Traditional Clinical Criteria Research Articles

A deep dive into burn-mediated ARDS severity assessment: a retrospective study on hematological markers

Acute Respiratory Distress Syndrome (ARDS) is a critical form of Acute Lung Injury (ALI), challenging clinical diagnosis and severity assessment. This study evaluates the potential utility of various hematological markers in burn-mediated ARDS, including Neutrophil-to-Lymphocyte Ratio (NLR), Mean Platelet Volume (MPV), MPV-to-Lymphocyte Ratio (MPVLR), Platelet count, and Platelet Distribution Width (PDW). Employing a retrospective analysis of data collected over 12 years, this study focuses on the relationship between these hematological markers and ARDS diagnosis and severity in hospitalized patients. The study establishes NLR as a reliable systemic inflammation marker associated with ARDS severity. Elevated MPV and MPVLR also emerged as significant markers correlating with adverse outcomes. These findings suggest these economical, routinely measured markers can enhance traditional clinical criteria, offering a more objective approach to ARDS diagnosis and severity assessment. Hematological markers such as NLR, MPV, MPVLR, Platelet count, and PDW could be invaluable in clinical settings for diagnosing and assessing ARDS severity. They offer a cost-effective, accessible means to improve diagnostic accuracy and patient stratification in ARDS. However, further prospective studies are necessary to confirm these findings and investigate their integration with other diagnostic tools in diverse clinical settings.

Multi-Marker Approach in Patients with Acute Chest Pain in the Emergency Department.

Chest pain is a prevalent reason for emergency room referrals and presents diagnostic challenges. The physician must carefully differentiate between cardiac and noncardiac causes, including various vascular and extracardiovascular conditions. However, it is crucial not to overlook serious conditions such as acute coronary syndrome (ACS). Diagnosis of acute myocardial infarction (AMI) and early discharge management become difficult when traditional clinical criteria, ECG, and troponin values are insufficient. Recently, the focus has shifted to a "multi-marker" approach to improve diagnostic accuracy and prognosis in patients with chest pain. This observational, prospective, single-center study involved, with informed consent, 360 patients presenting to the emergency department with typical chest pain and included a control group of 120 healthy subjects. In addition to routine examinations, including tests for hsTnI (Siemens TNIH kit), according to the 0-1 h algorithm, biochemical markers sST2 (tumorigenicity suppression-2) and suPAR (soluble urokinase plasminogen activator receptor) were also evaluated for each patient. A 12-month follow-up was conducted to monitor outcomes and adverse events. We identified two groups of patients: a positive one (112 patients) with high levels of hsTnI, sST2 > 24.19 ng/mL, and suPAR > 2.9 ng/mL, diagnosed with ACS; and a negative one (136 patients) with low levels of hsTnI, suPAR < 2.9 ng/mL, and sST2 < 24.19 ng/mL. During the 12-month follow-up, no adverse events were observed in the negative group. In the intermediate group, patients with hsTnI between 6 ng/L and the ischemic limit, sST2 > 29.1 ng/mL and suPAR > 2.9 ng/mL, showed the highest probability of adverse events during follow-up, while those with sST2 < 24.19 ng/mL and suPAR < 2.9 ng/mL had a better outcome with no adverse events at 12 months. Our data suggest that sST2 and suPAR, together with hsTnI, may be useful in the prognosis of cardiovascular patients with ACS, providing additional information on endothelial damage. These biomarkers could guide the clinical decision on further diagnostic investigations. In addition, suPAR and sST2 emerge as promising for event prediction in patients with chest pain. Their integration into the standard approach in PS could facilitate more efficient patient management, allowing safe release or timely admission based on individual risk.

Multiple biomarkers improve diagnostic accuracy across Lewy body and Alzheimer's disease spectra.

More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α-synuclein seed amplification assay (αSyn-SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co-pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD. Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn-SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra. Following a decade-long follow-up, the clinically or autopsy-defined diagnosis changed for nine participants. αSyn-SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non-LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co-pathology, amyloidosis was present in 18%, 48%, and 71% (χ2 (2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2 (2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co-occurring biomarkers for αSyn-SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ2 (3) = 13.87, p = 0.003). Our study shows that using a combination of αSyn-SAA and AD biomarkers can identify people with αSyn, ADNC, and co-pathology better and earlier than traditional clinical diagnostic criteria alone.

