Baseline extracellular vesicle TGF-ß is a predictive biomarker for response to immune checkpoint inhibitors and survival in non-small cell lung cancer.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) are an effective therapeutic strategy, improving the survival of patients with lung cancer compared with conventional treatments. However, novel predictive biomarkers are needed to stratify which patients derive clinical benefit because the currently used and highly heterogenic histological PD-L1 has shown low accuracy. Liquid biopsy is the analysis of biomarkers in body fluids and represents a minimally invasive tool that can be used to monitor tumor evolution and treatment effects, potentially reducing biases associated with tumor heterogeneity associated with tissue biopsies. In this context, cytokines, such as transforming growth factor-ß (TGF-ß), can be found free in circulation in the blood and packaged into extracellular vesicles (EVs), which have a specific delivery tropism and can affect in tumor/immune system interaction. TGF-ß is an immunosuppressive cytokine that plays a crucial role in tumor immune escape, treatment resistance, and metastasis. Thus, we aimed to evaluate the predictive value of circulating and EV TGF-ß in patients with non-small-cell lung cancer receiving ICIs. METHODS: Plasma samples were collected in 33 patients with advanced non-small-cell lung cancer before and during treatment with ICIs. EV were isolated from plasma by serial ultracentrifugation methods and circulating and EV TGF-ß expression levels were evaluated by enzyme-linked immunosorbent assay. RESULTS: Baseline high expression of TGF-ß in EVs was associated with nonresponse to ICIs as well as shorter progression-free survival and overall survival, outperforming circulating TGF-ß levels and tissue PD-L1 as a predictive biomarker. CONCLUSION: If validated, EV TGF-ß could be used to improve patient stratification, increasing the effectiveness of treatment with ICIs and potentially informing combinatory treatments with TGF-ß blockade. PLAIN LANGUAGE SUMMARY: Treatment with immune-checkpoint inhibitors (ICIs) has improved the survival of some patients with lung cancer. However, the majority of patients do not benefit from this treatment, making it essential to develop more reliable biomarkers to identify patients most likely to benefit. In this pilot study, the expression of transforming growth factor-ß (TGF-ß) in blood circulation and in extracellular vesicles was analyzed. The levels of extracellular vesicle TGF-ß before treatment were able to determine which patients would benefit from treatment with ICIs and have a longer survival with higher accuracy than circulating TGF-ß and tissue PD-L1, which is the currently used biomarker in clinical practice.

Overcoming metallic artefacts from orthopaedic wrist volar plating on a low-field MRI scanner.

PURPOSE: To quantitatively compare the artefact reduction between standard and metallic artefact reduction (MAR) fast spin echo (FSE) T2 sequences in a low-field magnetic resonance imaging (MRI) scanner (0.3 T) in patients with titanium volar wrist plating. MATERIALS AND METHODS: Sixteen patients with fractures of the distal radius, treated with titanium volar wrist plating and screws, were examined using a dedicated 0.3 T MRI scanner. Coronal standard FSE T2, FSE T2 high bandwidth (HiBW) and FSE T2 view angle tilting (VAT) sequences were performed. Metallic artefact volume, consisting of both "black" and "bright" artefacts, was calculated for each sequence. Quantitative differences were compared using repeated measures ANOVA test (P < 0.05). RESULTS: FSE T2 HiBW and FSE T2 VAT showed a significant reduction in artefact volume compared to the standard sequence. Differences between the artefact volume of the standard FSE T2, HiBW and VAT sequences were statistically significant for both the "black" and "bright" artefacts (P < 0.0001). Differences between the 1.5 HiBW and VAT sequences were statistically significant (black P < 0.0001, bright P < 0.0302). CONCLUSIONS: MAR sequences significantly reduced metallic artefacts in vivo using a 0.3 T MRI scanner.

Predictive value of pre-treatment apparent diffusion coefficient (ADC) in radio-chemiotherapy treated head and neck squamous cell carcinoma.

