IDH–wild-type glioblastoma cell density and infiltration distribution influence on supramarginal resection and its impact on overall survival: a mathematical model

2021 ◽  
pp. 1-9
Author(s):  
Shashwat Tripathi ◽  
Tito Vivas-Buitrago ◽  
Ricardo A. Domingo ◽  
Gaetano De Biase ◽  
Desmond Brown ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Overall Survival ◽  
Cell Density ◽  
Patient Specific ◽  
Wild Type ◽  
Tumor Invasiveness ◽  
Postoperative Mri ◽  
T1 Contrast ◽  
Supramarginal Resection ◽  
The Impact

OBJECTIVE Recent studies have proposed resection of the T2 FLAIR hyperintensity beyond the T1 contrast enhancement (supramarginal resection [SMR]) for IDH–wild-type glioblastoma (GBM) to further improve patients’ overall survival (OS). GBMs have significant variability in tumor cell density, distribution, and infiltration. Advanced mathematical models based on patient-specific radiographic features have provided new insights into GBM growth kinetics on two important parameters of tumor aggressiveness: proliferation rate (ρ) and diffusion rate (D). The aim of this study was to investigate OS of patients with IDH–wild-type GBM who underwent SMR based on a mathematical model of cell distribution and infiltration profile (tumor invasiveness profile). METHODS Volumetric measurements were obtained from the selected regions of interest from pre- and postoperative MRI studies of included patients. The tumor invasiveness profile (proliferation/diffusion [ρ/D] ratio) was calculated using the following formula: ρ/D ratio = (4π/3)2/3 × (6.106/[VT21/1 − VT11/1])2, where VT2 and VT1 are the preoperative FLAIR and contrast-enhancing volumes, respectively. Patients were split into subgroups based on their tumor invasiveness profiles. In this analysis, tumors were classified as nodular, moderately diffuse, or highly diffuse. RESULTS A total of 101 patients were included. Tumors were classified as nodular (n = 34), moderately diffuse (n = 34), and highly diffuse (n = 33). On multivariate analysis, increasing SMR had a significant positive correlation with OS for moderately and highly diffuse tumors (HR 0.99, 95% CI 0.98–0.99; p = 0.02; and HR 0.98, 95% CI 0.96–0.99; p = 0.04, respectively). On threshold analysis, OS benefit was seen with SMR from 10% to 29%, 10% to 59%, and 30% to 90%, for nodular, moderately diffuse, and highly diffuse, respectively. CONCLUSIONS The impact of SMR on OS for patients with IDH–wild-type GBM is influenced by the degree of tumor invasiveness. The authors’ results show that increasing SMR is associated with increased OS in patients with moderate and highly diffuse IDH–wild-type GBMs. When grouping SMR into 10% intervals, this benefit was seen for all tumor subgroups, although for nodular tumors, the maximum beneficial SMR percentage was considerably lower than in moderate and highly diffuse tumors.

scholarly journals Characterization of Hematopoietic Differentiation Profiles of MPN Patient-Derived Inducible Pluripotent Stem Cells Harboring Homozygous Vs Heterozygous Calreticulin Mutations

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3065-3065
Author(s):  
Lijuan Han ◽  
Marcelo A. Szymanski Toledo ◽  
Alexandre Theocharides ◽  
Angela Maurer ◽  
Tim H. Brümmendorf ◽  
...  
Keyword(s):  
Ips Cells ◽  
Patient Specific ◽  
Hematopoietic Differentiation ◽  
In Vitro Differentiation ◽  
Wild Type ◽  
Ips Cell ◽  
Cell Clones ◽  
Calr Mutations ◽  
The Impact

