scholarly journals Divergent Modes of Tumor Evolution Underlie Histological Transformation and Early Progression of Follicular Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1091-1091
Author(s):  
Fong Chun Chan ◽  
Robert Kridel ◽  
Anja Mottok ◽  
Merrill Boyle ◽  
Pedro Farinha ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Genetic Drift ◽  
Early Treatment ◽  
Research Funding ◽  
Tumor Evolution ◽  
Clinical Events ◽  
Mutational Burden ◽  
Histological Transformation ◽  
Early Progression ◽  
Evolution Modeling

Abstract Introduction: Follicular lymphoma (FL) remains a significant clinical burden as it is an incurable disease and most patients will eventually suffer from disease progression. Two clinical events are associated with poor outcomes for patients with FL: (1) histological transformation (TFL) of their original FL into a high-grade, aggressive lymphoma subtype (2-3% of patients per year) and (2) early disease progression (PFL) where patients experience treatment failure within 2 years of receiving therapy (20% of patients). Despite recent high-throughput sequencing studies, the nature of tumor clonal dynamics leading to TFL or PFL is poorly understood and it is unknown if similar, or contrasting, modes of selection underpin these FL clinical events. Materials & Methods:We assembled a study cohort consisting of 21 patients: 15 experiencing TFL and 6 PFL. For each TFL and PFL patient, we obtained primary biopsies (T1; taken at the time of the initial FL diagnosis), biopsies at transformation/progression (T2) and matched normal samples. We performed whole genome sequencing on each specimen and identified single point mutations and copy number alterations using MutationSeq and TITAN, respectively. We compared T1 to T2 somatic mutation profiles and identified mutations associated with extinction of T1 clones and expansion of T2 clones. To validate these patterns, we selected 192 positions from each patient for deep-targeted sequencing validation (~10733X) in their T1, T2, and normal samples. We applied a statistical model (PyClone) to estimate cancer cell fraction (CCF) of each validated mutation. These CCF estimates were used to construct clonal phylogenies (Citup) and infer clonal dynamic patterns during their evolutionary histories. The Wright-Fisher model of genetic drift was used to model tumor evolution. Results: Temporal analysis of mutational burden revealed that mutational burden was significantly higher in T2 (8162 mutations ± 2146) than in T1 (6373 ± 2630) tumors for both TFL and PFL patients (Wilcox P < 0.001). This was independent of time interval between sampling (Spearman R2 = 0.029, P = 0.456). Mutation variant allelic fraction (VAF) distributions revealed that all distributions showed evidence of shared clonal ancestry between T1 and T2 tumors accompanied by substantial numbers of T1 and T2-specific mutations. We selected ≥ 192 mutations per patient from these distributions and performed deep-targeted amplicon sequencing, validating 96.3% of mutations and acquiring precise VAFs to infer clonal dynamics. In 13 of 15 TFL patients (87%), we observed dramatic clonal dynamics, characteristic of T2 tumors dominated by clones (or phylogenetic lineages) that were absent or extremely rare in T1 tumors (< 1% CCF). Digital droplet PCR was used to confirm the existence of both scenarios (confirming a clone as rare as 2 out of approximately 105 cells). Tumor evolution modeling demonstrated that this mode of evolution was driven through positive selection for mutations that confer fitness advantages and not by genetic drift. In contrast, PFL patients exhibited markedly different patterns of clonal dynamics compared to TFL patients. 4 of 6 PFL patients (67%) harbored readily detectable clones at T1, which expanded to full clonal prevalence during treatment with immuno-chemotherapy. Tumor evolution modeling demonstrated that this mode of evolution could be explained under neutral evolutionary dynamics (drift). Conclusions: We have shown that histological transformation and early progression manifest through divergent modes of tumor evolution. As the transformation phenotype may arise after diagnosis, more frequent monitoring of these patients will be required to determine the exact timing of the evolutionary inflection point that elicits transformation. In comparison, prediction of early treatment resistance should be achievable through comprehensive characterization of the genetic and clonal composition at diagnosis; this would ultimately identify patients who may benefit from upfront alternative therapies without the need to first endure predictable early treatment failure. Disclosures Sehn: roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Connors:Millennium Takeda: Research Funding; Seattle Genetics: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding; NanoString Technologies: Research Funding. Scott:Janssen: Consultancy; Celgene: Consultancy; Roche: Honoraria; BC Cancer Agency: Patents & Royalties: Inventor on a patent licensed to NanoString Technologies.

