Multimodal Detection and Targeting of Biopsy-Proven Myocardial Inflammation in Genetic Cardiomyopathies: A Pilot Report.

The authors present a clinical report focused on the overlap between myocarditis and genetic cardiomyopathies of the dilated and arrhythmogenic spectrum. Our cohort was composed of 25 patients undergoing extensive baseline characterization and prospective reassessment by a dedicated multidisciplinary disease unit during a median follow-up of 69 months. We showed that the use of multimodal imaging allowed both discrimination of specific genotypes and identification of myocardial inflammation proven using endomyocardial biopsy. In addition, we showed that the use of immunomodulatory therapy was beneficial for most patients.

Radionuclide Imaging of Infective Endocarditis.

Infective endocarditis (IE) is associated with high morbidity and mortality. Early diagnosis is crucial for adequate patient management. Due to difficulties in the diagnosis, a multidisciplinary discussion in addition to the integration of clinical signs, microbiology data, and imaging data is used. Imaging, including echocardiography, molecular imaging techniques, and coronary CT angiography (CTA) is central to detect infections involving heart valves and implanted cardiovascular devices, also allowing for early detection of septic emboli and metastatic. This article describes the main clinical application of white blood cell SPECT/CT and [18F]FDG-PET/CT and CTA in IE and infections associated with cardiovascular implantable electronic devices.

Clinical Applications of FDG-PET Scan in Arrhythmic Myocarditis.

BACKGROUND: 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan has no recognized role in diagnosis, prognosis, and disease monitoring in patients with arrhythmic myocarditis. OBJECTIVES: The purpose of this study was to investigate the value of FDG-PET scan in arrhythmic myocarditis. METHODS: The authors enrolled 75 consecutive patients (age 47 ± 14 years, 65% men) undergoing FDG-PET scan for arrhythmic myocarditis. Myocarditis was diagnosed by endomyocardial biopsy (EMB) and, whenever applicable, cardiac magnetic resonance (CMR). RESULTS: Indications for FDG-PET scan included either contraindication to CMR (n = 50) or mismatch between CMR and EMB (n = 25). Overall, 50 patients (67%) had positive FDG-PET. Sensitivity was 75% referring to EMB, and 73% to CMR. Specificity was 67% referring to EMB, and 59% to CMR. FDG-PET accuracy was lower in the presence of borderline myocarditis, and either late (>30 days) or on-immunosuppression FDG-PET scanning. Anteroseptal distribution pattern, found in 12 of 50 (24%) patients including 7 of 7 cardiac sarcoidosis cases, was associated with greater occurrence of ventricular arrhythmias and atrioventricular blocks in 4.2 ± 1.7 years of follow-up (10 of 12 vs 7 of 38, and 7 of 12 vs 0 of 38, respectively; both P < 0.001). In 39 patients (52%), FDG-PET was repeated by 13 ± 2 months, allowing immunosuppression withdrawal after FDG uptake normalization either by first (76%) or second reassessment (24%). CONCLUSIONS: FDG-PET scan may be a clinically useful diagnostic technique in arrhythmic myocarditis, in particular when CMR is unsuitable because of irregular heartbeat or implantable cardioverter-defibrillator-related artifacts. Anteroseptal FDG distribution is associated with a worse arrhythmic outcome and should raise the suspicion of cardiac sarcoidosis. During follow-up, repeated FDG-PET allows myocarditis monitoring to guide immunosuppression withdrawal.

Clinical and prognostic 18F-FDG PET/CT role in recurrent vulvar cancer: a multicentric experience.

