scholarly journals CLINICAL, DEMOGRAPHIC, ANATOMOPATHOLOGICAL, AND MOLECULAR FINDINGS IN PATIENTS WITH MEDULLOBLASTOMA TREATED IN A SINGLE HEALTH FACILITY

2021 ◽  
Vol 39 ◽  
Author(s):  
Iva Loureiro Hoffmann ◽  
Izilda Aparecida Cardinalli ◽  
José Andrés Yunes ◽  
Ana Luiza Seidinger ◽  
Ricardo Mendes Pereira
Keyword(s):  
Overall Survival ◽  
Tumor Resection ◽  
Signs And Symptoms ◽  
Molecular Profile ◽  
Rank Test ◽  
Molecular Characteristics ◽  
Incomplete Resection ◽  
Event Free Survival ◽  
Free Survival ◽  
Kaplan Meier

ABSTRACT Objective: To describe the clinical, demographic, anatomopathological, molecular, and survival characteristics of patients with medulloblastoma. Methods: Retrospective study based on patient information obtained from the review of medical records. Overall and event-free survival were analyzed using the Kaplan-Meier estimator, and the curves were compared by the log-rank test. Results: Among the patients investigated, 70 were male (66%), and age at diagnosis ranged from 2 months to 22 years. The most frequent signs and symptoms were headache (80.8%) and vomiting (75.8%). Regarding treatment, most patients (63.2%) underwent complete surgical resection, with a predominance of classic histology (63.2%). The 5-year overall survival rate was 67.9%, and the 10-year rate was 64.2%. Patients with molecular profile characteristic of the wingless (WNT) subgroup had a better prognosis, with 5-year overall survival of 75%. Conclusions: The clinical, demographic, anatomopathological, and molecular characteristics of patients with medulloblastoma described in the present study were mostly similar to those reported in the literature. Patients submitted to complete tumor resection had better clinical outcomes than those who underwent incomplete resection/biopsy. Patients classified as high-risk showed worse overall and event-free survival than those in the standard-risk group, and the presence of metastasis at diagnosis was associated with recurrence.

scholarly journals OP0294 SJÖGREN’S SYNDROME ASSOCIATED LYMPHOMAS: CLINICAL DESCRIPTION AND 10-YEAR SURVIVAL

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 180-181
Author(s):  
L. Chatzis ◽  
V. Pezoulas ◽  
A. Goules ◽  
I. Stergiou ◽  
C. Mavragani ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Histologic Type ◽  
Single Center ◽  
Event Free Survival ◽  
Survival Curves ◽  
Free Survival ◽  
Kaplan Meier