Targeted Sequencing Reveals Novel Gene Mutations Associated with Transformation and Early Progression in Follicular Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2919-2919
Author(s):  
Robert Kridel ◽  
Fong Chun Chan ◽  
Anja Mottok ◽  
Merrill Boyle ◽  
Pedro Farinha ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Research Funding ◽  
Progressive Disease ◽  
High Risk Patient ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Aggressive Lymphoma ◽  
Lower Sensitivity ◽  
Histological Transformation ◽  
Early Progression

Abstract Introduction : Follicular lymphoma (FL) remains an incurable malignancy as patients eventually experience progressive disease. A subset of patients is at risk of early lymphoma-related mortality due to histological transformation (TFL) to aggressive lymphoma (2-3% of patients per year) or early progression after immuno-chemotherapy, each of which leads to shortened survival. Mutations associated with transformation and/or early progression have been reported in the literature (e.g. CDKN2A, TP53, B2M) and the m7-FLIPI clinico-genetic risk model defines a high-risk patient group with poor failure-free survival after first-line treatment. However, the current knowledge of genetic alterations underlying transformation and/or early progression is inadequate to explain the majority of transformed cases and accurately predict early progressive disease. Materials and Methods: We performed targeted capture-based sequencing of 94 genes in a large cohort of fresh-frozen and formalin-fixed and paraffin-embedded patient specimens (402 samples in total). This cohort comprised 277 samples from 159 patients that experienced transformation (including 128 samples at T1 (the time of FL) and 149 samples at T2 (the time of transformation) with 118 paired biopsies) and 125 samples from 125 patients (pre-treatment samples only) presenting with either early progression within 2.5 years after starting immunochemotherapy (n=41) or late or never progression for at least 5 years after starting immunochemotherapy or observation (n=84). Mutations were called using MutationSeq and putative single nucleotide polymorphisms were filtered out using either matching germline samples (n=84) or dbSNP (v147). Bayesian proportion tests were used to compare the prevalence of gene mutations between groups. Results : We first compared T1 (n=128) and T2 (n=149) samples from 159 patients experiencing transformation. Eleven genes were more commonly altered in transformed lymphoma. These included genes that had previously been associated with transformation, such as TP53, B2M, MYC and EBF1, as well as genes that have not yet been implicated as contributing to this process, for example EZH2, CCND3, PIM1 and ITPKB. Moreover, mutations in GNA13, S1PR2 and P2RY8, that have been implicated in dissemination of germinal centre B cells, were enriched in T2 samples. In addition, cell-of-origin classification was available for 108 of the TFL cases with DLBCL histology, 18 and 90 of which were of the ABC and GCB subtype, respectively. Although the number of ABC-TFL cases was small, we observed higher percentages of BCL10 (16% versus 1%, Fisher P=0.004), CD79B (22% versus 4%, Fisher P=0.005) and MYD88 mutations (28% versus 9%, P=0.006) in ABC-TFL than in GCB-TFL, suggesting that B-cell receptor signaling and NF-κB signaling are important contributors to the ABC phenotype in TFL. Next, we assessed the association of gene mutations with patient outcomes contrasting early progressers (n=41) and late or non-progressers (n=84). Eleven genes were mutated more commonly in early progressers than in late progressers, including KMT2C, TP53, BTG1, MKI67, XBP1 and SOCS1. Overall, 32 out of 41 early progressers (78%) had mutations in at least one of the 11 early progression-associated genes, but none of the individual early progression-associated genes were mutated at a frequency > 22%. Thus, early progression appears to be related to relatively infrequent genetic alterations. None of the early progression-associated gene mutations form part of the m7-FLIPI outcome predictor. Furthermore, in our cohort that was enriched for clinical extremes, the m7-FLIPI was similarly associated with early progression when compared to the FLIPI but it was not superior, having higher specificity (89% versus 76%), but lower sensitivity (36% versus 63%). Conclusions: We found novel associations of gene mutations with transformation and showed that TFL is molecularly heterogeneous, with the ABC subtype being characterized by differential gene mutation when compared to the GCB subtype. With regards to progressive disease after immuno-chemotherapy, our approach identified early progression as a distinct clinico-genetic disease category that is imperfectly captured by traditional prognostic tools. Disclosures Connors: Seattle Genetics: Research Funding; Bristol Myers Squib: Research Funding; F Hoffmann-La Roche: Research Funding; NanoString Technologies: Research Funding; Millennium Takeda: Research Funding. Scott:NanoString Technologies: Patents & Royalties: named inventor on a patent for molecular subtyping of DLBCL that has been licensed to NanoString Technologies.

