Clinical Outcome Variables Research Articles

Clinical improvement of teens participating in a dbt skills training

IntroductionDialectical behavioural therapy (DBT) developed by Linehan has been shown to be widely effective in improving emotional regulation capacity in patients diagnosed with borderline personality disorder in adults and adolescents, but also for other profiles of emotional dysregulation, even in the general non-clinical population through emotional regulation skills training programs in schools.ObjectivesThe objective was to describe psychopathological characteristics and to evaluate clinical outcome variables (self-harm, suicide attempts, admissions and emotional regulation difficulties) in young patients who participated in the DBT skills training group carried out by the child and adolescent psychiatry team of Hospital del Mar (Barcelona) between February 2020 and April 2022.MethodsProspective longitudinal study with two evaluations (before starting the group and after finishing it). The clinical variables were evaluated by reviewing the medical records, and the improvement in emotional regulation difficulties was evaluated through the Difficulties in Emotion Regulation Scale (DERS) adaptation to adolescents before and after the intervention.ResultsA total of 36 participants have been referred and assessed to participate in the previously mentioned emotional regulation program. The mean age was 15.6 years (14-17 years old). 100% of the participants were female. All of them met criteria for BPD according to the SCID-II questionnaire; but only 23 patients (63.9%) had BPD as their main diagnosis. 63.9% (n=23) presented psychiatric comorbidities, being 27.8% (n= 10) ADHD, 30.6% (n= 11) substance use disorder and 47.2% (n= 17) eating disorders,77.8% (n=28) had presented self-injurious behaviour, 52% (n=18) had committed a suicide attempt, requiring hospital admission in 36.2% (n=13) at some point in their lives before the therapy group. In the three months after the end of the group, admissions were reduced to 17% (n=6), suicide attempts to 14.8% (n=5) and non-suicidal self-injurious behaviours to 27.8% (n=10).The mean score of all participants on the DERS scale was 129.91 points before participating in the DBT skills group and 105 points right after the group finished. Higher scores translate into greater emotional regulation difficulties.ConclusionsThe reduction in DERS scores, self-injurious behaviours, suicide attempts, and admissions was notable for all participants. It remains to add the results of the groups currently in operation and perform the statistical analysis of all the results. It is necessary to continue studying and testing the benefits of DBT both in the clinical adolescent population and in the general child and adolescent population in order to generalize the promising results observed in our sample. At Hospital del Mar, we will continue to expand the DBT program so that more children and adolescents with emotional dysregulation can benefit.Disclosure of InterestNone Declared

Abstract PD4-04: PD4-04 A quantitative spatial analysis of microenvironmental biomarkers for breast cancer outcome

