Dynamic Risk Stratification Research Articles

Biomarker Risk Score Algorithm and Preoperative Stratification of Patients with Pancreatic Cystic Lesions

Pancreatic cysts are incidentally detected in up to 13% of patients undergoing radiographic imaging. Of the most frequently encountered types, mucin-producing (mucinous) pancreatic cystic lesions may develop into pancreatic cancer, while nonmucinous ones have little or no malignant potential. Accurate preoperative diagnosis is critical for optimal management, but has been difficult to achieve, resulting in unnecessary major surgery. Here, we aim to develop an algorithm based on biomarker risk scores to improve risk stratification. Patients undergoing surgery and/or surveillance for a pancreatic cystic lesion, with diagnostic imaging and banked pancreatic cyst fluid, were enrolled in the study after informed consent (n= 163 surgical, 67 surveillance). Cyst fluid biomarkers with high specificity for distinguishing nonmucinous from mucinous pancreatic cysts (vascular endothelial growth factor [VEGF], glucose, carcinoembryonic antigen [CEA], amylase, cytology, and DNA mutation) were selected. Biomarker risk scores were used to design an algorithm to predict preoperative diagnosis. Performance was tested using surgical (retrospective) and surveillance (prospective) cohorts. In the surgical cohort, the biomarker algorithm outperformed the preoperative clinical diagnosis in correctly predicting the final pathologic diagnosis (91% vs 73%; p < 0.000001). Specifically, nonmucinous serous cystic neoplasms (SCN) and mucinous cystic neoplasms (MCN) were correctly classified more frequently by the algorithm than clinical diagnosis (96% vs 30%; p < 0.000008 and 92% vs 69%; p= 0.04, respectively). In the surveillance cohort, the algorithm predicted a preoperative diagnosis with high confidence based on a high biomarker score and/or consistency with imaging from ≥1 follow-up visits. A biomarker risk score-based algorithm was able to correctly classify pancreatic cysts preoperatively. Importantly, this tool may improve initial and dynamic risk stratification, reducing overdiagnosis and underdiagnosis.

Magnetic Resonance Assessment of Left Ventricular Ejection Fraction at Any Time Post-Infarction for Prediction of Subsequent Events in a Large Multicenter STEMI Registry.

Magnetic resonance imaging (MRI) is the most accurate imaging technique for left ventricular ejection fraction (LVEF) quantification, but as yet the prognostic value of LVEF assessment at any time after ST-segment elevation myocardial infarction (STEMI) for subsequent major adverse cardiac event (MACE) prediction is uncertain. To explore the prognostic impact of MRI-derived LVEF at any time post-STEMI to predict subsequent MACE (cardiovascular death or re-admission for acute heart failure). Prospective. One thousand thirteen STEMI patients were included in a multicenter registry. 1.5-T. Balanced steady-state free precession (cine imaging) and segmented inversion recovery steady-state free precession (late gadolinium enhancement) sequences. Post-infarction MRI-derived LVEF (reduced [r]: <40%; mid-range [mr]: 40%-49%; preserved [p]: ≥50%) was sequentially quantified at 1 week and after >3 months of follow-up. Multi-state Markov model to determine the prognostic value of each LVEF state (r-, mr- or p-) at any time point assessed to predict subsequent MACE. A P-value <0.05 was considered to be statistically significant. During a 6.2-year median follow-up, 105 MACE (10%) were registered. Transitions toward improved LVEF predominated and only r-LVEF (at any time assessed) was significantly related to a higher incidence of subsequent MACE. The observed transitions from r-LVEF, mr-LVEF, and p-LVEF states to MACE were: 15.3%, 6%, and 6.7%, respectively. Regarding the adjusted transition intensity ratios, patients in r-LVEF state were 4.52-fold more likely than those in mr-LVEF state and 5.01-fold more likely than those in p-LVEF state to move to MACE state. Nevertheless, no significant differences were found in transitions from mr-LVEF and p-LVEF states to MACE state (P-value=0.6). LVEF is an important MRI index for simple and dynamic post-STEMI risk stratification. Detection of r-LVEF by MRI at any time during follow-up identifies a subset of patients at high risk of subsequent events. 2 TECHNICAL EFFICACY STAGE: 2.

Improving Stroke Risk Prediction in the General Population: A Comparative Assessment of Common Clinical Rules, a New Multimorbid Index, and Machine-Learning-Based Algorithms.

