions. Magnetic resonance imaging (MRI) was performed at the time of treatment planning, at fraction 10, 20, 30, and three weeks after the end of radiotherapy. The gross tumour volume (GTV) was defined as the T1w contrast-enhanced region plus the surgical cavity on each MRI set. The relative GTV volume and the maximum distance (Dmax) of the extent of the actual GTV outside the original GTV were measured. Based on the location of the actual GTV during radiotherapy and the original planned dose, a prospective clinical decision was made whether to adapt the treatment. RESULTS: Dose coverage of the GTV during radiotherapy was not compromised, and none of the radiotherapy plans was adapted. The median Dmax (range) was 5.7 (2.0-18.9) mm, 8.0 (2.0-27.4) mm, 8.0 (1.9-27.3) mm, and 8.9 (1.9-34.4) mm at fraction 10, 20, 30, and follow-up. The relative GTV volume and Dmax observed at fraction 10 were correlated with the values observed at follow-up (R = 0.74, p < 0.001 and R = 0.79, p < 0.001, respectively). CONCLUSION: Large variations in the GTV extent were observed, and changes often occurred early in the treatment. Plan adaptation for geographical misses was not performed in our cohort due to sufficient CTV margins.

[Seminal vesicle cyst with ipsilateral renal agenesis]. / Vesicula seminalis-cyste med ipsilateral nyreagenesi.

A formerly healthy 41-year-old male with monosymptomatic swelling of his left testicle was diagnosed with testicular cancer (seminoma). During staging of the cancer a computed tomography showed left renal agenesis and an 8 x 6 cm retrovesical space-occupying lesion in the left side of the pelvis. The lesion was interpreted as a group of enlarged lymph nodes, but PET/CT and MRI later demonstrated that it was a left seminal vesicle cyst. An association between congenital seminal vesicle cysts and ipsilateral renal agenesis is rare and can be explained by their common embryologic origin.

Acute gastric incarceration from thoracic herniation in pregnancy following laparoscopic antireflux surgery.

Diaphragmatic hernia is a rare complication in pregnancy which due to misdiagnosis or management delays may be life-threatening. We report a case of a woman in the third trimester of pregnancy who presented with sudden onset of severe epigastric and thoracic pain radiating to the back. Earlier in the index pregnancy, she had undergone laparoscopic antireflux surgery (ARS) for a hiatus hernia because of severe gastro-oesophageal reflux. Owing to increasing epigastric pain a CT scan was carried out which diagnosed wrap disruption with gastric herniation into the thoracic cavity and threatened incarceration. This is, to our knowledge, the first report of severe adverse outcome after ARS during pregnancy, with acute intrathoracic gastric herniation. We recommend the avoidance of ARS in pregnancy, and the need to advise women undergoing ARS of the postoperative risks if pregnancy occurs within a few years of ARS.