Comprehensive genomic sequencing of high-grade neuroendocrine neoplasms.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 624-624
Author(s):  
Thomas Yang Sun ◽  
Paul Van Hummelen ◽  
Brock Martin ◽  
Charlie Xia ◽  
Hojoon Lee ◽  
...  
Keyword(s):  
Copy Number ◽  
Cox Model ◽  
Predictive Biomarkers ◽  
Neuroendocrine Neoplasms ◽  
Tumor Mutation Burden ◽  
Risk Of Death ◽  
Mutation Burden ◽  
Increased Risk ◽  
Poorly Differentiated ◽  
Copy Number Changes

624 Background: Grade 3 neuroendocrine neoplasms (G3 NENs), if poorly differentiated, have a median survival of only 10-19 months. Little is known regarding their underlying genomics. Methods: We applied multiomics analysis to 46 cases of G3 NEN that included copy number analysis, whole exome, and transcriptomic sequencing. Results: Of the 46 unique cases, 17 were lung, 16 gastroenteropancreatic (GEP), 13 other; 5 well-differentiated, 39 poorly differentiated and 2 mixed. Using a multivariate Cox model, we found histology characteristics (including differentiation, Ki67 and mitotic index) did not correlate with changes in overall survival (OS). The clinical variables that did correlate with OS included: number of lines of treatment (hazard ratio for death [HR], 0.72; p < 0.05), GEP primary site (HR, 5.36; p < 0.005), and non-resected primary tumor (HR, 14.52; p < 0.001). Two copy number changes were associated with worse prognosis: focal deletion 22q13 (HR, 10.23; p < 0.005), and arm amplification 19q (HR, 7.09; p < 0.01). The median OS of the top quartile compared to the rest for 22q13 deletion carriers was 9.9 months vs. 24 months, and for 19q amplification carriers was 8.7 months vs. 36.7 months. We estimated a median tumor mutation burden (TMB) of 3.7 mutations/Mb, with 20% (8/40) of patients showing high TMB ( > 10 mutations/Mb). The top five mutated genes were USH2A, RB1, APC, TP53, and MUC16. We also observed high transcriptomic similarity across all NENs regardless of their site of origin. Conclusions: We identified two copy number changes that can serve as predictive biomarkers in G3 NENs, as they confer an increased risk of death by as high as 10x to the carriers. Further, G3 NENs are characterized by a distinct group of somatic mutations, and a significant number have high tumor mutation burden. Lastly, G3 NENs across different organs were relatively homogeneous in expression profile.

Prognostic impact of chemoradiation-related lymphopenia in patients with gastric and gastroesophageal cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 249-249
Author(s):  
Daniel W Kim ◽  
Grace Lee ◽  
Theodore S. Hong ◽  
Guichao Li ◽  
Eric Roeland ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Cox Model ◽  
Gastroesophageal Junction ◽  
Concurrent Chemotherapy ◽  
Rank Test ◽  
Prognostic Impact ◽  
Poor Prognostic Factor ◽  
Risk Of Death ◽  
Increased Risk ◽  
Ecog Ps