OBJECTIVE: This study aimed at evaluating the role of "baseline" apparent diffusion coefficent (ADC), in patients affected by head and neck cancer treated with radio-chemotherapy, as a potential marker of response to therapy. METHODS: Fifty-seven patients underwent pretreatment ADC maps. Minimum, maximum, and medium ADC were computed. Age, dose, treatment time, and ADC values were compared between the two groups (Group 1: local control; Group 2: relapse/persistence of disease) using the Student t test two-tailed unpaired. Two-tailed Fischer exact test was used to compare T stage, N stage, grading and type of treatment between two groups. We have analyzed the receiver operating characteristic (ROC) of statistically significant variables. RESULTS: In patients with local control, values of pre-treatment medium and minimum ADC were lower than ADC values of patients with persistent or recurrent disease, with values, respectively, of 0.83 ± 0.02 × 10-3 mm2/s and 0.59 ± 0.02 × 10-3 mm2/s (vs 0.94 ± 0.05 × 10-3 mm2/s and 0.70 ± 0.05 × 10-3 mm2/s). ROC curve analysis displayed statistical significance as regarding the medium ADC value, showing a sensitivity of 50% and a specificity of 84.8%. ROC analysis of the values minimum ADC showed a sensitivity of 42.9% and specificity of 87.9%. CONCLUSION: The value of the ADC pre-treatment of patients with local control of the disease is lower than that of patients with persistent disease or recurrence.

Can neuroimaging differentiate PFO and AF-related cardioembolic stroke from the other embolic sources? Clinical-radiological correlation on a retrospective study.

PURPOSE: The aim of this retrospective study was to map the specific ischemic lesion patterns of distribution in patent foramen ovale-related stroke (PFO-stroke) and atrial fibrillation-related stroke (AF-stroke) in patients with idiopatic ischemic stroke. MATERIALS AND METHODS: 750 ischaemic strokes were screened on basis of diagnostic imaging and tests: patients with known causes were excluded. 171 patients with unknown cause were selected and divided in two groups: AF-stroke (43 patients) and PFO-stroke (128 patients). Vascular territories of ischemic involvement were divided into four classes in each group: the anterior cerebral artery, the middle cerebral artery, the vertebro-cerebral artery (including the posterior cerebral artery) and multisite (MS) involvement. RESULTS: Infarcts in vertebro-basilar territory and multisite represented each one about 32% of infarcts in PFO-stroke group and their involvement are more frequent than AF-stroke group (p = 0.03). Ischemic lesions in PFO-group were predominantly cortical (34.3%), and in AF-group cortical-subcortical (60.4%). Multisite pattern of ischemic lesion was more frequent in patients with severe degree of right to left shunts (37.5%). CONCLUSION: In clinical practice, PFO may be considered a cause of cortical stroke on the basis of radiological findings, when VB vascular territory or MS brain involvement is present in younger patients (<50 age).

Comparison of retrospective PET and MRI-DWI (PET/MRI-DWI) image fusion with PET/CT and MRI-DWI in detection of cervical and endometrial cancer lymph node metastases.

OBJECTIVES: The aim of this study was to compare the accuracy of retrospective image fusion of PET/MRI-DWI with that of PET/CT and MRI-DWI alone in detecting metastatic lymph nodes in patients with cervical and endometrial carcinoma. MATERIALS AND METHODS: Twenty-seven patients with endometrial (n = 14) and cervical (n = 13) cancer who had undergone preoperative MRI-DWI and PET/CT for staging were retrospectively evaluated. The accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PET/CT, MRI-DWI, and PET/MRI-DWI image fusion were calculated on a per-patient basis and on a per-node basis. Histopathological and follow-up imaging results were used as the gold standard. RESULTS: On a per-patient basis PET/MRI-DWI had the same sensitivity (87.5 %), specificity (84.2 %), diagnostic accuracy (85.1 %), PPV (70 %), and NPV (94.1 %) as PET-CT, but on a per-node basis PET/MRI-DWI showed better sensitivity (89 vs 70.2 %), specificity (91.6 vs 90.5 %), diagnostic accuracy (91.2 vs 87 %), PPV (68.7 vs 60.4 %), and NPV (97.6 vs 93.6 %) than PET-CT. Comparison of the areas under the ROC curves for the detection of metastatic lymph nodes demonstrated a non-significant difference (p = 0.055) between PET/CT and fused PET/MRI-DWI. CONCLUSION: PET/MRI-DWI may be a valuable technique for N-staging patients with endometrial and cervical cancer, but more studies are needed to investigate its potential clinical utility.