There are few large studies examining and predicting the diversified cardiovascular/noncardiovascular comorbidity relationships with stroke. We investigated stroke risks in a very large prospective cohort of patients with multimorbidity, using two common clinical rules, a clinical multimorbid index and a machine-learning (ML) approach, accounting for the complex relationships among variables, including the dynamic nature of changing risk factors. We studied a prospective U.S. cohort of 3,435,224 patients from medical databases in a 2-year investigation. Stroke outcomes were examined in relationship to diverse multimorbid conditions, demographic variables, and other inputs, with ML accounting for the dynamic nature of changing multimorbidity risk factors, two clinical risk scores, and a clinical multimorbid index. Common clinical risk scores had moderate and comparable c indices with stroke outcomes in the training and external validation samples (validation-CHADS2: c index 0.812, 95% confidence interval [CI] 0.808-0.815; CHA2DS2-VASc: c index 0.809, 95% CI 0.805-0.812). A clinical multimorbid index had higher discriminant validity values for both the training/external validation samples (validation: c index 0.850, 95% CI 0.847-0.853). The ML-based algorithms yielded the highest discriminant validity values for the gradient boosting/neural network logistic regression formulations with no significant differences among the ML approaches (validation for logistic regression: c index 0.866, 95% CI 0.856-0.876). Calibration of the ML-based formulation was satisfactory across a wide range of predicted probabilities. Decision curve analysis demonstrated that clinical utility for the ML-based formulation was better than that for the two current clinical rules and the newly developed multimorbid tool. Also, ML models and clinical stroke risk scores were more clinically useful than the "treat all" strategy. Complex relationships of various comorbidities uncovered using a ML approach for diverse (and dynamic) multimorbidity changes have major consequences for stroke risk prediction. This approach may facilitate automated approaches for dynamic risk stratification in the significant presence of multimorbidity, helping in the decision-making process for risk assessment and integrated/holistic management.

Dynamic risk allows us to adequately select patients with differentiated thyroid cancer who do not require radioiodine treatment.

The treatment of patients with differentiated thyroid cancer (DTC) was modified in the last decade towards a more individualized approach according to the risk of recurrence (RR). We compared the outcomes of patients with low and intermediate RR (LRR and IRR) who received or did not receive radioiodine remnant ablation (RRA) after assessing the dynamic risk. We included 307 DTC patients with LRR and IRR submitted to total thyroidectomy. All patients were reclassified according to the dynamic risk stratification (low or high). Patients with high dynamic risk received RRA (141 patients). LRR patients who received RRA presented a frequency of structural incomplete response (SIR) of 5% at the end of the follow-up, compared to 2% in those who did not receive it (p=0.353). IRR patients treated with RRA had a frequency of SIR of 22%, compared to 5% in patients without RRA (p=0.008). This study demonstrates the usefulness of dynamic risk assessment to decide RRA in a cohort with a long-term follow-up. The lower prevalence of SIR at the end of the follow-up in patients who did not receive RRA highlights the adequate selection of those who would not benefit from RRA, even with an intermediate risk of recurrence.

Dynamic risk allows us to adequately select patients with differentiated thyroid cancer who do not require radioiodine treatment.

The treatment of patients with differentiated thyroid cancer (DTC) was modified in the last decade towards a more individualized approach according to the risk of recurrence (RR). We compared the outcomes of patients with low and intermediate RR (LRR and IRR) who received or did not receive radioiodine remnant ablation (RRA) after assessing the dynamic risk. We included 307 DTC patients with LRR and IRR submitted to total thyroidectomy. All patients were reclassified according to the dynamic risk stratification (low or high). Patients with high dynamic risk received RRA (141 patients). LRR patients who received RRA presented a frequency of structural incomplete response (SIR) of 5% at the end of the follow-up, compared to 2% in those who did not receive it (p=0.353). IRR patients treated with RRA had a frequency of SIR of 22%, compared to 5% in patients without RRA (p=0.008). This study demonstrates the usefulness of dynamic risk assessment to decide RRA in a cohort with a long-term follow-up. The lower prevalence of SIR at the end of the follow-up in patients who did not receive RRA highlights the adequate selection of those who would not benefit from RRA, even with an intermediate risk of recurrence.

Optimal Timing of Initiating Dynamic Risk Stratification During the Early Postoperative Period in Patients with Differentiated Thyroid Carcinoma After Thyroidectomy and Radioactive Iodine Remnant Ablation.