249 Background: Limited data exists on how chemoradiation (CRT)-induced lymphopenia affects survival outcomes in patients with gastric and gastroesophageal junction (GEJ) cancer. We evaluated the association between severe lymphopenia and its association with survival in gastric and GEJ cancer patients treated with CRT. We hypothesized that severe lymphopenia would be a poor prognostic factor. Methods: We performed a retrospective analysis of 154 patients with stage 1-3 gastric or GEJ cancer who underwent CRT at our institution. Patients underwent photon-based radiation therapy (RT) with a median dose of 50.4 Gy (IQR 45.0-50.4 Gy) over 28 fractions and concurrent chemotherapy (CTX) with carboplatin/paclitaxel, 5-fluorouracil based regimen, or capecitabine. 49% received CTX prior to RT. 84% underwent surgical resection, 57% pre-CRT and 26% post-CRT. Absolute lymphocyte count (ALC) at baseline and at 2 months since initiating RT were analyzed. Severe lymphopenia, defined as Grade 3 or worse lymphopenia (ALC < 0.5 k/μl), was analyzed for any association with overall survival (OS). Results: Median time of follow up was 48 months. Median age was 65. 77% were male and 86% were Caucasian. ECOG PS was 0 or 1 in 90% and 2 in 10%. Tumor location was stomach in 38% and GEJ in 62%. Timing of CRT was preoperative among 68% and postoperative among 32%. The median ALC at baseline for the entire cohort was 1.6 k/ul (range 0.3-7.0 k/ul). At 2 months post-CRT, 49 (32%) patients had severe lymphopenia. Patients with severe lymphopenia post-CRT had a slightly lower baseline TLC compared to patients without severe lymphopenia (median TLC 1.4 k/ul vs. 1.6 k/ul; p = 0.005). There were no differences in disease and treatment characteristics between the two groups. On the multivariable Cox model, severe lymphopenia post-CRT was significantly associated with increased risk of death (HR = 3.99 [95% CI 1.55-10.28], p = 0.004). ECOG PS 2 (HR = 34.97 [95% CI 2.08-587.73], p = 0.014) and postoperative CRT (HR = 5.55 [95% CI 1.29-23.86], p = 0.021) also predicted worse OS. The 4-year OS among patients with severe lymphopenia was 41% vs. 61% among patients with vs. without severe lymphopenia (log-rank test p = 0.041). Conclusions: Severe lymphopenia significantly correlated with poorer OS in patients with gastric or GEJ cancer treated with CRT. CRT-induced lymphopenia may be an important prognostic factor for survival in this patient population. Closer observation in high-risk patients and treatment modifications may be potential approaches to mitigating CRT-induced lymphopenia.

scholarly journals Malondialdehyde and Uric Acid as Predictors of Adverse Outcome in Patients with Chronic Heart Failure

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Ewa Romuk ◽  
Celina Wojciechowska ◽  
Wojciech Jacheć ◽  
Aleksandra Zemła-Woszek ◽  
Alina Momot ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Uric Acid ◽  
Chronic Heart Failure ◽  
Predictive Biomarkers ◽  
Cox Regression Analysis ◽  
Risk Of Death ◽  
Increased Risk ◽  
Baseline Levels

In chronic heart failure (HF), some parameters of oxidative stress are correlated with disease severity. The aim of this study was to evaluate the importance of oxidative stress biomarkers in prognostic risk stratification (death and combined endpoint: heart transplantation or death). In 774 patients, aged 48-59 years, with chronic HF with reduced ejection fraction (median: 24.0 (20-29)%), parameters such as total antioxidant capacity, total oxidant status, oxidative stress index, and concentration of uric acid (UA), bilirubin, protein sulfhydryl groups (PSH), and malondialdehyde (MDA) were measured. The parameters were assessed as predictive biomarkers of mortality and combined endpoint in a 1-year follow-up. The multivariate Cox regression analysis was adjusted for other important clinical and laboratory prognostic markers. Among all the oxidative stress markers examined in multivariate analysis, only MDA and UA were found to be independent predictors of death and combined endpoint. Higher serum MDA concentration increased the risk of death by 103.0% (HR=2.103; 95% CI (1.330-3.325)) and of combined endpoint occurrence by 100% (HR=2.000; 95% CI (1.366-2.928)) per μmol/L. Baseline levels of MDA in the 4th quartile were associated with an increased risk of death with a relative risk (RR) of 3.64 (95% CI (1.917 to 6.926), p<0.001) and RR of 2.71 (95% CI (1.551 to 4.739), p<0.001) for the occurrence of combined endpoint as compared to levels of MDA in the 1st quartile. Higher serum UA concentration increased the risk of death by 2.1% (HR=1.021; 95% CI (1.005-1.038), p<0.001) and increased combined endpoint occurrence by 1.4% (HR=1.014; 95% CI (1.005-1.028), p<0.001), for every 10 μmol/L. Baseline levels of UA in the 4th quartile were associated with an increased risk for death with a RR of 3.21 (95% CI (1.734 to 5.931)) and RR of 2.73 (95% CI (1.560 to 4.766)) for the occurrence of combined endpoint as compared to the levels of UA in the 1st quartile. In patients with chronic HF, increased MDA and UA concentrations were independently related to poor prognosis in a 1-year follow-up.