Abstract Background: Understanding breast cancer progression and the relationships among biomarkers in the tumor and tumor microenvironment could go beyond established prognostic markers of breast cancer. Poor response and recurrence may indeed be a consequence of the highly heterogeneous spatial distribution of biomarkers within cancers, and/or the synergistic and antagonistic relationship between co-localized biomarkers. Recently, mechanical and physical microenvironmental signatures have emerged as relevant in determining cancer aggressiveness and invasiveness. This suggests that physical structures in the tumor tissue may drive favorable immune-tumor-stroma cell patterns. However, current assessment of tumor biopsies is limited in the ability to quantify and spatially resolve several different subtypes of cells and biomarkers within tumors. Methods: We developed a 60-marker imaging mass cytometry panel to resolve high-plex spatial patterns of cells, signaling, and microenvironmental biomarkers within tumor tissues. Our panel includes 16 tumor markers, 20 immune markers and 24 microenvironmental markers. We built an innovative computational tool to identify recurring spatial patterns of these markers within the tumor microenvironment, and define the spatial scale of heterogeneity of such patterns. We correlated the results from this spatial analysis to prospectively collected long term clinical outcome variables (e.g. 10 year survival, local and distant recurrence) in primary breast cancers sampled at baseline. Our patient cohort comprised 287 samples of patients treated with surgery and a radiation, chemotherapy, endocrine therapy, or combinations of these post-surgery. Of these, 174 were from patients alive 5 years post diagnosis, and 113 from patients lost to breast cancer deaths. Living patients were evaluated for recurrence, and of these 94% were disease free at the end of the study, while 4% had local recurrence and 2% distant metastasis. Of the dead patients, 59% had local recurrence while 27% had distant metastasis. Results: We investigated first all patients independent of tumor subtype; in this analysis the presence of both endothelial (CD31+) or HLADR+ cells were consistently associated with long term survival. We further investigated the distribution of all 60 markers in Lum A, Lum B, Lum like, Her2+ and triple negative subtypes. Among the results we confirmed the prognostic role of known biomarkers such as p53+ as a biomarker for poor survival in Luminal B. We also identified complex microenvironmental patterns associated with outcome. For example, the presence of PD1+ cells in collagen rich environments were generally associated with long terms survival in Luminal B patients. With our spatial analysis tool we further investigated intra-patient and inter-patient spatial distribution and classified clusters predictive of outcome beyond heterogeneity. We found that beyond the mere positivity of each marker, the spatial distribution and co-localization of different immune, tumor and mechanical markers determines long term outcome in different subtypes. Specifically, we investigated the role of vimentin within different microenvironments and tumor subtypes. We identified the co-localization of hCa9 and vimentin as strongly associated with poor 5 year outcome, independent of tumor subtype. Moreover, in Luminal A patients while the presence of clusters exclusively positive for vimentin was associated with poor survival, vimentin co-expression with β actin and co-localization of XBP1+ cancer cells and immune cells in a collagen matrix was associated with longer survival. Conclusion: These results suggest the importance of mechanics and physics in determining spatial distribution of tumor-promoting and tumor-inhibiting immune cells, offering new avenues of physics-based therapeutic targets. Citation Format: Sara Nizzero, Maria Pelaez Soni, Yitian Xu, Licheng Zhang, Junjun Zheng, Brian A. Menegaz, Lee B Jordan, Colin A Purdie, Philip R Quinlan, Chandandeep Nagi, Karla A Sepulveda, Philipp Oertle, Tobias A Appenzeller, Marko Loparic, Zhihui Wang, Shu-Hsia Chen, Vittorio Cristini, Marija Plodinec, Alastair M. Thompson. PD4-04 A quantitative spatial analysis of microenvironmental biomarkers for breast cancer outcome [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD4-04.

Stromal grading predicts pathologic complete response and prognosis in triple-negative breast cancer.

Do traditional prognostic factors fully account for the diversity of clinical behavior in breast cancer? Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer seen to have a poor prognosis, although there is great variation in clinical outcomes. Most recently, novel approaches have targeted the tumoral microenvironment (TME) to determine prognosis and tumor-associated stroma has become increasingly recognized as a potential biomarker to predict treatment response and prognosis in TNBC. The principle aim of this paper is to demonstrate an approach to stromal grading in TNBC, with consideration of its utility for predicting pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and clinical survival outcomes. We evaluated 152 TNBC cases from the Firehose Legacy TCGA Cohort and validated our findings in a series of 110 patients from our health system. Stromal grading correlated with clinical outcomes related to prognosis and response to NAC, advanced pathologic stage, as well as clinical demographics like age over 50years with good interobserver reliability (83.6-89.1%). Looking forward, the TME could carve out a more precision-based care in TNBC and breast cancer generally.

Relationship between the prosthesis scapular neck angle and clinical outcomes in reverse shoulder arthroplasty.

Optimal glenosphere positioning in reverse shoulder arthroplasty (RSA) remains highly debated. We aimed to characterize the association between the prosthesis scapular neck angle (PSNA) and postoperative range of motion (ROM) and clinical outcome scores. A retrospective review of 284 RSAs using a single design with minimum 2-year follow-up was performed. Glenosphere tilt was measured postoperatively using PSNA. ROM and functional outcome scores were assessed preoperatively and at latest follow-up. The PSNA was dichotomized to inferior or superior groups (>90° vs ≤ 90°, respectively) and stratified into quartiles; ROM and outcome score measures were compared between groups controlling for inferior glenosphere overhang. No range of PSNA was consistently associated with superior ROM, clinical outcome scores, or rates of complications including scapular notching. However, greater preoperative to postoperative improvement in active FE was found for superiorly (PSNA ≤ 90°) versus inferiorly tilted glenospheres (37° ± 33° vs 53° ± 35°, P = 0.005) and the greater improvement in active FE (57° ± 35°, P = 0.004) was further isolated to the first quartile (mean 85.1° ± 3.5°). A lack of variation in clinical outcomes based on PSNA suggests negligible short-term (median follow-up 3.1 years) clinical significance when glenosphere tilt falls within the distribution of this cohort (mean 92.6° ± 6.2°).