Background:Sjögren’s Syndrome (SS) is a chronic systemic autoimmune disease of unknown etiology, carrying the highest lymphoma risk among autoimmune diseases, with significant impact on mortality and morbidity of patients.Objectives:To describe: i) the clinical phenotype of SS, ii) the histologic type, stage, treatment options regarding lymphomas and iii) the prognosis of patients with SS related lymphoproliferative disorders.Methods:Eight hundred and fifteen consecutive SS patients’ records from a single center fulfilling the 2016 ACR/EULAR were reviewed retrospectively for the purpose of this study. One hundred twenty-one patients with a diagnosis of non-Hodgkin Lymphoma (NHL) were identified and enrolled in the study population. Cumulative clinical, laboratory and histologic data were recorded and overall survival as well as event free survival curves were constructed using the Kaplan-Meier method. An event was defined as a disease progression, lymphoma relapse, treatment failure, histologic transformation, development of a 2nd lymphoma or death from any cause.Results:From 121 pSS patients with lymphoma the most common histologic type encountered was MALT lymphoma (92/121, 76,0%) followed by DLBCL (11/121, 9.0%) and NMZL (8/119, 6.6%). The remaining 10 patients had various lymphomas of B (follicular, lymphoplasmacytic, chronic lymphocytic leukemia} and T cell origin (peripheral T cell lymphoma not otherwise specified, primary cutaneous T cell lymphoma, angioimmunoblastic t-cell lymphoma). Permanent salivary gland enlargement (66.1%, 80/121), palpable purpura (34,7% 42/121), peripheral nervous involvement (9,9%, 12/121), interstitial lung disease (8,2%, 10/121) presence of serum cryoglobulins (38,7%, 43/111) and C4 hypocomplementemia (69,8% 81/116) present at least 1 year before the development of lymphoma were the main pSS related features. The median age at lymphoma diagnosis was 58 years old (range 29-82) while MALT lymphomas developed earlier compared to DLBCL from pSS diagnosis (8 vs 3 OR= 3.84, 95%CI: 0.29 to 10.46; p=0.0266). The commonest biopsy proven extranodal sites included the labial minor salivary (43,8% patients) and parotid glands (30,5%) while 11% of patients had more than 1 extranodal sites affected. Bone marrow involvement was evident in 24,3% of patients (29/119) while nodal involvement in 35,5% (42/118). The majority of patients (65%) had limited disease (stage I or II). A watch and wait therapeutic policy was chosen in 40 patients while the rest received rituximab with or without chemotherapy. The 10-year survival and event free rates were 79% and 45,5% for MALT lymphomas, 40,9% and 24,2% for DLBCL and 46% and 31% for NMZL respectively (Figure 1). The Mantel-Cox log-rank comparison of the overall survival curves revealed a statistically significant difference (p=0.0016) among lymphoma subtypes.Figure 1.Overall and event free survival of SS-associated lymphoma patients. A. Kaplan-Meier overall survival analysis. B. A Kaplan-Meier event free survival analysis.Conclusion:This is the largest single center series of SS- associated lymphoma patients, providing a detailed description of SS and lymphoma related features, combined with a 10-year survival and event free curves for the first time in the literature.Disclosure of Interests:None declared.

scholarly journals Hasil Pengobatan Leukemia Mieloblastik Akut pada Anak

Sari Pediatri ◽  
2016 ◽  
Vol 14 (1) ◽  
pp. 40
Author(s):  
Hikari Ambara Sjakti ◽  
Djajadiman Gatot ◽  
Endang Windiastuti
Keyword(s):  
Overall Survival ◽  
Event Free Survival ◽  
Free Survival ◽  
Kaplan Meier

Latar belakang. Leukemia mieloblastik akut (LMA) merupakan penyakit keganasan yang sering ditemukan pada anak. Hasil pengobatan LMA di Departemen Ilmu Kesehatan Anak RSCM dalam satu dekade terakhir belum pernah dievaluasi. Tujuan. Mengetahui karakteristik pasien LMA dan evaluasi hasil pengobatan serta protokol pengobatan.Metode. Penelitian deskritif dilakukan secara retrospektif terhadap rekam medis pasien LMA yang didiagnosis antara Januari 2007-Desember 2010 di Departemen Ilmu Kesehatan Anak RSCM. Karakteristik pasien secara klinis dan laboratoris dicatat, dan hasil pengobatan dianalisis. Estimasi kesintasan dihitung menggunakan metode Kaplan-Meier dengan bantuan program statistik.Hasil. Selama rentang waktu penelitian didapatkan 93 pasien baru LMA. Overall survival (OS) adalah 46,2% (95% IK: 21,1%;31,2%) dan event-free survival(EFS) 6,5% (95% IK: 3,1%;6,2%). Angka loss to follow-upmencapai sepertiga jumlah pasien yang mempengaruhi hasil estimasi kesintasan (overall survival). Rendahnya EFS disebabkan oleh angka kematian yang tinggi mencapai 50 dari 93 pasien dan 62% di antaranya disebabkan oleh sepsis.Kesimpulan. Keberhasilan pengobatan LMA masih sangat rendah dibandingkan laporan penelitian dari negara lain. Faktor yang paling berperan terhadap hal ini adalah kematian yang tinggi akibat infeksi berat atau sepsis. Komplikasi infeksi mungkin terjadi akibat toksisitas obat dan fasilitas perawatan untuk pasien LMA kurang memadai. Stratifikasi risiko pasien LMA dan evaluasi protokol kemoterapi yang diberikan serta penyediaan fasilitas perawatan yang baik akan memperbaiki hasil pengobatan LMA