scholarly journals Genetic Profile of Adenoid Cystic Carcinomas (ACC) with High-Grade Transformation versus Solid Type

2010 ◽  
Vol 33 (5-6) ◽  
pp. 217-228 ◽  
Author(s):  
Ana Flávia Costa ◽  
Albina Altemani ◽  
Hedy Vékony ◽  
Elisabeth Bloemena ◽  
Florentino Fresno ◽  
...  
Keyword(s):  
Copy Number ◽  
Genetic Profile ◽  
High Grade ◽  
Ki 67 ◽  
Genetic Changes ◽  
Genome Wide ◽  
Genetic Complexity ◽  
Poorly Differentiated ◽  
High Grade Transformation ◽  
Copy Number Changes

Background: ACC can occasionally undergo dedifferentiation also referred to as high-grade transformation (ACC-HGT). However, ACC-HGT can also undergo transformation to adenocarcinomas which are not poorly differentiated. ACC-HGT is generally considered to be an aggressive variant of ACC, even more than solid ACC. This study was aimed to describe the genetic changes of ACC-HGT in relation to clinico-pathological features and to compare results to solid ACC.Methods: Genome-wide DNA copy number changes were analyzed by microarray CGH in ACC-HGT, 4 with transformation into moderately differentiated adenocarcinoma (MDA) and two into poorly differentiated carcinoma (PDC), 5 solid ACC. In addition, Ki-67 index and p53 immunopositivity was assessed.Results: ACC-HGT carried fewer copy number changes compared to solid ACC. Two ACC-HGT cases harboured a breakpoint at 6q23, near the cMYB oncogene. The complexity of the genomic profile concurred with the clinical course of the patient. Among the ACC-HGT, p53 positivity significantly increased from the conventional to the transformed (both MDA and PDC) component.Conclusion: ACC-HGT may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form in which the poorly differentiated forms (PDC) presents a genetic complexity similar to the solid ACC.

scholarly journals Genomic features and tumor immune microenvironment alteration in NSCLC treated with neoadjuvant PD-1 blockade

2022 ◽  
Vol 6 (1) ◽  
Author(s):  
Shuhang Wang ◽  
Pei Yuan ◽  
Beibei Mao ◽  
Ning Li ◽  
Jianming Ying ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Gain ◽  
Pathological Response ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Neoadjuvant Immunotherapy ◽  
Mutation Burden ◽  
Tumor Immune Microenvironment ◽  
Nsclc Patients ◽  
Insight Into

AbstractSeveral clinical trials have shown the safety and effectiveness of PD-1/PD-L1 inhibitors in neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC). However, 18–83% patients can benefit from it. In this study, we aimed to assess the association of PD-L1 expression, tumor mutation burden, copy number alteration (CNA, including copy number gain and loss) burden with the pathologic response to neoadjuvant PD-1 blockade and investigate the changes in the tumor immune microenvironment (TIME) during neoadjuvant immunotherapy in NSCLC. Pre-immunotherapy treatment tumor samples from twenty-nine NSCLC patients who received neoadjuvant immunotherapy with sintilimab, an anti-PD-1 drug, were subjected to targeted DNA sequencing and PD-L1 immunochemistry staining. The pathological response was positively correlated with tumor proportion score (TPS) of PD-L1 and negatively correlated with copy number gain (CNgain) burden. Of note, the combination of CNgain burden and TPS can better stratify major pathological response (MPR) patients than did CNgain or TPS alone. Whereas, TMB showed a limited correlation with pathological regression. Additionally, PD-1 blockade led to an increase in CD8+PD-1−T cells which was clinically relevant to MPR as evaluated by multiplex immunofluorescence. A significant reduction in CD19+ cells was observed in the Non-MPR group but not in the MPR group, indicating the involvement of B cells in improving neoadjuvant immunotherapy response in NSCLC. Together, our study provides new data for the correlation of PD-L1 expression and genomic factors with drug response in neoadjuvant immunotherapy settings in NSCLC. The changes of TIME may provide novel insight into the immune responses to neoadjuvant anti-PD-1 therapy.