PURPOSE: The aim of this retrospective multicentric study was to investigate the diagnostic performance, the prognostic value and the impact of 18F-FDG PET/CT on treatment decision-making in patients with suspected recurrent vulvar cancer (VC). MATERIALS AND METHODS: Sixty-three patients affected by VC performed 18F-FDG-PET/CT for restaging purposes in case of suspected clinical and/or radiological recurrence. Histopatology results if available and/or clinical-imaging follow-up for at least 12 months were considered as reference standard. The diagnostic accuracy and the clinical impact of 18F-FDG PET/CT were investigated. Progression free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier curves. RESULTS: Fifty-two (82.5%) PET/CT showed the presence of recurrence, while the remaining 11 (17.5%) were negative. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of PET/CT were 100% (95%CI 93-100%), 92% (95%CI 62-100%), 98% (95%CI 89-99%), 100% and 98% (95%CI 92-100%). A relevant impact of 18F-FDG PET/CT imaging was registered in 28 cases: in 12 cases moving from local therapy to chemotherapy due to the recognition of disseminate localizations; in 10 showing the site of recurrence in presence of negative conventional imaging, and in 6 cases confirming to be true negative and avoiding unnecessary therapies. Beside advanced age and HPV status, a positive restaging 18F-FDG PET/CT scan was significantly correlated with shorter PFS and OS compared to negative scan (p < 0.001). CONCLUSIONS: 18F-FDG PET/CT demonstrated to be an accurate tool in the assessing of recurrent VC with high sensitivity and specificity and with a significant impact on clinical decision-making. Restaging 18F-FDG PET/CT findings were associated with survival.

Pilot Study to Evaluate Serum Soluble Mesothelin-Related Peptide (SMRP) as Marker for Clinical Monitoring of Pleural Mesothelioma (PM): Correlation with Modified RECIST Score.

A soluble mesothelin-related peptide (SMRP) is the only FDA-approved biomarker for diagnosis of pleural mesothelioma (PM) and the most used for monitoring treatment. Radiological assessment of PM, based on modified RECIST (mRECIST) criteria, is challenging. This pilot study was designed to evaluate whether SMRP levels correlated over time with mRECIST score. Serial serum samples from PM patients were collected and SMRP levels were measured and compared with the mRECIST score obtained through centralized CT scans by blinded review. The within-patient SMRP-mRECIST relationship over time was estimated through a normal random-effects regression approach applied to the log-transformed mRECIST score. Overall, 58 PM patients were included (46 males and 12 females) with a median age at diagnosis of 67 years (min-max = 48-79), 44 (76%) with epithelioid and 14 (24%) with non-epithelioid histology. The total number of SMRP measurements and CT scans considered for analysis was 183. There was a statistically significant correlation between SMRP and mRECIST score in the 2 cohorts considered both separately and jointly. These results, although exploratory, suggest that SMRP measurement might be considered as an adjunct to monitor PM patients in order to delay CT scans time interval, thus warranting further investigation.

The Spectrum of COVID-19-Associated Myocarditis: A Patient-Tailored Multidisciplinary Approach.

BACKGROUND: Myocarditis lacks systematic characterization in COVID-19 patients. METHODS: We enrolled consecutive patients with newly diagnosed myocarditis in the context of COVID-19 infection. Diagnostic and treatment strategies were driven by a dedicated multidisciplinary disease unit for myocarditis. Multimodal outcomes were assessed during prospective follow-up. RESULTS: Seven consecutive patients (57% males, age 51 ± 9 y) with acute COVID-19 infection received a de novo diagnosis of myocarditis. Endomyocardial biopsy was of choice in hemodynamically unstable patients (n = 4, mean left ventricular ejection fraction (LVEF) 25 ± 9%), whereas cardiac magnetic resonance constituted the first exam in stable patients (n = 3, mean LVEF 48 ± 10%). Polymerase chain reaction (PCR) analysis revealed an intra-myocardial SARS-CoV-2 genome in one of the six cases undergoing biopsy: in the remaining patients, myocarditis was either due to other viruses (n = 2) or virus-negative (n = 3). Hemodynamic support was needed for four unstable patients (57%), whereas a cardiac device implant was chosen in two of four cases showing ventricular arrhythmias. Medical treatment included immunosuppression (43%) and biological therapy (29%). By the 6-month median follow-up, no patient died or experienced malignant arrhythmias. However, two cases (29%) were screened for heart transplantation. CONCLUSIONS: Myocarditis associated with acute COVID-19 infection is a spectrum of clinical manifestations and underlying etiologies. A multidisciplinary approach is the cornerstone for tailored management.

Assessment of interferon-γ in pleural fluid as a prognostic factor of survival in malignant pleural mesothelioma.