Understanding Neutrophil Dynamics during COVID-19 Infection

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in varied clinical outcomes, with virus-induced chronic inflammation and tissue injury being associated with enhanced disease pathogenesis. To determine the role of tissue damage on immune populations recruitment and function, a mathematical model of innate immunity following SARS-CoV-2 infection has been proposed. The model was fitted to published longitudinal immune marker data from patients with mild and severe COVID-19 disease and key parameters were estimated for each clinical outcome. Analytical, bifurcation, and numerical investigations were conducted to determine the effect of parameters and initial conditions on long-term dynamics. The results were used to suggest changes needed to achieve immune resolution.

Consensus proposal for revised International Working Group 2023 response criteria for higher-risk myelodysplastic syndromes

AbstractMyelodysplastic syndromes/myelodysplastic neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. Although the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS (HR-MDS) and their ability to fully capture the clinical benefits of novel investigational drugs or serve as valid surrogates for longer-term clinical end points (eg, overall survival). Further, issues related to the ambiguity and practicality of some criteria lead to variability in interpretation and interobserver inconsistency in reporting results from the same sets of data. Thus, we convened an international panel of 36 MDS experts and used an established modified Delphi process to develop consensus recommendations for updated response criteria that would be more reflective of patient-centered and clinically relevant outcomes in HR-MDS. Among others, the IWG 2023 criteria include changes in the hemoglobin threshold for complete remission (CR), the introduction of CR with limited count recovery and CR with partial hematologic recovery as provisional response criteria, the elimination of marrow CR, and specific recommendations for the standardization of time-to-event end points and the derivation and reporting of responses. The updated criteria should lead to a better correlation between patient-centered outcomes and clinical trial results in an era of multiple emerging new agents with novel mechanisms of action.

Reducing Barriers to Care in Screening Mammography Among Underserved Populations Through a Quality Improvement Approach.

Health care quality and access are estimated to influence 20% of the variability in clinical outcomes, whereas social determinants of health, such as education, race, and income, are estimated to influence up to 50% [1]. Social determinants of health play a significant role in breast cancer outcomes among racial and ethnic minorities, with literature demonstrating historically lower participation rates in screening mammography (SM) among Black people and persistently lower rates among Hispanic, Latina, and Asian women today, resulting in worse outcomes due to advanced stage at the time of presentation [2,3].

CLINICAL PROFILE, RADIOLOGICAL AND LABORATORY PARAMETER, AND OUTCOME OF MYOCARDITIS

Background & objectives – Myocarditis is an inammatory disease of the cardiac tissue, as myocarditis has a variable clinical presentation and outcome. We studied the clinical prole, radiological & laboratory parameters in patients having myocarditis and the outcomes of the patients. We conducted an observational and Methods – cross-sectional study on 50 patients, who fullled the case denition, inclusion & exclusion criteria. The study was conducted over 18 months. Data was collected and analyzed in standard proforma. The mean age of the study population was found to be 47.6 years. Males are more Results – affected than females, 64% and 36% respectively. The most common presenting complaint was breathlessness (70%) followed by fever (62%) and cough (52%). The most common etiology causing myocarditis was, viral infections (60%). The most common ECG and 2d echo ndings were sinus tachycardia (50%) and global RWMA (24%). Overall mortality among the cases was 18%. High clinical suspi Conclusion – cion of myocarditis should always be kept even in patients having mild complaints and sinus tachycardia, as timely diagnosis and appropriate intervention can prevent irreversible myocardial damage.

Congenital Portosystemic Shunts: Variable Clinical Presentations Requiring a Tailored Endovascular or Surgical Approach.

