scholarly journals Genetic variants as determinants of outcome in lamin A/C-related cardiac disease

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Garcia Hernandez ◽  
M Ortiz-Genga ◽  
J P Ochoa ◽  
A Lamounier ◽  
X Fernandez ◽  
...  
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Adverse Outcomes ◽  
Cardiac Events ◽  
Private Company ◽  
Missense Variants ◽  
Funding Sources ◽  
Familial Dilated Cardiomyopathy ◽  
Pathogenic Variants

Abstract Background Current guidelines for the diagnosis and management of familial dilated cardiomyopathy highlight the variables “male sex” and “non-missense type variants” as risk factors for malignant ventricular arrhythmias. Objective Quantitative evaluation of prognostic differences between different LMNA variants associated with cardio-laminopathy. Method Analysis of cardiac event-free survival (sudden death, major arrhythmic events, death from heart failure and transplantation) with Kaplan-Meier approach in relation to gender & variant LMNA type. The data come from a specific database containing information on more than 1200 carriers of disease-causing LMNA variants. In the first analysis, the groups of comparison were truncating-type variants (LMNAtv) VS the global of pathogenic missense variants in the gene associated with cardiolaminopathy (LMNAm), segregated by gender. In the second analysis, it was considered missense LMNA affecting different residues (p.Arg190, p.Arg377 and p.Arg541), located in different functional domains, with enough data for comparison and with statistically different clinical behavior from that of global pathogenic variants in the gene. They were compared with the group of LMNAtv variants, as reference. The variants included were p.Arg377Cys/His, p.Arg541Cys/Ser/Gly/Pro/His and p.Arg190Trp/Gln/Pro, all of them pathogenic and associated with cardio-laminopathy. Results No significant differences were observed in survival between LMNAtv versus LMNAm variants (log rank=0.56) with slightly worse outcomes in males (log rank 0.03). Median survival time was 56 years for men compared to 60 years for women with LMNAtv, and 55 years compared to 66 years, respectively, among carriers of LMNAm (analysis A). In analysis B, statistically significant differences were observed between the groups considered (Log Rank p<0.001). These differences were also clinically relevant (median survival time in groups p.Arg377, LMNAtv, p.Arg190 and p.Arg541 was 60, 58, 50 and 35 years, respectively). Importantly, more than 70% of the cardiac events observed were related to major ventricular arrhythmic episodes. Conclusions This quantitative analysis demonstrates that certain missense variants in LMNA may have a similar and even more adverse clinical course than the set of truncation-type variants. These findings highlight the relevance of the specific variant rather than the variant type in guiding actionable therapies to prevent adverse outcomes. Regarding the differences observed between genders, even though they are statistically significant, their magnitude could be clinically not relevant. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Health in Code

scholarly journals Narrowing of the neonatal region in the FBN1 gene

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
M N Brogger ◽  
G Fernandez Ferro ◽  
I Cardenas Reyes ◽  
J P Ochoa ◽  
S Garcia Hernandez ◽  
...  
Keyword(s):  
Heart Failure ◽  
Genetic Variants ◽  
Severe Form ◽  
Private Company ◽  
Missense Variants ◽  
Funding Sources ◽  
Fbn1 Gene ◽  
Pathogenic Variants ◽  
Kaplan Meier ◽  
Worse Prognosis

Abstract Background Neonatal Marfan syndrome (MFS) is considered the most severe form of MFS and is characterized by early childhood death due to congestive heart failure. It has been suggested that genetic variants associated with this clinical presentation, cluster in a specific region between exons 24 and 32. It has been reported that patients carrying genetic variants in these exons have worse prognosis. Purpose Our purpose was to analyze cardiovascular outcome by location of the genetic variants in the “neonatal region” of the FBN1 gene. Materials and methods We analyzed clinical data on 1353 carriers and affected relatives with 683 missense pathogenic or likely pathogenic genetic variants of FBN1 gene (including cases identified in our laboratory and cases described in the literature) in whom age at last follow-up was available. Kaplan-Meier survival curves were generated to examine location of the genetic variant in the FBN1 gene in relation to survival free of surgical intervention or cardiovascular (CV) death (composite of deaths related to aortic dissection, heart failure/transplant, sudden, stroke or CV surgery). Missense genetic variants were classified as located in the “neonatal region” (residues 952–1363, corresponding to exons 24–32) and in the “non-neonatal region” (residues 45–951 and 1364–2731). In the “neonatal region”, we have also analyzed a sub-region of “over-representation” of heart failure deaths in the first year of life, which we called “critical neonatal region” (amino acids 1028–1088, corresponding to exon 25 and few residues from exon 26) in comparison to the “non-critical neonatal region”. Results Data were examined on 1060 patients with missense variants located in the “non neonatal region” and on 293 patients with missense variants located in the “neonatal region”. Of these, 96 patients were carriers of missense variants in the “critical neonatal region”, the rest of patients carried variants in the neonatal region, outside this particular domain (“non-critical neonatal region”). Patients carrying missense variants in the neonatal region had worse prognosis than those carrying variants outside this region. This poorer outcome was due to events occurring in patients carrying variants in the “critical neonatal region” (see Figure). These patients had the worse prognosis (p=0.000108, vs. the other groups). Furthermore, events in the non-critical neonatal region were similar to other missense variants located outside the neonatal region. There were no differences in the “neonatal region” when analyzing by gender. Conclusion In our cohort, the worse prognosis seen in patients carrying missense pathogenic or likely pathogenic variants in the “neonatal region” compared to the “non-neonatal region”, was due to events in patients carrying missense variants in a small subregion which we called the “critical-neonatal region” (exons 25 and 26). These patients had the worse prognosis, irrespective of gender. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Health in Code Figure 1. Neonatal region FBN1