scholarly journals Early Treatment Failure in Intermediate-Risk Rhabdomyosarcoma: Results From IRS-IV and D9803—A Report From the Children's Oncology Group

2010 ◽  
Vol 28 (27) ◽  
pp. 4228-4232 ◽  
Author(s):  
A. Yuriko Minn ◽  
Elizabeth R. Lyden ◽  
James R. Anderson ◽  
Lynn Million ◽  
Carola A. Arndt ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Treatment Failure ◽  
Early Treatment ◽  
Progressive Disease ◽  
Intermediate Risk ◽  
Oncology Group ◽  
Early Failure ◽  
Early Treatment Failure ◽  
Local Progression ◽  
Early Progression

Purpose The goal of this study was to determine the frequency and clinical features of early treatment failure during induction chemotherapy before protocol radiation therapy for children with intermediate-risk rhabdomyosarcoma (RMS). Patients and Methods Patients with intermediate-risk RMS enrolled onto the Intergroup Rhabdomyosarcoma Study-IV and the Children's Oncology Group D9803 study were reviewed for an early treatment failure. Early failure was defined as failure caused by progressive disease, death as a result of progressive disease, or death as a result of other causes occurring fewer than 120 days from study entry. Patients with parameningeal site RMS with high-risk features who received radiation therapy at week 1 were excluded from analysis. Overall survival (OS) was estimated using the Kaplan-Meier method. Fisher's exact test was used to compare differences between groups. Cumulative incidence of progression was estimated. Results Of 916 patients, 20 (2.2%) were found to have an early disease progression and did not receive planned protocol radiotherapy. Three additional early failures resulted from treatment-related death without progression. Median time to failure was 48 days (range, 7 to 106 days). Nineteen (95%) of the 20 patients experienced progression at their primary site. Five-year OS was 32% (95% CI, 12% to 54%) for patients experiencing an early progression. Conclusion A small proportion of patients with intermediate-risk RMS suffer an early failure as a result of early progression (2.2%) or treatment-related mortality (0.3%). The majority of patients with early progression had a local failure. Earlier radiotherapy could potentially improve outcome by preventing early local progression.

scholarly journals Patterns of Clonal Evolution Assessed By Whole Exome Sequencing during Progression from MDS to AML Are Related to Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4309-4309
Author(s):  
María Abáigar ◽  
Jesús M Hernández-Sánchez ◽  
David Tamborero ◽  
Marta Martín-Izquierdo ◽  
María Díez-Campelo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Clonal Expansion ◽  
Driver Mutations ◽  
Advisory Committees ◽  
Disease Evolution ◽  
Mutational Burden ◽  
Whole Exome ◽  
Leukemic Phase