BACKGOUND: Literature reports suggest that the host immune system may control Malignant Pleural Mesothelioma (MPM) growth, although its activity is limited by regulatory mechanisms. In this retrospective study, we analyzed the levels of pro-inflammatory (IL-1, IL-6, TNF), immune-regulatory (IL-10) and Th1/CTL-related cytokines (IL-12p70, IFN-γ) in the pleural exudate and their relationship with overall survival (OS) in MPM. METHODS: Cytokines were quantified by multiplexed immunoassay. Concentrations were dichotomized with respect to the median value. Correlation between cytokine level and OS was assessed using univariate (Kaplan-Meier curves) and multivariate (Cox regression) analyses. RESULTS: Regarding outcome, tumor histology, therapies undergone and IFN-γ were independent prognostic factors of OS in a 72 MPM training cohort. Notably, high concentrations of IFN-γ halved death probability (HR of high vs low IFN-γ concentration = 0.491, 95%CI 0.3-0.8, p = 0.007). Also in patients with epithelioid histology and those receiving at least one line of therapy, high IFN-γ level was an independent factor predictive of OS (HR of high vs low IFN-γ concentration were 0.497, p = 0.007 and 0.324, p = 0.006, respectively). However, these data were not confirmed in a 77 MPM validation cohort, possibly due to the low IFN-γ levels encountered in this population, and the heterogeneous distribution of disease stages between the training and the validation cohorts. None of the other cytokines showed any effect on survival. CONCLUSIONS: High level of IFN-γ in pleural effusion may be associated with better survival in MPM patients and potentially serve as a prognostic biomarker. Larger prospective studies are needed to ascertain this hypothesis.

Potential role of serum mesothelin in predicting survival of patients with malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor survival rates. Therefore, it is essential to have effective biological markers predicting the course of the disease and prognosis. The aim of the present study was to highlight the prognostic significance of serum soluble mesothelin-related protein (Se-SMRP) in patients with MPM at diagnosis. Se-SMRP was determined in 60 patients using an ELISA commercial kit. Se-SMRP levels were subdivided into three tertile-based categories and in each category overall survival (OS) indexes were determined using the Kaplan-Meier and Cox regression analyses. The association between Se-SMRP levels and OS was also assessed by restricted cubic spline (RCS) analysis. No notable differences in the Kaplan-Meier probabilities were identified across the Se-SMRP categories (<0.66 nM, 0.66-1.46 nM, >1.46 nM) although an upward trend in death rate ratios (RR) was pointed out by comparing the higher (RR=1.95) and intermediate (RR=1.86) categories with the lower category (RR=1.00). In addition, such an increasing tendency, particularly when the biomarker exceeded 1.0 nM, was confirmed by an RCS function of Se-SMPR levels fitted to survival data using the Cox regression equation. The present study provided evidence in favor of a prognostic value of Se-SMRP in patients with MPM.

Role of quantitative myocardial blood flow and 13N-ammonia washout for viability assessment in ischemic cardiomyopathy.

OBJECTIVE: Positron emission tomography (PET) integrating assessment of perfusion with 13N-ammonia (NH3) and viability with 18F-fluorodeoxyglucose (FDG) has high accuracy to identify viable, hibernating myocardium. We tested whether quantification of myocardial blood flow (MBF) and washout (k2) can predict myocardial viability using FDG as standard of reference. METHODS: In 180 consecutive patients with ischemic cardiomyopathy, myocardium was categorized on a segment-level into normal, ischemic, hibernating, and scar. From dynamic images, stress MBF, rest MBF, and k2 were derived and myocardial flow reserve (MFR) and volume of distribution (VD) were calculated. RESULTS: Across myocardial tissues, all parameters differed significantly. The area under the curve (AUC) was 0.564 (95% CI 0.527-0.601), 0.635 (0.599-0.671), 0.553 (0.516-0.591), 0.520 (0.482-0.559), and 0.560 (0.522-0.597) for stress MBF, rest MBF, MFR, k2, and VD. The generalized linear mixed model correctly classified 81% of scar as viable, hibernating myocardium. If the threshold of rest MBF to predict viability was set to 0.45 mL·min-1·g-1, sensitivity and specificity were 96% and 12%, respectively. CONCLUSION: Quantitative NH3 PET parameters have low to moderate diagnostic performance to predict viability in ischemic cardiomyopathy. However, if rest MBF falls below 0.45 mL·min-1·g-1, viability testing by FDG-PET may be safely deferred.