Infants on the move: bibliometric analyses of observational vs. digital means of screening infant development.

Neurodevelopmental disorders are on the rise, yet their average diagnosis is after 4.5 years old. This delay is partly due to reliance on social-communication criteria, which require longer maturation than scaffolding elements of neuromotor control. Much earlier criteria could include reflexes, monitoring of the quality of spontaneous movements from central pattern generators and maturation of intentional movements and their overall sensation. General Movement Assessment (GMA) studies these features using observational means, but the last two decades have seen a surge in digital tools that enable non-invasive, continuous tracking of infants' spontaneous movements. Despite their importance, these tools are not yet broadly used. In this work, using CiteSpace, VOSViewer and SciMAT software, we investigate the evolution of the literature on GMA and the methods in use today, to estimate how digital techniques are being adopted. To that end, we created maps of key word co-occurrence networks, co-author networks, document co-citation analysis and strategic diagrams of 295 publications based on a search in the Web of Science, Dimensions and SCOPUS databases for: 'general movement assessment' OR 'general movements assessment'. The nodes on the maps were categorized by size, cluster groups and year of publication. We found that the state-of-the-art methodology to diagnose neurodevelopmental disorders still relies heavily on observation. Several groups in classical GMA research have branched out to incorporate new techniques, but few groups have adopted digital means. We report on additional analyses of methods and biosensors usage and propose that combining traditional clinical observation criteria with digital means may allow earlier diagnoses and interventional therapies for infants.

Generation and validation of a classification model to diagnose familial hypercholesterolaemia in adults

Background and aimsThe early diagnosis of familial hypercholesterolaemia is associated with a significant reduction in cardiovascular disease (CVD) risk. While the recent use of statistical and machine learning algorithms has shown promising results in comparison with traditional clinical criteria, when applied to screening of potential FH cases in large cohorts, most studies in this field are developed using a single cohort of patients, which may hamper the application of such algorithms to other populations. In the current study, a logistic regression (LR) based algorithm was developed combining observations from three different national FH cohorts, from Portugal, Brazil and Sweden. Independent samples from these cohorts were then used to test the model, as well as an external dataset from Italy. MethodsThe area under the receiver operating characteristics (AUROC) and precision-recall (AUPRC) curves was used to assess the discriminatory ability among the different samples. Comparisons between the LR model and Dutch Lipid Clinic Network (DLCN) clinical criteria were performed by means of McNemar tests, and by the calculation of several operating characteristics. ResultsAUROC and AUPRC values were generally higher for all testing sets when compared to the training set. Compared with DLCN criteria, a significantly higher number of correctly classified observations were identified for the Brazilian (p < 0.01), Swedish (p < 0.01), and Italian testing sets (p < 0.01). Higher accuracy (Acc), G mean and F1 score values were also observed for all testing sets. ConclusionsCompared to DLCN criteria, the LR model revealed improved ability to correctly classify observations, and was able to retain a similar number of FH cases, with less false positive retention. Generalization of the LR model was very good across all testing samples, suggesting it can be an effective screening tool if applied to different populations.

Associations between indicators of new semi-quantitative express-test for procalcitonin and indicators of saturation in patients with community-acquired pneumonia

