Genetic and phenotypic attributes of splenic marginal zone lymphoma.

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.

Thyroglobulin measurement is the most powerful outcome predictor in differentiated thyroid cancer: a decision tree analysis in a European multicenter series.

OBJECTIVES: An accurate prognostic assessment is pivotal to adequately inform and individualize follow-up and management of patients with differentiated thyroid cancer (DTC). We aimed to develop a predictive model for recurrent disease in DTC patients treated by surgery and 131I by adopting a decision tree model. METHODS: Age, sex, histology, T stage, N stage, risk classes, remnant estimation, thyroid-stimulating hormone (TSH), thyroglobulin (Tg), administered 131I activities and post-therapy whole body scintigraphy (PT-WBS) were identified as potential predictors and put into regression algorithm (conditional inference tree, c-tree) to develop a risk stratification model for predicting persistent/recurrent disease over time. RESULTS: The PT-WBS pattern identified a partition of the population into two subgroups (PT-WBS positive or negative for distant metastases). Patients with distant metastases exhibited lower disease-free survival (either structural, DFS-SD, and biochemical, DFS-BD, disease) compared to those without metastases. Meanwhile, the latter were further stratified into three risk subgroups based on their Tg values. Notably, Tg values >63.1 ng/mL predicted a shorter survival time, with increased DFS-SD for Tg values <63.1 and <8.9 ng/mL, respectively. A comparable model was generated for biochemical disease (BD), albeit different DFS were predicted by slightly different Tg cutoff values (41.2 and 8.8 ng/mL) compared to DFS-SD. CONCLUSIONS: We developed a simple, accurate and reproducible decision tree model able to provide reliable information on the probability of structurally and/or biochemically persistent/relapsed DTC after a TTA. In turn, the provided information is highly relevant to refine the initial risk stratification, identify patients at higher risk of reduced structural and biochemical DFS, and modulate additional therapies and the relative follow-up.

Postoperative thyroglobulin as a yard-stick for radioiodine therapy: decision tree analysis in a European multicenter series of 1317 patients with differentiated thyroid cancer.

PURPOSE: An accurate postoperative assessment is pivotal to inform postoperative 131I treatment in patients with differentiated thyroid cancer (DTC). We developed a predictive model for post-treatment whole-body scintigraphy (PT-WBS) results (as a proxy for persistent disease) by adopting a decision tree model. METHODS: Age, sex, histology, T stage, N stage, risk classes, remnant estimation, TSH, and Tg were identified as potential predictors and were put into regression algorithm (conditional inference tree, ctree) to develop a risk stratification model for predicting the presence of metastases in PT-WBS. RESULTS: The lymph node (N) stage identified a partition of the population into two subgroups (N-positive vs N-negative). Among N-positive patients, a Tg value > 23.3 ng/mL conferred a 83% probability to have metastatic disease compared to those with lower Tg values. Additionally, N-negative patients were further substratified in three subgroups with different risk rates according to their Tg values. The model remained stable and reproducible in the iterative process of cross validation. CONCLUSIONS: We developed a simple and robust decision tree model able to provide reliable informations on the probability of persistent/metastatic DTC after surgery. These information may guide post-surgery 131I administration and select patients requiring curative rather than adjuvant 131I therapy schedules.

CT-based body composition in diffuse large B cell lymphoma patients: changes after treatment and association with survival.