Congenital portosystemic shunts (CPSS) are rare developmental anomalies resulting in diversion of portal flow to the systemic circulation. These shunts allow intestinal blood to reach the systemic circulation directly, and if persistent or large, may lead to long-term complications. CPSS can have a variety of clinical presentations that depend on the substrate that is bypassing hepatic metabolism or the degree of hypoperfusion of the liver. Many intrahepatic shunts spontaneously close by 1 year of age, but extrahepatic and persistent intrahepatic shunts require intervention by a single session or staged closure with a multidisciplinary approach. Early detection and appropriate management are important for a good prognosis. The aim of this case series is to describe the varied clinical presentations, treatment approaches, and outcomes of 5 children with CPSS at our institution. Management of these patients should involve a multidisciplinary team, including interventional radiology, surgery, hepatology, and other medical services as the patient's clinical presentation warrants. Regardless of clinical presentation, if a CPSS persists past 1-2 years of age, closure is recommended.

Periventricular Heterotopia and Novel FLNA Gene Variant: Clinical and Neuroimaging Clues for an Early Diagnosis

Pathogenic variants in the X-linked FLNA gene encoding filamin A cause a wide range of manifestations, such as periventricular nodular heterotopia (PNH), cardiovascular malformations, connective tissue disorders, and pulmonary involvement with progressive lung disease and variable clinical outcomes ranging from lung transplantation to death. We report a case of a term female newborn with patent ductus arteriosus (PDA) and unexplained respiratory distress in whom cranial ultrasound (cUS) was suggestive of PNH. Brain magnetic resonance imaging confirmed PNH and FLNA gene analysis identified a novel heterozygous pathogenic variant, c.3951C>G (p.Tyr1317Ter). She had complete resolution of her respiratory disease and spontaneous closure of her ductus arteriosus around 10 months. Since then, she developed chronic constipation and joint hypermobility. Early recognition of cUS clues for PNH, associated with PDA and pulmonary involvement in a female newborn, guided genetic testing, allowing for a correct diagnosis and multidisciplinary surveillance of this heterogeneous disorder. We also highlight the good clinical outcome concerning lung involvement in contrast with cases reported in the literature.

Association of organizational culture and climate with variation in the clinical outcomes of collaborative care for maternal depression in community health centers.

Organizational factors may help explain variation in the effectiveness of evidence-based clinical innovations through implementation and sustainment. This study tested the relationship between organizational culture and climate and variation in clinical outcomes of the Collaborative Care Model (CoCM) for treatment of maternal depression implemented in community health centers. Organizational cultures and climates of 10 community health centers providing CoCM for depression among low-income women pregnant or parenting were assessed using the organizational social context (OSC) measure. Three-level hierarchical linear models tested whether variation in culture and climate predicted variation in improvement in depression symptoms from baseline to 6.5-month post-baseline for N = 468 women with care ±1 year of OSC assessment. Depression symptomology was measured using the Patient Health Questionnaire (PHQ-9). After controlling for patient characteristics, case mix, center size, and implementation support, patients served by centers with more proficient cultures improved significantly more from baseline to 6.5-month post-baseline than patients in centers with less proficient cultures (mean improvement = 5.08 vs. 0.14, respectively, p = .020), resulting in a large adjusted effect size of dadj = 0.78. A similar effect was observed for patients served by centers with more functional climates (mean improvement = 5.25 vs. 1.12, p < .044, dadj = 0.65). Growth models indicated that patients from all centers recovered on average after 4 months of care. However, those with more proficient cultures remained stabilized whereas patients served by centers with less proficient cultures deteriorated by 6.5-month post-baseline. A similar pattern was observed for functional climate. Variation in clinical outcomes for women from historically underserved populations receiving Collaborative Care for maternal depression was associated with the organizational cultures and climates of community health centers. Implementation strategies targeting culture and climate may improve the implementation and effectiveness of integrated behavioral health care for depression.

Demographics, Radiological Findings, and Predictors of Prolonged Hospitalization in Civilian Gunshot Wound Patients.