Objective. To evaluate the associations between the indicators of a new semi-quantitative express-test for procalcitonin and saturation levels in hospitalized patients with community-acquired pneumonia.&#x0D; Due to a high rate of growth of the incidence of severe community-acquired pneumonia, which leads to disability of the working population and claims thousands of lives, there is a need for early verification of the severity degree and a timely initiation of treatment. Traditional clinical, radiologic, laboratory and bacteriological criteria for inflammatory reactions (fever, increased pulmonary infiltration and leukocytosis, detection of potential pathogens in sputum or hemocultures) are not specific for pneumonia. Similar clinical and radiologic manifestations can also be noted in other pathological conditions, for example, in atelectasis of the lung, lung infarction, congestive heart failure, as well as acute respiratory distress syndrome. In this regard, the study of new diagnostic markers of community-acquired pneumonia is an actual direction in modern therapeutic diagnostics. Being a fast and highly sensitive method, the express test for procalcitonin can be a valuable predictive marker for the severe course of community-acquired pneumonia. Of interest is the relationship of procalcitonin with an indicator reflecting the presence of respiratory failure the level of saturation.&#x0D; Materials and methods. A single-stage comparative study involved 123 patients admitted to the hospital with a confirmed diagnosis of community-acquired pneumonia. On the first day after admission to the hospital, all patients underwent a general clinical examination, an overview X-ray of the chest organs, and determination of the plasma procalcitonin level using a semi-quantitative express-test as well as the saturation level. According to the results of the examination, the patients were divided into two groups: patients with saturation 94 % (n=43), and patients with saturation 94 % (n=80). The group of patients with saturation values 94 % consisted of 23 (53.5 %) women and 20 (46.5 %) men. The group of patients with saturation values 94 % consisted of 42 (52.5 %) women and 38 (47.5 %) men. The mean age of the patients was 56.719.1 and 45.620.7 (MSD) years, respectively, p=0.005. Statistical processing of the obtained data was carried out using the SPSS 13.0 software package.&#x0D; Results. Patients with low saturation values ( 94 %) had higher heart rate (p=0.001) and respiratory rate (p=0.001), and the levels of erythrocytes (p=0.001), hemoglobin (p=0.003) and albumin (p=0.001) were significantly lower than in patients with higher saturation levels 94 %. For patients with signs of respiratory failure and saturation indices 94 %, a more pronounced increase in the level of express-test for procalcitonin was characteristic (p=0.001). According to regression analysis, the express-test for procalcitonin 2 ng/ml by 13.8 % (CI 1.5131.3), age by 3 %, and heart rate by 11 % increase the risk of low saturation in patients with community-acquired pneumonia.&#x0D; Conclusion. Low values of blood oxygen saturation 94 % in hospitalized patients with community-acquired pneumonia are directly associated with high values of the new semi-quantitative express-test for procalcitonin (more than 2 ng/ml), that can be used for individual risk stratification.

COVID-19-associated schizophrenia-like psychosis during the COVID-19 pandemic

IntroductionThe viral theory of the development of psychoses was formulated in the 19th century, but the role of viral agents in the pathogenesis of psychoses remains a matter of debate. In the context of the 2020 pandemic, the results of several papers on the characteristics of psychotic disorders in COVID-19 have been published. Coronaviruses are neuroinvasive, capable of affecting mental and body functions.ObjectivesThe aim of the study was to identify patients with acute psychosis without a history of mental disorders in order to test the hypothesis about the possibility of manifestation of schizophreniform psychosis due to a viral attack.MethodsWithin a year and a half, 50 patients with mental disorders associated with COVID-19 were identified. The reason for hospitalization in a psychiatric hospital is the development of acute schizophreniform psychosis against the background of a new coronavirus infection. The diagnosis was verified according to traditional clinical criteria and modern psychometric tools. Inclusion criteria: no previous visits to a psychiatrist; verified acute polymorphic psychotic disorder and coronavirus infection COVID-19 (ICD-10); manifestation of psychosis against the background of infection with COVID-19; age 18-60 years; consent to participate in the study. Exclusion criteria: signs of organic brain damage; indications of substance abuse; delirium of any etiology; somatic pathology in the stage of decompensation.Results27 women (54%) and 23 men (46%), aged 20 to 57 years (average age 34.5±7.6), of which 18 people (36%) worked, 2 (4%) studied , 29 (58%) people are unemployed. 27 people (54%) are single, 16 (32%) are married, 7 (14%) are divorced; 18 people (36%) were raising children, which indirectly indicated a relatively favorable premorbid functioning. At the time of the examination, the condition was determined by polymorphic psychotic symptoms with a predominance of dissociative-delusional, paraphrenic and oneiric phenomena with plots containing plots of infection and the spread of coronavirus. At the same time, the sum of PANSS is from 53 to 130 (85) points, including PANSS P - from 15 to 37 (27), PANSS N - from 7 to 44 (18), PANSS G - from 23 to 57 (39.9 ); P1 - 5.7; P3 - 5.1. When comparing the obtained data with the world experience, we found some differences. Delusional symptoms were diagnosed twice as rarely, cases with tactile hallucinations were not detected, but catatonic symptoms were observed twice as often, and manic arousal was twice as rare. In general, the studied data are comparable with the results published in the world practice.ConclusionsThe unique experience of the coronavirus pandemic will allow us to assess the influence of environmental factors, namely the role of infections, in the manifestation or predisposition to schizophrenia spectrum disorders. It is planned to evaluate the dynamics of the course of the disorder after the relief of the acute period.Disclosure of InterestNone Declared