Characterization of soluble PD-L1 in pleural effusions of mesothelioma patients: potential implications in the immune response and prognosis.

PURPOSE: Programmed death-ligand 1 (PD-L1) protein plays a central role in the antitumor immune response, and appears to be a predictor of prognosis and efficacy for PD-L1 and programmed death 1 (PD-1) blockade therapy. The immunoregulatory role and prognostic impact of PD-L1 soluble form (sPD-L1) have been investigated in biological fluids of patients with different tumors. In malignant pleural mesothelioma (MPM), circulating sPD-L1 has been recently reported in patients' sera, but no data are available in pleural effusions (PE). In our study, we evaluated the baseline expression levels of sPD-L1 in PE from 84 MPM patients and correlated them with PD-L1-status in matched tumors and patients' overall survival (OS). METHODS: sPD-L1 in PE was determined by ELISA and tumor PD-L1 by immunohistochemistry. Association of sPD-L1 with OS was estimated using the Cox regression model. RESULTS: We observed that sPD-L1 was variably expressed in all the PE and tended to be higher (by 30%) in patients with PD-L1-positive tumors (cut-off ≥ 1% stained cells) as compared to patients with PD-L1-negative tumors (geometric mean ratio = 1.28, P value = 0.288). sPD-L1 levels were significantly higher than those of sPD-1 (P value = 0.001) regardless of the MPM histotypes and they were positively correlated (r = 0.50, P value < 0.001). Moreover, high PE sPD-L1 concentrations were associated with a trend towards increased OS (hazard ratio 0.79, 95% CL 0.62-1.01, P value = 0.062). CONCLUSIONS: Our study documents the presence of sPD-L1 in PE of MPM patients, and suggests its possible biological and prognostic role in MPM.

The Role of 18F-FDG PET/CT in Staging and Prognostication of Mantle Cell Lymphoma: An Italian Multicentric Study.

Mantle cell lymphoma (MCL) is an aggressive lymphoma subtype with poor prognosis in which 18F-FDG-PET/CT role in treatment response evaluation and prediction of outcome is still unclear. The aim of this multicentric study was to investigate the role of 18F-FDG-PET/CT in staging MCL and the prognostic role of Deauville criteria (DC) in terms of progression-free survival (PFS) and overall survival (OS). We retrospectively enrolled 229 patients who underwent baseline and end-of-treatment (eot) 18F-FDG-PET/CT after first-line therapy. EotPET/CT scans were visually interpreted according to DC. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of PET/CT for evaluation of bone marrow (BM) were 27%, 100%, 100%, 48% and 57%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of PET/CT for evaluation of the gastrointestinal (GI) tract were 60%, 99%, 93%, 90% and 91%, respectively. At a median follow-up of 40 months, relapse occurred in 104 cases and death in 49. EotPET/CT results using DC significantly correlated with PFS, not with OS. Instead, considering OS, only MIPI score was significantly correlated. In conclusion, we demonstrated that MCL is an FDG-avid lymphoma and 18F-FDG-PET/CT is a useful tool for staging purpose, showing good specificity for BM and GI evaluation, but suboptimal sensitivity. EotPET/CT result was the only independent significant prognostic factor that correlated with PFS.

Determination of Mesothelin Levels in Pleural Effusion Does Not Help Predict Survival of Patients With Malignant Pleural Mesothelioma.

AIM: This study evaluated the prognostic value of soluble mesothelin-related protein (SMRP) levels in pleural effusions (PE) from patients with pleural mesothelioma (MPM). PATIENTS AND METHODS: SMRP level in PE was tested using an enzyme-linked immunosorbent assay (ELISA) in 109 patients with MPM at diagnosis before any treatment. The Kaplan-Meier method and the Cox regression were applied to compare overall survival probabilities across tertile categories of SMRP level. RESULTS: No significant differences in Kaplan-Meier overall survival probabilities among the SMRP categories were found. A statistically non-significant trend for increased death rate ratio (RR) was computed (p=0.327) when the higher (>46.5 nM, RR=1.38) and intermediate (8.5-46.5 nM, RR=1.18) SMRP categories were compared to the lower category (<8.5 nM, RR=1.00). Cox regression modelling including a restricted cubic spline showed a moderately rising non-linear trend in death rate. CONCLUSION: The SMRP level in PE does not appear to have prognostic significance and its detection is not recommended in routine clinical management of patients with MPM.