Abstract Introduction: Myelodysplastic syndromes (MDS) are hematological disorders at high risk of progression to acute myeloid leukemia (AML). Although, next-generation sequencing has increased our understanding of the pathogenesis of these disorders, the dynamics of these changes and clonal evolution during progression have just begun to be understood. This study aimed to identify the genetic abnormalities and study the clonal evolution during the progression from MDS to AML. Methods: A combination of whole exome (WES) and targeted-deep sequencing was performed on 40 serial samples (20 MDS/CMML patients evolving to AML) collected at two time-points: at diagnosis (disease presentation) and at AML transformation (disease evolution). Patients were divided in two different groups: those who received no disease modifying treatment before they transformed into AML (n=13), and those treated with lenalidomide (Lena, n=2) and azacytidine (AZA, n=5) and then progressed. Initially, WES was performed on the whole cohort at the MDS stage and at the leukemic phase (after AML progression). Driver mutations were identified, after variant calling by a standardized bioinformatics pipeline, by using the novel tool "Cancer Genome Interpreter" (https://www.cancergenomeinterpreter.org). Secondly, to validate WES results, 30 paired samples of the initial cohort were analyzed with a custom capture enrichment panel of 117 genes, previously related to myeloid neoplasms. Results: A total of 121 mutations in 70 different genes were identified at the AML stage, with mostly all of them (120 mutations) already present at the MDS stage. Only 5 mutations were only detected at the MDS phase and disappeared during progression (JAK2, KRAS, RUNX1, WT1, PARN). These results suggested that the majority of the molecular lesions occurring in MDS were already present at initial presentation of the disease, at clonal or subclonal levels, and were retained during AML evolution. To study the dynamics of these mutations during the evolution from MDS/CMML to AML, we compared the variant allele frequencies (VAFs) detected at the AML stage to that at the MDS stage in each patient. We identified different dynamics: mutations that were initially present but increased (clonal expansion; STAG2) or decreased (clonal reduction; TP53) during clinical course; mutations that were newly acquired (BCOR) or disappearing (JAK2, KRAS) over time; and mutations that remained stable (SRSF2, SF3B1) during the evolution of the disease. It should be noted that mutational burden of STAG2 were found frequently increased (3/4 patients), with clonal sizes increasing more than three times at the AML transformation (26>80%, 12>93%, 23>86%). Similarly, in 4/8 patients with TET2 mutations, their VAFs were double increased (22>42%, 15>61%, 50>96%, 17>100%), in 2/8 were decreased (60>37%, 51>31%), while in the remaining 2 stayed stable (53>48%, 47>48%) at the AML stage. On the other hand, mutations in SRSF2 (n=3/4), IDH2 (n=2/3), ASXL1 (n=2/3), and SF3B1 (n=3/3) showed no changes during progression to AML. This could be explained somehow because, in leukemic phase, disappearing clones could be suppressed by the clonal expansion of other clones with other mutations. Furthermore we analyzed clonal dynamics in patients who received treatment with Lena or AZA and after that evolved to AML, and compared to non-treated patients. We observed that disappearing clones, initially present at diagnosis, were more frequent in the "evolved after AZA" group vs. non-treated (80% vs. 38%). By contrast, increasing mutations were similar between "evolved after AZA" and non-treated patients (60% vs. 61%). These mutations involved KRAS, DNMT1, SMC3, TP53 and TET2among others. Therefore AZA treatment could remove some mutated clones. However, eventual transformation to AML would occur through persistent clones that acquire a growth advantage and expand during the course of the disease. By contrast, lenalidomide did not reduce the mutational burden in the two patients studied. Conclusions: Our study showed that the progression to AML could be explained by different mutational processes, as well as by the occurrence of unique and complex changes in the clonal architecture of the disease during the evolution. Mutations in STAG2, a gene of the cohesin complex, could play an important role in the progression of the disease. [FP7/2007-2013] nº306242-NGS-PTL; BIO/SA52/14; FEHH 2015-16 (MA) Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Arry: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Which One, Generic Vs Original Glivec Is More Effective in Patients with Chronic Myeloid Leukemia?

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4156-4156
Author(s):  
Ekin Kircali ◽  
Guldane Cengiz Seval ◽  
Sinem Civriz Bozdag ◽  
Selami Kocak Toprak ◽  
Meltem Kurt Yuksel ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Research Funding ◽  
Chronic Phase ◽  
Response Rates ◽  
Molecular Response ◽  
Optimal Response ◽  
Generic Group ◽  
Significant Difference ◽  
Generic Groups ◽  
Support Research