Predicting the Need for Intubation among COVID-19 Patients Using Machine Learning Algorithms: A Single-Center Study.

Background: Owing to the shortage of ventilators, there is a crucial demand for an objective and accurate prognosis for 2019 coronavirus disease (COVID-19) critical patients, which may necessitate a mechanical ventilator (MV). This study aimed to construct a predictive model using machine learning (ML) algorithms for frontline clinicians to better triage endangered patients and priorities who would need MV. Methods: In this retrospective single-center study, the data of 482 COVID-19 patients from February 9, 2020, to December 20, 2020, were analyzed by several ML algorithms including, multi-layer perception (MLP), logistic regression (LR), J-48 decision tree, and Naïve Bayes (NB). First, the most important clinical variables were identified using the Chi-square test at P < 0.01. Then, by comparing the ML algorithms' performance using some evaluation criteria, including TP-Rate, FP-Rate, precision, recall, F-Score, MCC, and Kappa, the best performing one was identified. Results: Predictive models were trained using 15 validated features, including cough, contusion, oxygen therapy, dyspnea, loss of taste, rhinorrhea, blood pressure, absolute lymphocyte count, pleural fluid, activated partial thromboplastin time, blood glucose, white cell count, cardiac diseases, length of hospitalization, and other underline diseases. The results indicated the J-48 with F-score = 0.868 and AUC = 0.892 yielded the best performance for predicting intubation requirement. Conclusion: ML algorithms are potentials to improve traditional clinical criteria to forecast the necessity for intubation in COVID-19 in-hospital patients. Such ML-based prediction models may help physicians with optimizing the timing of intubation, better sharing of MV resources and personnel, and increase patient clinical status.

Performance comparison of different classification algorithms applied to the diagnosis of familial hypercholesterolemia in paediatric subjects

Familial Hypercholesterolemia (FH) is an inherited disorder of lipid metabolism, characterized by increased low density lipoprotein cholesterol (LDLc) levels. The main purpose of the current work was to explore alternative classification methods to traditional clinical criteria for FH diagnosis, based on several biochemical and biological indicators. Logistic regression (LR), decision tree (DT), random forest (RF) and naive Bayes (NB) algorithms were developed for this purpose, and thresholds were optimized by maximization of Youden index (YI). All models presented similar accuracy (Acc), specificity (Spec) and positive predictive values (PPV). Sensitivity (Sens) and G-mean values were significantly higher in LR and RF models, compared to the DT. When compared to Simon Broome (SB) biochemical criteria for FH diagnosis, all models presented significantly higher Acc, Spec and G-mean values (p < 0.01), and lower negative predictive value (NPV, p < 0.05). Moreover, LR and RF models presented comparable Sens values. Adjustment of the cut-off point by maximizing YI significantly increased Sens values, with no significant loss in Acc. The obtained results suggest such classification algorithms can be a viable alternative to be used as a widespread screening method. An online application has been developed to assess the performance of the LR model in a wider population.

Endometrial cancer in Lynch syndrome.