PURPOSE: Primary purpose was to assess changes of bone mineral density (BMD) in diffuse large B cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone R-CHOP (like) chemotherapy regimen. Secondary purposes were to assess other body composition features changes and to assess the association of pre-therapy values and their changes over time with survival. MATERIAL AND METHODS: Patients selected underwent R-CHOP(like) regimen for DLBCL, and underwent PET-CT before and after treatment. Main clinical data collected included body mass index, date of last follow-up, date of progression, and date of death. From the low-dose CT images, BMD was assessed at the L1 level; the other body composition values, including muscle and fat distribution, were assessed at the L3 level by using a dedicated software. Descriptive statistics were reported as median and interquartile range, or frequencies and percentages. Statistical comparisons of body composition variables between pre- and post-treatment assessments were performed using the Wilcoxon matched pairs signed rank test. Non-normal distribution of variables was tested with the Shapiro-Wilk test. For qualitative variables, the Fisher exact test was used. Log rank test was used to compare survival between different subgroups of the study population defined by specific body composition cutoffs. The significance level was set at p < 0.05. RESULTS: Eighty-two patients were included. The mean follow-up was 37.5 ± 21.4 months. A significant difference was found in mean BMD before and after R-CHOP(like) treatment (p < 0.0001). The same trend was observed for mean skeletal muscle area (SMA) (p = 0.004) and mean skeletal muscle index (SMI) (p = 0.006). No significant association was demonstrated between body composition variables, PFS and OS. CONCLUSION: R-CHOP(like) treatment in DLBCL patients was associated with significant reduction of BMD, SMA and SMI.

Generation and validation of a PET radiomics model that predicts survival in diffuse large B cell lymphoma treated with R-CHOP14: A SAKK 38/07 trial post-hoc analysis.

Functional parameters from positron emission tomography (PET) seem promising biomarkers in various lymphoma subtypes. This study investigated the prognostic value of PET radiomics in diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP given either every 14 (testing set) or 21 days (validation set). Using the PyRadiomics Python package, 107 radiomics features were extracted from baseline PET scans of 133 patients enrolled in the Swiss Group for Clinical Cancer Research 38/07 prospective clinical trial (SAKK 38/07) [ClinicalTrial.gov identifier: NCT00544219]. The international prognostic indices, the main clinical parameters and standard PET metrics, together with 52 radiomics uncorrelated features (selected using the Spearman correlation test) were included in a least absolute shrinkage and selection operator (LASSO) Cox regression to assess their impact on progression-free (PFS), cause-specific (CSS), and overall survival (OS). A linear combination of the resulting parameters generated a prognostic radiomics score (RS) whose area under the curve (AUC) was calculated by receiver operating characteristic analysis. The RS efficacy was validated in an independent cohort of 107 DLBCL patients. LASSO Cox regression identified four radiomics features predicting PFS in SAKK 38/07. The derived RS showed a significant capability to foresee PFS in both testing (AUC, 0.709; p < 0.001) and validation (AUC, 0.706; p < 0.001) sets. RS was significantly associated also with CSS and OS in testing (CSS: AUC, 0.721; p < 0.001; OS: AUC, 0.740; p < 0.001) and validation (CSS: AUC, 0.763; p < 0.0001; OS: AUC, 0.703; p = 0.004) sets. The RS allowed risk classification of patients with significantly different PFS, CSS, and OS in both cohorts showing better predictive accuracy respect to clinical international indices. PET-derived radiomics may improve the prediction of outcome in DLBCL patients.

Is thyroglobulin a reliable biomarker of differentiated thyroid cancer in patients treated by lobectomy? A systematic review and meta-analysis.

OBJECTIVES: The prognostic role of thyroglobulin in predicting recurrence in differentiated thyroid cancer (DTC) patients treated by lobectomy is controversial. This systematic review with meta-analysis aimed to update the current evidence deepening the reliability of circulating thyroglobulin in assessing the early response and in predictive recurrence. METHODS: The methodology was registered in the PROSPERO database under the protocol number CRD42021288189. A systematic search was carried out on PubMed, Embase, Web of Science, and Scopus from September to November 2021 without time and language restrictions. The literature search strategy was based on the following keywords: Thyroglobulin AND (Lobectomy OR Hemithyroidectomy). RESULTS: After screening 273 articles, seven studies were included in the systematic review, and only six of them were included in the meta-analysis for a total of 2,455 patients. Circulating thyroglobulin was found non-reliable in assessing early response and predicting recurrence in patients with hemithyroidectomy, especially those with a low initial ATA classification. CONCLUSIONS: Our study does not support serum thyroglobulin levels for monitoring patients with low-risk DTC treated with lobectomy, and weak evidence supports its role for intermediate- or high-risk patients. Studies with longer follow-up, different study designs, and stringent inclusion/exclusion criteria are needed to evaluate the role of thyroglobulin in recurrence prediction.

