scholarly journals Post-azacitidine clone size predicts long-term clinical outcome of patients with myelodysplastic syndromes and related myeloid neoplasms

2021 ◽  
Author(s):  
Seishi Ogawa ◽  
Magnus Tobiasson ◽  
Shinya Sato ◽  
Elsa Bernard ◽  
Shigeki Ohtake ◽  
...  
Keyword(s):  
High Risk ◽  
Clinical Outcome ◽  
Clinical Response ◽  
Post Treatment ◽  
Clone Size ◽  
Myeloid Neoplasms ◽  
Mutational Profiling ◽  
Before And After ◽  
Pre Treatment ◽  
Next Generation Sequencing Ngs

Abstract Azacitidine is a mainstay of therapy for high-risk MDS and other myeloid neoplasms. A significant correlation between azacitidine response and clinical outcome suggests a potential role of mutational profiling based on next-generation sequencing (NGS) before and after therapy in evaluating response and predicting overall survival (OS), which however has not fully elucidated. Here through NGS-based mutational profiling of large cohorts (n=451) of azacitidine-treated patients with high-risk MDS and other myeloid neoplasms, we show significant roles of multi-hit TP53 and germline DDX41 mutations in pre-treatment samples and post-treatment clone size in the evaluation/prediction of azacitidine response and OS after azacitidine therapy, which outperformed the prediction based only on clinical response and IPSS-R score. Post-treatment clone size strongly correlated with clinical response with exception of large persistent mutations frequently affecting TET2 after achieving complete remission and those with DDX41 mutations, which poorly correlated with clinical response. Our results highlight the importance of evaluating mutations in both pre- and post-treatment samples in the assessment of response and the prediction of OS after azacitidine therapy.

scholarly journals Post-Treatment Clone Size Predicts Survival Independently of IPSS-R and Response after Azacitidine Therapy for MDS.

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-13
Author(s):  
Yasuhito Nannya ◽  
Magnus Tobiasson ◽  
Shinya Sato ◽  
Elsa Bernard ◽  
Maria Creignou ◽  
...  
Keyword(s):  
Clinical Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Post Treatment ◽  
Private Company ◽  
Advisory Committees ◽  
Clone Size ◽  
Otsuka Pharmaceutical ◽  
Pre Treatment