scholarly journals Identification of Prognostic Biomarkers of Cutaneous Melanoma Based on Analysis of Tumor Mutation Burden

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Jiaqiong Lin ◽  
Yan Lin ◽  
Zena Huang ◽  
Xiaoyong Li
Keyword(s):  
Cutaneous Melanoma ◽  
Prognostic Model ◽  
Cox Regression ◽  
Risk Group ◽  
Predictive Biomarkers ◽  
Tumor Mutation Burden ◽  
Skin Development ◽  
Cox Regression Analysis ◽  
Immune Infiltration ◽  
Mutation Burden

Background. Immunotherapy offers a novel approach for the treatment of cutaneous melanoma, but the clinical efficiency varies for individual patients. In consideration of the high cost and adverse effects of immunotherapy, it is essential to explore the predictive biomarkers of outcomes. Recently, the tumor mutation burden (TMB) has been proposed as a predictive prognosticator of the immune response. Method. RNA-seq and somatic mutation datasets of 472 cutaneous melanoma patients were downloaded from The Cancer Genome Atlas (TCGA) database to analyze mutation type and TMB. Differently expressed genes (DEGs) were identified for functional analysis. TMB-related signatures were identified via LASSO and multivariate Cox regression analysis. The association between mutants of signatures and immune cells was evaluated from the TIMER database. Furthermore, the Wilcox test was applied to assess the difference in immune infiltration calculated by the CIBERSORT algorithm in risk groupings. Results. C>T substitutions and TTN were the most common SNV and mutated gene, respectively. Patients with low TMB presented poor prognosis. DEGs were mainly implicated in skin development, cell cycle, DNA replication, and immune-associated crosstalk pathways. Furthermore, a prognostic model consisting of eight TMB-related genes was developed, which was found to be an independent risk factor for treatment outcome. The mutational status of eight TMB-related genes was associated with a low level of immune infiltration. In addition, the immune infiltrates of CD4+ and CD8+ T cells, NK cells, and M1 macrophages were higher in the low-risk group, while those of M0 and M2 macrophages were higher in the high-risk group. Conclusion. Our study demonstrated that a higher TMB was associated with favorable survival outcome in cutaneous melanoma. Moreover, a close association between prognostic model and immune infiltration was identified, providing a new potential target for immunotherapy.

Patient-reported KPS and other measures as predictors of survival in patients with advanced cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19606-e19606
Author(s):  
Victor T Chang ◽  
Charles B. Scott ◽  
Melanie L. Gonzalez ◽  
Houling Yan ◽  
Jan Einhorn ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Cox Regression ◽  
Cox Model ◽  
Karnofsky Performance Status ◽  
Metastatic Cancer ◽  
Performance Status ◽  
Risk Of Death ◽  
Increased Risk ◽  
Patient Reported ◽  
Patient Responses