This study investigated the optimal timing to initiate assessment of the response to initial therapy during the early postoperative period in patients with differentiated thyroid carcinoma (DTC) using dynamic risk stratification (DRS). This historical cohort study included 510 patients with DTC who underwent a total thyroidectomy followed by radioactive iodine (RAI) remnant ablation. DRS for these patients was categorized into subgroups according to the time into the follow-up period at which the response to initial therapy was assessed. The ability of each DRS subgroup to predict the long-term structural recurrence of cancer was compared using the proportion of variance explained (PVE) from logistic regression models. The median follow-up period was 108 months. Structural recurrence occurred in 7.6% of patients (n=39/510). The PVE for long-term structural recurrence was higher among DRS subgroups (28.8-34.19%) compared with the American Joint Committee on Cancer/Union for International Cancer Control tumor-node-metastasis staging system (both the 7th and 8th editions; 4.01% and 6.13%, respectively) and the American Thyroid Association initial risk estimate (4.59%). Among the DRS subgroups, DRS assessed between 2 and 3years after the initial surgery was associated with the highest PVE (34.19%). The first assessment of DRS optimally predicts long-term structural recurrence in patients with DTC who underwent a total thyroidectomy and subsequent RAI remnant ablation at that 2- to 3-year postoperative period.

Incidencia y estadificación dinámica del riesgo del carcinoma diferenciado de tiroides en una unidad de alta resolución. periodo 2002-2017

ObjectiveWe evaluated the incidence, progression and the dynamic risk stratification in differentiated thyroid cancer (DTC) under follow-up in a high-resolution clinic (HRC). MethodsThis was a retrospective observational study on incident cases in the tumor registry from 2002 to 2017 and their evolution under follow-up in HRC. ResultsA total of 444 patients (78.5% women, 52.1±14.9 mean years old) were DTC diagnosed from 2002 to 2017. The incidence rate of DTC increased from 5.2 to 25.7x105 habitants/year in women and from 2.3 to 7.1x105 habitants/year in men (P<0.0001). This increased incidence was not associated with an increment in the incidental papillary microcarcinoma diagnosed (from 29.4% to 32%).In those patients undergoing follow-up at the HRC (84% papillary carcinomas), 65.7% were classified as being at a low risk of recurrence compared to 14.5% at high risk. Of those, 88.8% classified as making an excellent response at diagnosis remained disease-free at the final follow-up visit. However, those patients with an indeterminate or structurally incomplete response at diagnosis evolved to an excellent response in 55.8% and 42.9% of the cases, respectively, compared to 14.8% of those with a biochemically incomplete response (P<0.001) ConclusionsThe increased incidence of DTC is similar to results published previously in other countries. Dynamic risk stratification systems adequately classify DTC patients and assess diagnostic and treatment procedures, especially in low-risk subgroups.

Thyroid lobectomy in patients with differentiated thyroid cancer: an analysis of the clinical outcomes in a nationwide multicenter study.

Total thyroidectomy is the standard initial surgery for differentiated thyroid carcinoma (DTC), but the extent of the thyroidectomy remains controversial. Thyroid lobectomy (TL) has been widely used in eastern countries; however, its use has not been generalized in western countries, including Spain. Our aims were to analyse the clinical outcome of a multicentre nation-wide cohort of DTC patients treated by TL and to assess the proportion of patients who required completion of the thyroidectomy and who presented disease recurrence. We retrospectively analyzed patients who underwent TL for DTC and were followed-up for ≥12 months. We collected demographic, clinical, and histopathological data. Dynamic risk stratification (DRS) was performed at 12 months and at last visit. One hundred and sixty-four patients (128 women, mean age 50.8 years, median follow-up 45.4 months) from 9 hospitals were included. There were 158 cases of papillary and 6 of follicular thyroid carcinoma (FTC). Remission of the disease (excellent response) was shown in 71.6% of the patients at 12 months and in 74.4% at the end of follow-up. At that time, there were 34 patients (20.7%) with indeterminate response, 6 (3.7%) with biochemical incomplete response, and 2 (1.2%) with structural incomplete response. Completion of the thyroidectomy was necessary in 8 patients (4.9%), but only 3 of them (1.8%) had disease recurrence. These results, obtained in real clinical practice, suggest that TL is a safe operative option for selected patients with DTC and that the intensity of the treatment must be tailored according to the presurgical tumor-associated risk, in line with a personalized medicine.