Background DNA hypomethylating agents (HMAs), including azacytidine (AZA) have been established as key drugs for higher-risk myelodysplastic syndromes (MDS). We and others have explored the role of mutation profile before AZA administration on predicting outcomes. Actually, we have previously identified mutated-TP53 as a marker associated with higher rate of achieving complete remission (CR). In addition, mutations in TP53 and DDX41 predicted reduced and prolonged survival after treatment, respectively. However, the clinical significance of evaluating clone size changes early after treatment has not been determined. In this study, we explored the role of post-treatment clone size in predicting outcomes of AZA treatment for MDS and related diseases. Methods We enrolled 290 AZA-treated cases, including 88 from a Japanese prospective study (JALSG MDS-212 trial), 149 from Karolinska Institute, and 53 from a retrospectively collected Japanese cases. The diagnoses were MDS (n=242), MDS/MPN (n=25), and AML-MRC (n=23). For all patients, tumor samples were collected both before and after AZA administration and were analyzed for mutations in 66 genes implicated in myeloid neoplasms using targeted-capture sequencing. The median cycles of AZA treatment before sampling was 4 (range 1-7). Clone size was calculated from variant allele frequency adjusted for ploidy or allelic imbalances.Survival was calculated with a Cox regression model. Results In post-treatment samples, we identified 870 mutations in 51 genes in 255 (88%) patients with a median of 3 mutations per sample, while 943 mutations were seen in 279 (96%) patients in the pre-treatment samples. Most frequently detected mutations in post-treatment samples were seen in TET2, TP53, RUNX1, and ASXL1. Germline DDX41 mutations were excluded from clone size evaluation. Median clone sizes were 0.63 and 0.54 for pre-treatment and post-treatment samples (P=.011), respectively. The largest clone sizes (max(VAF)) in post-treatment samples had a strong negative correlation with hematological response according to IWG criteria (P < .0001). We next explored whether max(VAF) in post-treatment samples provides a more precise estimation of long-term survival than IPSS-R. Max(VAF) further stratified each IPSS-R risk group in subgroups with discrete OS (P < .0001 for IPSS-R very high and P = .0004 for high risk group). Incorporating pre-treatment mutation data (mutations in TP53 and DDX41) and max(VAF) values in addition to IPSS-R scores and clinical response, we constructed a multivariate model and found that all these factors had an independent and significant impact on OS (Figure 1A). Next, we examined whether max(VAF) combined with IPSS-R and clinical response can improve the model. For this purpose, we randomly split the cohort into 75% training and 25% validation subsets and for each split, we constructed different models using the training set, performance of which was evaluated by calculating the concordance index (c-index) using the validation set. The mean c-index in 10,000 simulation sets increased by 0.025 by adding response data to IPSS-R score (I versus IR in Fig 1B). Further improvements were obtained by adding gene mutation and max(VAF), in which the c-index increased by 0.034 (IR versus IGR in Fig 1B) and 0.010 (IGR versus IGRP in Fig 1B), respectively. For the 53 patients who received allogeneic stem cell transplantation, the median post-transplant OS was 82.6 months (range, 36.3 to not reached). Notably, max(VAF) significantly stratified OS after allo-SCT (HR, 3.3; 95%CI, 1.3 to 8.3; P = .014). Conclusions Our study revealed that post-treatment clone size significantly correlated with clinical response and the evaluation of post-treatment clone size allows for more precise prognostication after AZA treatment compared with IPSS-R and clinical response alone. Table Disclosures Naoe: NIPPON SHINYAKU CO.,LTD.: Speakers Bureau; Sysmex co.: Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Speakers Bureau; Bristol-Myers Squibb Company: Speakers Bureau. Miyazaki:Celgene: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Novartis Pharma KK: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Otsuka Pharmaceutical: Honoraria; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Papaemmanuil:Kyowa Hakko Kirin: Consultancy, Honoraria; Prime Oncology: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Illumina: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; MSKCC: Patents & Royalties; Isabl: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Ogawa:Eisai Co., Ltd.: Research Funding; Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding.

Cytoprotective Effect of Tocotrienol-Rich Fraction and α-Tocopherol Vitamin E Isoforms Against Glutamate-Induced Cell Death in Neuronal Cells

2014 ◽  
Vol 84 (3-4) ◽  
pp. 0140-0151 ◽  
Author(s):  
Thilaga Rati Selvaraju ◽  
Huzwah Khaza’ai ◽  
Sharmili Vidyadaran ◽  
Mohd Sokhini Abd Mutalib ◽  
Vasudevan Ramachandran ◽  
...  
Keyword(s):  
Vitamin E ◽  
Cell Viability ◽  
Neuronal Cells ◽  
Positive Control ◽  
Post Treatment ◽  
Mitochondrial Activity ◽  
Before And After ◽  
Pre Treatment ◽  
Tocotrienol Rich Fraction ◽  
Major Mediator

Glutamate is the major mediator of excitatory signals in the mammalian central nervous system. Extreme amounts of glutamate in the extracellular spaces can lead to numerous neurodegenerative diseases. We aimed to clarify the potential of the following vitamin E isomers, tocotrienol-rich fraction (TRF) and α-tocopherol (α-TCP), as potent neuroprotective agents against glutamate-induced injury in neuronal SK-N-SH cells. Cells were treated before and after glutamate injury (pre- and post-treatment, respectively) with 100 - 300 ng/ml TRF/α-TCP. Exposure to 120 mM glutamate significantly reduced cell viability to 76 % and 79 % in the pre- and post-treatment studies, respectively; however, pre- and post-treatment with TRF/α-TCP attenuated the cytotoxic effect of glutamate. Compared to the positive control (glutamate-injured cells not treated with TRF/α-TCP), pre-treatment with 100, 200, and 300 ng/ml TRF significantly improved cell viability following glutamate injury to 95.2 %, 95.0 %, and 95.6 %, respectively (p < 0.05).The isomers not only conferred neuroprotection by enhancing mitochondrial activity and depleting free radical production, but also increased cell viability and recovery upon glutamate insult. Our results suggest that vitamin E has potent antioxidant potential for protecting against glutamate injury and recovering glutamate-injured neuronal cells. Our findings also indicate that both TRF and α-TCP could play key roles as anti-apoptotic agents with neuroprotective properties.