Abstract Introduction: Somatic calreticulin (CALR) mutations were discovered in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) and have been shown to be mutually exclusive with Janus kinase 2 (JAK2) and thrombopoietin receptor (MPL) mutations. Recent studies demonstrated that the binding of CALR mutant proteins to MPL induces constitutive activation of the JAK/STAT pathway, thus causing cellular transformation and abnormal megakaryopoiesis. Additionally, it has been reported that patients carrying homozygously mutated CALR ins5 exhibit myeloperoxidase (MPO) deficiency as a result of the absence of CALR chaperone function. However, the impact of CALR mutant homozygosity vs. heterozygosity in CALR del52 mutations as well as on hematopoietic differentiation has not yet been studied. Furthermore, clonal heterogeneity of hematopoietic stem/progenitor cell (HSPC) populations in a patient, together with technical limitations isolating single clones, are major challenges, when determining the impact of CALR mutant zygosity on clonal composition and diversity in MPN. To overcome these limitations, we generated patient-specific iPS cells carrying homozygous or heterozygous CALR mutations or their wild-type counterparts to study their roles in hematopoietic differentiation. Methods: iPS cells were generated by reprogramming peripheral blood-derived mononuclear cells from three patients carrying CALR del52, ins5, or del31 mutations using a CytoTune iPS 2.0 Sendai Reprogramming Kit. Individual colonies were picked and screened for CALR genotypes by PCR. Pluripotency of iPS cells was confirmed by immunofluorescences, and the clones were screened for additional mutations using panel-based next generation sequencing (NGS). Subsequently, CALR iPS cells were subjected to embryonic body formation, mesoderm commitment, and hematopoietic differentiation using our standard in vitro differentiation protocol. CD34+ HSPCs were MACS-sorted and characterized by flow cytometry, cytospins and RNA expression analysis on days 10, 15, and 20 during differentiation. Hematopoietic progenitors, erythrocytes, granulocytes, and megakaryocytes were identified by defined lineage markers. MPO expression was assessed by flow cytometry and cytochemical staining. Results: We established patient-specific iPS cells carrying CALR del52, ins5 or del31 mutation after written informed consent (Table 1). Pluripotency markers OCT4, Tra-1-60 and Tra-1-81 expression were confirmed in all iPS cell clones. In accordance with findings in peripheral blood cells, we detected MPO deficiency in homozygous iPS cell-derived CD15+ cells from CALRins5- and, in addition, also from CALRdel52-mutated patients (pMFI=0.0106 and pMFI=0.0187, resp.). Intriguingly, in vitro hematopoietic differentiation assays revealed additional abnormalities, such as decreased CD66b+ granulocytes derived from homozygous CALR del52 or ins5 iPS cells vs. heterozygous iPS cells on day 10 (pdel52=0.0303 and pins5=0.0253, resp.) and a trend towards increased KIThigh+CD45+ cells. Megakaryopoiesis, defined by CD41+CD42b+ cells, was increased in CALRins5 homozygous vs. heterozygous clones (p=0.0031). However, this bias was not observed in all clones, indicating clone-specific megakaryocytic differentiation potential. No phenotypic differences during hematopoietic differentiation were observed in iPS cell-derived progenitors carrying heterozygous CALRdel31 mutation and its isogenic unmutated CALR controls. Furthermore, our NGS data revealed patient-specific sets of co-occurring mutations in iPS cell clones, which may have contributed to the observed patient-specific phenotypes. As an example, the IDH2 R140Q mutation, reported to block cell differentiation, was found in approximately half of the CALRdel52 iPS clones, and these clones failed to differentiate into the hematopoietic lineage in vitro. Conclusions: We successfully generated patient-specific CALR mutant iPS cells. Upon in vitro differentiation, we detected MPO deficiency and aberrant granulocytic differentiation in CALR homozygous but not heterozygous or wild-type clones. Thus, it is now possible at the single stem cell level to further analyze the molecular mechanisms of CALR-mutant induced MPO deficiency and altered hematopoietic differentiation, in order to better understand disease biology in ET and PMF. Disclosures Brümmendorf: Merck: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Takeda: Consultancy.