Timing of Second Autologous Transplantations in Multiple Myeloma: Results of a Multicenter Sequential Randomized Clinical Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 59-59 ◽  
Author(s):  
Abderrahman Abdelkefi ◽  
Saloua Ladeb ◽  
Tarek Ben Othman ◽  
Lamia Torjman ◽  
Amel Lakhal ◽  
...  
Keyword(s):  
Overall Survival ◽  
Randomized Trial ◽  
Rank Test ◽  
Optimal Timing ◽  
High Dose ◽  
Consolidation Therapy ◽  
Event Free Survival ◽  
Free Survival ◽  
Log Rank Test

Abstract Background: Autologous stem cell transplantation (ASCT) is now considered standard therapy in young patients (<65 years) with multiple myeloma (MM). The Intergroupe Francophone du Myelome conducted a randomized trial of the treatment of MM with high-dose chemotherapy followed by either one or two successive ASCTs. The probabilities of event-free-survival and overall survival were doubled with a double transplant. However, no randomized trial has compared tandem transplant up-front with a strategy including planned second ASCT at relapse or progression. Therefore, we performed a multicenter, sequential, randomized trial designed to assess the optimal timing of a second ASCT. Methods: From May 2003 to April 2006, 140 patients with symptomatic MM (de novo) and less than 60 years of age, were randomly assigned to receive either tandem transplantation up-front (within 6 months of the first transplantation) [Arm A, n=69] or one ASCT followed by a consolidation therapy with thalidomide (day +90, 100 mg/per day during 5 months) [Arm B, n=71]. Patients included in the arm B received a second transplant in case of disease progression on consolidation therapy, or in case of relapse in responders. Clinical characteristics of each group were similar. In both arms of the study, ASCT was preceded by first-line therapy with thalidomide-dexamethasone and subsequent collection of peripheral blood stem cells with high-dose cyclophosphamide (4 g/m2) and G-CSF. Data were analyzed on an intent-to-treat basis. Results: With a median follow-up of 23 months (range: 6–34), the 2-year overall survival was 55% in the arm A and 75% in the arm B. Survival curves were not different (P=0.28, log-rank test). The 2-year event-free survival was 41% in the arm A and 60% in the arm B (P=0.4, log-rank-test). In the arm B, relapse-free survival of ≥ 16 months following the first transplantation was an important predictor of overall survival (p< 0.001). Conclusion: Data from the present study suggest that up-front single ASCT followed by a consolidation therapy with thalidomide and a second ASCT after relapse or progression is a safe and effective global strategy to treat MM patients. Longer follow-up is needed before definite conclusions can be given concerning the optimal timing of second autologous transplantations in patients with MM.

Induction with an Oral Chemotherapy-Cyclophosphamide in Combination with Idarubicin and Dexamethasone (CID) Followed by Early Autologous Stem Cell Transplantation for Multiple Myeloma Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5456-5456
Author(s):  
Nalini K. Pati ◽  
Yiu-Lam Kwan ◽  
Arumugam Manoharan ◽  
Michael Teh
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Stem Cell ◽  
Induction Treatment ◽  
Event Free Survival ◽  
Cell Content ◽  
Free Survival ◽  
Kaplan Meier ◽  
Bone Marrow Plasma