scholarly journals CTNI-30. THERAPEUTIC EFFECTS OF RADIOTHERAPY WITH CONCOMITANT AND ADJUVANT TEMOZOLOMIDE VERSUS RADIOTHERAPY WITH CONCOMITANT TEMOZOLOMIDE ALONE IN CHILDREN WITH DIPG: A SINGLE-CENTER EXPERIENCE WITH 82 CASES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii49-ii49
Author(s):  
Mingyao Lai ◽  
Juan Li ◽  
Qingjun Hu ◽  
Jiangfen Zhou ◽  
Shaoqun Li ◽  
...  
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Disease Recurrence ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Hematological Toxicity ◽  
Therapeutic Effects ◽  
Single Center Experience ◽  
Adjuvant Temozolomide ◽  
Temozolomide Chemotherapy

Abstract OBJECTIVE To retrospectively analyze the therapeutic effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy with concomitant temozolomide alone for pediatric diffuse intrinsic pontine glioma (DIPG), and to evaluate the value of temozolomide in the treatment of pediatric DIPG. METHODS The clinical data of children with confirmed DIPG in Guangdong Sanjiu Brain Hospital between January 1, 2010 and December 30, 2019 were collected. The inclusive criteria included (1) receiving a total radiotherapy dose of 54 Gy in 27 fractions, (2) treated with concomitant temozolomide chemotherapy, and (3) with or without adjuvant temozolomide chemotherapy. RESULTS A total of 82 pediatric patients were eligible for the study, with a median age of 7 years (range 2–16 years). The median follow-up was 8.6 months (range 2–28 months) and the median survival time was 9.4 months. The median survival time of 66 patients treated with radiotherapy with concomitant and adjuvant temozolomide was 9.8 months, longer than 7.5 months of the other 16 patients treated with radiotherapy with concomitant temozolomide alone, with statistical differences (P=0.010). Moreover, bevacizumab and nimotuzumab didn’t bring survival benefits to patients with disease recurrence or progression. Hematological toxicity (Grade IV) was not found. CONCLUSION Radiotherapy with concomitant and adjuvant temozolomide prolongs the survival time of children with DIPG.

scholarly journals Survival after surgery among patients with cholangiocarcinoma in Northeast Thailand according to anatomical and morphological classification

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chaiwat Tawarungruang ◽  
Narong Khuntikeo ◽  
Nittaya Chamadol ◽  
Vallop Laopaiboon ◽  
Jaruwan Thuanman ◽  
...  
Keyword(s):  
Survival Rate ◽  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Cox Regression ◽  
Survival Rates ◽  
Care Program ◽  
Tumor Location ◽  
Northeast Thailand ◽  
Curative Surgery

Abstract Background Cholangiocarcinoma (CCA) has been categorized based on tumor location as intrahepatic (ICCA), perihilar (PCCA) or distal (DCCA), and based on the morphology of the tumor of the bile duct as mass forming (MF), periductal infiltrating (PI) or intraductal (ID). To date, there is limited evidence available regarding the survival of CCA among these different anatomical and morphological classifications. This study aimed to evaluate the survival rate and median survival time after curative surgery among CCA patients according to their anatomical and morphological classifications, and to determine the association between these classifications and survival. Methods This study included CCA patients who underwent curative surgery from the Cholangiocarcinoma Screening and Care Program (CASCAP), Northeast Thailand. The anatomical and morphological classifications were based on pathological findings after surgery. Survival rates of CCA and median survival time since the date of CCA surgery and 95% confidence intervals (CI) were calculated. Multiple cox regression was performed to evaluate factors associated with survival which were quantified by hazard ratios (HR) and their 95% CIs. Results Of the 746 CCA patients, 514 had died at the completion of the study which constituted 15,643.6 person-months of data recordings. The incidence rate was 3.3 per 100 patients per month (95% CI: 3.0–3.6), with median survival time of 17.8 months (95% CI: 15.4–20.2), and 5-year survival rate of 24.6% (95% CI: 20.7–28.6). The longest median survival time was 21.8 months (95% CI: 16.3–27.3) while the highest 5-year survival rate of 34.8% (95% CI: 23.8–46.0) occurred in the DCCA group. A combination of anatomical and morphological classifications, PCCA+ID, was associated with the longest median survival time of 40.5 months (95% CI: 17.9–63.0) and the highest 5-year survival rate of 42.6% (95% CI: 25.4–58.9). The ICCA+MF combination was associated with survival (adjusted HR: 1.45; 95% CI: 1.01–2.09; P = 0.013) compared to ICCA+ID patients. Conclusions Among patients receiving surgical treatment, those with PCCA+ID had the highest 5-year survival rate, which was higher than in groups classified by only anatomical characteristics. Additionally, the patients with ICCA+MF tended to have unfavorable surgical outcomes. Showed the highest survival association. Therefore, further investigations into CCA imaging should focus on patients with a combination of anatomical and morphological classifications.