e19606 Background: Understanding determinants of survival remains a challenge in patients(pts) with advanced cancer. Prognostic factors of interest include pts rating of their own performance status, and patient responses from the EQ-5D. Methods: This prospective study was approved by the VA New Jersey HCS IRB. Pts with metastatic cancer whose cancer had already been treated with standard or experimental chemotherapy with KPS < 80%, or who did not wish to receive systemic chemotherapy, were recruited in a specified manner. At entry, Karnofsky performance status (KPS) was estimated, pts rated their own KPS, and answered a modified version of the EQ-5D. Cox regression survival analyses were performed. Results: Of 242 pts enrolled, 237 pts were analyzable. Median (M) age was 67 years (range 44-88), with 56% white, 41% black and 3% other; lung (26%) and prostate (18%) were the 2 most common primary sites and M KPS was 60% (range 30-100%). The majority (97%) of pts have died, with M survival of 95 days, range 4-2032 days. Higher KPS is associated with decreased risk of death (p<.0001). Both patient KPS (p<0.0319) and physician rated KPS were predictive of survival (p<0.004). Discrepancy between physician and pt KPS was noted, with upstaging by pts 48%, same for 27%, and downstaging in 25%, with no effect on survival. Physician KPS was a better predictor than pt KPS at each level. The EQ-5D pain item showed an increased risk of death with increasing pain (p<0.0001). The pain item was associated with KPS: pts with no pain had average KPS 75; moderate pain average KPS 63; extreme pain average KPS 48. The patient’s EQ-5D health rating was positively correlated with survival (p=0.0054), and with KPS (r=0.36). The other items in the EQ-5D did not predict survival. When all the factors (physician KPS, pt KPS, pain, health) were incorporated into a Cox model, only physician KPS was statistically significant (p=0.0033). Conclusions: Pts ratings of health and pain are significantly associated with KPS. Pts have a more positive outlook on their performance status. Physician KPS may be a better predictor because physicians have a wider frame of reference. Physician KPS can contribute to determination of hospice eligibility. Supported by VA HSRD IIR 2-103

Chemoradiation-related lymphopenia and its association with survival in patients with anal cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 3-3
Author(s):  
Grace Lee ◽  
Daniel W. Kim ◽  
Vinayak Muralidhar ◽  
Devarati Mitra ◽  
Nora Horick ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Anal Cancer ◽  
Cox Regression ◽  
Cox Model ◽  
Rank Test ◽  
Anal Squamous Cell Carcinoma ◽  
Cox Regression Analysis ◽  
Risk Of Death ◽  
Kaplan Meier ◽  
Increased Risk

3 Background: While treatment-related lymphopenia (TRL) is common and associated with poorer survival in multiple solid malignancies, little data exists for anal cancer. We evaluated TRL and its association with survival in anal cancer patients treated with chemoradiation (CRT). Methods: A retrospective analysis of 140 patients with non-metastatic anal squamous cell carcinoma (SCC) treated with definitive CRT was performed. Total lymphocyte counts (TLC) at baseline and monthly intervals up to 12 months after initiating CRT were analyzed. Multivariable Cox regression analysis was performed to evaluate the association between overall survival (OS) and TRL, dichotomized by G4 TRL ( < 0.2k/μl) two months after initiating CRT. Kaplan-Meier and log-rank tests were used to compare OS between patients with versus without G4 TRL. Results: Median time of follow-up was 55 months. Prior to CRT, 95% of patients had a normal TLC ( > 1k/μl). Two months after initiating CRT, there was a median of 71% reduction in TLC from baseline and 84% of patients had TRL: 11% G1, 31% G2, 34% G3, and 8% G4. On multivariable Cox model, G4 TRL at two months was associated with a 3.7-fold increased risk of death (p = 0.013). On log-rank test, the 5-year OS rate was shorter in the cohort with versus without G4 TRL at two months (32% vs. 86%, p < 0.001). Conclusions: TRL is common and may be another prognostic marker of OS in anal cancer patients treated with CRT. The association between TRL and OS supports the hypothesis that host immunity plays an important role in survival among patients with anal cancer. These results support ongoing efforts of randomized trials underway to evaluate the potential role of immunotherapy in localized anal cancer.