Combined multimodal co-registration of PET/CT and MRI images increases diagnostic accuracy in squamous cell carcinoma staging.

OBJECTIVES: The purpose of our study was to assess the diagnostic value of multi-modal imaging through co-registration of short tau inversion recovery (STIR) and diffusion-weighted imaging (DWI) MRI with (18)FDG-PET/CT in T and N staging of head and neck tumours. MATERIALS AND METHODS: 25 patients with head and neck squamous cell carcinoma who had undergone MRI and PET/CT before treatment were retrospectively evaluated. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PET/CT, MRI and their combined use were assessed in T and N staging. Histopathology and follow-up imaging results were used as the gold standard. RESULTS: In assessing trans-compartmental extensions, PET-MRI showed 93 % sensitivity, 88 % specificity, 94 % PPV, and 88 % NPV, as compared to the 94 and 53 % sensitivity, 75 and 75 % specificity, 89 and 82 % PPV, and 86 and 43 % demonstrated by MRI and PET, respectively. In the identification of pathological lymph nodes, PET-MRI showed 92 % sensitivity, 89 % specificity, 96 % PPV, and 89 % NPV, whereas PET/CT displayed 72 % sensitivity, 89 % specificity, 95 % PPV and 53 % NPV. The corresponding figures for DWI and STIR sequences were 84 and 100 % sensitivity, 67 and 56 % specificity, 88 and 86 % PPV, and 60 and 100 % NPV, respectively. CONCLUSIONS: Multi-modal imaging assessment of co-registered MRI and PET/CT images provides more accurate results for trans-compartmental extensions in T and N staging than the individual techniques alone.

Evolution of Severe Closed Head Injury: Assessing Ventricular Volume and Behavioral Measures at 30 and 90 Days Post-Injury.

Background: Assessing functional outcomes in Severe Closed Head Injury (SCHI) is complex due to brain parenchymal changes. This study examines the Ventricles to Intracranial Volume Ratio (VBR) as a metric for these changes and its correlation with behavioral scales. Methods: Thirty-one SCHI patients were included. VBR was derived from CT scans at 3, 30, and 90 days post-injury and compared with Levels of Cognitive Functioning (LCF), Disability Rating Scale (DRS), and Early Rehabilitation Barthel Index (ERBI) assessments at 30 and 90 days. Results: Ten patients were excluded post-decompressive craniectomy or ventriculoperitoneal shunt. Findings indicated a VBR decrease at 3 days, suggesting acute phase compression, followed by an increase from 30 to 90 days, indicative of post-acute brain atrophy. VBR correlated positively with the Marshall score in the initial 72 h, positioning it as an early indicator of subsequent brain atrophy. Nevertheless, in contrast to the Marshall score, VBR had stronger associations with DRS and ERBI at 90 days. Conclusions: VBR, alongside behavioral assessments, presents a robust framework for evaluating SCHI progression. It supports early functional outcome correlations informing therapeutic approaches. VBR's reliability underscores its utility in neurorehabilitation for ongoing SCHI assessment and aiding clinical decisions.

Can neutrophil gelatinase-associated lipocalin help depict early contrast material-induced nephropathy?