CT evaluation of lung infiltrates in the two months preceding the Coronavirus disease 19 pandemic in Canton Ticino (Switzerland): were there suspicious cases before the official first case?

PURPOSE: The main objective of this study was to assess the presence of pulmonary infiltrates with computed tomography (CT) appearance compatible with infection by coronavirus disease 2019 (COVID-19), in Canton Ticino in the 2 months preceding the first official case. Secondary aims were to compare the classification of infiltrates in the same time frame in 2020 and 2019; to compare the number of chest CT scans in the same period; to search for pathological confirmation of the virus. MATERIALS AND METHODS: Chest CT scans performed between January 1 and February 24 in 2019 and 2020 were collected and classified by COVID-19 Reporting and Data System (CO-RADS). Pathological presence of the virus was searched for when appropriate material was available. RESULTS: The final cohort included 881 patients. Among the CO-RADS 3 and 4 categories, 30 patients had pneumonitis of unknown etiology. Pathological specimens were available in six patients but they were negative for COVID-19. CONCLUSION: Before the first official case of COVID-19 infection, in Canton Ticino there were about 30 cases of pneumonitis of uncertain origin, with CT appearance compatible with infection by COVID-19, but with no confirmation of the disease. The number of chest CT scans in the first two months of 2020 was > 12% compared to 2019.

Circulating pro-gastrin releasing peptide (ProGRP) in patients with medullary thyroid carcinoma.

OBJECTIVES: Serum calcitonin (CT) is pivotal in medullary thyroid cancer (MTC) management. Recently, progastrin releasing peptide (ProGRP) has been proposed as a candidate complementary tumor marker of MTC. As current data are sparse our study was undertaken to evaluate the distribution of ProGRP in patients with MTC and its relationship with the tumor burden. Additionally, serial measurement of CT, carcinoembryonic antigen (CEA) and ProGRP was evaluated in three patients undergoing tyrosine kinase inhibitors (TKI). METHODS: Seventy-eight, 125 and 62 sera from patients with MTC, non-medullary malignant and benign thyroid diseases were collected, respectively. ProGRP measurement was performed by Elecsys® assays on Cobas e601 platform (Roche Diagnostics). RESULTS: Significantly higher ProGRP levels were found in MTC compared to non-MTC patients. Among MTC patients ProGRP levels accurately discriminate patients with active from those with cured disease and, respectively, patients with loco-regional active disease from those with distant metastasis. Finally, ProGRP performed better than CT and CEA in monitoring the response to TKI therapy in three patients monitored serially. CONCLUSIONS: Serum ProGRP is promising as a complementary tumor marker in MTC patients. Further studies will be required, mainly focused on monitoring ProGRP during TKI treatment for early detection of resistance and assessing its usefulness to avoid the observed false positive fluctuations that occur with CT and carcinoembryonic antigen.

Clinical performance of calcitonin and procalcitonin Elecsys® immunoassays in patients with medullary thyroid carcinoma.