scholarly journals Low frequency of pre-treatment and post-treatment haematological abnormalities in dogs with non-infectious meningoencephalitis treated with cytosine arabinoside and prednisolone

2019 ◽  
Vol 6 (1) ◽  
pp. e000315 ◽  
Author(s):  
Sarah Keegan ◽  
Jeremy H Rose ◽  
Zohra Khan ◽  
Francois-Xavier Liebel
Keyword(s):  
Cytosine Arabinoside ◽  
Standard Dose ◽  
Low Frequency ◽  
Post Treatment ◽  
Inclusion Criteria ◽  
Presumptive Diagnosis ◽  
Prednisolone Treatment ◽  
Before And After ◽  
Pre Treatment ◽  
The Uk

BackgroundCytosine arabinoside (CA) and prednisolone are drugs commonly used together in the management of canine non-infectious meningoencephalitis (NIME). The aim of this study was to report the haematological findings before and after CA and prednisolone treatment and identify any adverse haematological events in this clinical setting, following the veterinary cooperative oncology group established common terminology criteria for recording adverse events following administration of chemotherapy or biological antineoplastic therapy.ResultsWhile 48 patients with a presumptive diagnosis of NIME had pretreatment haematology results, only 12 patients met the inclusion criteria of also having post-treatment haematology results available for review after being treated with prednisolone and CA at a standard dose (200 mg/m2) in a single referral hospital in the UK. Forty-nine post-treatment haematology results were available for these 12 patients.ConclusionsFour adverse haematological events were identified in four patients. None of these events were convincingly attributable to CA administration.

OCT-Angiography as a reliable prognostic tool in laser-treated proliferative diabetic retinopathy: The RENOCTA Study

2020 ◽  
pp. 112067212096345
Author(s):  
Marco Lupidi ◽  
Ramkailash Gujar ◽  
Alessio Cerquaglia ◽  
Jay Chhablani ◽  
Daniela Fruttini ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Proliferative Diabetic Retinopathy ◽  
Additional Treatment ◽  
Post Treatment ◽  
Vascular Perfusion ◽  
Significant Difference ◽  
Before And After ◽  
The Mean ◽  
Pre Treatment ◽  
Induced Changes

Purpose: To quantitatively assess retinal neovascularizations (RNVs) in proliferative diabetic retinopathy (PDR) before and after photocoagulative laser treatment (PLT) using Optical Coherence Tomography Angiography (OCT-A). Methods: Consecutive patients with PDR were examined with fluorescein angiography (FA) and OCT-A before and after PLT. Baseline and after-treatment FA images were quantitatively analyzed to assess both the RNVs area and leakage area. On OCT-A RNVs area, vascular perfusion density (VPD), vessel length density (VLD) and fractal dimension were computed. VPD of the full-retina OCT-A underneath the RNV was determined to evaluate potential laser-induced changes in vascular perfusion. Results: Fifteen eyes of 13 patients with PDR were enrolled. The mean area of the RNVs was 0.47 ± 0.50 mm2 in the baseline OCT-A and 0.32 ± 0.40 mm2 in the post-treatment assessment ( p = 0.0002). The mean RNV VPD of RNV was 2% ± 4% in pre-treatment and 1% ± 1% for the post-treatment ( p = 0.0001). The mean VLD of RNV was 7.26 ± 1.53 at baseline and 6.64 ± 1.65 in the post treatment ( p = 0.0002). A significant difference in terms of mean RNVs area and VPD reduction between eyes that needed additional treatment and those that did not (~40% vs ~20%; p < 0.05), was observed. Mean VPD of full-retinal thickness OCT-angiogram was 55% ± 10% for the pre-treatment and 53% ± 8% for the post treatment scan ( p = 0.02). Conclusion: The quantitative OCT-A assessment of laser-induced changes of RNVs can be a useful non-invasive approach for determining treatment efficacy. A reduction of RNVs area or VPD ⩾ 40% might reveal those eyes that won’t require additional treatment. Retinal perfusion impairment seemed to progress independently from the treatment.