scholarly journals Culex quinquefasciatus (Diptera: Culicidae) survivorship following the ingestion of bird blood infected with Haemoproteus sp. parasites

2021 ◽  
Author(s):  
Dayvion R. Adams ◽  
Andrew J. Golnar ◽  
Sarah A. Hamer ◽  
Michel A. Slotman ◽  
Gabriel L. Hamer
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Culex Quinquefasciatus ◽  
Median Survival Time ◽  
Bird Species ◽  
Protozoan Parasite ◽  
Cardinalis Cardinalis ◽  
Vector Borne ◽  
And Behavior ◽  
Negative Controls

AbstractArthropod vectors are frequently exposed to a diverse assemblage of parasites, but the consequence of these infections on their biology and behavior are poorly understood. We experimentally evaluated whether the ingestion of a common protozoan parasite of avian hosts (Haemoproteus spp.; Haemosporida: Haemoproteidae) impacted the survivorship of Culex quinquefasciatus (Say) (Diptera: Culicidae). Blood was collected from wild northern cardinals (Cardinalis cardinalis) in College Station, Texas, and screened for the presence of Haemoproteus spp. parasites using microscopic and molecular methods. Experimental groups of Cx. quinquefasciatus mosquitoes were offered Haemoproteus-positive cardinal blood through an artificial feeding apparatus, while control groups received Haemoproteus-negative cardinal blood or domestic canary (Serinus canaria domestica) blood. Culex quinquefasciatus mosquitoes exposed to Haemoproteus infected cardinal blood survived significantly fewer days than mosquitoes that ingested Haemoproteus-negative cardinal blood. The survival of mosquitoes fed on positive cardinal blood had a median survival time of 18 days post-exposure and the survival of mosquitoes fed on negative cardinal blood exceeded 50% across the 30 day observation period. Additionally, mosquitoes that fed on canary controls survived significantly fewer days than cardinal negative controls, with canary control mosquitoes having a median survival time of 17 days. This study further supports prior observations that Haemoproteus parasites can be pathogenic to bird-biting mosquitoes, and suggests that Haemoproteus parasites may indirectly suppress the transmission of co-circulating vector-borne pathogens by modulating vector survivorship. Our results also suggest that even in the absence of parasite infection, bloodmeals from different bird species can influence mosquito survivorship.

scholarly journals 3217 Catatonia, Delirium and Coma: Implications for Mortality

2019 ◽  
Vol 3 (s1) ◽  
pp. 37-37
Author(s):  
Jo Ellen Wilson ◽  
Sarasota Mihalko ◽  
Stephan Heckers ◽  
Pratik P. Pandharipande ◽  
Timothy D. Girard ◽  
...  
Keyword(s):  
Survival Time ◽  
Critically Ill ◽  
Median Survival ◽  
Critically Ill Patients ◽  
Median Survival Time ◽  
Rating Scale ◽  
Brain Dysfunction ◽  
Survival Times ◽  
Dsm 5 ◽  
Acute Brain Dysfunction