Metastases resection in colorectal cancer patients with mutation in oncogene BRAF or tumors located on the right side: Experience at the HGUGM.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4041-4041
Author(s):  
Laura Ortega ◽  
Marianela Bringas Beranek ◽  
Natalia Gutiérrez Alonso ◽  
Javier Soto Alsar ◽  
Manuel Alva Bianchi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Disease ◽  
Positive Impact ◽  
Wild Type ◽  
Primary Tumors ◽  
Metastatic Lesions ◽  
Common Location ◽  
The Right ◽  
The Impact

4041 Background: Approximately 25% of patients with colorectal cancer (CRC) debut with metastatic disease. In addition, 25-35% of patients with localized disease at diagnosis develop metastatic lesions during the evolution of their disease. Consequently, approximately 50-60% of patients with CRC will present metastatic lesions at some point in their lives. Metastasis resection has improved the prognosis of these patients, achieving overall survival (OS) that exceed 40 months. However, there are doubts about the benefit of this approach in patients with mutations in oncogene BRAF or tumors located on the right-side, due their poor prognosis. The aim of the study is to analyze the impact of metastases resection on OS of these populations. Methods: We conducted a retrospective analysis of patients with mCRC attended in the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón (Spain) between January 2010 and 2018. Results: 487 patients were identified and included in the analysis. Median age was 71 years (62-81). Most patients were males (62.4%). 55.2% had metastatic lesions at diagnosis. Most patients had ECOG 0-1 at diagnosis of metastatic disease (91.0%). 8.9% of patients had BRAF mutations (n = 21) and 31.8% of patients had primary tumors located on the right-side (n = 152). 474 patients received first-line chemotherapy (97.3%). OS of the entire cohort was 29.67 months; 30.69 months in BRAF mutated patients vs 35.89 in wild-type patients (p = 0.161); 25.29 months in right-side tumors vs 31.02 in left-side tumors (p = 0.044). 306 patients (62.8%) underwent metastases resection. Most common location was liver (51.4%). 147 patients (30.2%) underwent a second metastases resection. Mean number of metastases surgeries was 1.35 (+/-1.40). OS since metastases resection was 24.83 months in BRAF mutated patients vs 41.55 months in wild-type patients (p = 0.020). According to location, it was 35.49 months in right-side tumors vs 43.78 months in left-side tumors (p = 0.106). In BRAF mutated patients, OS was 38.19 months in patients underwent metastases resection vs 18.52 months in non-surgical patients (p = 0.043); 41.51 months vs 16.18 months respectively in patients with tumors located on the right-side (p < 0.001). Conclusions: Metastases resection has a positive impact on overall survival of patients with mutations in oncogene BRAF or right-side tumors, even though their prognosis is still poor compared to patients without these alterations.

scholarly journals Impact of splicing mutations in acute myeloid leukemia treated with hypomethylating agents combined with venetoclax

2021 ◽  
Vol 5 (8) ◽  
pp. 2173-2183
Author(s):  
Curtis A. Lachowiez ◽  
Sanam Loghavi ◽  
Ken Furudate ◽  
Guillermo Montalban-Bravo ◽  
Abhishek Maiti ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Cohort Analysis ◽  
Cancer Center ◽  
Hypomethylating Agents ◽  
Wild Type ◽  
The Impact ◽  
Acute Myeloid