WT1-Peptide Vaccination Shows High Immunogenicity and Clinical Activity in Patients with Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 406-406 ◽  
Author(s):  
Keilholz Ulrich ◽  
Carmen Scheibenbogen ◽  
Anne Letsch ◽  
Anne Marie Asemissen ◽  
Wolf Karsten Hofmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
High Risk ◽  
Clinical Outcome ◽  
Peripheral Blood ◽  
Great Promise ◽  
Clinical Activity ◽  
Peptide Vaccination ◽  
Before And After ◽  
Disease Stabilization

Abstract BACKGROUND: The transcription factor Wilms tumor protein 1 (WT1) holds great promise for immunotherapy of leukemia. WT1 is strongly expressed in the majority of leukemic blasts, is essential for blast proliferation, and is spontaneously immunogenic. METHODS: In the present phase II trial, 12 HLA-A2+ patients with AML without curative treatment option, were vaccinated with WT1.126–134 peptide mixed with adjuvant KLH as T-helper protein and GM-CSF 4 times bi-weekly, then monthly. RESULTS: Patients characteristics, immune responses and clinical outcome are shown in table 1. Patient characteristics, immunologic response, and clinical outcome Pat FAB/caryotype previous chemotherapy disease status at study onset no. of vaccinations clinical outcome WT1Tetr+ T cells in PB after vaccination WT1Tetr+ T cells in BM after vaccination *PB, peripheral blood; BM, bone marrow; MDS, myelodysplastic syndrome; MPD, myeloproliferative disease. 1 M4 yes 2.PR 15 CR 12 months 0.49% 0.87% 2 M2 11q23 yes 1.CR 18 cCR 30+ months 0.43% 0.91% 3 M2 no PD 4 SD 3 months 0.42% 0.80% 4 M6 yes PD 4 PD neg. neg. 5 M2 yes 1.PR 6 PD 0.37% 0.51% 6 M1 yes 2. PR 9 PD 0.43% 0.40% 7 M2 yes 2.PR 9 PD 2.00% 1.36% 8 M7 yes PD 4 PD neg. neg. 9 M5b yes 2.CR 12 cCR 8+ months 0.44% 0.33% 10 sAML from MDS no PD 12 SD 8 months 0.23% 0.13% 11 sAML from MPS no PD 12 SD 9+ months 0.22% 0.53% 12 M4 no PD 8 SD 3 months 1.11% 1.35% WT1-specific T cells could be detected in 3 patients before vaccination. An induction or enhancement of a T cell response against WT1 was observed in 10 of 12 patients after 2 – 6 vaccinations ranging from 0.22 to 2.00% (median 0.43%) in peripheral blood and from 0.33 to 1.36% (median 0.80%) in bone marrow as analysed by tetramer and cytokine staining. At study onset 6 patients had progressive AML (PD) with 40 – 90% marrow blasts, 4 patients partial remission (PR) following chemotherapy and two patients complete remission (CR) at high risk for relapse. Four of the 6 patients with progressive AML had disease stabilization for 3, 3, 8 and 9 months, which is ongoing in the latter patient. Disease stabilization was accompanied by a decrease/normalization of peripheral blasts in two patients and a &gt;50% decrease in RBC transfusion requirements in a patient with AML evolved from MDS. One patient with PR at study onset had an early relapse and then achieved CR for 12 months (patient 1). Both patients vaccinated in CR are in continuous hematological CR (cCR) for 8+ and 30+ months (patient 2 and 9). The remaining 5 patients had PD after 4 – 9 vaccinations. Bone marrow WT1 RNA levels as molecular disease marker paralleled the clinical course as they decreased 1 – 2 logs in the 3 patients with CR or cCR after 6 vaccinations (Fig. 1A), stabilized or decreased in all 4 patients with SD (Fig. 1B), and increased 1 – 2 logs in 4 of the 5 patients with PD (Fig. 1B). No significant toxic effects were observed. CONCLUSION: WT1 peptide vaccination can efficiently induce a specific immune response and has clinical activity in the absence of significant toxicity. These results warrant further studies of WT1 vaccination in AML patients at high risk for relapse. Fig. 1 WT1 levels in bone marrow before and after 6 vaccinations in patients with CR or cCR (A), SD (B) or PD (C) after vaccination. Fig. 1. WT1 levels in bone marrow before and after 6 vaccinations in patients with CR or cCR (A), SD (B) or PD (C) after vaccination.