OBJECTIVES/SPECIFIC AIMS: Delirium, a form of acute brain dysfunction, characterized by changes in attention and alertness, is a known independent predictor of mortality in the Intensive Care Unit (ICU). We sought to understand whether catatonia, a more recently recognized form of acute brain dysfunction, is associated with increased 30-day mortality in critically ill older adults. METHODS/STUDY POPULATION: We prospectively enrolled critically ill patients at a single institution who were on a ventilator or in shock and evaluated them daily for delirium using the Confusion Assessment for the ICU and for catatonia using the Bush Francis Catatonia Rating Scale. Coma, was defined as a Richmond Agitation Scale score of −4 or −5. We used the Cox Proportional Hazards model predicting 30-day mortality after adjusting for delirium, coma and catatonia status. RESULTS/ANTICIPATED RESULTS: We enrolled 335 medical, surgical or trauma critically ill patients with 1103 matched delirium and catatonia assessments. Median age was 58 years (IQR: 48 - 67). Main indications for admission to the ICU included: airway disease or protection (32%; N=100) or sepsis and/or shock (25%; N=79. In the unadjusted analysis, regardless of the presence of catatonia, non-delirious individuals have the highest median survival times, while delirious patients have the lowest median survival time. Comparing the absence and presence of catatonia, the presence of catatonia worsens survival (Figure 1). In a time-dependent Cox model, comparing non-delirious individuals, holding catatonia status constant, delirious individuals have 1.72 times the hazards of death (IQR: 1.321, 2.231) while those with coma have 5.48 times the hazards of death (IQR: 4.298, 6.984). For DSM-5 catatonia scores, a 1-unit increase in the score is associated with 1.18 times the hazards of in-hospital mortality. Comparing two individuals with the same delirium status, an individual with a DSM-5 catatonia score of 0 (no catatonia) will have 1.178 times the hazard of death (IQR: 1.086, 1.278), while an individual with a score of 3 catatonia items (catatonia) present will have 1.63 times the hazard of death. DISCUSSION/SIGNIFICANCE OF IMPACT: Non-delirious individuals have the highest median survival times, while those who are comatose have the lowest median survival times after a critical illness, holding catatonia status constant. Comparing the absence and presence of catatonia, the presence of catatonia seems to worsen survival. Those individual who are both comatose and catatonic have the lowest median survival time.

MEDIAN SURVIVAL TIME

The Lancet ◽  
1982 ◽  
Vol 319 (8280) ◽  
pp. 1076
Author(s):  
P.M. Stell
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Median Survival Time

Repeated confidence intervals for the median survival time

Biometrika ◽  
1985 ◽  
Vol 72 (3) ◽  
pp. 619-625 ◽  
Author(s):  
CHRISTOPHER JENNISON ◽  
BRUCE W. TURNBULL
Keyword(s):  
Survival Time ◽  
Confidence Intervals ◽  
Median Survival ◽  
Median Survival Time

Phase II study with the combination etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer.

1989 ◽  
Vol 7 (9) ◽  
pp. 1310-1317 ◽  
Author(s):  
P Preusser ◽  
H Wilke ◽  
W Achterrath ◽  
U Fink ◽  
L Lenaz ◽  
...  
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Phase Ii ◽  
Metastatic Disease ◽  
Median Survival Time ◽  
Response Rate ◽  
Response Duration ◽  
World Health ◽  
Who Grade ◽  
Median Response

In this phase II multicenter trial, 67 evaluable patients with advanced measurable gastric carcinoma were treated with a combination of etoposide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (EAP). The overall response rate was 64%, including 21% complete responses (CRs). In 55 patients with metastatic disease, 31 responses (51%) including eight CRs (15%) were achieved. Responses were seen in all metastatic sites, but the response rate was lower in patients with peritoneal carcinomatosis. In 12 patients with locoregional disease, six CRs and six partial responses (PRs) were observed. Eight CRs (three and five in patients with metastatic and locoregional disease, respectively) were pathologically confirmed. The overall median response duration was 7 months; it was 16 months for patients achieving CR (22 months for pathologically confirmed CR [pCR]), and 6 months for PR. The median survival time for all patients was 9 months, for the patients who achieved CR 17 months, for pCR 23 months, and for PR 9.5 months. Median survival time for all patients with metastatic disease was 8 months, and for locoregional disease 12.5 months. Six patients (9%) (four local, two metastatic disease) were alive at 2 years, and four patients are alive and disease free at 35+ to 56+ months. Main toxicities were leukopenia and thrombocytopenia, with 64% of patients developing grade 3 to 4 myelosuppression and 12% severe infections. Nonhematologic toxicities of World Health Organization (WHO) grade 4 were not observed.

scholarly journals Promising potential of [177Lu]Lu-DOTA-folate to enhance tumor response to immunotherapy—a preclinical study using a syngeneic breast cancer model

2020 ◽  
Author(s):  
Patrycja Guzik ◽  
Klaudia Siwowska ◽  
Hsin-Yu Fang ◽  
Susan Cohrs ◽  
Peter Bernhardt ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Survival Time ◽  
Tumor Cells ◽  
Median Survival ◽  
Breast Tumor ◽  
Median Survival Time ◽  
Therapy Outcome ◽  
Minor Effect

Abstract Purpose It was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [177Lu]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy. Methods In vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [177Lu]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [177Lu]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 × 200 μg; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment. Results [177Lu]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [177Lu]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [177Lu]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls. Conclusion Application of [177Lu]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates.

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