Introduction:Generic imatinib formulations are increasingly being used as more affordable alternatives worldwide and a few studies have evaluated the safety and efficacy of these formulations prospectively. We have retrospectively analyzed our CML cohort in terms of first line treatment of Glivec versus generic imatinib. This study aims to evaluate the safety and efficacy of generic imatinib products in chronic phase chronic myeloid leukemia as first line treatment. Methods:We have retrospectively analyzed our CML cohort from January 2000 to December 2018 treated with either Glivec or one of generic imatinib formulations. All of our patients (with 1 exception) were initiated imatinib in chronic phase in less than 56 days from diagnosis. All of our patients were followed in accordance with European Leukemia Net (ELN) 2013 recommendations and national hematology association CML guidelines and response definitions were applied according to ELN 2013 criteria. Event free survival (EFS) was defined as the time between treatment initiation and either loss of hematological response, progression to accelerated phase (AP) or blastic phase (BP), or death from any cause. Progression free survival was defined as the time between treatment initiation and transformation to AP, BP or death while on imatinib. For statistical analyses SPSS version 21.0 was used. All p values < 0.05 were considered statistically significant. Results:A total of 192 patients were analyzed comparing 102 (53.1 %) patients on Glivec with 90 patients on (476.9 %) generic formulations. 99 (51.6 %) were female patients. The median age of our population was median 46 years (14-88 years) for Glivec and median 51 years (19-79 years) for generic group (p=0.01). Risk stratifications according to Sokal, Hasford and ELTS scores were run for both Glivec and generic formulation groups. Most of the patients had low risk according to Sokal (137, 71.4%) and Hasford (116, 60.4 %) but intermediate risk according to ELTS (113, 58.9 %) scoring systems. There was no statistically significant difference in the gender distribution, Sokal, Hasford, ELTS scores and ECOG between the two groups. The median time to initiate imatinib treatment was 23.5 (1- 156) days for Glivec group and 13 (1- 51) days generic group (p< 0.05). But the late onset of the treatment was not associated with treatment failure or death. The median follow up was 119.8 (3.7- 250.5) months for Glivec group and 43.6 (2- 150) months for generic groups, respectively (p< 0.05). This difference might be explained by the fact that Glivec has been on the market for about two decades. Similar rates of grade> 2 hematological and non- hematological toxicity were seen in Glivec (4.9 %) and generic groups (3.3 %), respectively (p> 0.05). The rates of treatment failure at 3 months were significantly higher in generic formulation (6.7 %) group than Glivec (2.9 %) group (p< 0.05). Also, the rates of treatment failure at 6 months were significantly higher in generic formulation (3.3 %) group than Glivec (0.9 %) group (p< 0.05). Optimal molecular response rate at 3 months was 76.5 % (n=78) for Glivec and 32.2 % (n=29) for generic groups (p< 0.001). Also, optimal molecular response rate at 6 months was 69.6 % (n=71) for Glivec and 45.6 % (n=41) for generic groups (p= 0.01). Median EFS was found significantly higher for Glivec group compared to generic group (168 mos (95% CI: 159-177 mos) vs 74.6 mos (95% CI: 56-93); p<0.001) (Figure). Conclusion: We found that complete hematological response rates at 3 and 6 months were similar in both groups, but in early phase of treatment the optimal response rates of Glivec group was statistical significantly higher than generic group. Generic group presented with a lower rate of optimal response at 3 months but 13.4 % improvement in optimal response rates was observed at six months. No significant difference in safety concerns was observed between the groups. We recommend that these results from single center should be clarified in a prospective, randomized study including larger population. Figure Disclosures Özcan: AbbVie: Other: Travel support, Research Funding; MSD: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Other: Travel support; BMS: Other: Travel support; Jazz: Other: Travel support; Sanofi: Other: Travel support; Abdi Ibrahim: Other: Travel support; Janssen: Other: Travel support, Research Funding; Bayer: Research Funding; Celgene Corporation: Research Funding, Travel support; Takeda: Honoraria, Other: Travel support, Research Funding; Archigen: Research Funding; Roche: Other: Travel support, Research Funding. Beksac:Celgene: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Mycobacterium abscessus Complex Infections: A Retrospective Cohort Study

2018 ◽  
Vol 5 (2) ◽  
Author(s):  
Maroun Sfeir ◽  
Marissa Walsh ◽  
Rossana Rosa ◽  
Laura Aragon ◽  
Sze Yan Liu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cohort Study ◽  
Renal Disease ◽  
Treatment Failure ◽  
Retrospective Cohort Study ◽  
Early Treatment ◽  
Retrospective Cohort ◽  
Positive Culture ◽  
Mycobacterium Abscessus ◽  
Early Treatment Failure