Genetic Landscape and Clonal Evolution Following 5-Aza Therapy in Patients with High-Risk Myelodysplastic Syndromes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4304-4304
Author(s):  
June Takeda ◽  
Yusuke Shiozawa ◽  
Yuichi Shiraishi ◽  
Yusuke Okuno ◽  
Keisuke Kataoka ◽  
...  
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Clonal Evolution ◽  
Clone Size ◽  
Chugai Pharmaceutical ◽  
Before And After ◽  
Targeted Capture ◽  
Post Therapy ◽  
Capture Sequencing

Abstract Background: DNA hypomethylating agents, such as 5-azacitidine (5-aza) and decitabine, comprise the current standard in therapy for patients with high-risk myelodysplastic syndromes (MDS), with dramatic responses in some patients. However, the responses are poorly predictable and their impact on clonal dynamics has not been fully elucidated. Patients and Methods: We enrolled a total of 119 patients with high-risk MDS who were treated with 5-aza . Bone marrow samples were collected before (n = 71) and both before and after (n = 48) treatment and analyzed by targeted-capture sequencing using RNA baits designed for 67 known or putative driver genes in myeloid neoplasms and 1,674 single nucleotide polymorphisms, which enabled detection of both mutations and copy number alterations on the same platform. In 9 of the 48 patients, pre- and post-therapy samples were further analyzed by whole exome sequencing (WES). Results: Average number of driver mutations before 5-aza was 2.8 per patient and 107 (90%) patients had multiple mutations. Most frequently mutated were TP53 (27%), followed by RUNX1, TET2, DNMT3A, and ASXL1. Reflecting high-risk disease subtypes of the subjects, splicing factor mutations were relatively rare (29 %) in the current cohort. Chromosomal abnormalities were identified in 65 (55%) patients, where 7q- and /or 5q- were the most frequent. Among 48 patients with serially collected samples, 46 had one or more mutations, enabling an evaluation of clone dynamics. In total 163 and 146 mutations were detected before and after treatment, respectively. About two thirds (110/163) of the mutations before 5-aza remained detectable after treatment. By contrast, the remaining one third showed a dynamic clonal behavior; 36 mutations in 22 cases were newly acquired, whereas 53 in 28 cases disappeared. Among those newly acquired, most frequently observed were mutations in STAG2 and EP300 (n = 3), of which STAG2 (7 cases) also represented the most frequent targets of disappeared mutations after treatment. In WES in 9 patients, a total of 112 mutations were identified either before or after 5-aza treatment with a mean of 10.4 or 8.9 mutations per sample, respectively. Among these, 63 were found at both pre- and post-therapy samples, whereas 17 and 32 mutations were newly acquired or disappeared during treatment, Given that only 4 newly acquired and 8 lost mutations had been detected by targeted-capture sequencing, respectively, WES enabled more sensitive detection of alternation of clones during 5-aza treatment, which were demonstrated in 8 (89%) subjects, rather than 5 (56%) in targeted-capture sequencing. Clinical outcomes have been reported for 22 patients as of the time of abstract submission; 5 achieved complete remission (CR), 9 stable disease (SD), and 5 progressive disease (PD). Alteration in clone size was frequently associated with clinical response. The size of dominant clones significantly decreased in 4 of 5 cases with CR, whereas stable or increased in 12 of 14 patients with SD or PD. In patients with SD or PD, acquisition of new mutations was common (10/14) during 5-aza treatment and potentially implicated in the resistance to 5-aza-treatment. Of interest, newly acquired mutations were also found in 2 CR samples, albeit at low allele frequency, even though the clone size of dominant clones was substantially reduced, suggesting the evolution of alternative MDS subclones or expansion of preexisting non-leukemic hematopoietic clone. Although CR was achieved in 3 of 6 patients with TP53 mutations, the TP53-mutationsdid not totally disappeared but were still detectable in CR samples in 2 cases, suggesting that TP53 mutated clones have not been completely eradicated by 5-aza treatment. Conclusion: Our study successfully depicted the structure of clones and their dynamics in high-risk MDS on 5-aza treatment. Alteration in the size of the dominant clones was frequently associated with a clinical response. Clonal evolution was common even in patients who achieved CR. Tracking the mutations in MDS patients during 5-aza treatment provides the opportunity to detect clones resistant to 5-aza and might be used to guide 5-aza therapy. Disclosures Kataoka: Kyowa Hakko Kirin: Honoraria; Boehringer Ingelheim: Honoraria; Yakult: Honoraria. Kiyoi:Celgene Corporation: Consultancy; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; AlexionpharmaLLC.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Alexion Pharmaceuticals: Research Funding; MSD K.K.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Phizer Japan Inc.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Zenyaku Kogyo Co.LTD.: Research Funding; Kyowa-Hakko Kirin Co.LTD.: Research Funding; Chugai Pharmaceutical Co. LTD.: Research Funding. Naoe:Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; Astellas Pharma Inc.: Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Amgen Astellas BioPharma K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene K.K.: Honoraria, Research Funding; CMIC Co., Ltd.: Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Pfizer Inc.: Research Funding. Makishima:The Yasuda Medical Foundation: Research Funding. Ogawa:Sumitomo Dainippon Pharma: Research Funding; Kan research institute: Consultancy, Research Funding; Takeda Pharmaceuticals: Consultancy, Research Funding.