This study aims to characterize the demographic, clinical, and radiological features of gunshot wound (GSW) patients as well as identify predictors of prolonged hospitalization. In this retrospective study, a consecutive sampling method was used, including all patients with GSWs in any anatomical region. Data collection included demographic and clinical information, radiological findings, treatment specifics, and outcome variables, such as hospitalization length of stay (LOS) as the primary outcome. To identify predictive factors associated with prolonged LOS, logistic regression analysis was used. We studied 212 GSW cases, including 95.8% were men and 4.2% were women. The mean age of the studied group was 30.17±7.80 years. GSWs occurred in extremities (80.2%), abdomen (9.0%), thorax (4.7%), and head or neck (5.2%). Two patients (0.9%) had both abdominal and thoracic GSWs. The most prevalent radiological study was an X-ray (83.0%). Patients with head and neck GSWs had the longest emergency department stay, while patients with abdominal GSW patients had the shortest (p=0.068). The highest rates of blood product transfusion were observed in abdominal GSWs (63.2%), emergency surgery (63.2%), and ICU admission (42.1%). Head and neck GSWs had the longest hospitalization LOS (7.5 days). Longer LOS was significantly associated with abnormalities in radiological findings, receiving blood products, and ICU admission (p≤0.001). Significant predictors of prolonged LOS were major abnormalities in radiological findings [odds ratio (OR)=5.3; 95% confidence interval (CI):2.8-10.2], head and neck GSWs (OR=6.1; 95% CI:1.2-31.9), and blood product transfusion (OR=4.1; 95% CI: 1.0-16.3). This study provides insights into factors influencing prolonged hospitalization in GSW patients, highlighting the importance of radiological findings, head and neck injuries, and blood product transfusion.

Clinical Profile, Management and Outcome in Paediatric Patients with Tetanus: A Case Series

Tetanus is an acute infectious disease, caused by spores of the bacterium Clostridium tetani. The spores are found everywhere in the environment, particularly in soil, ash, intestinal tracts/faeces of animals and humans, on the surfaces of skin and rusty tools like nails, needles, barbed wires, etc. Being very resistant to heat and most antiseptics, the spores can survive for years. Anyone can get tetanus, but the disease is particularly common and serious in new born babies and pregnant women, who have not been sufficiently immunised with Tetanus Toxoid (TT) containing vaccines. The disease remains an important public health problem in many parts of the world, but especially in low income countries or districts, where immunisation coverage is low and unclean birth practices are common. There are no particular diagnostic tests for tetanus, the diagnosis is made clinically. Hence, early identification of cases of tetanus becomes important for early intervention. Herein, the authors reported four cases (1 male and 3 females) of tetanus, with varied clinical manifestations, management and outcome. The patients were diagnosed with severe generalised tetanus, otogenic tetanus, mild generalised tetanus and severe generalised tetanus respectively. The patients were treated with inj. diazepam, inj. tetanus toxoid, inj. methocarbamol. Two of them recovered completely and two could not be revived.

Effect of Pranayama as Adjuvant to Medical Treatment on Severity, Frequency, and Duration of Headache in Migraine Patients: An Open-Label Randomized Controlled Trial.

Migraine is the second leading cause of disability worldwide with high rates of dissatisfaction for allopathic treatment among patients. Pranayama is an easy, convenient, and cost-effective method that can supplement existing standard medical treatment of migraine. To study the effect of pranayama as an adjuvant to standard medical treatment of migraine on clinical outcome variables of migraine. This was a randomized controlled trial conducted on 80 consecutive migraine patients who were diagnosed as per International Classification of Headache Disorders-3 (ICHD-3) criteria and were randomly allocated into two groups, that is, standard medical treatment (SMT) group and standard medical treatment plus pranayama (SMT + P) group. The effect of pranayama on clinical outcome variables of migraine was evaluated by using standardized questionnaires. The data was statistically analyzed using SPSS Statistics 20 software. A P value of ≤0.05 was considered statistically significant. Intragroup analysis showed all clinical outcome variables of migraine reduced significantly in the SMT + P group whereas all clinical outcome variables of migraine except the duration of headache episodes reduced significantly in the SMT group. Although statistically non-significant, intergroup analysis demonstrates that reduction in headache severity, duration of headache episodes, and headache impact test-6 (HIT-6) score was more in the SMT + P group whereas reduction in headache frequency and migraine disability assessment (MIDAS) score was more in the SMT group. Pranayama supplements the standard medical treatment of migraine by reducing the duration of headache episodes in addition to the reduction in headache severity, headache frequency, HIT-6 scores, and MIDAS scores.