Abstract Spliceosome mutations (SRSF2, SF3B1, U2AF1, ZRSR2), are encountered in ∼50% of secondary acute myeloid leukemia cases (sAML) and define a molecular subgroup with outcomes similar to sAML in de novo AML patients treated with intensive chemotherapy. Outcomes in patients with spliceosome mutations treated with hypomethylating agents in combination with venetoclax (HMA+VEN) remains unknown. The primary objective was to compare outcomes in patients with spliceosome mutations vs wild-type patients treated with HMA+VEN. Secondary objectives included analysis of the mutational landscape of the spliceosome cohort and assessing the impact of co-occurring mutations. We performed a retrospective cohort analysis of patients treated with HMA+VEN–based regimens at The University of Texas MD Anderson Cancer Center. A total of 119 patients (spliceosome mutated n = 39 [SRSF2, n = 24; SF3B1, n = 8; U2AF1, n = 7]; wild-type, n = 80) were included. Similar responses were observed between spliceosome and wild-type cohorts for composite complete response (CRc; 79% vs 75%, P = .65), and measurable residual disease–negative CRc (48% vs 60%, P = .34). Median overall survival for spliceosome vs wild-type patients was 35 vs 14 months (P = .58), and was not reached; 35 months and 8 months for patients with SRSF2, SF3B1, and U2AF1 mutations, respectively. IDH2 mutations were enriched in patients with SRSF2 mutations and associated with favorable outcomes (1- and 2-year overall survival [OS] of 100% and 88%). RAS mutations were enriched in patients with U2AF1 mutations and associated with inferior outcomes (median OS, 8 months). Comparable outcomes were observed between patients with vs without spliceosome mutations treated with HMA+VEN regimens, with specific co-mutation pairs demonstrating favorable outcomes.

scholarly journals Superior Overall Survival in Patients with Colorectal Cancer, Regular Aspirin Use, and Combined Wild-Type PIK3CA and KRAS-Mutated Tumors

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4959
Author(s):  
Leonie Gebauer ◽  
Andrea Nist ◽  
Marco Mernberger ◽  
Thorsten Stiewe ◽  
Roland Moll ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Survival Data ◽  
Wild Type ◽  
Curative Intent ◽  
Mutational Status ◽  
Regular Aspirin ◽  
Overall Survival Benefit ◽  
The Impact ◽  
Prognostic Data

The impact of aspirin use after the diagnosis of colorectal cancer is unknown. Among others, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutational status was proposed as a molecular biomarker for the response to adjuvant aspirin therapy. However, prognostic data on aspirin use after a colorectal cancer diagnosis in relation to KRAS mutational status is limited. In a single-center retrospective study, we obtained KRAS and PIK3CA mutational status in a cohort of 153 patients with a first diagnosis of colorectal cancer receiving tumor surgery with curative intent. PIK3CA mutational status was determined by pyrosequencing, and KRAS mutational status was determined by next-generation sequencing. Clinicopathological data and survival data were assessed using patient records and reporting registers. We observed a significant 10-year overall survival benefit in patients with aspirin use and combined wild-type PIK3CA and mutated-KRAS tumors (HR = 0.38; 95% CI = 0.17–0.87; p = 0.02), but not in patients without aspirin use. Our data indicate a benefit of aspirin usage particularly for patients with combined wild-type PIK3CA and mutated-KRAS tumor characteristics.

Survival Outcomes in Patients with FLT3-Itd Positive Acute Myeloid Leukaemia Relative to Biological Stratification: Smaller FLT3-Itd Clone Size Predict Better Overall Survival