Development and Validation of a Dynamic 48-Hour In-Hospital Mortality Risk Stratification for COVID-19 in a UK Teaching Hospital: A Retrospective Cohort Study

Background: While numerous point-of-admission disease severity models for COVID-19 have been proposed, disease stratification that accounts for changes in a patient’s condition while in hospital is urgently needed to facilitate patient management and resource allocation.Methods: We developed a prognostic model for 48-hour in-hospital mortality using 473 consecutive patients with COVID-19 presenting to a UK hospital between March 1 and September 12, 2020; and temporally validated using data on 405 patients presenting between September 13, 2020 and January 3, 2021.The primary outcome was all-cause in-hospital mortality. We additionally considered the competing risks of discharge from hospital and transfer to a tertiary Intensive Care Unit for extracorporeal membrane oxygenation. We adopted a landmarking approach to dynamic prediction that accounts for competing risks and informative missingness, and selected predictors using penalised regression. The model estimates, at any point during a hospital visit, the probability of in-hospital mortality during the next 48 hours.Results: Our final model includes age, Clinical Frailty Scale score, heart rate, respiratory rate, SpO2/FiO2 ratio, white cell count, presence of acidosis (pH Interpretation: Our model uniquely incorporates both static risk factors (e.g. age) and evolving clinical and laboratory data, to provide a dynamic risk prediction model that adapts to both sudden and gradual changes in an individual patient’s clinical condition. External validation outside the study hospital will be required before adoption.Funding: NIHR Cambridge Biomedical Research Centre, UKRI Medical Research CouncilDeclaration of Interest: None to declare. Ethical Approval: The study was approved by a UK Health Research Authority ethics committee (20/WM/0125). Patient consent was waived because the de-identified data presented here were collected during routine clinical practice; there was no requirement for informed consent.

Current Understanding of Papillary Thyroid Carcinoma

The term thyroid neoplasm incorporates tumors that originate from follicular cells and those that arise from parafollicular cells (C cells). Differentiated thyroid cancer, which originates from follicular cells, includes papillary thyroid carcinoma (PTC), follicular thyroid carcinoma (FTC), oncocytic cell carcinoma (Hürthle), poorly differentiated carcinoma, and anaplastic thyroid carcinoma (ATC). PTC tends to have an indolent clinical course with low morbidity and mortality. However, this entity has a broad range of biological and clinical behavior that can result in disease recurrence and death, depending on patient and tumor characteristics and the initial treatment approach. PTC is the most common form of well-differentiated thyroid cancer (WDTC) and based on the most recent statistics, accounts for approximately 89.4% of all thyroid malignancies. PTC appears as an irregular solid or cystic nodule in normal thyroid parenchyma. PTC has the propensity for lymphatic invasion, but it is less likely to have hematogenous spread. Around 11% of patients with PTC present with distant metastases outside the neck and mediastinum. This manuscript with review the current understanding of the epidemiology, pathology, molecular characteristics, prognostic factors, and dynamic risk stratification of PTC centered on an evidence-based and personalized approach.

Development and Evaluation of a Machine Learning-Based In-Hospital COVID-19 Disease Outcome Predictor (CODOP): A Multicontinental Retrospective Study

Background: More contagious SARS-CoV-2 virus variants, breakthrough infections, waning immunity, and differential access to COVID-19 vaccines account for the worst yet numbers of hospitalization and deaths during the COVID-19 pandemic, particularly in resource-limited countries. There is an urgent need for clinically valuable, generalizable, and parsimonious triage tools assisting appropriate allocation of hospital resources during the pandemic. We aimed to develop and extensively validate a machine learning-based tool for accurately predicting the clinical outcome of hospitalized COVID-19 patients.Methods: CODOP was built using modified stable iterative variable selection and linear regression with lasso regularisation. To avoid generalization problems, CODOP was trained and tested with three time-sliced and geographically distinct cohorts encompassing 40 511 blood-based analyses of COVID-19 patients from more than 110 hospitals in Spain and the USA during 2020-21. We assessed the discriminative ability of the model using the Area Under the Receiving Operative Curve (AUROC) as well as horizon and Kaplan-Meier risk stratification analyses. To reckon the fluctuating pressure levels in hospitals through the pandemic, we offer two online CODOP calculators suited for undertriage or overtriage scenarios. We challenged their generalizability and clinical utility throughout an evaluation with datasets gathered in five hospitals from three Latin American countries. Findings: CODOP uses 12 clinical parameters commonly measured at hospital admission and associated with the pathophysiology of COVID-19. CODOP reaches high discriminative ability up to nine days before clinical resolution (AUROC: 0·90-0·96, 95% CI 0·879-0·970), it is well calibrated, and it enables an effective dynamic risk stratification during hospitalization. The two CODOP online calculators predicted the clinical outcome of the majority of patients (73-100% sensitivity and 84-100% specificity) from the distinctive Latin American evaluation cohort.Interpretation: The high predictive performance of CODOP in geographically disperse patient cohorts and the easiness-of-use, strongly suggest its clinical utility as a global triage tool, particularly in resource-limited countries.Funding: The Max Planck Society.Declaration of Interest: The authors declare no conflict of interest.Ethical Approval: This study was approved by the Provincial Research Ethics Committee of Málaga (Spain) and the Institutional Research Ethics Committees of each participating hospital.