Phenotyping for percutaneous coronary intervention and long-term recurrent weighted outcomes

IntroductionPercutaneous coronary interventions (PCI) are often performed in multimorbid patients with heterogeneous characteristics and variable clinical outcomes. We aimed to identify distinct clinical phenotypes utilizing machine learning and explore their relationship with long-term recurrent and weighted outcomes. MethodsThis prospective observational cohort study enrolled all-comer PCI patients in 2020‐2021. Multiple imputation k-means clustering was utilized to detect specific phenotypes. The study endpoints were patient-oriented and device oriented composite endpoints (POCE, DOCE), its individual components, and major bleeding. We applied semiparametric regression models for recurrent and weighted endpoints. ResultsThe study included a total of 643 patients. We unveiled three phenotype clusters: 1) inflammatory (n = 44, with high white blood cell counts, high values of C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio), 2) high erythrocyte sedimentation rate (ESR) (n = 204), and 3) non-inflammatory (n = 395). For ACS-only population, we four distinct phenotypes (high-CRP, high-ESR, high aspartate-aminotransferase, and normal). For all-comer PCI patients, identified phenotypes had a higher risk of POCE (mean ratio (MR) 1.42 (95% confidence interval (CI) 1.11–1.81) and MR 2.01 (95% CI 1.58–2.56), respectively), DOCE (MR 1.61 (95% CI 1.20–2.16), MR 2.60 (95%CI 1.94–3.48), respectively), and stroke (hazard ratio (HR) 2.86 (95% CI 1.10–7.4), 6.83 (95% CI 2.01–23.2)). Similarly, high-ESR and high-CRP phenotypes of ACS patients were significantly associated with the development of clinical composite outcomes. ConclusionMachine learning unveiled three distinct phenotype clusters in patients after PCI that were linked with the risk of recurrent and weighted clinical endpoints.German Clinical Trial Registry number: DRKS00020892.

Genetics, shared environment, or individual experience? A cross-sectional study of the health status following SARS-CoV-2 infection in monozygotic and dizygotic twins.

The clinical presentation of COVID-19 shows a remarkably broad spectrum of symptoms. Although studies with adult twins on SARS-CoV-2 infection are rare so far, the fact that there is a genetic component associated with the highly variable clinical outcomes of COVID-19 has already been highlighted in recent studies investigating potential candidate genes and polymorphisms. This is the first study of adult monozygotic (MZ) and dizygotic (DZ) twins concordantly affected by SARS-CoV-2 infection to estimate variances explained by genetic, shared, and individual environmental components of both somatic and psychological symptoms following SARS-CoV-2 infection. Data were collected from 10 adult twin pairs (5 MZ, 5 DZ) in which both twins already had a SARS-CoV-2 infection. A self-designed questionnaire, the Barthel Index, and the Multidimensional Fatigue Inventory (MFI) were used to assess various symptoms and health status following SARS-CoV-2 infection. Intra-class correlations were calculated, and the Falconer formula was used to quantify and differentiate the percentages of genetic influences as well as common environment and personal experiences on the examined traits. In addition, potential factors influencing symptom burden were examined and discussed. We found high estimated heritability for mental impairment after SARS-CoV-2 infection (h 2 = 1.158) and for general fatigue (h 2 = 1.258). For symptom burden, reduced activity, and reduced motivation the individual environment appears to have the strongest influence. Other fatigue symptoms are influenced by genetic effects which range between 42.8 and 69.4%. Both genetics and individual environment play a role in health status after SARS-CoV-2 infection-mental status could be influenced primarily by genetic make-up, whereas for symptom burden and certain fatigue dimensions, non-shared environment could play a more critical role. Possible individual factors influencing the course of the disease were identified. However, gene-environment interactions may still be a source of differences between twins, and the search for candidate genes remains crucial on the road to personalized medicine.

Platelets' morphology, metabolic profile, exocytosis, and heterotypic aggregation with leukocytes in relation to severity and mortality of COVID-19-patients.