PURPOSE: To evaluate the utility of serum and urinary neutrophil gelatinase-associated lipocalin (NGAL) in depicting an event of contrast material-induced nephropathy (CIN) in patients who received iodinated contrast media, gadoterate meglumine, or radiopharmaceutical technetium-99m ((99m)Tc) and to evaluate the protective effect exerted by isotonic saline infusion, sodium bicarbonate administration, or N-acetylcysteine administration. MATERIALS AND METHODS: Institutional ethics committee approval was given, and informed consent was obtained. One hundred twenty patients were enrolled in a prospective study and divided into three groups: iomeprol group, magnetic resonance (MR) imaging group (gadoterate meglumine), and renal scintigraphy group ((99m)Tc). They randomly received N-acetylcysteine, physiologic saline, or sodium bicarbonate. Receiver operating characteristic (ROC) analysis, Kaplan-Meier curves, and Cox proportional hazard regression analysis were used. RESULTS: In the MR imaging and renal scintigraphy groups, there were significant changes in serum creatinine and NGAL levels, and there were no cases of CIN. In the iomeprol group, an early rise in NGAL was found, while serum creatinine level changes occurred 24 hours after contrast material administration. At ROC analysis, NGAL showed high sensitivity and specificity (serum NGAL: area under the curve, 0.995; 95% confidence interval [CI]: 0.868, 0.992; urinary NGAL: area under the curve, 0.992; 95% CI: 0.925, 1.000) in identifying CIN 8 hours after iomeprol administration. Regression analysis showed that NGAL independently predicted CIN. Administration of N-acetylcysteine, sodium bicarbonate, or physiologic saline did not influence NGAL level. CONCLUSION: NGAL depicted CIN in patients who received iodinated contrast material within 8 hours of contrast material administration. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120578/-/DC1.

Hepatic Portal Venous Gas (HPVG) after Ingestion of Chlorine Bleach: A Transient Phenomenon.

We present a case involving a 32-year-old man who ingested chlorine bleach with self-defeating intent. The ingestion of bleach can lead to a wide range of consequences, from mild mucosal burns to severe complications, rarely resulting in death. This case highlights the association between chlorine bleach ingestion and the development of hepatic portal venous gas (HPVG), a radiological finding traditionally thought to carry poor prognoses. The HPVG in this case resolved spontaneously within 24 h with conservative management, indicating its transient nature. The exact pathophysiological mechanisms responsible for HPVG after the ingestion of toxic substances .remain only partially understood. One hypothesis suggests that extensive damage to the gastrointestinal wall caused by caustic agent may allow enteric gas to enter the portal system. While HPVG after toxic ingestion is often transient, its consequences and potential risks should be carefully considered. Hyperbaric oxygen therapy is suggested in cases with neurological symptoms. In conclusion, HPVG is not a specific disease but rather a manifestation of various underlying factors, and its development in the context of chlorine bleach ingestion represents an additional insight to its understanding. It can be associated with severe medical conditions, but it is also found in less severe cases that can be managed conservatively.

Extracellular vesicle PD-L1 dynamics predict durable response to immune-checkpoint inhibitors and survival in patients with non-small cell lung cancer.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) changed the therapeutic landscape of patients with lung cancer. However, only a subset of them derived clinical benefit and evidenced the need to identify reliable predictive biomarkers. Liquid biopsy is the non-invasive and repeatable analysis of biological material in body fluids and a promising tool for cancer biomarkers discovery. In particular, there is growing evidence that extracellular vesicles (EVs) play an important role in tumor progression and in tumor-immune interactions. Thus, we evaluated whether extracellular vesicle PD-L1 expression could be used as a biomarker for prediction of durable treatment response and survival in patients with non-small cell lung cancer (NSCLC) undergoing treatment with ICIs. METHODS: Dynamic changes in EV PD-L1 were analyzed in plasma samples collected before and at 9 ± 1 weeks during treatment in a retrospective and a prospective independent cohorts of 33 and 39 patients, respectively. RESULTS: As a result, an increase in EV PD-L1 was observed in non-responders in comparison to responders and was an independent biomarker for shorter progression-free survival and overall survival. To the contrary, tissue PD-L1 expression, the commonly used biomarker, was not predictive neither for durable response nor survival. CONCLUSION: These findings indicate that EV PD-L1 dynamics could be used to stratify patients with advanced NSCLC who would experience durable benefit from ICIs.