Phase II breast cancer chemoprevention study with celecoxib in women at increased risk for breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1010-1010
Author(s):  
B. Arun ◽  
V. Valero ◽  
G. Yin ◽  
G. Babiera ◽  
J. L. Murray ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Atypical Hyperplasia ◽  
Post Treatment ◽  
Short Term ◽  
Ki 67 ◽  
High Risk Women ◽  
Before And After ◽  
The Difference ◽  
Er Expression

1010 Background: Short-term chemoprevention trials offer a convenient model to screen chemopreventive agents and identify endpoint biomarkers. One of the potential agents is celecoxib (C), which has antiproliferative and apoptosis inducing properties. In this prospective study, our primary aim was to evaluate changes in proliferation induced by C in breast tissue of high risk women. Here, we report changes in estrogen receptor (ER) proliferation index. Methods: 42 eligible high risk women were enrolled into the study, underwent fine needle aspiration (FNA) and started celecoxib treatment at 400 mg BID. Median age: 51.9 years. Risk factors: Gail risk > 1.67% (n=13), lobular carcinoma insitu (n=13), atypical hyperplasia (n=11), previous history of breast cancer (n=5). For ER and Ki-67 testing, thin preparations slides were incubated with primary mouse monoclonal antibody 6F11 against the ER and clone MIB-1, respectively. Appropriate negative and positive controls were included. At least 100 epithelial cells were evaluated per slide. Immunoreactivity for each marker was scored as the percentage of positive nuclei. We assessed the difference in ER and Ki-67 levels before and after treatment using a Wilcoxon signed rank test. Results: The average pre-treatment ER expression in FNA samples was 35.9% and Ki-67 was 2.4%. 19 (45%) showed hyperplasia or atypical hyperplasia. 39 patients underwent also post-treatment FNAs. The pre-and post treatment ER expression in this group was 35.7% (range 0–100%) and 27.4% (range: 0–100%), respectively. The difference in ER levels was statistically significant (p = 0.04). Twenty-six patients had Ki-67 levels measured both before and after treatment. The median difference in Ki-67 levels was 0 (range 0- 5). This change was not statistically significant (p = 0.63). Conclusions: We have completed accrual to a prospective short-term chemoprevention trial with celecoxib. We have found a significant downregulation of ER expression with 6 months celecoxib. Since ER expression is a marker of proliferation, this finding confirms celecoxibs antiproliferative properties. Currently, we have not observed a change in Ki-67; this could be partly due to the small number of samples and the fact that Ki-67 is low in normal epithelium. [Table: see text]