OBJECTIVES: Medullary thyroid carcinoma (MTC) is caused by a malignant transformation in the parafollicular C-cells of the thyroid, where calcitonin (CT) is released. Nowadays, CT is the main tumor marker used in the diagnosis and follow-up of MTC patients. Nonetheless, procalcitonin (PCT) has recently been proposed as a useful complementary/alternative biomarker in MTC. Our aims were to investigate the diagnostic performance of CT and PCT and their combination in the differential diagnosis between active and inactive MTC and between MTC and non-MTC thyroid diseases, respectively. METHODS: Serum samples were collected from 16 patients with active (i.e. primary tumour before surgery or post-surgical recurrent disease) and 23 with inactive (i.e. complete remission) MTC, 125 patients with non-MTC benign thyroid disease and 62 patients with non-MTC thyroid cancers, respectively. Elecsys® CT and PCT measurements were simultaneously performed on the Cobas e601 platform (Roche Diagnostics, Rotkreutz, Switzerland). RESULTS: Both CT and PCT median values in active MTC (94 pmol/L and 1.17 ng/mL, respectively) were significantly higher compared with inactive MTC (0.28 and 0.06) and either benign (0.37 and 0.06) or malignant (0.28 and 0.06) non-MTC. Undetectable PCT was found in five non-MTC patients with false positive CT results. CONCLUSIONS: Elecsys® PCT assay is a highly sensitive and specific alternative MTC marker. At the very least it appears useful in patients with positive CT results as negative PCT values securely exclude active MTC. The availability of both markers on the same automated platform facilitates reflex or reflective strategies to refine the laboratory diagnosis.

Metabolic heterogeneity on baseline 18FDG-PET/CT scan is a predictor of outcome in primary mediastinal B-cell lymphoma.

An important unmet need in the management of primary mediastinal B-cell lymphoma (PMBCL) is to identify the patients for whom first-line therapy will fail to intervene before the lymphoma becomes refractory. High heterogeneity of intratumoral 18F-fluorodeoxyglucose (18FDG) uptake distribution on positron emission tomography/computed tomography (PET/CT) scans has been suggested as a possible marker of chemoresistance in solid tumors. In the present study, we investigated the prognostic value of metabolic heterogeneity (MH) in 103 patients with PMBCL prospectively enrolled in the International Extranodal Lymphoma Study Group (IELSG) 26 study, aimed at clarifying the role of PET in this lymphoma subtype. MH was estimated using the area under curve of cumulative standardized uptake value-volume histogram (AUC-CSH) method. Progression-free survival at 5 years was 94% vs 73% in low- and high-MH groups, respectively (P = .0001). In a Cox model of progression-free survival including dichotomized MH, metabolic tumor volume, total lesion glycolysis (TLG), international prognostic index, and tumor bulk (mediastinal mass > 10 cm), as well as age as a continuous variable, only TLG (P < .001) and MH (P < .001) retained statistical significance. Using these 2 features to construct a simple prognostic model resulted in early and accurate (positive predictive value, 89%; negative predictive value, ≥90%) identification of patients at high risk for progression at a point that would allow the use of risk-adapted treatments. This may provide an important opportunity for the design of future trials aimed at helping the minority of patients who harbor chemorefractory PMBCL. The study is registered at ClinicalTrials.gov as NCT00944567.

Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma.

The rarity of neoplastic cells in the biopsy imposes major technical hurdles that have so far limited genomic studies in classical Hodgkin lymphoma (cHL). By using a highly sensitive and robust deep next-generation sequencing approach for circulating tumor DNA (ctDNA), we aimed to identify the genetics of cHL in different clinical phases, as well as its modifications on treatment. The analysis was based on specimens collected from 80 newly diagnosed and 32 refractory patients with cHL, including longitudinal samples collected under ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy and longitudinal samples from relapsing patients treated with chemotherapy and immunotherapy. ctDNA mirrored Hodgkin and Reed-Sternberg cell genetics, thus establishing ctDNA as an easily accessible source of tumor DNA for cHL genotyping. By identifying STAT6 as the most frequently mutated gene in ∼40% of cases, we refined the current knowledge of cHL genetics. Longitudinal ctDNA profiling identified treatment-dependent patterns of clonal evolution in patients relapsing after chemotherapy and patients maintained in partial remission under immunotherapy. By measuring ctDNA changes during therapy, we propose ctDNA as a radiation-free tool to track residual disease that may integrate positron emission tomography imaging for the early identification of chemorefractory patients with cHL. Collectively, our results provide the proof of concept that ctDNA may serve as a novel precision medicine biomarker in cHL.

