scholarly journals CTLA-4 Genetic Variants Predict Survival in Patients with Sepsis

2019 ◽  
Vol 8 (1) ◽  
pp. 70 ◽  
Author(s):  
Caspar Mewes ◽  
Benedikt Büttner ◽  
José Hinz ◽  
Ayelet Alpert ◽  
Aron-Frederik Popov ◽  
...  

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a coinhibitory checkpoint protein expressed on the surface of T cells. A recent study by our working group revealed that the rs231775 single nucleotide polymorphism (SNP) in the CTLA-4 gene was associated with the survival of patients with sepsis and served as an independent prognostic variable. To further investigate the impact of CTLA-4 genetic variants on sepsis survival, we examined the effect of two functional SNPs, CTLA-4 rs733618 and CTLA-4 rs3087243, and inferred haplotypes, on the survival of 644 prospectively enrolled septic patients. Kaplan–Meier survival analysis revealed significantly lower 90-day mortality for rs3087243 G allele carriers (n = 502) than for AA-homozygous (n = 142) patients (27.3% vs. 40.8%, p = 0.0024). Likewise, lower 90-day mortality was observed for TAA haplotype-negative patients (n = 197; compound rs733618 T/rs231775 A/rs3087243 A) than for patients carrying the TAA haplotype (n = 447; 24.4% vs. 32.9%, p = 0.0265). Carrying the rs3087243 G allele hazard ratio (HR): 0.667; 95% confidence interval (CI): 0.489–0.909; p = 0.0103) or not carrying the TAA haplotype (HR: 0.685; 95% CI: 0.491–0.956; p = 0.0262) remained significant covariates for 90-day survival in the multivariate Cox regression analysis and thus served as independent prognostic variables. In conclusion, our findings underscore the significance of CTLA-4 genetic variants as predictors of survival of patients with sepsis.

2020 ◽  
Vol 21 (21) ◽  
pp. 8318
Author(s):  
Caspar Mewes ◽  
Tessa Alexander ◽  
Benedikt Büttner ◽  
José Hinz ◽  
Ayelet Alpert ◽  
...  

Background: Previous studies have reported the fundamental role of immunoregulatory proteins in the clinical phenotype and outcome of sepsis. This study investigated two functional single nucleotide polymorphisms (SNPs) of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), which has a negative stimulatory function in the T cell immune response. Methods: Patients with sepsis (n = 712) were prospectively enrolled from three intensive care units (ICUs) at the University Medical Center Goettingen since 2012. All patients were genotyped for the TIM-3 SNPs rs1036199 and rs10515746. The primary outcome was 28-day mortality. Disease severity and microbiological findings were secondary endpoints. Results: Kaplan–Meier survival analysis demonstrated a significantly lower 28-day mortality for TIM-3 rs1036199 AA homozygous patients compared to C-allele carriers (18% vs. 27%, p = 0.0099) and TIM-3 rs10515746 CC homozygous patients compared to A-allele carriers (18% vs. 26%, p = 0.0202). The TIM-3 rs1036199 AA genotype and rs10515746 CC genotype remained significant predictors for 28-day mortality in the multivariate Cox regression analysis after adjustment for relevant confounders (adjusted hazard ratios: 0.67 and 0.70). Additionally, patients carrying the rs1036199 AA genotype presented more Gram-positive and Staphylococcus epidermidis infections, and rs10515746 CC homozygotes presented more Staphylococcus epidermidis infections. Conclusion: The studied TIM-3 genetic variants are associated with altered 28-day mortality and susceptibility to Gram-positive infections in sepsis.


2021 ◽  
Author(s):  
Guo-Shuai Duo ◽  
Ji-Long Feng ◽  
En-Yi Zhang ◽  
Li-jun Wang