IL10, An Independent Predictor of Outcome in HNSCC Patients

2008 ◽  
Vol 139 (2_suppl) ◽  
pp. P90-P90
Author(s):  
Osama Alhamarneh ◽  
Nicholas D. Stafford ◽  
John Greenman
Keyword(s):  
Treatment Group ◽  
Clinical Outcome ◽  
Oral Cavity ◽  
Potential Role ◽  
Tumor Stage ◽  
Post Treatment ◽  
Kaplan Meier ◽  
Tumor Load ◽  
Pre Treatment

Problem To determine the correlation between IL10, a Th2-type inhibitory cytokine, clinical outcome and survival in HNSCC patients. Methods IL10 levels in the serum of newly-presenting, untreated, patients with HNSCC were measured pre-treatment (n=107) and 4–6 weeks after treatment (n=43), and were compared with a cohort of healthy controls (n=40) of similar age and sex. A commercial IL10 ELISA (Biosource) with a minimum detectable level of 0.2 pg/ml was used. Statistical analysis of associations between the levels and detectability of IL10 and clinical outcome and survival were done. Results Both IL10 detectability and levels were significantly higher in patients than in controls (p=0.001). Post treatment, IL10 levels dropped significantly (p=0.02). Pretreatment, IL10 levels were significantly elevated in the advanced stage of the disease (III/IV vs. I/II), in node positive patients and in patients with bulkier tumor load (T3/T4 vs. T1/T2); p=0.005, 0.037 and 0.001 respectively. The larynx (n=36), oropharynx (n=25) and pharynx (n=16) showed significantly higher levels and increased detectability of IL10 in the pre-treatment group when compared to the post treatment group, however, oral cavity tumors (n=21) showed the opposite. Finally, the detectability of IL10 significantly correlated with poorer survival (Kaplan-Meier, p=0.026) after a mean follow up of 15 (range 1–36) months. Conclusion IL10 levels drop significantly once the tumor mass is removed suggesting that this is the most important source of the circulating cytokine. IL10, as well as the tumor bulk, the nodal status and the overall tumor stage, were shown to be independent factors in predicting a poorer clinical outcome and worse survival in tumors originating in the larynx, pharynx and oropharynx, but not oral cavity, suggesting distinct inter-tumour differences. Significance IL10 could play a potential role as a prognostic marker in HNSCC, in addition to the possible manipulation of IL10 in future immunotherapeutic agents.

Association of CD133 expression levels with the k-ras mutation status in rectal cancers before and after preoperative radiochemotherapy.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 400-400
Author(s):  
Thilo Sprenger ◽  
Jochen Gaedcke ◽  
Lena-Christin Conradi ◽  
Peter Jo ◽  
Klaus Jung ◽  
...  
Keyword(s):  
Stem Cells ◽  
Rectal Cancer ◽  
Prognostic Marker ◽  
Tumor Regression ◽  
Post Treatment ◽  
Preoperative Radiochemotherapy ◽  
Cd133 Expression ◽  
Before And After ◽  
Rectal Cancers ◽  
Pre Treatment