Prognostic models integrating quantitative parameters from baseline and interim positron emission computed tomography in patients with diffuse large B-cell lymphoma: post-hoc analysis from the SAKK38/07 clinical trial.

Positron emission computed tomography (PET/CT) in patients with diffuse large B-cell lymphoma (DLBCL) enrolled in a prospective clinical trial were reviewed to test the impact of quantitative parameters from interim PET/CT scans on overall (OS) and progression-free (PFS) survival. We centrally reviewed baseline and interim PET/CT scans of 138 patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone given every 14 days (R-CHOP14) in the SAKK38/07 trial (ClinicalTrial.gov identifier: NCT00544219). Cutoff values for maximum standardized uptake value (SUVmax ), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and metabolic heterogeneity (MH) were defined by receiver operating characteristic analysis. Responses were scored using the Deauville scale (DS). Patients with DS 5 at interim PET/CT (defined by uptake >2 times higher than in normal liver) had worse PFS (P = 0.014) and OS (P < 0.0001). A SUVmax reduction (Δ) greater than 66% was associated with longer PFS (P = 0.0027) and OS (P < 0.0001). Elevated SUVmax , MTV, TLG, and MH at interim PET/CT also identified patients with poorer outcome. At multivariable analysis, ΔSUVmax and baseline MTV appeared independent outcome predictors. A prognostic model integrating ΔSUVmax and baseline MTV discriminated three risk groups with significantly (log-rank test for trend, P < 0.0001) different PFS and OS. Moreover, the integration of MH and clinical prognostic indices could further refine the prediction of OS. PET metrics-derived prognostic models perform better than the international indices alone. Integration of baseline and interim PET metrics identified poor-risk DLBCL patients who might benefit from alternative treatments.

Baseline PET features to predict prognosis in primary mediastinal B cell lymphoma: a comparative analysis of different methods for measuring baseline metabolic tumour volume.

PURPOSE: This study assessed the performance of four different methods for the estimation of metabolic tumour volume (MTV) in primary mediastinal B cell lymphoma (PMBCL). METHOD: MTV was estimated using either a region growing automatic software program (RG) or a fixed threshold (FT) segmentation algorithm with the three most common cut-offs proposed in the literature (i.e., 25% and 41% of the SUVmax and SUV value ≥2.5). We compared these four methods using phantoms that simulated different set-ups of the main imaging characteristics of PMBCL (volume, shape, 18-FDG uptake and intra-lesion distribution) and assessed their performance in 103 PMBCL patients enrolled in the International Extranodal Lymphoma Study Group-26 (IELSG-26) study. RESULTS: There was good correlation between MTV values estimated in vitro and in vivo using the different methods. The 25% FT cut-off (FT25%) provided the most accurate MTV evaluation in the phantoms. The cut-off at SUV 2.5 (FT2.5) resulted in MTV overestimation that particularly increased with high SUV values. The 41% cut-off (FT41%) showed MTV underestimation that was more evident when there were high levels of heterogeneity in tracer distribution. Shape of the lesion did not affect MTV computation. The RG algorithm provided a systematic slight MTV underestimation without significant changes due to lesion characteristics. We observed analogous trends for the MTV estimation in patients, with very different derived thresholds for the four methods. Optimal cut-offs for predicting progression-free survival (PFS) ranged from 213 to 831 ml. All methods predicted PFS with similar negative predictive values (94-95%) but different positive predictive values (23-45%). CONCLUSIONS: The different methods result in significantly different MTV cut-off values. All allow risk stratification in PMBCL, but FT25% showed the best capacity to predict disease progression in the patient cohort and provided the best accuracy in the phantom model.

Measuring thyroglobulin in patients with thyroglobulin autoantibodies: evaluation of the clinical impact of BRAHMS Kryptor® Tg-minirecovery test in a large series of patients with differentiated thyroid carcinoma.