Natural Course of the American Thyroid Association Response to Therapy Statuses (Dynamic Risk Stratification) in Differentiated Thyroid Cancer

The concept of response to therapy in differentiated thyroid cancer (DTC) was introduced as a dynamic risk stratification used to assess the status of the disease at the time of the evaluation during the follow-up and the risk of recurrence in the future. Our aim in this study was to evaluate the natural course over time of different response to therapy statuses. Methods: We studied 501 nonselected DTC patients (102 males and 399 females) with a median age of 37 years (interquartile range [IQR] 29–48). All patients underwent near-total or total thyroidectomy followed by I-131 ablation (initial management). Results: Of the 501 patients, 387 patients (77.2%) did not have any additional therapuetic interventions after the initial management. In this group, the response to therapy status at the time of the first evaluation after I-131 (median 17 months, IQR 14–22) was an excellent response in 258 (66.7%), an indeterminate response in 101 (26.1%), biochemically incomplete in 17 (4.4%), and structurally incomplete in 11 patients (2.8%). The status changed spontaneously without any intervention in many of them. At the last follow-up visit (median duration 101 months, IQR 71–126), 357 patients (92.2%) achieved an excellent response, 4 (1%) an indeterminate response, 8 (2.1%) a biochemically incomplete status, 16 (4.1%) a structurally incomplete status, and 2 (0.5%) died secondary to DTC with a structurally incomplete status. The response to therapy in the other 114 patients who underwent additional interventions changed from before intervention to the last evaluation as follows: excellent response, 0 to 60 patients (52.6%), indeterminate response, 20 (17.5%) to 1 patient (0.9%), biochemically incomplete 25 (21.9%) to 10 patients (9%), and structurally incomplete 69 (60.5%) to 43 patients (37.7%). Overall, at the last evaluation, 417 (83.2%) were in an excellent response, 5 (1%) in an indeterminate response, 18 (3.6%) in a biochemically incomplete status, 50 (10.2%) in a structurally incomplete status, and 11 (2.2%) died secondary to DTC with a structurally incomplete status. Conclusions: The response to therapy at the initial evaluation is predictive of the long-term outcome. Most patients with the indeterminate response and some in the biochemically incomplete statuses spontaneously regress to an excellent status. Mortality and progression of DTC occur mostly in the structurally incomplete status.

Clinical Relevance of Morphologic and Molecular Complete Remission in AML Patients Undergoing Reduced Intensity or Non-Myeloablative Conditioning