Abstract BackgroundTo evaluate the impact of postoperative radiotherapy (PORT) on survival in olfactory neuroblastoma (ONB) patients with different stages. MethodsPatients with ONB were selected in the Surveillance, Epidemiology, and End Results (SEER) database during 2004–2016. Survival analyses were performed using Kaplan Meier (K-M) method, Cox regression analysis, and competing risk model. ResultsA total of 513 patients were included in the study. Univariate and multivariate analysis results demonstrated that PORT was not an independent prognostic factor for overall survival (OS) of patients with modified Kadish stage A and B (p=0.699 and p=0.248, respectively). For C and D cases, patients who underwent PORT had significantly better OS than those who did not undergo PORT (p=0.03 and p< 0.0001, respectively). K-M curves illustrated that the 5- and 10-year OS rates according to radiotherapy (PORT vs. non-PORT) were 70.4% vs. 85.3% and 56.8% vs. 68.2% in stage C, respectively. For stage D patients, the 5-year OS rates were 42.6% and 70.7%, and 10-year OS rates were 29.5% and 53.4% in the PORT and non-PORT groups, respectively. The competitive risk model revealed that the 5-year cancer-specific cumulative mortality incidence decreased by 26.6% and the 10-year mortality incidence by 41.4% in patients with stage C who were treated using PORT; meanwhile, for patients with stage D who were treated with PORT, the 5- and 10-year mortality incidence reduced by 35.3% and 42.6%, respectively. Chemotherapy was not related to the prognosis of ONB (all p> 0.05).ConclusionsOur results indicate that PORT improved survival outcomes in ONB patients with modified Kadish stage C and D. However, for modified Kadish stage A and B cases, PORT may not affect survival. Chemotherapy was not recommended for ONB patients until more studies determine the role of chemotherapy.


2020 ◽  
Vol 18 (5) ◽  
pp. 575-581
Author(s):  
Omar Abdel-Rahman ◽  
Hatim Karachiwala ◽  
Jacob C. Easaw

Background: This study assessed the patterns of opioid use among patients with advanced gastrointestinal cancers who were included in 8 clinical trials and evaluated the impact of opioid use on survival outcomes of included patients. Methods: Deidentified datasets from 8 clinical trials evaluating first-line systemic treatment of advanced gastrointestinal cancers were accessed from the Project Data Sphere platform (ClinicalTrial.gov identifiers: NCT01124786, NCT00844649, NCT00290966, NCT00678535, NCT00699374, NCT00272051, NCT00305188, and NCT00384176). These trials evaluated patients with pancreatic carcinoma, gastric carcinoma, hepatocellular carcinoma (HCC), and colorectal carcinoma. Multivariable logistic regression analysis was used to evaluate factors predicting the use of opioids. Kaplan-Meier survival estimates were used to compare survival outcomes in each disease entity among patients who did or did not receive opioid treatment. Multivariable Cox regression analysis was then used to further assess the impact of opioid use on survival outcomes in each disease entity. Results: A total of 3,441 participants were included in the current analysis. The following factors predicted a higher probability of opioid use within logistic regression analysis: younger age at diagnosis (odds ratio [OR], 0.990; 95% CI, 0.984–0.997; P=.004), nonwhite race (OR for white vs nonwhite, 0.749; 95% CI, 0.600–0.933; P=.010), higher ECOG score (OR for 1 vs 0, 1.751; 95% CI, 1.490–2.058; P<.001), and pancreatic primary site (OR for colorectal vs pancreatic, 0.241; 95% CI, 0.198–0.295; P<.001). Use of opioids was consistently associated with worse overall survival (OS) in Kaplan-Meier survival estimates of each disease entity (P=.008 for pancreatic cancer; P<.001 for gastric cancer, HCC, and colorectal cancer). In multivariable Cox regression analysis, opioid use was associated with worse OS among patients with pancreatic cancer (hazard ratio [HR], 1.245; 95% CI, 1.063–1.459; P=.007), gastric cancer (HR, 1.725; 95% CI, 1.403–2.122; P<.001), HCC (HR, 1.841; 95% CI, 1.480–2.290; P<.001), and colorectal cancer (HR, 1.651; 95% CI, 1.380–1.975; P<.001). Conclusions: Study findings suggest that opioid use is consistently associated with worse OS among patients with different gastrointestinal cancers. Further studies are needed to understand the underlying mechanisms of this observation and its potential implications.


2018 ◽  
Vol 22 (6) ◽  
pp. 47-55
Author(s):  
V. A. Dobronravov ◽  
A. O. Mukhametdinova ◽  
M. S. Khrabrova ◽  
A. Nabokow ◽  
H. -J. Gröne ◽  
...  