Roles of platelets during infections surpass the classical thrombus function and are now known to modulate innate immune cells. Leukocyte-platelet aggregations and activation-induced secretome are among factors recently gaining interest but little is known about their interplay with severity and mortality during the course of SARS-Cov-2 infection. The aim of the present work is to follow platelets' bioenergetics, redox balance, and calcium homeostasis as regulators of leukocyte-platelet interactions in a cohort of COVID-19 patients with variable clinical severity and mortality outcomes. We investigated COVID-19 infection-related changes in platelet counts, activation, morphology (by flow cytometry and electron microscopy), bioenergetics (by Seahorse analyzer), mitochondria function (by high resolution respirometry), intracellular calcium (by flow cytometry), reactive oxygen species (ROS, by flow cytometry), and leukocyte-platelet aggregates (by flow cytometry) in non-intensive care unit (ICU) hospitalized COVID-19 patients (Non-ICU, n=15), ICU-survivors of severe COVID-19 (ICU-S, n=35), non-survivors of severe COVID-19 (ICU-NS, n=60) relative to control subjects (n=31). Additionally, molecular studies were carried out to follow gene and protein expressions of mitochondrial electron transport chain complexes (ETC) in representative samples of isolated platelets from the studied groups. Our results revealed that COVID-19 infection leads to global metabolic depression especially in severe patients despite the lack of significant impacts on levels of mitochondrial ETC genes and proteins. We also report that severe patients' platelets exhibit hyperpolarized mitochondria and significantly lowered intracellular calcium, concomitantly with increased aggregations with neutrophil. These changes were associated with increased populations of giant platelets and morphological transformations usually correlated with platelets activation and inflammatory signatures, but with impaired exocytosis. Our data suggest that hyperactive platelets with impaired exocytosis may be integral parts in the pathophysiology dictating severity and mortality in COVID-19 patients.

A relook at gastroenteropancreatic neuroendocrine tumours as per 2019 WHO classification-A tertiary centre experience.

Neuroendocrine neoplasm of GIT (gastrointestinal tract) and pancreas is heterogenous with variable clinical features and disease outcomes. Despite multiple attempts of risk stratification by grading and staging, some have unpredictable clinical courses. Well-differentiated grade 3 neuroendocrine tumour (G3NET) is a recent subcategory introduced in the 2019 WHO classification based on morphology, molecular profile and prognosis distinguishing it from neuroendocrine carcinoma(NEC). This study aimed at describing the spectrum of NENs encountered in a tertiary centre with focus on reclassifying previously reported G3 tumours into G3 NET and NEC and comparing the survival between them. This is an 8-year retrospective study of all gastro-entero-pancreatic neuroendocrine neoplasms reclassified according to the 2019 WHO classification based on morphology and Ki-67 index with analysis of the survival rates between the categories. Minimum follow-up period was 20months. Eighty-six patients with NENs of gastro-entero-pancreas were included, with median age group of 40-60years (age range 9 to 79years) and male:female ratio of 1.7:1. The tumour grade correlated with the TNM staging and most of the syndromic NETs were low grade. Eleven percent of the tumours were reclassified as well-differentiated G3NETs. The survival of G3 NETs was higher than NEC. Grading of NEN is vital for therapeutic decisions and for prognostication. Currently, morphology is the key to recognise the well-differentiated G3 NETs, but can be subject to interobserver variability. Molecular surrogates may play a role in accurately identifying these entities, the validity of which is warranted.

Association of genetic variants and survival in patients with acute myeloid leukemia in rural Appalachia.

Previous population health studies examining adults with acute myeloid leukemia (AML); however many of these, such as the Cancer Genome Atlas, are derived from databases collected by large urban centers. Due to its unique industry and environmental exposures, we hypothesized the West Virginia Appalachian population may have different mutational trends and clinical outcomes. To address the concern of under-representation of rural minorities in cancer genomic databases, we performed exploratory whole exome sequencing in patients with newly diagnosed AML in rural Appalachia. Correlations between genetic variants and clinical outcome variables were examined via retrospective chart review. A total of 26 patients were identified and whole exome sequencing was performed. Median age was 68 years old. Twenty-one patients had de novo AML (84%). As per European LeukemiaNet (ELN) criteria, 8 patients were favorable (32%), 12 were intermediate (48%), and 5 were adverse risk (20%). Eight patients proceeded to transplant. The median progression-free survival and overall survival were 16.5months and 26.6months, respectively. We noted an increased tumor mutation burden and a higher frequency of specific known driver mutations when compared to The Cancer Genome Atlas database; we also found novel mutations in MUC3A, MUC5AC, HCAR3, ORT2B, and PABPC. Survival outcomes were slightly lower than national average and BCOR mutation correlated with inferior outcomes. Our findings provide novel insight into detrimental mutations in AML in a rural, underrepresented population. We discovered several novel mutations and higher frequency of some known driver mutations, which will help us identify therapeutic targets to improve patient outcomes.