Background The present study was undertaken to evaluate the clinical impact of a thyroglobulin (Tg) minirecovery test (Tg-mRec) in a large series of differentiated thyroid carcinoma (DTC) patients treated and monitored homogeneously in a tertiary referral center. Methods Included were 1120 serum samples from 798 DTC patients. Tg, Tg autoantibodies (TgAb) and Tg-mrec measurements were performed on the automated Kryptor® platform and results compared to the corresponding clinical status. Results Among included samples 228 (20%) were TgAb-positive (TgAb+) and 892 (80%) TgAb-negative (TgAb-), respectively. Tg cutoff points were settled at 0.31 µg/L and 0.15 µg/L for TgAb- and TgAb+ patients, respectively, by ROC curve analysis. The diagnostic performance of serum Tg was reduced in TgAb+ compared to TgAb- patients, however, 87% of TgAb+ patients with recurrent disease and, particularly, all patients with distant metastases were correctly detected by adopting an optimized Tg cutoff for TgAb+ patients. A disturbed recovery was found in only 1% of TgAb- patients and in these cases no clinically relevant information was added by the Tg-mRec. Among TgAb+ patients with undetectable Tg and undisturbed Tg-mRec, no one had recurrent disease. However, a falsely undetectable Tg was demonstrated in two patients with recurrent disease who next to increased TgAb also had a disturbed Tg-mRec test. Conclusions There is no additional clinical benefit from performing Tg-mRec in most patients. It can however be considered in TgAb+ patients with undetectable Tg levels as it may help differentiate between patients with true negative and false negative Tg levels in the presence of such antibodies.

Fine-needle aspiration in all thyroid incidentalomas at 18 F-FDG PET/CT: Can EU-TIRADS revise the dogma?

OBJECTIVE: Focal thyroid incidentalomas (TIs) are observed in 2% of 18 F-FDG PET/CT representing malignancy in one-third of cases. Currently, due to the lack of evidence on their optimal management, guidelines suggest fine-needle aspiration cytology (FNAC). The study aim was to evaluate the role of ultrasound evaluation according to EU-TIRADS to assess the risk of TIs and inform FNAC prescriptions. DESIGN: We retrospectively reviewed 18 F-FDG PET/CT TIs recorded during the period 2014-2017. Enrolled were TIs with histological outcome and autonomous nodules. Cases with uncertain matching between 18 F-FDG PET/CT, ultrasound and histology were excluded. RESULTS: According to the selection criteria, 75 TIs, being 13 (17.3%) malignant and 62 (82.7%) benign, were included. Cancers had significantly higher SUVmax and SUVmax ratio (Mann-Whitney P < 0.01) than benign, and the most accurate cut-offs were >7.1 and >3.65, respectively. At ultrasound, the cancer rate was 0% in EU-TIRADS 2, 2.9% in EU-TIRADS 3, 4.2% in EU-TIRADS 4% and 78.6% in EU-TIRADS 5 (chi-squared P < 0.001). Sensitivity, specificity, PPV, NPV and accuracy for malignancy were 92%, 64%, 35%, 98% and 69% for SUVmax; 85%, 68%, 36%, 96% and 71% for SUVmax ratio; and 85%, 95%, 79%, 97% and 93% for EU-TIRADS, respectively. The absence of all these three features reached a specificity of 97.1%. CONCLUSIONS: EU-TIRADS, within a clinical careful approach, can discriminate with significant accuracy lesions at high risk of malignancy from those at low risk among TIs at 18 F-FDG PET/CT. Additionally, a centre-based threshold for SUV parameters should be useful for the initial assessment of these lesions during PET/CT reading and reporting.

Diagnostic accuracy of bone scintigraphy in the assessment of cardiac transthyretin-related amyloidosis: a bivariate meta-analysis.