Abstract INTRODUCTION: In many centers an initial period of induction treatment followed by peripheral blood stem cell (PBSC) harvest and autologous stem cell transplantation (ASCT) has become standard of care for multiple myeloma (MM) in patients =< 65 years of age. Commonly induction regimens contain intravenous cytotoxic agents and oral corticosteroids. There are interests in oral regimens, including thalidomide-containing combinations (1). Recently Spencer et al from Australia reported a small multicenter study in which the induction treatment prior to ASCT comprised an outpatient-based oral chemotherapeutic regimen CID-- cyclophosphamide, idarubicin, dexamethasone, in previously untreated MM patients (2). AIM: To evaluate the efficacy of oral CID in MM in our own institution. METHODS: thirteen patients with MM (relapsed n=2, previously untreated n=11) were treated with CID. Courses were repeated every four weeks, with the aim of harvesting PBSC after 3 to 6 courses, depending on response. Efficacy of treatment was assessed on the following parameters: paraprotein level, b2 microglubulin and bone marrow plasma cell content. Wilcoxon Signed Ranks Test was used to analyze treatment outcomes and Kaplan-Meier curves were used for analysis of overall survival and event free survival. RESULTS: All 13 patients (median age 61 yrs, range-41–72 yrs; male-7, female-6) were evaluable for response, with a median follow up of 40 (12–84) weeks. In total, eleven patients (10 previously untreated, and one relapsed) were planned to have an elective ASCT. All had successful stem cell mobilization after 3–6 cycles of chemotherapy, and subsequently received an ASCT. One patient died 42 days post transplantation due to infection and ARDS. The median time between completion of CID and ABMT was 6 weeks (range 4–16). One previously untreated patient and one relapsed patient, both aged >65, received CID only without an ASCT. Comparison of pre and post chemotherapy levels of paraprotein, b2 microglubulin and bone marrow plasma cell content showed statistically significant results with p values of 0.002, 0.001 and 0.002 respectively. According to International standard criteria, 3/13 achieved complete response (CR), 7/13 had very good partial response (VGPR) or partial response (PR), 1/13 stable disease (SD) and 2/13 had relapse or progressive disease (PD), resulting in an overall response rate (>/=SD) of 84%. The median time to maximum response was 4 months. The Kaplan-Meier estimates of event-free survival and overall survival at 1 year were 64% and 84%, respectively. There were no major toxicities except weight gain (National Cancer Institute Common Toxicity Criteria Grade III) was seen in 23% of the patients, possibly due to the dexamethasone component in CID. CONCLUSIONS: Our results confirm the efficacy and safety of this outpatient based all oral induction regimen for patients with MM. The favorable side effect profile, the convenience of drug delivery with oral dosing, and the ease of PBSC mobilisation are the main advantages.

scholarly journals Analysis of p16 gene mutations and deletions in childhood acute lymphoblastic leukemias

2003 ◽  
Vol 121 (2) ◽  
pp. 58-62 ◽  
Author(s):  
José Alexandre Rodrigues Lemos ◽  
Ricardo Defavery ◽  
Carlos Alberto Scrideli ◽  
Luiz Gonzaga Tone
Keyword(s):  
T Cell ◽  
Rank Test ◽  
Event Free Survival ◽  
P16 Gene ◽  
Exon 2 ◽  
Free Survival ◽  
Direct Dna Sequencing ◽  
Log Rank Test ◽  
Kaplan Meier ◽  
Exon 1

CONTEXT: The p16 tumor suppressor gene encodes a cyclin-dependent kinase 4 inhibitor that blocks cell division during the G1 phase of the cell cycle. Alterations in this gene have been reported for various neoplasia types, including acute lymphoblastic leukemias (ALL), especially T-cell acute lymphoblastic leukemias (ALL). OBJECTIVE: To determine probable alterations in the p16 gene in children with acute lymphoblastic leukemias using the polymerase chain reaction (PCR) and direct DNA sequencing and also to analyze event-free survival (EFS). DESIGN: Retrospective study. SETTING: Department of Child Care and Pediatrics, Faculty of Medicine of Ribeirão Preto, Universidade Federal de São Paulo. PARTICIPANTS: Fifty-six children with ALL (mean age 4 years). Forty (71.43%) had B-cell and 12 (21.43%) had T-cell ALL; 4 (7.1%) were biphenotypic. SAMPLE: DNA samples were extracted from bone marrow upon diagnosis and/or relapse. In 2 T-cell cases, DNA from cerebrospinal fluid (CSF) was analyzed. MAIN MEASUREMENTS: Deletions or nucleotide substitutions in exons 1, 2 and 3 of the p16 gene were determined by PCR and nucleotide sequencing. Event-free survival was determined by the Kaplan-Meyer and log-rank test for patients carrying normal and altered p16. RESULTS: Deletions in exon 3 were observed in five cases. Abnormal migration in PCR was observed in seven cases for exon 1, six for exon 2, and five for exon 3. Mutations in exon 1 were confirmed by direct DNA sequencing in four cases and in exon 2 in two cases. The Kaplan-Meyer survival curves and the log-rank test showed no significant differences in 5-year EFS between children with normal or altered p16, or between patients with B-ALL carrying normal or altered p16 gene. Patients with T-ALL could not be evaluated via Kaplan-Meier due to the small number of cases. CONCLUSIONS: Our results, particularly regarding deletion frequency, agree with others suggesting that deletions in the p16 are initial events in leukemia genesis. The small number of samples did not allow stablishment of correlation between childhood ALL and the p16 point mutations found in our study. Kaplan-Meier analysis revealed no significant correlation between EFS and alterations in ALL. The p16 alterations frequency observed for B and T-ALL agreed with reports from other centers.