Lynch syndrome (LS) is an autosomal dominant inherited disease caused by germline pathogenic variants (PVs) in mismatch repair (MMR) genes. LS-associated endometrial cancer (LS-EC) is the most common extraintestinal sentinel cancer caused by germline PVs in MMR genes, including MLH1, MSH2, MSH6 and PMS2. The clinicopathologic features of LS-EC include early age of onset, lower body mass index (BMI), endometrioid carcinoma and lower uterine segment involvement. There has been significant progress in screening, diagnosis, surveillance, prevention and treatment of LS-EC. Many studies support universal screening for LS among patients with EC. Screening mainly involves a combination of traditional clinical criteria and molecular techniques, including MMR-immunohistochemistry (MMR-IHC), microsatellite instability (MSI) testing, MLH1 promoter methylation testing and gene sequencing. The effectiveness of endometrial biopsy and transvaginal ultrasound (TVS) for clinical monitoring of asymptomatic women with LS are uncertain yet. Preventive strategies include hysterectomy and bilateral salpingo-oophorectomy (BSO) as well as chemoprophylaxis using exogenous progestin or aspirin. Recent research has revealed the benefits of immunotherapy for LS-EC. The NCCN guidelines recommend pembrolizumab and nivolumab for treating patients with advanced or recurrent microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) EC.

Evaluation of Salivary Level of Heat Shock Protein 70 in Patients with Chronic Periodontitis.

Statement of the Problem: Traditional clinical criteria are usually not sufficient for determining the sites of active periodontal disease, monitoring the response to treatment, or measuring the susceptibility to future disease development. Past studies have shown that heat shock protein 70 (HSP70) are involved in the etiology of periodontal disease.Purpose: The aim of this study was to evaluate the level of HSP70 in saliva of patients with chronic periodontitis (CP).Materials and Method: In our case-control study, the saliva samples of 45 patients with CP and 45 age- and sex-matched healthy subjects were collected. Salivary HSP70 was measured by enzyme-linked immunosorbent assay method. The results were analyzed by statistical tests using SPSS 16 and the statistically significant difference was set at p< 0.05.Results: In this study, the mean salivary HSP70 level was 2.81±0.61ng/ml in the patient group and 1.96±0.77ng/ml in the healthy group, with a significant difference (p< 0.05). In addition, the results of spearman correlation analysis showed a positive correlation between salivary HSP 70 and clinical periodontal index.Conclusion: The results of this study showed that the salivary HSP70 level in patients with CP is higher than that in healthy subjects. As a result, salivary HSP70 might be considered as a marker in the pathogenesis of CP.

Development and Prospective Validation of a Deep Learning Algorithm for Predicting Need for Mechanical Ventilation

BackgroundObjective and early identification of hospitalized patients, and particularly those with novel coronavirus disease 2019 (COVID-19), who may require mechanical ventilation (MV) may aid in delivering timely treatment.Research QuestionCan a transparent deep learning (DL) model predict the need for MV in hospitalized patients and those with COVID-19 up to 24 h in advance?Study Design and MethodsWe trained and externally validated a transparent DL algorithm to predict the future need for MV in hospitalized patients, including those with COVID-19, using commonly available data in electronic health records. Additionally, commonly used clinical criteria (heart rate, oxygen saturation, respiratory rate, Fio2, and pH) were used to assess future need for MV. Performance of the algorithm was evaluated using the area under receiver operating characteristic curve (AUC), sensitivity, specificity, and positive predictive value.ResultsWe obtained data from more than 30,000 ICU patients (including more than 700 patients with COVID-19) from two academic medical centers. The performance of the model with a 24-h prediction horizon at the development and validation sites was comparable (AUC, 0.895 vs 0.882, respectively), providing significant improvement over traditional clinical criteria (P < .001). Prospective validation of the algorithm among patients with COVID-19 yielded AUCs in the range of 0.918 to 0.943.InterpretationA transparent deep learning algorithm improves on traditional clinical criteria to predict the need for MV in hospitalized patients, including in those with COVID-19. Such an algorithm may help clinicians to optimize timing of tracheal intubation, to allocate resources and staff better, and to improve patient care.