Radiomic Detection of EGFR Mutations in NSCLC.

Radiomics is defined as the use of automated or semi-automated post-processing and analysis of multiple features derived from imaging exams. Extracted features might generate models able to predict the molecular profile of solid tumors. The aim of this study was to develop a predictive algorithm to define the mutational status of EGFR in treatment-naïve patients with advanced non-small cell lung cancer (NSCLC). CT scans from 109 treatment-naïve patients with NSCLC (21 EGFR-mutant and 88 EGFR-wild type) underwent radiomics analysis to develop a machine learning model able to recognize EGFR-mutant from EGFR-WT patients via CT scans. A "test-retest" approach was used to identify stable radiomics features. The accuracy of the model was tested on an external validation set from another institution and on a dataset from the Cancer Imaging Archive (TCIA). The machine learning model that considered both radiomic and clinical features (gender and smoking status) reached a diagnostic accuracy of 88.1% in our dataset with an AUC at the ROC curve of 0.85, whereas the accuracy values in the datasets from TCIA and the external institution were 76.6% and 83.3%, respectively. Furthermore, 17 distinct radiomics features detected at baseline CT scan were associated with subsequent development of T790M during treatment with an EGFR inhibitor. In conclusion, our machine learning model was able to identify EGFR-mutant patients in multiple validation sets with globally good accuracy, especially after data optimization. More comprehensive training sets might result in further improvement of radiomics-based algorithms. SIGNIFICANCE: These findings demonstrate that data normalization and "test-retest" methods might improve the performance of machine learning models on radiomics images and increase their reliability when used on external validation datasets.

Prognostic value of relative cerebral blood volume in patients with recurrent glioblastoma multiforme treated with bevacizumab.

BACKGROUND: The aim of this study was to assess whether the early monitoring of the effects of bevacizumab in patients with recurrent glioblastoma multiforme (GBM) using perfusional dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) before and after the beginning of antiangiogenic therapy is predictive of treatment response. METHODS: Thirteen patients with recurrent GBM underwent perfusion MRI with relative cerebral blood volume (rCBV) mapping before (T0) and after the beginning (T1) of bevacizumab treatment. Recurrence Regions of Interest (RoIs) were positioned on the enhancing component of tumoral tissue revealed by postcontrast T1-weighted images. The rCBV measurements on the corresponding maps were made before and after the start of the antiangiogenic therapy. The Cox proportional hazards model and the Kaplan-Meier method were used with the log-Rank Test to establish whether pre- and postbevacizumab rCBV predicted progression-free survival (PFS). We tried to assess if there was a correlation between rCBV at T0 and rCBV at T1 using the Pearson's correlation coefficient. RESULTS: In the univariable analysis, rCBV was significantly predictive of PFS at T0 (HR=5.3, P=0.003) and at T1 (HR=4.14, P=0.04). Similarly, in the multivariate Cox model analysis, rCBV was predictive of PFS at T0 (HR=4.4, P=0.04) and T1 (HR=4.2, P=0.02). PFS was longer in patients whose rCBV was less than 4.50 mL/100g at T0 and less than 1.83 mL/100g at T1 than in patients with higher rCBV values. There was a moderate positive correlation between rCBV at T0 and rCBV at T1 (P=0.032, R=0.546). CONCLUSIONS: Despite the limited number of enrolled patients, rCBV assessed using DSC-MRI through the parameter rCBV is proved reliable in predicting the effects of antiangiogenic treatment in patients with recurrent GBM.

Apparent diffusion coefficient and tumor volume measurements help stratify progression-free survival of bevacizumab-treated patients with recurrent glioblastoma multiforme.