THE OBJECTIVEof the study was to assess the impact of the count of interstitial CD3+, CD68+ and CD20+ cells on long-term prognosis of renal allograft (RA).PATIENTS AND METHODS.86 RA recipients with biopsy-proven according to the Banff 2013- 2017 criteria glomerulitis were enrolled in this retrospective study. The patients were subdivided into the following groups: 1) isolated glomerulitis with negative donor-specific antibodies (DSA) at the biopsy (n=53); 2) glomerulitis with positive DSA (n=22); 3) glomerulitis with undetermined DSA (n=11). Quantitative assay of interstitial positive cells was performed after immunohistochemical staining for CD68+, CD3+, CD20+. The Kaplan-Meier method and Cox proportional hazards regression model were used for the analysis of the relationship between interstitial CD3+, CD68+, CD20+ cells and risk of RA loss.RESULTS.CD68+ and CD3+ cells prevailed in interstitium in RA glomerulitis. CD20+ infiltrates were found in 60% of cases. CD20+ cells tended to form infiltrates, in 9 cases these infiltrates reached large sizes (≥ 50 CD20+ lymphocytes) and formed nodular structures. There was no difference in the count of interstitial CD3+ and CD68+ cells and in the presence of CD20+ infiltrates between DSA subgroups. Interstitial CD68+ ≥ 5 cells per field of view (FOV) (x400) and CD3+ ≥ 8 cells per FOV (x400), as well as the presence of large CD20+ infiltrates were associated with a lower RA survival (plog-rank < 0,05). Interstitial CD68+ (≥ 5 cells/FOV), CD3 + (≥ 8 cells/FOV) and the presence of large CD20+ interstitial infiltrates were independently associated with the risk of RA loss in the multivariable Cox regression analysis adjusted for DSA, cold and warm ischemia time (p < 0.05). CONCLUSION. Grade of interstitial infiltration by CD68+, CD3+ and CD20+ cells in RA glomerulitis could be independent predictor of RA loss.


2021 ◽  
Author(s):  
Omar Abdel-Rahman ◽  
Sheryl L. Koski

Objective: To assess the survival differences between cisplatin/etoposide versus carboplatin/etoposide chemotherapy regimens in the management of extra-pulmonary neuroendocrine carcinomas (NECs). Methods: Administrative cancer care databases in the province of Alberta, Canada were reviewed, and patients with extra-pulmonary NECs (including those with small cell and large cell neuroendocrine carcinomas) who were treated with either cisplatin/ etoposide or carboplatin/ etoposide, 2004-2019, were reviewed. Kaplan-Meier survival estimates were used to compare the survival outcomes according to the type of platinum agent, and multivariable Cox regression analysis was used to assess the impact of the type of platinum agent on overall survival outcomes. Results: A total of 263 eligible patients were included in this analysis. These include 176 patients who received cisplatin/ etoposide and 87 patients who received carboplatin/etoposide. Using Kaplan-Meier survival estimates, patients treated with cisplatin have better overall survival compared to patients treated with carboplatin (P=0.005). Multivariable Cox regression analysis suggested that the following factors were associated with worse overall survival: higher Charlson comorbidity index (HR: 1.17; 95% CI: 1.05-1.30), gastrointestinal primary site (HR: 1.55; 95% CI: 1.12-2.14), stage IV disease (HR: 1.75; 95% CI: 1.28-2.38) and use of carboplatin (HR: 1.40; 95% CI: 1.02-1.92). Conclusions: The current study suggested that cisplatin/etoposide might be associated with better overall survival compared to carboplatin/etoposide among patients with extra-pulmonary NECs. It is unclear if this is related to differences in inherent responsiveness to the two platinum agents, or due to differences in comorbidity burden between the two treatment groups.


2020 ◽  
Author(s):  
Gang Wang ◽  
Ling Wen Wang ◽  
Jie Hai Jin ◽  
min Hong Dong ◽  
wei Wei Chen ◽  
...  