Abstract Background Infections caused by Mycobacterium abscessus group strains are usually resistant to multiple antimicrobials and challenging to treat worldwide. We describe the risk factors, treatment, and clinical outcomes of patients in 2 large academic medical centers in the United States. Methods A retrospective cohort study of hospitalized adults with a positive culture for M. abscessus in Miami, Florida (January 1, 2011, to December 31, 2014). Demographics, comorbidities, the source of infection, antimicrobial susceptibilities, and clinical outcomes were analyzed. Early treatment failure was defined as death and/or infection relapse characterized either by persistent positive culture for M. abscessus within 12 weeks of treatment initiation and/or lack of radiographic improvement. Results One hundred eight patients were analyzed. The mean age was 50.81 ± 21.03 years, 57 (52.8%) were females, and 41 (38%) Hispanics. Eleven (10.2%) had end-stage renal disease, 34 (31.5%) were on immunosuppressive therapy, and 40% had chronic lung disease. Fifty-nine organisms (54.6%) were isolated in respiratory sources, 21 (19.4%) in blood, 10 (9.2%) skin and soft tissue, and 9 (8.3%) intra-abdominal. Antimicrobial susceptibility reports were available for 64 (59.3%) of the patients. Most of the isolates were susceptible to clarithromycin, amikacin, and tigecycline (93.8%, 93.8%, and 89.1%, respectively). None of the isolates were susceptible to trimethoprim/sulfamethoxazole, and only 1 (1.6%) was susceptible to ciprofloxacin. Thirty-six (33.3%) patients early failed treatment; of those, 17 (15.7%) died while hospitalized. On multivariate analysis, risk factors significantly associated with early treatment failure were disseminated infection (odds ratio [OR], 11.79; 95% confidence interval [CI], 1.53–81.69; P = .04), acute kidney injury (OR, 6.55; 95% CI, 2.4–31.25; P = .018), organ transplantation (OR, 2.37; 95% CI, 2.7–23.1; P = .005), immunosuppressive therapy (OR, 2.81; 95% CI, 1.6–21.4; P = .002), intravenous amikacin treatment (OR, 4.1; 95% CI, 0.9–21; P = .04), clarithromycin resistance (OR,79.5; 95% CI, 6.2–3717.1, P &lt; .001), and presence of prosthetic device (OR, 5.43; 95% CI, 1.57–18.81; P = .008). Receiving macrolide treatment was found to be protective against early treatment failure (OR, 0.13; 95% CI, 0.002–1.8; P = .04). Conclusions Our cohort of 108 M. abscessus complex isolates in Miami, Florida, showed an in-hospital mortality of 15.7%. Most infections were respiratory. Clarithromycin and amikacin were the most likely agents to be susceptible in vitro. Resistance to fluoroquinolone and trimethoprim/sulfamethoxazole was highly common. Macrolide resistance, immunosuppression, and renal disease were significantly associated with early treatment failure.

scholarly journals Predictors of recurrence, early treatment failure and death from Staphylococcus aureus bacteraemia: Observational analyses within the ARREST trial

2019 ◽  
Vol 79 (4) ◽  
pp. 332-340 ◽  
Author(s):  
Alexander Szubert ◽  
Sarah Lou Bailey ◽  
Graham S. Cooke ◽  
Tim Peto ◽  
Martin J. Llewelyn ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Treatment Failure ◽  
Early Treatment ◽  
Early Treatment Failure ◽  
Predictors Of Recurrence

Elevated Pretreatment CEA and CA19-9 Levels are Related to Early Treatment Failure in Esophageal Adenocarcinoma

2019 ◽  
Vol 42 (4) ◽  
pp. 345-350
Author(s):  
Rosa T. van der Kaaij ◽  
Francine E.M. Voncken ◽  
Jolanda M. van Dieren ◽  
Petur Snaebjornsson ◽  
Catharina M. Korse ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Esophageal Adenocarcinoma ◽  
Early Treatment ◽  
Early Treatment Failure

Limited Value of CA 19-9 in Predicting Early Treatment Failure in Patients with Advanced Pancreatic Cancer

Oncology ◽  
2009 ◽  
Vol 77 (2) ◽  
pp. 140-146 ◽  
Author(s):  
Laurenz Vormittag ◽  
Andreas Gleiss ◽  
Werner Scheithauer ◽  
Fritz Lang ◽  
Friedrich Laengle ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Treatment Failure ◽  
Early Treatment ◽  
Advanced Pancreatic Cancer ◽  
Early Treatment Failure

The Efficacy of Retreatment With the Same Medication for Early Treatment Failure of Bacterial Vaginosis

2009 ◽  
Vol 36 (11) ◽  
pp. 711-713 ◽  
Author(s):  
Katherine E. Bunge ◽  
Richard H. Beigi ◽  
Leslie A. Meyn ◽  
Sharon L. Hillier
Keyword(s):  
Treatment Failure ◽  
Bacterial Vaginosis ◽  
Early Treatment ◽  
Early Treatment Failure