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1460-1460 ◽  
Author(s):  
Justin Ching Ting Loke ◽  
Susanna Akiki ◽  
Joanne Ewing ◽  
Syed W Bokhari ◽  
Deepak Chandra ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Conflicts Of Interest ◽  
Wild Type Allele ◽  
Wild Type ◽  
Relative Expression ◽  
Type Allele ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 1460 Background: FLT3 internal tandem duplication (itd) mutations are found in 25% of adult patients with acute myeloid leukaemia (AML) and are associated with an adverse prognosis. This mutation results in constitutive activation of downstream pathways. Distinct biological subgroups can be identified based on FLT3-itd mutation type: clones with heterozygous FLT3-itd mutated/wildtype; homozygous mutated FLT3 allele; FLT3 heterozygous biallelic mutant and clones with evidence of overexpression of FLT3-itd. There is evidence to suggest that these mechanisms are important in the clonal evolution of AML cells. We sought to investigate their clinical impact. Method: Itd mutation analysis within exon 14 and/or exon 15 of the FLT3 gene was carried out at diagnosis by PCR of genomic DNA (gDNA) and cDNA for all new AML referrals in the region over 8 years. PCR products were identified and sized using fluorescent based fragment analysis. Allelic ratio (AR) and expression ratio (ER) (mutation: wild type ratio in gDNA and cDNA respectively) was determined from the relative peak heights. High relative expression was defined as 10 fold difference of ER/AR. Copy neutral loss of heterozygosity for the wild type allele resulting in homozygosity of the FLT3-itd mutation (acquired isodisomy (AID)) was determined by analysis of microsatellite markers along chromosome 13. Overall survival (OS) (time of diagnosis to death), event free survival (EFS) (time from diagnosis to induction failure, relapse or death) was calculated. Survival rates were estimated by the Kaplan-Meier method. Differences between the survival distributions were compared with the log-rank test. Results: 177 patients positive for the FLT3-itd mutation were identified. Median follow-up for patients alive was 3.4 years. A separate group of 49 patients tested negative for this mutation during this period had better OS and EFS (p=0.02) compared to the patients who were FLT3-itd positive (median survival 1715 and 307 days respectively). Patients who were FLT3-itd positive had statistically significant (p<0.05) differences in outcomes based on age, presenting white cell count, treatment intensity and cytogenetic risk. The characteristics of this group of patients are described below. Patients with lower AR (less than/equal to 0.3) as compared to higher AR (greater than 0.3) had an improved OS (p=0.018) and EFS (p=0.02). The impact of AR on OS had borderline significance (p=0.05) when only patients treated with intensive chemotherapy were considered. AID provides true evidence of FLT3 mutant homozygosity and was detected in 15 (142 tested) patients. In 38 patients who relapsed and had samples at these stages, 5 had developed AID, but were heterozygous (mutant/wildtype) at diagnosis. 6 patients with multiple FLT3-itd products may comprise patients who have multiple different mutant/wildtype clones but may include patients with a second, independent FLT3-itd mutation resulting in biallelic heterozygous mutations, although this cannot be confirmed. A high relative expression level of FLT3-itd was seen in 12 patients. The clinical significance of these findings is uncertain due to the small numbers. Conclusion: The impact of FLT3-itd mutation and other known prognostic factors has been confirmed in a heterogeneous, real life cohort of patients. An AR over 1 provides firm evidence of loss of the wild type allele (9 patients). AID also occurs at an AR of less than 1 because of the presence of normal cells or due to preferential amplification of the wildtype allele. Direct testing for AID is a more sensitive measure of FLT3 mutant homozygosity (detected in 14% of tested patients). The development of AID in patients who relapse may be an important mechanism by which an AML clone gains a further advantage. Lower AR was associated with improved survival. In the context of a high blast count (median bone marrow blast 80%), this implies having a small sub-clone of FLT3-itd positive cells is advantageous to having a larger FLT3-itd clone in their population of AML cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals SURG-18. THE IMPACT OF NEUROLOGIC IMPAIRMENTS ON THE RELATIVE BENEFIT OF MAXIMAL EXTENT OF RESECTION IN NEWLY DIAGNOSED IDH-WILD TYPE GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii207-ii207
Author(s):  
Shawn Hervey-Jumper ◽  
Annette Molinaro ◽  
Cecilia Dalle Ore ◽  
Desmond Brown ◽  
Yalan Zhang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Surgical Resection ◽  
Univariate Analysis ◽  
Residual Tumor ◽  
Neurological Deficits ◽  
Survival Models ◽  
Newly Diagnosed ◽  
Wild Type ◽  
Prognostic Importance ◽  
The Impact