PURPOSE: Cardiac transthyretin-related amyloidosis (ATTR) is a progressive and fatal cardiomyopathy. The diagnosis of this disease is frequently delayed or missed due to the limited specificity of echocardiography. An increasing amount of data in the literature demonstrate the ability of bone scintigraphy with bone-seeking radiopharmaceuticals to detect myocardial amyloid deposits, in particular in patients with ATTR. Therefore we performed a systematic review and bivariate meta-analysis of the diagnostic accuracy of bone scintigraphy in patients with suspected cardiac ATTR. METHODS: A comprehensive computer literature search of studies published up to 30 November 2017 on the role of bone scintigraphy in patients with ATTR was performed using the following search algorithm: (a) "amyloid" OR "amyloidosis" AND (b) "TTR" OR "ATTR" OR "transthyretin" AND (c) "scintigraphy" OR "scan" OR "SPECT" OR "SPET" OR "bone" OR "skeletal" OR "skeleton" OR "PYP" OR "DPD" OR "HMDP" OR "MDP" OR "HDP". Pooled sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-) and diagnostic odds ratio (DOR) of bone scintigraphy were calculated. RESULTS: The meta-analysis of six selected studies on bone scintigraphy in cardiac ATTR including 529 patients provided the following results: sensitivity 92.2% (95% CI 89-95%), specificity 95.4% (95% CI 77-99%), LR+ 7.02 (95% CI 3.42-14.4), LR- 0.09 (95% CI 0.06-0.14), and DOR 81.6 (95% CI 44-153). Mild heterogeneity was found among the selected studies. CONCLUSION: Our evidence-based data demonstrate that bone scintigraphy using technetium-labelled radiotracers provides very high diagnostic accuracy in the non-invasive assessment of cardiac ATTR.

Prognostic models for primary mediastinal (thymic) B-cell lymphoma derived from 18-FDG PET/CT quantitative parameters in the International Extranodal Lymphoma Study Group (IELSG) 26 study.

The International Extranodal Lymphoma Study Group-26 study evaluated the prognostic role of 18-fluorodeoxyglucose positron-emission tomography (PET) in primary mediastinal large B-cell lymphoma. We assessed quantitative PET parameters at diagnosis and post-treatment in 100 patients. The end-of-therapy total lesion glycolysis (TLG) was the best individual outcome predictor, but the combination of baseline TLG and end-of-therapy visual analysis with Deauville Score (DS) showed a better positive predictive value. A model in which baseline TLG is combined with interim DS might identify patients with shorter progression-free survival. PET metrics combined with interim DS may allow early risk assessment and warrants further studies.

Utility of baseline 18FDG-PET/CT functional parameters in defining prognosis of primary mediastinal (thymic) large B-cell lymphoma.

The International Extranodal Lymphoma Study Group (IELSG) 26 study was designed to evaluate the role of (18)F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) in the management of primary mediastinal (thymic) large B-cell lymphoma (PMBCL). We examined the prognostic impact of functional PET parameters at diagnosis. Metabolic activity defined by the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) was measured on baseline 18FDG PET/CT following a standard protocol in a prospectively enrolled cohort of 103 PMBCL patients. All received combination chemoimmunotherapy with doxorubicin- and rituximab-based regimens; 93 had consolidation radiotherapy. Cutoff values were determined using the receiver-operating characteristic curve. At a median follow-up of 36 months, progression-free survival (PFS) and overall survival (OS) were 87% and 94%, respectively. In univariate analysis, elevated MTV and TLG were significantly associated with worse PFS and OS. Only TLG retained statistical significance for both OS (P = .001) and PFS (P < .001) in multivariate analysis. At 5 years, OS was 100% for patients with low TLG vs 80% for those with high TLG (P = .0001), whereas PFS was 99% vs 64%, respectively (P < .0001). TLG on baseline PET appeared to be a powerful predictor of PMBCL outcomes and warrants further validation as a biomarker. The IELSG 26 study was registered at www.clinicaltrials.gov as #NCT00944567.