Racial Variations in Mutational Profile in Newly Diagnosed Acute Myeloid Leukemia Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-41
Author(s):  
Tahsin Anwar ◽  
Mohammed Mian ◽  
Mahran Shoukier ◽  
Achuta K Guddati ◽  
Moinul Hossain ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Suppressors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Cohesin Complex ◽  
Newly Diagnosed ◽  
Mutational Burden ◽  
Epigenetic Modifiers ◽  
Kinase Pathway ◽  
Acute Myeloid

Background: Increasing evidence shows the impact of mutational burden in acute myeloid leukemia (AML) and impact on clinical response. Classifying these mutations into exclusive sub-types that are mutually exclusive was recently attempted. We sought to identify differences in mutational burden in AML patients based on race. Methods: We retrospectively reviewed the patient charts to distinguish the mutational markers of AML that substantially impact the outcome of AML. We categorized the mutations in seven functional groups with mutually exclusive mutations Signaling and kinase pathway (FLT3, KRAS, NRAS, KIT, PNPN1, JAK2, CBL), Epigenetic modifiers (DNMT3A, IDH1, IDH2, TET2, ASXL1, EZH2, and MLL/KMT2A), Nucleophosmin (NPM1), Transcription factors (CEBPA, RUNX1, and GATA2), Tumor suppressors (TP53), Spliceosome complex (SRSF2, U2AF1, SF3B1, and ZRSR2), and Cohesin complex (RAD21, STAG1, STAG2, SMC1A, and SMC3). For estimating racial distribution, we included only Whites and African Americans (AA) in the study as they represent 95% of the total population at our Cancer Center. Remission and relapse were defined per standard guidelines. We compiled data of all newly diagnosed AML patients treated at our institution between 2016 to the end of 2019. Both next generation sequencing (NGS) and Polymerase Chain Reaction (PCR) methods of genetic marker recognition techniques were included in the study. Results: 159 patients with AML were included in the analysis. We excluded seven patients of different race, including Asian (n=2), Hispanic (n=3), and unknown (n=2). The median age of the patients at diagnosis were 47 years (range 14 - 84 years), 73.3 % were white Caucasian, and 52.8% were female. The median age for white and African American (AA) patients was similar (47 vs 42 year respectively, p=0.55659), however, AAs have more female than Whites (65.9% vs. 47.8%, p=0.04164). In descriptive analysis of genetic marker mutation distributions between Whites and AA we observed signaling and kinase pathway 26.9% vs 25%, p=0.80231; epigenetic modifiers 14.8% vs 25%, p=0.13144; nucleophosmin 14.8% vs 13.6%, p=85460; transcription factors 5.2% vs 6.82%, p=0.69686; tumor suppressors 7.8% vs 0%; spliceosome complex 6.1% vs 2.3%, p=0.32647 and cohesin complex 1% vs 0%, respectively. Overall, 32.2% achieved complete remission (CR), 21.5% complete remission with incomplete hematologic recovery (CRi) and 45.6% Refractory. The CR + CRi rates of Whites and AA were not statistically significant (54.8% vs 52.3% respectively, p=0.77699). The median number of induction required for CR in both races was the same (2 and 2, respectively). We did not find any differences in number of induction for achieving CR by race. However, the rate of relapse was higher in white patients than in AA (49.1% vs 31.8%, respectively) (p=0.05039). Conclusion: This analysis suggests that there might be variations in functional categories of mutations markers in AML patients by race, tumor suppressors (TP53) found more frequently in whites and epigenetic modifiers in AA. This might be at least in part the reason for a higher relapse rate among whites. Additional studies and larger cohorts are needed to further explore the correlation between race, molecular markers and outcomes for AML. Figure Disclosures Cortes: Daiichi Sankyo:Consultancy, Research Funding;Astellas:Research Funding;BioPath Holdings:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda:Consultancy, Research Funding;Pfizer:Consultancy, Research Funding;Telios:Research Funding;Jazz Pharmaceuticals:Consultancy, Research Funding;Merus:Research Funding;Immunogen:Research Funding;BiolineRx:Consultancy, Research Funding;Bristol-Myers Squibb:Research Funding;Arog:Research Funding;Amphivena Therapeutics:Research Funding;Novartis:Consultancy, Research Funding;Sun Pharma:Research Funding.Kota:Novartis:Consultancy;Pfizer:Consultancy.

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