Diagnostic and Clinical Impact of Staging 18F-FDG PET/CT in Mantle-Cell Lymphoma: A Two-Center Experience.

INTRODUCTION: The diagnostic accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in staging mantle-cell lymphoma has not yet investigated. The aim of this 2-center retrospective study was to investigate the utility of 18F-FDG PET/CT in assessing nodal, splenic, bone marrow (BM), and gastrointestinal (GI) disease compared to CT, BM, and GI endoscopy; and to assess its clinical impact. PATIENTS AND METHODS: One hundred twenty-two patients with histologically proven mantle-cell lymphoma were included. PET/CT BM findings were considered positive if isolated/multiple focal uptake in the BM not explained by benign findings and/or diffuse BM uptake higher than liver with/without focal uptakes were present. PET/CT findings were considered positive for GI involvement in the presence of isolated/multiple focal uptake in the GI organ. RESULTS: All patients had positive PET/CT showing the presence of at least one hypermetabolic lesion, with the exception of one case. PET/CT results, compared to CT, detected more nodal and/or splenic lesions in 26 patients. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT for BM were 52%, 98%, 97%, 65%, and 74%; for GI 64%, 91%, 69%, 90%, and 85%; and for GI excluding diabetic patients, 78%, 92%, 72%, 94%, and 89%. PET/CT permitted upstaging of 21 cases and downstaging of 2. CONCLUSION: 18F-FDG PET/CT showed excellent detection rate in nodal and splenic disease-a rate better than CT. For BM and GI evaluation, in order to reach good accuracy, the selection of patients and the use of specific criteria for evaluation of these organs seems to be crucial. Moreover, PET/CT altered the management and therapeutic approach in about 20% of patients.

Downregulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal overall survival (OS) and to date no molecular markers are available to guide patient management. This study aimed to identify a prognostic miRNA signature in MPM patients who did not undergo tumor resection. Whole miRNA profiling using a microarray platform was performed using biopsies on 27 unresected MPM patients with distinct clinical outcome: 15 patients had short survival (OS<12 months) and 12 patients had long survival (OS>36 months). Three prognostic miRNAs (mir-99a, let-7c, and miR-125b) encoded at the same cluster (21q21) were selected for further validation and tested on publicly available miRNA sequencing data from 72 MPM patients with survival data. A risk model was built based on these 3 miRNAs that was validated by quantitative PCR in an independent set of 30 MPM patients. High-risk patients had shorter median OS (7.6 months) as compared with low-risk patients (median not reached). In the multivariate Cox model, a high-risk score was independently associated with shorter OS (HR=3.14; 95% CI, 1.18-8.34; P=0.022). Our study identified that the downregulation of the miR-99a/let-7/miR-125b miRNA cluster predicts poor outcome in unresected MPM.

Comparison of the Diagnostic Performance of Fibulin-3 and Mesothelin in Patients with Pleural Effusions from Malignant Mesothelioma.

BACKGROUND: In the literature, there exist conflicting data on the value of fibulin-3 (FBLN3) for the diagnosis of pleural effusion (PE) in malignant pleural mesothelioma (MPM). Therefore we compared the diagnostic performance of FBLN3 against that of soluble mesothelin-related peptide (SMRP) in a cohort of Italian patients. MATERIALS AND METHODS: FBLN3 and SMRP were detected in PE from 33 patients with MPM, 64 with pleural benign lesions and 23 with non-MPM pleural metastases using a commercial enzyme-linked-immunosorbent(ELISA)-assay kit according to manufacturers' instructions. RESULTS: Levels of FBLN3 were similar in PE from MPM and PE from other pathologies (geometric mean=68.1 vs. 66.2 ng/ml; p=0.872) in contrast to SMRP levels, which were significantly higher in PE from MPM (geometric mean=14.6 vs. 3.2 nM; p<0.001). Receiver operating characteristic analysis confirmed that SMRP showed a good performance (area under the curve=0.79, p<0.001), whereas FBLN3 was not able to discriminate MPM from other pathologies (area under the curve=0.44, p=0.838). CONCLUSION: FBLN3 detection in PE, in contrast to SMRP detection, is not useful as a biomarker for the diagnosis of PE from MPM.