Abstract BACKGROUND The prognostic importance of maximal resection of contrast enhancing and non-contrast enhancing disease has been established. Nonetheless, glioblastomas exist within the framework of complex neural circuitry serving cognition, movement, and behavior consequential leading to neurological impairments. The prognostic importance of neurological impairments on survival remains poorly understood. METHODS This is a retrospective, single cohort study from UCSF including 316 eligible patients diagnosed over 20 years with 9.6 years of follow-up. All patients underwent surgical resection for newly diagnosed glioblastoma for whom survival, molecular, preoperative and postoperative MRI images, and clinical data were available. All patients had chemoradiation treated IDH-wild-type glioblastoma with available preoperative and 1-month post-surgical resection neurological outcomes. We employed survival models and recursive partitioning (RPA) to investigate multivariate relationships of overall survival (OS). RESULTS Preoperative neurological impairments were present in 75.6% (n= 239) and new post resection impairments were identified in 37.3% (n=117). Univariate analysis confirmed that new postoperative cognitive impairment [HR 7.91, 95% CI 2.47-25.33] and hemiplegia [HR 3.38, 95% CI 0.83-13.67] (not hemiparesis) impact OS. Risk stratified grouping by RPA demonstrated that gross total resection of contrast enhancing tumor in patients with no new postoperative neurological impairments confers the longest OS (median OS 27.1 months 95%CI 21.5-33.7). Patients with any residual tumor volume after surgery but no new neurological deficits experience a similar survival to younger patients (under 65) with 1 or more new postoperative neurological deficits (median OS 16.6 months 95%CI 15.2-19.2). Shortest OS is identified in patients with any volume of residual tumor plus 1 or more new postoperative neurological deficits and age over 65 (median OS 11.4 months, 95%CI 9.3-13.5). CONCLUSIONS This study confirms that new postoperative neurological impairments impact overall survival in patients with chemoradiation treated IDH-wild-type glioblastoma.

Biallelic ATM Inactivation Significantly Reduces Survival in Patients Treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 Trial

2012 ◽  
Vol 30 (36) ◽  
pp. 4524-4532 ◽  
Author(s):  
Anna Skowronska ◽  
Anton Parker ◽  
Gulshanara Ahmed ◽  
Ceri Oldreive ◽  
Zadie Davis ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Alkylating Agents ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Disease Stage ◽  
Research Fund ◽  
Wild Type ◽  
The Impact ◽  
11Q Deletion

Purpose The prognostic significance of ATM mutations in chronic lymphocytic leukemia (CLL) is unclear. We assessed their impact in the context of a prospective randomized trial. Patients and Methods We analyzed the ATM gene in 224 patients treated on the Leukemia Research Fund Chronic Lymphocytic Leukemia 4 (LRF-CLL4) trial with chlorambucil or fludarabine with and without cyclophosphamide. ATM status was analyzed by denaturing high-performance liquid chromatography and was related to treatment response, survival, and the impact of TP53 alterations for the same patient cohort. Results We identified 36 ATM mutations in 33 tumors, 16 with and 17 without 11q deletion. Mutations were associated with advanced disease stage and involvement of multiple lymphoid sites. Patients with both ATM mutation and 11q deletion showed significantly reduced progression-free survival (median, 7.4 months) compared with those with ATM wild type (28.6 months), 11q deletion alone (17.1 months), or ATM mutation alone (30.8 months), but survival was similar to that in patients with monoallelic (6.7 months) or biallelic (3.4 months) TP53 alterations. This effect was independent of treatment, immunoglobulin heavy chain variable gene (IGHV) status, age, sex, or disease stage. Overall survival for patients with biallelic ATM alterations was also significantly reduced compared with those with ATM wild type or ATM mutation alone (median, 42.2 v 85.5 v 77.6 months, respectively). Conclusion The combination of 11q deletion and ATM mutation in CLL is associated with significantly shorter progression-free and overall survival following first-line treatment with alkylating agents and purine analogs. Assessment of ATM mutation status in patients with 11q deletion may influence the choice of subsequent therapy.

scholarly journals 34 Extent of resection in glioblastoma: Incorporating clinical and molecular data