Abstract Background: To evaluate the impact of primary tumor radiotherapy on survival in patients with unresectable metastatic rectal or rectosigmoid cancer. Methods: Form September 2008 to September 2017, 350 patients with unresectable metastatic rectal or rectosigmoid cancer were retrospectively reviewed in our center. All patients received at least 4 cycles of chemotherapy, and were divided into two groups according to with primary tumor radiotherapy or without. 163 patients received primary tumor radiotherapy, and the median radiation dose was 56.69Gy(50.4-60). Survival curves were estimated from the Kaplan–Meier procedure to roughly compare survival among two groups. Subsequently, 18-month survival was used as the outcome variable for this study. This study mainly evaluated the impact of primary tumor radiotherapy on survival of these patients through a series of multivariate Cox regression analyses after propensity score matching (PSM). Results: The median follow-up time was 21 months. All 350 patients received a median of 7 cycles of chemotherapy (range 4-12), 163 (46.67%) patients received primary tumor radiotherapy for local symptoms. The Kaplan–Meier survival curves showed a significant overall survival (OS) advantage for primary tumor radiotherapy group to without radiotherapy (20.07 vs 17.33 months; P=0.002). In this study, multivariate Cox regression analysis after adjusted covariates, multivariate Cox regression analysis after PSM, and inverse probability of treatment weighting (IPTW) analysis and propensity score (PS)-adjusted model analysis consistently showed that primary tumor radiotherapy could effectively reduce the risk of death for these patients at 18 months (HR: 0.62, 95% CI 0.40-0.98; HR:0.79, 95% CI:0.93-1.45; HR: 0.70, 95% CI 0.55-0.99 and HR: 0.74, 95% CI:0.59-0.94). Conclusion: Compared with patients with stage IV rectal or rectosigmoid cancer who did not receive primary tumor radiotherapy, received primary tumor radiotherapy reduced the risk of death in these patients. The radical doses(59.4Gy/ 33 fractions or 60Gy/ 30 fractions) of radiation for primary tumors might be considered for unresectable metastatic rectal or rectosigmoid cancer, not just for relieve symptoms. Keywords: Stage IV Rectal cancer, primary tumor radiotherapy, propensity score matching.


2021 ◽  
Vol 11 ◽  
Author(s):  
Dong-Dong Jia ◽  
Yanling Niu ◽  
Honglin Zhu ◽  
Sizhen Wang ◽  
Tonghui Ma ◽  
...  

Combination immunotherapy can overcome the limited objective response rates of PD-1 blockade. Interferon alpha (IFN-α) has been proven to be effective in modulating immune responses and may enhance the clinical responses to PD-1 blockade. According to clinical practice guidelines, IFN-α was recommended as adjuvant therapy for stage IIB/C melanoma patients. However, the impact of prior IFN-α therapy on the efficacy of subsequent PD-1 blockade in melanoma has not been previously reported. Therefore, we performed a retrospective analysis for melanoma patients and addressed whether prior IFN-α therapy enhanced adjuvant pembrolizumab as later-line treatment. Fifty-six patients with resectable stage III/IV melanoma who received adjuvant therapy with pembrolizumab were retrospectively enrolled in this study. Notably, 25 patients received adjuvant pegylated IFN-α (PEG-IFN-α) in the prior line of treatment while 31 patients did not receive prior PEG-IFN-α therapy. Cox regression analysis showed that prior PEG-IFN-α therapy was associated with the efficacy of later-line adjuvant pembrolizumab (hazard ratio=0.37, 95% CI 0.16-0.89; P = 0.026). The recurrence rates after treatment with adjuvant pembrolizumab were significantly reduced in the prior PEG-IFN-α group (P &lt; 0.001). The Kaplan-Meier analysis also showed that recurrence-free survival (RFS) after adjuvant pembrolizumab therapy was prolonged by prior PEG-IFN-α treatment (median RFSPem 8.5 months vs. 4.5 months; P = 0.0372). These findings indicated that prior PEG-IFN-α could enhance the efficacy of adjuvant pembrolizumab. The long-lasting effects of PEG-IFN-α provide a new rationale for designing combination or sequential immunotherapy.


2020 ◽  
Author(s):  
Chao Guo ◽  
Qian-qian Ju ◽  
Chun-xia Zhang ◽  
Ming Gong ◽  
Zhen-ling Li ◽  
...  

Abstract Background HOXA family genes were crucial transcription factors involving cell proliferation and apoptosis. While few studies have focused on HOXA10 in AML. We aimed to investigate the prognostic significance of HOXA10. Methods We downloaded datasets from GEO and BeatAML database, to compare HOXA expression level between AML patients and controls. Kaplan-Meier curves were used to estimate the impact of HOXA10 expression on AML survival. The differentially expressed genes, miRNAs, lncRNAs and methylated regions between HOXA10-high and -low groups were obtained using R (version 3.6.0). Accordingly, the gene set enrichment analysis (GSEA) was accomplished using MSigDB database. Moreover, the regulatory TFs/microRNAs/lncRNAs of HOXA10 were identified. A LASSO-Cox model fitted OS to clinical and HOXA10-associated genetic variables by glmnet package. Results HOXA10 was overexpressed in AML patients than that in controls. The HOXA10-high group is significantly associated with shorter OS and DFS. A total of 1219 DEGs, 131 DEmiRs, 282 DElncRs were identified to be associated with HOXA10. GSEA revealed that 12 suppressed and 3 activated pathways in HOXA10-high group. Furthermore, the integrated regulatory network targeting HOXA10 was established. The LASSO-Cox model fitted OS to AML-survival risk scores, which included age, race, molecular risk, expression of IKZF2/LINC00649/LINC00839/FENDRR and has-miR-424-5p. The time dependent ROC indicated a satisfying AUC (1-year AUC 0.839, 3-year AUC 0.871 and 5-year AUC 0.813). Conclusions Our study identified HOXA10 overexpression as an adverse prognostic factor for AML. The LASSO-COX regression analysis revealed novel prediction model of OS with superior diagnostic utility.