Correlation Between Clinical Features, CRLF2 Expression and Copy Number Alterations In Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4953-4953
Author(s):  
Juan Carlos Ponce Jarquin ◽  
Rosa M. Ayala ◽  
Ana Belen Dueñas Perez ◽  
Daniel Rueda ◽  
María Luisa Martin Ramos ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Copy Number Alterations ◽  
Free Survival ◽  
Risk Of Death ◽  
Increased Risk ◽  
Ph Chromosome

Abstract Background Acute lymphoblastic leukemia (ALL) is a heterogeneous disease comprising different genetic abnormalities. An increased cytokine receptor-like factor 2 (CRLF2) expression is associated with activating the JAK-STAT pathway and activation and leukemia initiation. Several studies have shown that some first events are insufficient to cause the development of ALL and other genetic changes are required. In 60% of cases, the altered genes are involved in lymphoid maturation (PAX, IKZF1, EBF, LEF1, BTALA/CD200, TOX), cell cycle control and tumour suppression (CDKN2A/B, PTEN, RB), or transcription factors and coactivators (ETV6, ERG, TBL1XR1). But the prognostic significance of deregulated CRLF2 mRNA expression in patients with CNA in the genes previously mentioned is not fully identified. Aims To analyze the frequency and prognostic significance of deregulated expression of  CRLF2 and the copy number alterations (CNA) in EBFF1, IKZF1, JAK2, CDKN, PAX, ETV, BTG1 and RB in a series of ALL patients enrolled in BFM, SHOP or PETHEMA clinical trials. Methods Bone Marrow samples at diagnosis from 69 ALL patients treated in Hospital Universitario 12 de Octubre, between January 2001 and December 2012, were studied by Multiplex ligation- dependent probe amplifications (MLPA) method was used to detect deletions or duplications of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1 and CDKN2A-CDKN2B genes (SALSA MLPA kit P335-B1 ALL-IKZF1; MRC- Holland). Raw data was analyzed using Coffalyzer software (MRC-Holland) Results The median age was 22 years (0.9-88), 40 (58%) male and 29 (42%) female, median WBC count 70,753 x109/L (1,000 – 633,780). B-ALL subtype in 64 cases (92%) and T-ALL subtype in 5 cases (8%). Cytogenetics: 10 normal (14.5%), 16 hyperdiploid (20,5%), 8 t(9;22)(10.3%),4 cases 11q23/MLL (5.1%), and 24 (30.8%) with  other translocations or deletions and no growth (23.1%).  Cytogenetics risk was favourable in 25 cases (26.6%), intermediate in 10 cases (10.6%) and poor in 25 cases (26.6%). CRLF2 expression and CAN results are shown in table 1. CRFL2 over expression was found in 18 cases (23%), it was associated with deletions of IKZF1 (p0.013). Deletions of CDNK were associated with T-ALL subtype (p0.049) and with a tendency to deletions TEL group (p0.081). Deletions of PAX were associated with JAK2 deletions (p0.027) and with a tendency to IKZF1 deletions (p0.064). Rb deletions were associated with ph+ ALL (p0.001) and it had a tendency to the risk of death. Other molecular alterations found were gains of gen EBF 2 (2.6%), IKZF 2 (2.6%), CDKN 4 (5.1%), PAX 5(6.4%), BTG   2 (2.6%), RB 2 (2.6%). There was no association between hyperdiploid karyotype and any of the gene gains analyzed. Regarding survival, CDKN deletions 2A/ B were associated with decreasing of progression free survival P (0.051), independent of the presence of Ph chromosome. Deletions of IKZF1 showed an increased risk of death (p0.011) and tendency for deletions of PAX (p0.064). Conclusions Our findings are consistent with those of other published series. CDKN deletions 2A / B were associated with a decreased progression free survival, independent of the presence of Ph chromosome as described in other series. RB deletions are associated with ph + and have not been described previously, but these findings must be confirm with additional studies. Disclosures: No relevant conflicts of interest to declare.

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