Introduction: For most acute myeloid leukemia (AML) patients (pts) an allogeneic stem cell transplantation (HSCT) offers the best chance for relapse-free long-term survival. Evaluation of measurable residual disease (MRD) at HSCT allows risk stratification additionally to genetic risk at diagnosis. Pts with active AML or with positive MRD status (MRD+) pre-HSCT have similar and dismal outcomes following myeloablative conditioning. Reduced intensity (ric) or non-myeloablative (nma) conditioning regimes have been developed to allow HSCT also in AML pts with higher age or comorbidities. Here, we analyzed and compared the clinical relevance of morphologic and MRD-based remission status in AML pts prior to nma- or ric-HSCT. Methods: We analyzed 345 AML pts who received an allogeneic peripheral blood HSCT at a median age of 63 (range 21-77) years with active disease (34%), or in first (49%) or second (17%) complete remission (CR, 87% of pts in remission) or CR with incomplete peripheral recovery (CRi, 13% of pts in remission) after nma (75%) or ric (25%) conditioning. Donors were HLA matched related (11%), matched unrelated (67%), antigen mismatched unrelated (21%) or haploidentical related (1%). At diagnosis, cytogenetics and the mutation status of CEBPA, NPM1 and presence of FLT3-ITD were assessed. Using a next-generation targeted amplicon sequencing approach we analyzed a panel comprising 54 recurrently mutated genes in myeloid malignancies on the MiSeq platform (Illumina). Pre-HSCT morphologic remission status as well as MRD status in pts in morphologic CR/CRi based on NPM1 mutations, BAALC, MN1 and WT1 expression were evaluated. MRD+ pts were defined by being positive for any of the analyzed markers. Median follow up after HSCT was 2.2 years. Results: Pts transplanted with active disease differed from pts in remission with or without MRD pre-HSCT: they were less likely to have de novo AML (P=.02 &amp; P=.09, respectively) and had higher genetic risk including a higher frequency of an abnormal (P=.001 &amp; P&amp;lt;.001, respectively), a complex (P=.06 &amp; P=.04, respectively) or a monosomal karyotype (P&amp;lt;.001 &amp; P=.003, respectively), a lower frequency of NPM1 mutations (P&amp;lt;.001 &amp; P&amp;lt;.001, respectively) and worse ELN genetic risk (P&amp;lt;.001 &amp; P&amp;lt;.001, respectively). They were also more likely to receive ric-HSCT (P&amp;lt;.001 &amp; P&amp;lt;.001) because pts with active AML were frequently transplanted after FLAMSA conditioning. Pre-HSCT MRD- pts only differed from pre-HSCT MRD+ pts regarding a lower white blood count (P=.006) and lower circulating blasts at diagnosis (P=.05) while the proportion of pts transplanted in CR or CRi did not differ between MRD- and MRD+ AML pts. Also the number of applied chemotherapy cycles prior to HSCT did not differ between the three pts groups. Pre-HSCT MRD- pts had a significantly lower cumulative incidence of relapse/progression (CIR) compared to both MRD+ pts (P&amp;lt;.001) and pts transplanted with active disease (P&amp;lt;.001) while CIR did not differ between MRD+ pts and pts transplanted with active disease (P=.24, Figure 1A). Pre-HSCT MRD- pts had longer overall survival (OS) than pre-HSCT+ pts (P=.04) who again had longer OS than pts transplanted with active disease (P=.01, Figure 1B). In multivariate analyses, the MRD corrected remission status prior to HSCT remained a significant factor for CIR (Hazard Ratio 1.65, Confidence interval [CI] 1.31-2.06) after adjustment for ELN risk and for OS (Odds Ratio 0.63, CI 0.49-0.84) after adjustment for ELN risk, hemoglobin and platelet count at diagnosis. Conclusion: AML pts transplanted with active disease showed a variety of high-risk diagnostic parameters compared to pre-HSCT MRD- or MRD+ pts, as secondary disease and adverse genetic risk. In contrast, pre-HSCT MRD- and MRD+ pts could not be discriminated by high risk factors at diagnosis, underlining the importance of a dynamic risk stratification during remission. Both pts with active disease or a MRD+ status in CR/CRi prior to nma- or ric-HSCT showed dismal outcomes with higher CIR and shorter OS than MRD- pts. However, while CIR was comparable in pts with molecular or morphologic detectable disease, OS was worst in pts transplanted with active disease, indicating that MRD+ pts might still be salvageable after suffering relapse and able to achieve long-term outcomes. Figure Disclosures Jentzsch: JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria. Platzbecker:AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Schwind:Pfizer: Honoraria; JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding.

Impact of the dynamics of ejection fraction on risk stratification in a large multicenter registry of STEMI patients using sequential CMR