Clinical Outcomes in Patients with Mantle Cell Lymphoma Who Received Autologous Stem Cell Transplant in the Second Line Setting

Background: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with a variable clinical outcome. The standard of care for transplant-eligible patients has been to employ autologous stem cell transplant (ASCT) in first remission and this strategy is currently being tested in the NCTN trial EA4151. The utilization and outcomes of ASCT in second line (2L) treatment is unclear and this knowledge is important for those in the non-transplant control arm in EA4151. In this report, we studied the outcomes of patients who received ASCT in 2L for relapsed/refractory (R/R) MCL. Methods: Patients with newly diagnosed MCL between August 2002 and April 2015 were enrolled in the Mayo Clinic/University of Iowa Lymphoma SPORE Molecular Epidemiology Resource (MER) prospective cohort study. Patients who received ASCT at 2L, or at 1L as a reference group, were included in this study. Clinical characteristics and treatment details were abstracted from MER and by additional chart review. Event-free Survival (EFS) was defined as time from ASCT to progression, retreatment, or death due to any cause, and overall Survival (OS) was defined as time from ASCT to death due to any cause. Survival rates were generated using the Kaplan-Meier method in Rv4.1.2. Results: Among a total of 343 patients with MCL enrolled in the MER, 177 had disease progression or relapse following 1L therapy and had complete 2L treatment information available. Eighteen patients were considered for ASCT as part of 2L therapy. Two (11%) patients did not have an adequate response to 2L induction therapy, and 1 (6%) patient did not meet criteria due to failure of the stem cell mobilization and harvest. Therefore, 15 (83%) patients went on to receive ASCT at the 2L. For the 15 patients who received ASCT at 2L, 1L therapies were R-CHOP (N=9, 60%), rituximab and bendamustine (R-bendamustine, N=2, 13%), rituximab and cladribine (N=3, 20%); 1 (7%) received surgical intervention. All 15 patients were considered for ASCT at 1L. Eight (53%) did not proceed due to inadequate response or progression of disease in the 1L setting; 2 (13%) were treated on clinical trials at 1L that precluded ASCT (one with R-CHOP with 90Yibritumomab tiuxetan and the other with R-Bendamustine); 2 (13%) were considered low risk for relapse and deferred ASCT, and 1 (7%) decided not to proceed (patient decision); the reason was unclear in 2 (13%) other patients. The median time from diagnosis to 1L disease progression/relapse was 6.4 months (range 1.1-35.8). Of the 15 patients who received ASCT as 2L therapy, the median age at time of ASCT was 58 years old, 14 (93%) were male, 13 (87%) had stage III/IV disease, and MCL international prognostic index (MIPI) score was low in 5 (63%) and intermediate in 3 (38%) (MIPI missing in 7 patients). Induction therapy at 2L prior to ASCT included R-CHOP alternating with R-DHAP (N=1, 7%), Hyper-CVAD (N=2, 13%), R-CHOP (N=3, 20%), R-DHAP (N=2, 13%), R-EPOCH (N=1, 7%), ROAD (N=1, 7%), R-ICE (N=1, 7%), R-bendamustine (N=3, 20%), and ibrutinib (N=1, 7%). At a median follow-up of 6.3 years from transplant for patients receiving ASCT at 2L, 9 patients had disease progression or relapse, and 8 patients died (3 without known progression or relapse). The median EFS was 3.8 years and the 2-year EFS rate was 59% (CI 38-91%) and 5-year EFS rate was 37% (CI 18-73%). The 2-year OS rate was 73% (CI 54-99%) and 5-year OS rate was 60% (CI 41-91%). As a reference, 113 patients in the MER received ASCT in the 1L setting. The median EFS from date of ASCT was 5.2 years and the 2-year EFS rate was 77% (CI 70-85%) and the 5-year rate was EFS 54% (CI 45-64%). The 2-year OS rate was 86% (CI 80-93%) and 5-year OS rate was 79% (CI 72-87%). Conclusion: ASCT consolidation after salvage therapy in the 2L setting appeared feasible in select patients with R/R MCL. The PFS and OS outcomes following 2L appeared reasonable. In the evolving landscape of R/R MCL treatment, it is unclear whether ASCT will still have a role. It is possible that select patients with R/R MCL would still benefit from ASCT. Larger studies, although likely limited to retrospective setting, are needed to further evaluate the feasibility, outcomes, and prognostic factors of ASCT at 2L and beyond. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal