scholarly journals Clinical relevance of TP53 hotspot mutations in high-grade serous ovarian cancers

2019 ◽  
Vol 122 (3) ◽  
pp. 405-412 ◽  
Author(s):  
Musaffe Tuna ◽  
Zhenlin Ju ◽  
Kosuke Yoshihara ◽  
Christopher I. Amos ◽  
Janos L. Tanyi ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Proportional Hazards ◽  
Expression Patterns ◽  
Cox Proportional Hazards ◽  
Response To Therapy ◽  
High Grade ◽  
Missense Mutations ◽  
Protein Levels ◽  
Hotspot Mutations ◽  
The Impact

Abstract Background Mutation of TP53 is the most frequent genetic alteration in high-grade serous ovarian cancer (HGSOC). The impact of hotspot mutations of TP53 and protein levels on patient outcomes in HGSOC has not been fully elucidated. Methods The study population (n = 791) comprised of HGSOC samples with TP53 mutation from TCGA and other publicly available data. Univariate and multivariate cox proportional hazards regression analyses were used to select variables that were correlated with patient survival. Results We assessed the effects of TP53 mutations based on type and individual hotspot mutations on patient outcomes in HGSOC. Only hotspot mutations were associated with outcomes. Three hotspot mutations: G266, Y163C, and R282, in aggregate were associated with a worsened overall and recurrence-free survival compared with other hotspot mutations (p < 0.0001 and p = 0.001), other non-hotspot missense mutations (p < 0.0001 and p = 0.008), truncated mutations (p < 0.0001 and p = 0.001), and all other mutations (p < 0.0001 and p = 0.001). Specific hotspot mutations were associated with different protein expression patterns consistent with different functions. Conclusions This study provides evidence that individual TP53 hotspot mutations have different impact on HGSOC patient outcomes and potentially TP53 function. Thus the status of particular TP53 aberrations could influence response to therapy and selection of therapeutic agents.

scholarly journals Impact of Pathological Stratification on the Clinical Outcomes of Advanced Well-Differentiated/Dedifferentiated Liposarcoma Treated with Trabectedin

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1453
Author(s):  
Chiara Fabbroni ◽  
Giovanni Fucà ◽  
Francesca Ligorio ◽  
Elena Fumagalli ◽  
Marta Barisella ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Proportional Hazards ◽  
Case Series ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Low Grade ◽  
High Grade ◽  
Retrospective Case ◽  
Well Differentiated ◽  
The Impact

Background. We previously showed that grading can prognosticate the outcome of retroperitoneal liposarcoma (LPS). In the present study, we aimed to explore the impact of pathological stratification using grading on the clinical outcomes of patients with advanced well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) treated with trabectedin. Patients: We included patients with advanced WDLPS and DDLPS treated with trabectedin at the Fondazione IRCCS Istituto Nazionale dei Tumori between April 2003 and November 2019. Tumors were categorized in WDLPS, low-grade DDLPS, and high-grade DDLPS according to the 2020 WHO classification. Patients were divided in two cohorts: Low-grade (WDLPS/low-grade DDLPS) and high-grade (high-grade DDLPS). Results: A total of 49 patients were included: 17 (35%) in the low-grade cohort and 32 (65%) in the high-grade cohort. Response rate was 47% in the low-grade cohort versus 9.4% in the high-grade cohort (logistic regression p = 0.006). Median progression-free survival (PFS) was 13.7 months in the low-grade cohort and 3.2 months in the high-grade cohort. Grading was confirmed as an independent predictor of PFS in the Cox proportional-hazards regression multivariable model (adjusted hazard ratio low-grade vs. high-grade: 0.45, 95% confidence interval: 0.22–0.94; adjusted p = 0.035). Conclusions: In this retrospective case series, sensitivity to trabectedin was higher in WDLPS/low-grade DDLPS than in high-grade DDLPS. If confirmed in larger series, grading could represent an effective tool to personalize the treatment with trabectedin in patients with advanced LPS.

scholarly journals Impact of Comorbidity, Race, and Marital Status in Men Referred for Prostate Biopsy with PSA >20 ng/mL: A Pilot Study in High-Risk Patients

2014 ◽  
Vol 2014 ◽  
pp. 1-5
Author(s):  
Zachary Klaassen ◽  
Roberto Muller ◽  
Qiang Li ◽  
Alexander J. Tatem ◽  
Sherita A. King ◽  
...  
Keyword(s):  
Marital Status ◽  
Prostate Biopsy ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
African American Men ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
High Grade ◽  
Multinomial Regression ◽  
The Impact

Objective. To assess the impact of comorbidity, race, and marital status on overall survival (OS) among men presenting for prostate biopsy with PSA >20 ng/mL. Methods. Data were reviewed from 2000 to 2012 and 78 patients were included in the cohort. We analyzed predictors of OS using a Cox proportional hazards model and the association between Charlson Comorbidity Index (CCI) score and PCa diagnosis or high-grade cancer using logistic regression and multinomial regression models, respectively. Results. The median age of patients was 62.5 (IQR 57–73) years. Median CCI was 3 (IQR 2–4), 69% of patients were African American men, 56% of patients were married, and 85% of patients had a positive biopsy. CCI (HR 1.52, 95% CI 1.19, 1.94), PSA (HR 1.62, 95% CI 1.09, 2.42), and Gleason sum (HR 2.04, 95% CI 1.17, 3.56) were associated with OS. CCI was associated with Gleason sum 7 (OR 4.06, 95% CI 1.04, 15.89) and Gleason sum 8–10 (OR 4.52, 95% CI 1.16, 17.54) PCa. Conclusions. CCI is an independent predictor of high-grade disease and worse OS among men with PCa. Race and marital status were not significantly associated with survival in this cohort. Patient comorbidity is an important component of determining the optimal approach to management of prostate cancer.

Age at Exposure to Parental Suicide and the Subsequent Risk of Suicide in Young People

Crisis ◽  
2018 ◽  
Vol 39 (1) ◽  
pp. 27-36 ◽  
Author(s):  
Kuan-Ying Lee ◽  
Chung-Yi Li ◽  
Kun-Chia Chang ◽  
Tsung-Hsueh Lu ◽  
Ying-Yeh Chen
Keyword(s):  
Young People ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Birth Registry ◽  
Data Set ◽  
Parental Suicide ◽  
The Impact ◽  
Age At Exposure

Abstract. Background: We investigated the age at exposure to parental suicide and the risk of subsequent suicide completion in young people. The impact of parental and offspring sex was also examined. Method: Using a cohort study design, we linked Taiwan's Birth Registry (1978–1997) with Taiwan's Death Registry (1985–2009) and identified 40,249 children who had experienced maternal suicide (n = 14,431), paternal suicide (n = 26,887), or the suicide of both parents (n = 281). Each exposed child was matched to 10 children of the same sex and birth year whose parents were still alive. This yielded a total of 398,081 children for our non-exposed cohort. A Cox proportional hazards model was used to compare the suicide risk of the exposed and non-exposed groups. Results: Compared with the non-exposed group, offspring who were exposed to parental suicide were 3.91 times (95% confidence interval [CI] = 3.10–4.92 more likely to die by suicide after adjusting for baseline characteristics. The risk of suicide seemed to be lower in older male offspring (HR = 3.94, 95% CI = 2.57–6.06), but higher in older female offspring (HR = 5.30, 95% CI = 3.05–9.22). Stratified analyses based on parental sex revealed similar patterns as the combined analysis. Limitations: As only register-­based data were used, we were not able to explore the impact of variables not contained in the data set, such as the role of mental illness. Conclusion: Our findings suggest a prominent elevation in the risk of suicide among offspring who lost their parents to suicide. The risk elevation differed according to the sex of the afflicted offspring as well as to their age at exposure.

Proliferation-dominant high-grade astrocytoma: survival benefit associated with extensive resection of FLAIR abnormality region

2020 ◽  
Vol 132 (4) ◽  
pp. 998-1005 ◽  
Author(s):  
Haihui Jiang ◽  
Yong Cui ◽  
Xiang Liu ◽  
Xiaohui Ren ◽  
Mingxiao Li ◽  
...  
Keyword(s):  
Survival Benefit ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Characteristic Curve ◽  
Extent Of Resection ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
High Grade ◽  
Extensive Resection ◽  
High Grade Astrocytoma

OBJECTIVEThe aim of this study was to investigate the relationship between extent of resection (EOR) and survival in terms of clinical, molecular, and radiological factors in high-grade astrocytoma (HGA).METHODSClinical and radiological data from 585 cases of molecularly defined HGA were reviewed. In each case, the EOR was evaluated twice: once according to contrast-enhanced T1-weighted images (CE-T1WI) and once according to fluid attenuated inversion recovery (FLAIR) images. The ratio of the volume of the region of abnormality in CE-T1WI to that in FLAIR images (VFLAIR/VCE-T1WI) was calculated and a receiver operating characteristic curve was used to determine the optimal cutoff value for that ratio. Univariate and multivariate analyses were performed to identify the prognostic value of each factor.RESULTSBoth the EOR evaluated from CE-T1WI and the EOR evaluated from FLAIR could divide the whole cohort into 4 subgroups with different survival outcomes (p < 0.001). Cases were stratified into 2 subtypes based on VFLAIR/VCE-T1WIwith a cutoff of 10: a proliferation-dominant subtype and a diffusion-dominant subtype. Kaplan-Meier analysis showed a significant survival advantage for the proliferation-dominant subtype (p < 0.0001). The prognostic implication has been further confirmed in the Cox proportional hazards model (HR 1.105, 95% CI 1.078–1.134, p < 0.0001). The survival of patients with proliferation-dominant HGA was significantly prolonged in association with extensive resection of the FLAIR abnormality region beyond contrast-enhancing tumor (p = 0.03), while no survival benefit was observed in association with the extensive resection in the diffusion-dominant subtype (p=0.86).CONCLUSIONSVFLAIR/VCE-T1WIis an important classifier that could divide the HGA into 2 subtypes with distinct invasive features. Patients with proliferation-dominant HGA can benefit from extensive resection of the FLAIR abnormality region, which provides the theoretical basis for a personalized resection strategy.

The Efficacy of Etoposide-Based Therapy in Adult Secondary Hemophagocytic Lymphohistiocytosis

2021 ◽  
pp. 1-9
Author(s):  
Leonard Naymagon ◽  
Douglas Tremblay ◽  
John Mascarenhas
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Proportional Hazards ◽  
Multivariable Analysis ◽  
Cox Proportional Hazards ◽  
Rank Test ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Significant Difference ◽  
The Impact

Data supporting the use of etoposide-based therapy in hemophagocytic lymphohistiocytosis (HLH) arise largely from pediatric studies. There is a lack of comparable data among adult patients with secondary HLH. We conducted a retrospective study to assess the impact of etoposide-based therapy on outcomes in adult secondary HLH. The primary outcome was overall survival. The log-rank test was used to compare Kaplan-Meier distributions of time-to-event outcomes. Multivariable Cox proportional hazards modeling was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Ninety adults with secondary HLH seen between January 1, 2009, and January 6, 2020, were included. Forty-two patients (47%) received etoposide-based therapy, while 48 (53%) received treatment only for their inciting proinflammatory condition. Thirty-three patients in the etoposide group (72%) and 32 in the no-etoposide group (67%) died during follow-up. Median survival in the etoposide and no-etoposide groups was 1.04 and 1.39 months, respectively. There was no significant difference in survival between the etoposide and no-etoposide groups (log-rank <i>p</i> = 0.4146). On multivariable analysis, there was no association between treatment with etoposide and survival (HR for death with etoposide = 1.067, 95% CI: 0.633–1.799, <i>p</i> = 0.8084). Use of etoposide-based therapy was not associated with improvement in outcomes in this large cohort of adult secondary HLH patients.

scholarly journals Rates and Correlates of Short Term Virologic Response among Treatment-Naïve HIV-Infected Children Initiating Antiretroviral Therapy in Ethiopia: A Multi-Center Prospective Cohort Study

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 161
Author(s):  
Birkneh Tilahun Tadesse ◽  
Adugna Chala ◽  
Jackson Mukonzo ◽  
Tolosssa Eticha Chaka ◽  
Sintayehu Tadesse ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Viral Load ◽  
Plasma Viral Load ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Virological Suppression ◽  
Virologic Suppression ◽  
Hiv Drug Resistance ◽  
Treatment Naïve ◽  
The Impact

There is limited data on virologic outcome and its correlates among HIV-infected children in resource-limited settings. We investigated rate and correlates of virologic outcome among treatment naïve HIV-infected Ethiopian children initiating cART, and were followed prospectively at baseline, 8, 12, 24 and 48 weeks using plasma viral load, clinical examination, laboratory tests and pretreatment HIV drug resistance (PDR) screening. Virologic outcome was assessed using two endpoints–virological suppression defined as having “undetectable” plasma viral load < 150 RNA copies/mL, and rebound defined as viral load ≥150 copies/mL after achieving suppression. Cox Proportional Hazards Regression was employed to assess correlates of outcome. At the end of follow up, virologic outcome was measured for 110 participants. Overall, 94(85.5%) achieved virological suppression, of which 36(38.3%) experienced virologic rebound. At 48 weeks, 9(8.2%) children developed WHO-defined virological treatment failure. Taking tenofovir-containing regimen (Hazard Ratio (HR) 3.1-[95% confidence interval (95%CI) 1.0–9.6], p = 0.049) and absence of pretreatment HIV drug resistance (HR 11.7-[95%CI 1.3–104.2], p = 0.028) were independently associated with earlier virologic suppression. In conclusion, PDR and cART regimen type correlate with rate of virologic suppression which was prominent during the first year of cART initiation. However, the impact of viral rebound in 38.3% of the children needs evaluation.

Impact of KRAS mutational status on outcomes in patients with pancreatic cancer (PDAC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4142-4142
Author(s):  
Lucy Xiaolu Ma ◽  
Gun Ho Jang ◽  
Amy Zhang ◽  
Robert Edward Denroche ◽  
Anna Dodd ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Advanced Disease ◽  
Cox Proportional Hazards ◽  
Prognostic Impact ◽  
First Line ◽  
Kras Mutations ◽  
Kaplan Meier ◽  
Mutational Status ◽  
Translational Research Program ◽  
The Impact