Abstract Background Left ventricular ejection fraction (LVEF) has traditionally been used as the cornerstone for risk stratification after ST-segment elevation myocardial infarction (STEMI) and it can be accurately quantified by cine cardiovascular magnetic resonance (CMR). In recent years, the additional prognostic value of contrast CMR-derived infarct size (IS) and microvascular obstruction (MVO) has been demonstrated. Purpose We explored the impact of sequential assessment of CMR-derived LVEF on dynamic risk stratification after STEMI. Methods Data were obtained from three prospective registries of reperfused STEMI patients (n=1036) in whom LVEF, IS and MVO were sequentially quantified by CMR (at least at 1 week and at 6 months). Major adverse cardiac events (MACE) were defined as a combined clinical end-point: death or re-admission for acute heart failure (HF), whichever occurred first. Late events were regarded as those occurring after the 6-month CMR. Results During a mean and median follow-up of 5 years, 105 first MACE (10%, 36 deaths and 69 HF) and 82 late MACE (8%, 35 deaths and 47 HF) were registered. From 1-week to 6-month CMR, LVEF improved (49±12 vs. 53±12%), IS decreased (21±14 vs 17±12% of LV mass) and MVO vanished (1.3±1.9 vs. 0.1±0.7% of LV mass), p&amp;lt;0.001 for all comparisons. At 1-week CMR, 207 patients (20%) displayed reduced LVEF (r-LVEF, &amp;lt;40%), 328 (32%) mid-range LVEF (mr-LVEF, 40–50%) and 501 (48%) preserved LVEF (p-LVEF, &amp;gt;50%). At 6-month CMR, 144 patients (14%) displayed r-LVEF, 247 (24%) mr-LVEF and 645 (62%) p-LVEF. The total MACE rate was higher (p&amp;lt;0.001) only in patients with r-LVEF at 1 week (22%) vs. 7% in those with mr-LVEF and 7% in those with p-LVEF. Similarly, the late MACE rate was higher (p&amp;lt;0.001) only in patients with r-LVEF at 6 months (20%) vs. 7% in those with mr-LVEF and 5% in those with p-LVEF. The late MACE rate was very low in patients with sustained mr- or p-LVEF (41/794, 5%), intermediate in those with improved LVEF from r-LVEF at 1 week to mr- or p-LVEF at 6 months (12/98, 12%) and high in patients with sustained r-LVEF (22/109, 20%) or worsened LVEF from mr- or p-LVEF at 1 week to r-LVEF at 6 months (7/35, 20%), p&amp;lt;0.001 for the trend. Using a Markov approach, only r-LVEF (at any time assessed) significantly related to a higher MACE rate. Conclusions Of available CMR parameters, LVEF persists as the pivotal index for simple post-STEMI risk stratification. Mid-range or preserved LVEF in acute phase associates with excellent long-term outcome. Changes in LVEF provide valuable dynamic prognostic information. Maintenance of mid-range or preserved LVEF in chronic phase occurs in the majority of patients and associates with a very low risk of late clinical events. Whereas late improvement reaching at least mid-range LVEF exerts salutary effects, detection of reduced LVEF at this point identifies the small subset of patients at high risk in the long term. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was funded by “Instituto de Salud Carlos III” and “Fondos Europeos de Desarrollo Regional FEDER” (PIE15/00013, PI17/01836, and CIBERCV16/11/00486 grants).

The ablative radioiodine therapy of differentiated thyroid carcinoma

The ablative radioiodine therapy of differentiated thyroid carcinoma Abstract. In the treatment of differentiated thyroid carcinoma, ablative radioiodine therapy holds a key role in curative intended therapy after total thyroidectomy and consideration of the appropriate indication. The benefit of ablation therapy extends from the completion of initial staging via post-therapeutic whole body scintigraphy via optimization of the value of thyreoglobuline measurement and implementation of dynamic risk stratification in follow-up care to decreasing the rate of tumor recurrence and mortality of thyroid cancer. Within this article, we discuss aims, indication, side reactions and specifics in preparation and execution of ablative radioiodine therapy.

Applicability of Dynamic Risk Stratification for Differentiated Thyroid Cancer (DTC) in a Resource Limited Setting.

Dynamic risk stratification (DRS) in DTC has been considered necessary to deliver correct follow-up (FU) treatment, avoiding overtreatment of low risk/intermediate risk patients as well as inadequate treatment of high risk patients. However, it's clinical applicability has been questioned in comparison with more conventional FU protocols. We aimed to know the predictive reliability of DRS in monitoring FU of DTC in a resource-constrained setting across various risk groups, especially when compared with clinical examination alone.

Dynamic Risk Stratification for Predicting Treatment Response in Differentiated Thyroid Cancer.

Prognosis in Differentiated Thyroid Cancer (DTC) patients is excellent, but a significant degree of overtreatment still exists because of the inability to accurately identify small patient cohorts who experience a more aggressive form of the disease, often associated with certain poor prognostic factors. Identifying these cohorts at an early stage would allow patients at high risk to receive more aggressive treatment while avoiding unnecessary and invasive treatments in those at low risk. Most risk stratification systems include age, tumor size, grade, presence of local invasion, and regional or distant metastases. Here we discuss these common factors as well as their association with treatment response, but also other upcoming markers including histology and multifocality of primary tumor, dose administered and preparation method for Radioiodine Therapy (RAI), Thyroglobulin (Tg), Anti-thyroglobulin Antibodies (Tg-Ab) levels both at initial management and during follow-up, and the presence of previously existing benign thyroid disease. In addition, we examine the role of remnant size and avidity as well as surgeons’ experience in performing thyroidectomies with recurrence rate, discussing its impact on disease prognosis. Our results reveal that treatment response has a statistically significant association with histology, T and M stages, surgeons’ experience, Tg levels and remnant score both during RAI and follow up and Tg-Ab levels during follow-up whole body scan (WBS).