2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 388-388 ◽  
Author(s):  
Andrea Wang-Gillam ◽  
Richard Hubner ◽  
Beloo Mirakhur ◽  
Floris A de Jong ◽  
Bruce Belanger ◽  
...  

388 Background: In NAPOLI-1 (NCT01494506), a randomized phase 3 study in patients with metastatic pancreatic cancer previously treated with gemcitabine-based therapy, nal-IRI+5-FU/LV improved overall survival (OS; primary endpoint) vs 5-FU/LV (6.1 mos vs 4.2 mos; HR = 0·67, 95% CI 0.49–0.92; P = 0.012). This exploratory analysis examined the impact of dose modifications or delays used to manage adverse events (AEs) on OS. The study protocol allowed ≤2 dose reductions for nal-IRI and 5-FU and for up to 3 weeks. Methods: Patient who had a dose delay or reduction within the planned first 6 weeks of the study were included. Delays were defined as any delay in dosing > 3 days from target dosing date and dose reductions were defined as any reduction in dose from initial administered dose. OS was compared within the nal-IRI+5-FU/LV arm and with the 5-FU/LV arm. Comparisons were made using the cohort of 5-FU/LV and nal-IRI+5-FU/LV patients enrolled under protocol version 2. Median OS was based on Kaplan-Meier estimates and Cox regression analysis was used to calculate HRs. Results: More patients in the nal-IRI+5-FU/LV treatment group experienced AEs that required dose delay and/or reduction than in the 5-FU/LV treatment group (62% vs 33%). Within the nal-IRI+5-FU/LV arm, median OS was numerically but not significantly different between patients who did (n = 34) vs did not (n = 83) have a dose reduction (9.3 vs 5.4 mos; HR = 0.66 [95% CI 0.43, 1.01]) and for those who did (n = 49) vs did not (n = 68) have a dose delay (8.4 vs 5.6 mos; 0.82 [95% CI 0.56, 1.23]). Between treatment arms, OS was greater in the nal-IRI+5-FU/LV arm regardless of dose delay or reduction (Table). Conclusions: Dose modifications in the nal-IRI+5-FU/LV arm did not significantly impact OS compared with those who did not need a dose modification, and OS remained greater than in 5-FU/LV-treated patients. This suggests that appropriate dose modification of nal-IRI+5-FU/LV for AEs may not adversely affect outcomes. Clinical trial information: NCT01494506. [Table: see text]


2021 ◽  
Vol 20 ◽  
pp. 153473542199123
Author(s):  
Jun-Yong Cha ◽  
Jae-Sung Park ◽  
Yong-Kil Hong ◽  
Sin-Soo Jeun ◽  
Stephen Ahn

Introduction: The impact of obesity on survival outcomes in patients with glioblastoma (GBM) has not been well reported and the results for patients are currently unclear. We investigated the effect of obesity on survival outcomes in patients with newly diagnosed GBM. Methods: Using electronic medical records, all GBM patients that visited the Seoul St. Mary’s Hospital between 2008 and 2018 were reviewed. A total of 177 patients met our eligibility criteria. The cut-off point for BMI was 23.0 kg/m2 based on previous studies which focused on Asian populations. Results: A total of 177 patients met our eligibility criteria. The overall median BMI of patients was 24.5 kg/m2 (range 15.82-39.26). About 62 patients who had a BMI less than the cut-off value were assigned to the “lower BMI” group, while 115 patients who had a BMI greater than the cut-off value were assigned to the “higher BMI” group. In Kaplan-Meier survival analysis, the median OS of the higher BMI group was longer than that of the lower BMI group (21.3 months vs 15.3 months, P = .002). In multivariate Cox regression analysis for OS, lower BMI was associated with inferior OS (HR 1.48 CI 1.06-2.08, P = .002). Conclusion: Our findings suggest that elevated BMI may be associated with better survival in patients with newly diagnosed GBM. Additional larger prospective studies could help validate our findings to confirm the effect of body composition and survival outcomes in GBM patients.


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