4142 Background: KRAS mutations (m) (KRASm) are present in over 90% of pancreatic adenocarcinomas (PDAC) with a predominance of G12 substitutions. KRAS wildtype (WT) PDAC relies on alternate oncogenic drivers, and the prognostic impact of these remains unknown. We evaluated alterations in WT PDAC and explored the impact of specific KRASm and WT status on survival. Methods: WGS and RNAseq were performed on 570 patients (pts) ascertained through our translational research program from 2012-2021, of which 443 were included for overall survival (OS) analyses. This included 176 pts with resected and 267 pts with advanced PDAC enrolled on the COMPASS trial (NCT02750657). The latter cohort underwent biopsies prior to treatment with first line gemcitabine-nab-paclitaxel or mFOLFIRINOX as per physician choice. The Kaplan-Meier and Cox proportional hazards methods were used to estimate OS. Results: KRAS WT PDAC (n = 52) represented 9% of pts, and these cases trended to be younger than pts with KRASm (median age 61 vs 65 years p = 0.1). In resected cases, the most common alterations in WT PDAC (n = 23) included GNASm (n = 6) and BRAFm/fusions (n = 5). In advanced WT PDAC (n = 27), alterations in BRAF (n = 11) and ERBB2/3/4 (n = 6) were most prevalent. Oncogenic fusions (NTRK, NRG1, BRAF/RAF, ROS1, others) were identified in 9 pts. The BRAF in-frame deletion p.486_491del represented the most common single variant in WT PDAC, with organoid profiling revealing sensitivity to both 3rd generation BRAF inhibitors and MEK inhibition. In resected PDAC, multivariable analyses documented higher stage (p = 0.043), lack of adjuvant chemotherapy (p < 0.001), and the KRAS G12D variant (p = 0.004) as poor prognostic variables. In advanced disease, neither WT PDAC nor KRAS specific alleles had an impact on prognosis (median OS WT = 8.5 mths, G12D = 8.2, G12V = 10.0, G12R = 12.0, others = 9.2, p = 0.73); the basal-like RNA subtype conferred inferior OS (p < 0.001). A targeted therapeutic approach following first line chemotherapy was undertaken in 10% of pts with advanced PDAC: MMRd (n = 1), homologous recombination deficiency (HRD) (n = 19), KRASG12C (n = 1), CDK4/6 amplification (n = 3), ERBB family alterations (n = 2), BRAF variants (n = 2). OS in this group was superior (14.7 vs 8.8 mths, p = 0.04), mainly driven by HRD-PDAC where KRASm were present in 89%. Conclusions: In our dataset, KRAS G12D is associated with inferior OS in resected PDAC, however KRAS mutational status was not prognostic in advanced disease. This suggests that improved OS in the WT PDAC population can only be achieved if there is accelerated access to targeted drugs for pts.

scholarly journals Age- and Sex-Specific In-Hospital Mortality after Myocardial Infarction in Routine Clinical Practice

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Chizobam Ani ◽  
Deyu Pan ◽  
David Martins ◽  
Bruce Ovbiagele
Keyword(s):  
Myocardial Infarction ◽  
Proportional Hazards ◽  
Length Of Hospital Stay ◽  
Mortality Rates ◽  
Cox Proportional Hazards ◽  
Mortality Trends ◽  
Male Mortality ◽  
Co Morbidity ◽  
The Impact ◽  
Age And Sex

Background. Literature regarding the influence of age/sex on mortality trends for acute myocardial infarction (AMI) hospitalizations is limited to hospitals participating in voluntary AMI registries.Objective. Evaluate the impact of age and sex on in-hospital AMI mortality using a nationally representative hospital sample.Methods. Secondary data analysis using AMI hospitalizations identified from the Nationwide-Inpatient-Sample (NIS). Descriptive and Cox proportional hazards analysis explored mortality trends by age and sex from 1997–2006 while adjusting for the influence of, demographics, co-morbidity, length of hospital stay and hospital characteristics.Results. From 1997–2006, in-hospital AMI mortality rates decreased across time in all subgroups (), except for males aged <55 years. The greatest decline was observed in females aged <55 years, compared to similarly aged males, mortality outcomes were poorer in 1997-1998 (RR 1.47, 95% CI  =  1.30–1.66), when compared with 2005-2006 (RR 1.03, 95% CI  =  0.90–1.18), adjusted value for trend demonstrated a statistically significant decline in the relative AMI mortality risk for females when compared with males (<0.001).Conclusion. Over the last decade, in-hospital AMI mortality rates declined for every age/sex group except males <55 years. While AMI female-male mortality disparity has narrowed, some room for improvement remains.