Ethically Allocating COVID-19 Drugs Via Pre-approval Access and Emergency Use Authorization

Allocating access to unapproved COVID-19 drugs available via Pre-Approval Access pathways or Emergency Use Authorization raises unique challenges at the intersection of clinical care and research. In conditions of scarcity, prioritization approaches should minimize harm, maximize benefit, and promote fairness. To promote continued data collection, patients seeking access to unproven COVID-19 drugs should receive lower priority for allocation when they decline to participate in clinical trials, either of the requested drug or other investigational products, offering a comparable balance of risks and benefits; special attention should be paid to concerns of voluntariness and distrust. In addition, institutional treatment protocols that can contribute more robust real world data should be preferred to single patient requests for access, with priority for inclusion based on traditional clinical allocation criteria relying on available evidence. Fairness demands distribution of these protocols across a diverse range of sites, particularly those serving marginalized populations, among other protections.

Tumor Characterization in Breast Cancer Identifies Immune-Relevant Gene Signatures Associated With Prognosis.

There has been increasing attention on immune-oncology for its impressive clinical benefits in many different malignancies. However, due to molecular and genetic heterogeneity of tumors, the activities of traditional clinical and pathological criteria are far from satisfactory. Immune-based strategies have re-ignited hopes for the treatment and prevention of breast cancer. Prognostic or predictive biomarkers, associated with tumor immune microenvironment, may have great prospects in guiding patient management, identifying new immune-related molecular markers, establishing personalized risk assessment of breast cancer. Therefore, in this study, weighted gene co-expression network analysis (WGCNA), single-sample gene set enrichment analysis (ssGSEA), multivariate COX analysis, least absolute shrinkage, and selection operator (LASSO), and support vector machine-recursive feature elimination (SVM-RFE) algorithm, along with a series of analyses were performed, and four immune-related genes (APOD, CXCL14, IL33, and LIFR) were identified as biomarkers correlated with breast cancer prognosis. The findings may provide different insights into prognostic monitoring of immune-related targets for breast cancer or can be served as reference for the further research and validation of biomarkers.

Hydrochlorothiazide Test as a Tool in the Diagnosis of Gitelman Syndrome in Chinese Patients.

Traditional clinical diagnostic criteria for Gitelman syndrome (GS) including hypomagnesemia and hypocalciuria have been challenged by reports of atypical manifestations recently, as well as the development of genetic testing. Hydrochlorothiazide (HCT) test is a diagnostic method different from the traditional biochemical parameters, which could evaluate the function of thiazide-sensitive sodium-chloride co-transporter (NCC) in vivo by a small dose of NCC inhibitor HCT. In this retrospective study, we compared the diagnostic significance of hypomagnesemia, hypocalciuria, and the reaction of HCT test, among Chinese patients with GS confirmed by genetic test. For patients who were clinically suspected of GS manifestations, SLC12A3 gene was sequenced to make genetic diagnosis. A total of 83 GS and 19 control patients were recruited, among which 37 underwent HCT test according to the standard process. Compared with the gold standard of genetic diagnosis, both the diagnostic sensitivity (93.10%) and specificity (100.00%) of the HCT test were much higher than those of hypomagnesemia and/or hypocalciuria. The area under the receiver operating characteristic (ROC) curve was 1.000 (95% CI 0.905–1.000) for HCT test, higher than the values using hypomagnesemia and/or hypocalciuria. The cost of HCT test was around $54, much lower than genetic diagnosis. In conclusion, besides traditional hypomagnesemia and hypocalciuria, HCT test could be a valuable tool in the clinical diagnosis of Chinese GS patients.

Point-of-Care Sinus Ultrasound: Impact Within a Large Internal Medicine Clinic and Review of Technique.

Outpatient diagnosis of acute bacterial sinusitis, using only traditional physical examination and clinical criteria, results in the overuse of antibiotics in patients with upper respiratory complaints. Point-of-care maxillary sinus ultrasound is easy to learn and quick to perform in a primary care clinic. The technique can reduce antibiotic prescribing by reassuring both patients and providers of the absence of fluid in the sinus, the hallmark of maxillary sinusitis. A review of the literature, description of technique, and results of sinus ultrasound implementation in a large internal medicine clinic are included.