2018 ◽  
Vol 45 (S3) ◽  
pp. S7-S7
Author(s):  
Julie Semenchuk ◽  
Marshall Pitz ◽  
Marco Essig ◽  
Pascal Lambert ◽  
Katie Galloway
Keyword(s):  
Overall Survival ◽  
Surgical Resection ◽  
Surgical Outcomes ◽  
Progression Free Survival ◽  
Residual Tumor ◽  
Extent Of Resection ◽  
Volumetric Analysis ◽  
Wild Type ◽  
Multivariable Models ◽  
The Impact

Background: The benefits of increasing extent of resection (EOR) for both overall survival and progression-free survival (PFS) in glioblastoma has been well documented. However, models predicting surgical outcomes have failed to incorporate a patient’s IDH status, a known prognostic factor. We isolate the impact of IDH on surgical outcomes. We determine the effect modification of increasing EOR and decreasing residual tumor volume (RTV) on IDH status. Methods: We performed a retrospective cohort study of 98 patients with glioblastoma who had undergone either biopsy or surgical resection. Tumor volumes were determined by volumetric analysis. Univariable and multivariable Cox PH Regression models were built using overall survival and PFS as endpoints. Results: Increasing EOR and decreasing RTV were both associated with prolonged overall survival and PFS. When IDH status was added to multivariable models, the model utilizing RTV provided a slightly better fit compared to EOR. An interaction term between RTV and IDH status was characterized, such that at low RTVs the prognosis of an IDH mutant is significantly better than that of an IDH wild-type, an effect that is less important as RTV increases. The significance of this term was confirmed by improved fit upon insertion into multivariable models. Conclusion: Minimizing RTV and increasing EOR are important prognostic factors for both IDH wild-type and IDH mutant glioblastoma. The protective benefit of the IDH mutation at lower RTVs suggests these patients are the best candidates for aggressive surgical resection.

scholarly journals Simpson's Paradox and the Impact of Different DNMT3A Mutations on Outcome in Younger Adults With Acute Myeloid Leukemia

2015 ◽  
Vol 33 (18) ◽  
pp. 2072-2083 ◽  
Author(s):  
Rosemary E. Gale ◽  
Katarina Lamb ◽  
Christopher Allen ◽  
Dima El-Sharkawi ◽  
Cassandra Stowe ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hazard Ratio ◽  
Prognostic Impact ◽  
Wild Type ◽  
Simpson’S Paradox ◽  
Simpson's Paradox ◽  
The Impact ◽  
Acute Myeloid

Purpose To evaluate the impact of DNMT3A mutations on outcome in younger patients with cytogenetic intermediate-risk acute myeloid leukemia. Patients and Methods Diagnostic samples from 914 patients (97% < 60 years old) were screened for mutations in DNMT3A exons 13 to 23. Clinical outcome was evaluated according to presence or absence of a mutation and stratified according to type of mutation (R882, non-R882 missense, or truncation). Results DNMT3A mutations (DNMT3AMUT) were identified in 272 patients (30%) and associated with a poorer prognosis than wild-type DNMT3A, but the difference was only seen when the results were stratified according to NPM1 genotype. This example of Simpson's paradox results from the high coincidence of DNMT3A and NPM1 mutations (80% of patients with DNMT3AMUT had NPM1 mutations), where the two mutations have opposing prognostic impact. In the stratified analyses, relapse in patients with DNMT3AMUT was higher (hazard ratio, 1.35; 95% CI, 1.07 to 1.72; P = .01), and overall survival was lower (hazard ratio, 1.37; 95% CI, 1.12 to 1.87; P = .002). The impact of DNMT3AMUT did not differ according to NPM1 genotype (test for heterogeneity: relapse, P = .4; overall survival, P = .9). Further analysis according to the type of DNMT3A mutation indicated that outcome was comparable in patients with R882 and non-R882 missense mutants, whereas in those with truncation mutants, it was comparable to wild-type DNMT3A. Conclusion These data confirm that presence of a DNMT3A mutation should be considered as a poor-risk prognostic factor, irrespective of the NPM1 genotype, and suggest that further consideration should be given to the type of DNMT3A mutation.

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