400 Background: The role of the potential stem cell marker CD133 as a predictive or prognostic marker in multimodal rectal cancer treatment is currently under debate. While CD133 has been identified as a prognostic marker in rectal cancers after preoperative radiochemotherapy (RCT) it was recently characterized as a very unspecific feature for colorectal cancer stem cells. We therefore analyzed the association between CD133 expression and mutations in the proto-oncogenes K-Ras and PI3K in rectal cancer patients receiving neoadjuvant RCT. Methods: CD133 expression was evaluated immunhistochemically in pre-treatment biopsies and surgical specimens of 128 patients with locally advanced rectal cancers (cUICC II/III) treated with preoperative RCT within the phase-III German Rectal Cancer Trials. K-Ras mutations were analyzed by sequencing of exons 1, 2, and 3. PI3K mutations were detected by sequencing the p110α subunit (PIK3CA) and correlated with histopathologic parameters, tumor regression and survival. Results: CD133 expression was significantly associated with mutations in the K-Ras gene in both pre-treatment biopsies and post-treatment tumor specimens in uni- and multivariate analyses. However, no significant correlation was observed between CD133 and PI3K mutations. Post-treatment CD133 levels were correlated with neoadjuvant RCT (50.4 Gy/5-FU vs. 50.4 Gy/5-FU+Ox) and tumor regression grading. Anyway, there was no significant association between pre- and post-treatment CD133 expression and disease-free survival. Conclusions: CD133 expression levels are strongly associated with mutations in the K-Ras proto-oncogene in rectal cancers before and after preoperative RCT. Our results strengthen the hypothesis that CD133 is not a specific marker for colorectal stem cells but might be integrated in proliferation pathways like the ras-raf axis.

Autologous Lipofilling Improves Clinical Outcome in Patients With Symptomatic Dermal Scars Through Induction of a Pro-Regenerative Immune Response

2021 ◽  
Author(s):  
Maroesjka Spiekman ◽  
Delia L Francia ◽  
Dieuwertje M Mossel ◽  
Linda A Brouwer ◽  
Gilles F H Diercks ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Outcome ◽  
Normal Skin ◽  
Scar Tissue ◽  
Cellular Level ◽  
Clinical Effects ◽  
Scar Assessment ◽  
Before And After ◽  
Pre Treatment ◽  
Epidermal Cell Proliferation

Abstract Background Autologous lipofilling is emerging procedure to augment and possibly reverse dermal scars and to reduce scar-related pain, but its efficacy and mechanisms are poorly understood. Objectives To test the hypothesis that repeated lipografts reverse dermal scars by re-initiation of wound healing. Methods In a prospective, non-placebo controlled clinical study, 27 adult patients with symptomatic scars were given two lipofilling treatments at 3-month intervals. As primary outcome, clinical effects were measured using the patient and observer scar assessment scale (POSAS). Scar biopsies were taken before and after treatments to assess scar remodeling at a cellular level. Results Twenty patients completed the study. Patients’ scars improved after lipofilling. The total POSAS scores (combined patient and observer scores) decreased from 73.2±14.7 points pre-treatment to 46.1±14.0 and 32.3±13.2 after the first and second treatment, respectively. Patient POSAS scores decreased from 37.3±8.8 points to 27.2±11.3 and 21.1±11.4 points, whereas Observer POSAS scores decreased from 35.9±9.5 points, which decreased to 18.9±6.0 and 11.3±4.5 points after the first and second lipofilling treatment, respectively. After each lipofilling treatment, T-lymphocytes, mast cells and M2 macrophages had invaded scar tissue and associated was increased vascularization. In addition, the scar-associated epidermis showed increase in epidermal cell proliferation which was akin to normal skin. Moreover, lipofilling treatment caused normalization of the extracellular matrix (ECM) organization towards that of normal skin. Conclusions Autologous lipofilling improves clinical outcome of dermal scars through the induction of a pro-regenerative immune response, increased vascularization, and epidermal proliferation and remodeling of scar tissue ECM.

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