Traditional clinical criteria outperform high-sensitivity C-reactive protein for the screening of hepatic nuclear factor 1 alpha maturity-onset diabetes of the young among young Asians with diabetes.

Young adults with diabetes in Asia represent a heterogeneous group. Using traditional clinical criteria to preselect individuals for testing for maturity-onset diabetes of the young (MODY) may exclude a large proportion from testing. High-sensitivity C-reactive protein (hs-CRP) has shown promise as a biomarker to differentiate hepatic nuclear factor 1 alpha (HNF1A)-MODY from type 2 diabetes. We aimed to compare the use of hs-CRP as a biomarker versus traditional criteria, to guide testing for HNF1A-MODY among a cohort of young adults with diabetes in Singapore. A total of 252 adults (age of onset ⩽45 years) and 20 children with diabetes were recruited. Using traditional criteria (family history of diabetes and onset of diabetes ⩽25 years) and an hs-CRP cut off of ⩽0.5 mg/l, 125 and 37 adults, respectively, were identified for HNF1A gene testing. All children underwent HNF1A gene testing. Five adults (5/143, 3.5%) with HNF1A-MODY were identified. There were no HNF1A gene mutations among the children. Traditional criteria correctly identified all five HNF1A-MODY individuals (5/125, 4%), while applying an hs-CRP level of ⩽0.5 mg/l selected just 1 of these 5 for HNF1A gene testing (1/37, 2.7%). None of those with a positive GAD antibody or undetectable C-peptide level had HNF1A-MODY. The use of hs-CRP to guide screening for HNF1A-MODY among Asian young adults with diabetes did not improve the diagnostic yield. Applying a combination of age of onset of diabetes under 25 years and a family history of diabetes alone could guide targeted HNF1A-MODY screening in Asians, with an expected yield of 4% diagnosed with HNF1A-MODY among those screened.

Dynamic Changes in the Clonal Structure of MDS and AML in Response to Epigenetic Therapy