Preablative stimulated thyroglobulin in predicting dynamic risk stratification after 1 year in patients with differentiated thyroid cancer

The aimThe aim of the study is to establish the utility of stimulated preablative stimulated thyroglobulin (ps-Tg) as a predictor of response to therapy and to determine a possible cut-off for ps-Tg as prognostic tool. Patients and methodsA total of 73 consecutive patients who underwent total thyroidectomy and remnant ablation with radioactive iodine therapy (RIT) were reviewed retrospectively. Patients were classified according to the dynamic risk stratification 1 year after initial treatment. The ps-Tg values were compared among the groups. ROC curve analysis was performed. ResultsThe mean age at diagnosis was 43.85 (range: 17–75) with a female-to-male ratio of 4.6. Ps-Tg value after total thyroidectomy and before RIT ranged from 0,1 to 256ng/mL. When patients were restaged, 74% had excellent response to treatment, 12.3% indeterminate and 13.7% incomplete response 1 year after initial therapy. ROC curve analysis showed that the optimal cut-off for ps-Tg was 15ng/mL with a sensivity of 61%; a specificity of 87%; PPV of 61% and NPV of 87%. Among the group of patients showing an excellent response to treatment after 1 year, 87% had ps-Tg<15ng/mL. ConclusionPs-Tg before RIT is associated with dynamic risk stratification at 1 year after therapy in patients with DTC. Higher ps-Tg levels were found in patients that had indeterminate, and particularly incomplete, response.

Comparison Between Familial and Sporadic Non-medullary Thyroid Carcinoma: A Retrospective Individual Risk Factor-Matched Cohort Study.

This study aimed to compare clinicopathologic features and outcomes between patients with familial non-medullary thyroid carcinoma (FNMTC) and patients with sporadic non-medullary thyroid carcinoma (SNMTC) after performing individual risk factor-matching. Additionally, the study evaluated a dynamic risk stratification (DRS) system to validate its usefulness for familial-type thyroid carcinoma. After individual risk factor-matching, 286 patients remained in the FNMTC group, and 858 patients were assigned to the SNMTC group consisting of papillary thyroid carcinoma (PTC). The prognostic outcomes were compared between the two groups in a matched cohort. During the mean follow-up period of 142months, recurrences were experienced by 64 patients in the sporadic group (7.5%) and 29 patients in the familial group (10.1%). In the multivariate analysis, the independent risk factors for recurrence were primary tumor size (p = 0.033), gross extrathyroidal extension (p = 0.001), and lymph node metastasis (p < 0.001). The independent risk factors did not include family history alone (p = 1.101) or the number of affected family members (p = 0.122 for 2 members and p = 0.625 for ≥ 3 members). In this matched-cohort study, the DRS system was well adjusted in the FNMTC and SNMTC groups. Moreover, the proportion of DRS categories and the recurrence rate in each DRS category were similar between the familial and sporadic groups. Family history did not present a statistically significant association with a poor prognosis for PTC patients. With a family history of PTC alone, less aggressive treatment could be considered. In this matched cohort, DRS was adjusted well and could be useful in predicting prognosis, even for PTC patients with a family history of PTC.

Medullary thyroid carcinoma and multiple endocrine neoplasiatype 2

Medullary thyroid carcinoma (MTC) is a rare malignancy and compromises only 3 % of all thyroid carcinomas. MTC cells secret calcitonin, which serves as a sensitive tumor marker for screening and follow-up of MTC. Calcitonin screening in patients with nodular goiter allows for early diagnosis of MTC and surgical curative treatment. In 25 % of patients MTC occurs as an integral part of multiple endocrine neoplasia type 2 (MEN2), an autosomal dominant inherited tumor syndrome. It is caused by germline mutations in the RET protooncogene. In gene carriers early diagnosis and treatment through prophylactic thyroidectomy is possible. MTC is a slowly growing tumor with a good prognosis and 5and 10 year survival rates up to 80 and 60 %. In the follow-up a dynamic risk stratification allows for a personalized disease management. In symptomatic and progressive metastasizing MTC tyrosine kinase inhibitors are an effective therapy.