BACKGROUND: The aim of this study was to determine whether apparent diffusion coefficient (ADC) bi-component curve-fitting histogram analysis and volume percentage change (VPC) prior to bevacizumab treatment can stratify progression-free survival (PFS) and overall survival (OS) in patients with glioblastoma multiforme (GBM) on first recurrence. METHODS: We retrospectively evaluated 17 patients with recurrent GBM who received bevacizumab and fotemustine (n = 13) or only bevacizumab (n = 4) on first recurrence at our institution between December 2009 and July 2015. Both T2/FLAIR abnormalities and enhancing tumor on T1 images were mapped to the ADC images. ADC-L and ADC-M values were obtained trough bi-Gaussian curve fitting histogram analysis. Furthermore, the study population was dichotomized into two subgroups: patients displaying a reduction in enhancing tumor volume of either >55% or <55% between the mean value calculated at baseline and first follow-up. Subsequently, a second dichotomization was performed according to a reduction in the T2 / FLAIR volume >41% or <41% at first check after treatment. OS and PFS were assessed using volume parameters in a Cox regression model adjusted for significant clinical parameters. RESULTS: In univariate analysis, contrast-enhanced (CE)-ADC-L was significantly predictive of PFS (p = 0.01) and OS (p = 0.03). When we dichotomized our sample using the 55% cut-off for enhancing tumor volume, CE-VPC was able to predict PFS (p = 0.01) but not OS (p = 0.08). In multivariate analysis, only the CE-ADC-L was predictive of PFS (p = 0.01), albeit not predictive of OS (p = 0.14). CE-ADC-M, T2/FLAIR-ADC-L, T2/FLAIR-ADC, and T2/FLAIR VPC were not significantly predictive of PFS and OS (p > 0.05) in both univariate and multivariate analysis. CONCLUSIONS: CE-ADC and CE-VPC can stratify PFS for patients with recurrent glioblastoma prior to bevacizumab treatment.

Current concepts in tumor imaging with whole-body MRI with diffusion imaging (WB-MRI-DWI) in multiple myeloma and lymphoma.

Whole-body MRI (WB-MRI) with diffusion-weighted imaging (DWI) can now be used to stage and restage multiple myeloma (MM) and lymphoma. Magnetic resonance imaging (MRI) is the standard tool to detect BM involvement (BMI). The 2016 diagnostic criteria of the International Myeloma Working Group identify WB-MRI and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) as the most sensitive imaging techniques for detecting skeletal and extra-skeletal MM invasion, respectively. Preliminary findings have also shown that WB-MRI is better than CT and equal to PET/CT in staging aggressive lymphoma and Hodgkin lymphoma, whereas MRI is better for diagnosing BMI in patients with low-grade lymphoma. Signal intensity (SI) and the apparent diffusion coefficient (ADC) are useful metrics to quantify the chemotherapy response in WB-MRI.

Staging of Primary Abdominal Lymphomas: Comparison of Whole-Body MRI with Diffusion-Weighted Imaging and (18)F-FDG-PET/CT.

Background. The purpose of this study was to compare the accuracy of whole-body MRI with diffusion-weighted sequences (WB-DW-MRI) with that of (18)F-FDG-PET/CT in the staging of patients with primary gastrointestinal lymphoma. Methods. This retrospective study involved 17 untreated patients with primary abdominal gastrointestinal lymphoma. All patients underwent (18)F-FDG-PET/CT and WB-DW-MRI. Histopathology findings or at least 6 months of clinical and radiological follow-up was the gold standard. The Musshoff-modified Ann Arbor system was used for staging, and diagnostic accuracy was evaluated on a per-node basis. Results. WB-DW-MRI exhibited 100% sensitivity, 96.3% specificity, and 96.1% and 100% positive and negative predictive values (PPV and NPV), respectively. The sensitivity, specificity, and PPV and NPV of PET/CT were 95.9%, 100%, and 100% and 96.4%, respectively. There were no statistically significant differences between the two techniques (p = 0.05). The weighted kappa agreement statistics with a 95% confidence interval were 0.97 (0.95-0.99) between the two MRI readers and 0.87 (0.82-0.92) between the two methods. Conclusions. WB-DW-MRI appears to have a comparable diagnostic value to (18)F-FDG-PET/CT in staging patients with gastrointestinal lymphoma.