Hematopoietic cells from patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) contain gene mutations that are variably distributed between the founding clone and daughter subclone(s). Traditional response criteria in MDS and AML are based on bone marrow morphology and may not accurately reflect antitumor activity and clinical benefit in patients treated with hypomethylating agents. We used digital sequencing of serial bone marrow samples to monitor tumor burden and to characterize the changes in the clonal structure of MDS and AML that occur during treatment with epigenetic therapy. We hypothesized that digital sequencing may provide an alternative measure of antitumor activity and identify the persistence or emergence of resistant clones during treatment which mediate disease relapse.We conducted a phase I/II study in older adults (age ≥ 60) with advanced MDS (IPSS ≥ 1.5) or AML. Subjects received a combination of decitabine 20 mg/m2 on d1-5 with the histone deacetylase inhibitor, panobinostat 10-40 mg po 3x/week every 28 days for up to 12 cycles. Serial bone marrow samples were collected for digital sequencing at baseline, after every 2 cycles of treatment and at the time of relapse.A total of 52 patients, 14 with MDS and 38 with AML were enrolled in this study. For AML patients, 10% achieved a complete remission (CR+CRi) with an additional 18% of patients achieving a morphologic leukemia-free state (mLFS) using IWG response criteria. For patients with MDS, 14% achieved a CR and 21% achieved a marrow CR. We identified 9 MDS and 16 AML patients that had banked, paired bone marrow and skin (as a source of normal DNA) samples and a somatic mutation in at least 1 of 54 recurrently mutated MDS/ AML genes. DNA was enriched for 285 genes commonly mutated in MDS and AML (n=24 patients) or whole exome probes spiked-in with the 285 genes (enhanced exome sequencing; EES) (n=7 patients), and sequenced on a HiSeq2000 instrument with 2x101bp reads. We detected an average of 4.9 SNVs and indels per patient (range 1-15) when only the 285 gene panel was used, compared to 27.4 mutations per patient (range 9-43) using EES. Ten genes were mutated in at least 3 pre-study samples. The presence of a TP53 mutation (N=8) was associated with a trend towards achieving a response (p=0.09).We then analyzed variant allele frequencies (VAF) of mutations in serial samples. We observed five distinct patterns that were associated with different clinical responses, including i) AML patients achieving a CR+CRi (n=2): mutation VAFs were undetectable by cycle 2 using standard sequencing, ii) AML with mLFS (n=2): mutation VAFs remained detectable but decreased to <10%, iii) MDS with CR/cCR+mCR (n=3): mutation VAFs decreased to <10% and were intermittently below the level of detection, iv) MDS with stable disease (n=2): mutation VAFs decreased but some remained >10%, and v) AML with treatment failure (n=5): mutation VAFs were essentially unchanged and remained >30%.We observed responding patients can have persistent measurable clonal hematopoiesis for at least one year without disease progression. Sequencing also revealed selective AML subclone clearance in a patient with treatment failure, nominating a set of mutations that may mark super-responder clones. We observed that the blast percentage decreases prior to mutation VAFs in some patients, suggesting that the differentiation of blasts could falsely underestimate tumor burden. Finally, sequencing revealed that tumor burden can be measured even in patients achieving a CR. Using an ultra-sensitive barcode sequencing approach, we sequenced 1 MDS and 1 AML patient achieving a clinical and molecular CR (based on standard sequencing). We detected extremely rare TP53 mutations months to years prior to disease relapse (VAFs = 0.23% in MDS and 0.05% in AML during a CR - equivalent to a sensitivity of 1 in 2000 heterozygous mutant cells). While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone drives relapse or progression from MDS to secondary AML. Digital sequencing provides an alternative measure of disease response which may augment traditional clinical response criteria and should be explored in future clinical trials. DisclosuresUy:Novartis: Research Funding. Off Label Use: Panobinostat in MDS/AML. Duncavage:Cofactor Genomics: Consultancy; DI&P Consulting: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy. Abboud:Teva Phamaceutical: Research Funding.

Universal Screening of Colorectal Cancers for Lynch Syndrome: Challenges and Opportunities.

Lynch syndrome (LS) is the most common heritable colorectal cancer (CRC) syndrome, accounting for approximately 3 % of CRC cases in the USA each year. LS results from a genetic mutation in one of the four mismatch repair genes, and clinically LS is associated with CRC and other gastrointestinal and extra-gastrointestinal malignancies. In this review, we describe the various clinical criteria utilized for the identification of LS patients and the inherent flaws with these criteria. We discuss the concept of universal testing for LS in all cases of newly diagnosed CRC, along with the potential benefits and challenges of universal testing. Several studies have shown that universal tumor testing is cost-effective and identifies cases of LS that are missed using traditional clinical criteria, which may result in reduced cancer mortality for probands and their families. Yet the full benefits of universal tumor testing may be limited by the availability and patient acceptance of genetic testing, and by logistical obstacles affecting the implementation of universal testing programs. Lastly, we comment on developing technologies such as massively parallel next-generation sequencing, which permits simultaneous sequencing of multiple genes involved in LS and other inherited colon cancer syndromes.

Accelerated Partial Breast Irradiation: A Review and Evaluation of Indications for Treatment

Accelerated partial breast irradiation (APBI) represents a well-studied treatment modality for the delivery of adjuvant radiation therapy following breast-conserving surgery. Interstitial APBI represents the APBI technique with the longest follow-up to date; data from randomized trials and matched pair analyses demonstrate equivalent local control to traditional whole-breast irradiation with comparable rates of toxicity and improved cosmesis. While less mature, prospective data support the efficacy and safety of applicator-based brachytherapy with new multilumen applicators offering the potential for improved outcomes. External beam APBI represents a noninvasive technique; however, concerns regarding toxicity with this technique have emerged though newer techniques may mitigate these concerns. Multiple guidelines have been published based on traditional clinical and pathologic criteria to help physicians offer APBI to appropriately selected patients.