scholarly journals Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Augusto Di Castelnuovo ◽  
Simona Costanzo ◽  
Andrea Antinori ◽  
Nausicaa Berselli ◽  
Lorenzo Blandi ◽  
...  
Keyword(s):  
Observational Study ◽  
Propensity Scores ◽  
Proportional Hazards ◽  
Real Life ◽  
Cox Proportional Hazards ◽  
Event Analysis ◽  
Multicenter Observational Study ◽  
Protein Levels ◽  
Cox Proportional Hazards Models ◽  
Increased Risk

Background: Protease inhibitors have been considered as possible therapeutic agents for COVID-19 patients.Objectives: To describe the association between lopinavir/ritonavir (LPV/r) or darunavir/cobicistat (DRV/c) use and in-hospital mortality in COVID-19 patients.Study Design: Multicenter observational study of COVID-19 patients admitted in 33 Italian hospitals. Medications, preexisting conditions, clinical measures, and outcomes were extracted from medical records. Patients were retrospectively divided in three groups, according to use of LPV/r, DRV/c or none of them. Primary outcome in a time-to event analysis was death. We used Cox proportional-hazards models with inverse probability of treatment weighting by multinomial propensity scores.Results: Out of 3,451 patients, 33.3% LPV/r and 13.9% received DRV/c. Patients receiving LPV/r or DRV/c were more likely younger, men, had higher C-reactive protein levels while less likely had hypertension, cardiovascular, pulmonary or kidney disease. After adjustment for propensity scores, LPV/r use was not associated with mortality (HR = 0.94, 95% CI 0.78 to 1.13), whereas treatment with DRV/c was associated with a higher death risk (HR = 1.89, 1.53 to 2.34, E-value = 2.43). This increased risk was more marked in women, in elderly, in patients with higher severity of COVID-19 and in patients receiving other COVID-19 drugs.Conclusions: In a large cohort of Italian patients hospitalized for COVID-19 in a real-life setting, the use of LPV/r treatment did not change death rate, while DRV/c was associated with increased mortality. Within the limits of an observational study, these data do not support the use of LPV/r or DRV/c in COVID-19 patients.

scholarly journals Nephrectomy Delay of More than 10 Weeks from Diagnosis Is Associated with Decreased Overall Survival in pT3 RCC

2021 ◽  
Vol 8 (2) ◽  
pp. 27-33
Author(s):  
Jiping Zeng ◽  
Ken Batai ◽  
Benjamin Lee
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Logistic Regression ◽  
Proportional Hazards ◽  
Surgical Margin ◽  
Cox Proportional Hazards ◽  
Cancer Center ◽  
Integrated Network ◽  
Factors Associated ◽  
The Impact

In this study, we aimed to evaluate the impact of surgical wait time (SWT) on outcomes of patients with renal cell carcinoma (RCC), and to investigate risk factors associated with prolonged SWT. Using the National Cancer Database, we retrospectively reviewed the records of patients with pT3 RCC treated with radical or partial nephrectomy between 2004 and 2014. The cohort was divided based on SWT. The primary out-come was 5-year overall survival (OS). Logistic regression analysis was used to investigate the risk factors associated with delayed surgery. Cox proportional hazards models were fitted to assess relations between SWT and 5-year OS after adjusting for confounding factors. A total of 22,653 patients were included in the analysis. Patients with SWT > 10 weeks had higher occurrence of upstaging. Using logistic regression, we found that female patients, African-American or Spanish origin patients, treatment in academic or integrated network cancer center, lack of insurance, median household income of <$38,000, and the Charlson–Deyo score of ≥1 were more likely to have prolonged SWT. SWT > 10 weeks was associated with decreased 5-year OS (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.15–1.33). This risk was not markedly attenuated after adjusting for confounding variables, including age, gender, race, insurance status, Charlson–Deyo score, tumor size, and surgical margin status (adjusted HR, 1.13; 95% CI, 1.04–1.24). In conclusion, the vast majority of patients underwent surgery within 10 weeks. There is a statistically significant trend of increasing SWT over the study period. SWT > 10 weeks is associated with decreased 5-year OS.

Sign in / Sign up

Export Citation Format

Share Document