Number of cycles of chemotherapy in patients with advanced non-small cell lung caner: Efficacy and relationship with histology.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18125-e18125
Author(s):  
Eduardo Richardet ◽  
Martin Eduardo Richardet ◽  
Nicolas Castagneris ◽  
Matias Nicolas Cortes ◽  
Perelli Laura ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Rank Test ◽  
Test Results ◽  
First Line ◽  
Free Survival ◽  
Log Rank Test ◽  
Kaplan Meier ◽  
Number Of Cycles

e18125 Background: Platinum based regimens are standard first-line treatment in patients with advanced non mall cell lung cancer. We intend to evaluate their effectiveness according to the number of cycles administered, and investigate whether histology is a predictor of benefit from a greater number of infusions. Methods: 124 patients with stage IV NSCLC were evaluated retrospectively. They were divided according to whether they made 4 or 6 cycles of chemotherapy. The schemes used were: Cisplatin / Gemcitabine and Carboplatin / Paclitaxel, at standard doses. We studied the efficacy in both groups according to the most common histologies (adenocarcinoma and squamous cell carcinoma). PFS (progression-free survival) and OS (overall survival) were calculated by the Kaplan-Meier curves and compared by the Log Rank Test. Results: Those who underwent 4 cycles had a PFS of 7.77 months and OS of 12.2 months vs. 8.64 and 10.8 months those who received 6 cycles (p = 0.47, p = 0.76). Within the subgroup with squamous histology (n = 43), PFS and OS were 7.38 and 13.38 months respectively in the group that received 4 cycles vs. 7.97 and 9.76 months in those receiving 6 (p = 0.70, p = 0.32 ). Within adenocarcinoma histology (n = 81), those who received 4 cycle, has a PFS of 8.17 months and they lived 11.56 month, vs 8.96 and 10.79 months for those receiving 6 cycles (p = 0.29, p = 0.88) Conclusions: In our population, a greater number of cycles showed no advantages in terms of progression-free survival or overall survival. Histology is not a predictive factor for deciding how many chemotherapy cycles administer.

scholarly journals Faktor yang Berpengaruh Terhadap Disease Free Survival dan Overall Survival pada Pasien Kanker Payudara Usia Muda di Kota Padang Tahun 2008 - 2018

2020 ◽  
Vol 9 (1S) ◽  
Author(s):  
Magdi Ayuza ◽  
Wirsma Arif Harahap ◽  
Rony Rustam ◽  
Richvan Dana Nindrea
Keyword(s):  
Overall Survival ◽  
Cohort Study ◽  
Disease Free Survival ◽  
Rank Test ◽  
Free Survival ◽  
Log Rank Test ◽  
Kaplan Meier ◽  
Disease Free ◽  
Data Register

Kanker Payudara (KPD) pada usia muda memiliki keistimewaan karakteristik. Rekurensi KPD dipengaruhi oleh berbagai faktor antara lain faktor klinis, regimen terapi dan biomolekuler dari tumor itu sendiri. Berbagai macam modalitas terapi KPD, namun masih terdapat risiko terjadinya rekurensi terutama pada pasien dewasa muda. Tujuan: Mengetahui faktor-faktor yang mempengaruhi Disease Free Survival (DFS) dan Overall Survival (OS) pada pasien KPD usia muda di Kota Padang. Metode: Penelitian ini menggunakan desain cohort study retrospectif pada pasien KPD usia muda yang telah mendapatkan pengobatan KPD yang memenuhi kriteria inklusi sebanyak 103 sample yang terdapat pada data register KPD PERABOI Padang. Analisis survival menggunakan Kaplan Meier dengan Log Rank Test. Apabila diperoleh nilai p < 0,05, maka terdapat hubungan bermakna. Hasil: Terdapat perbedaan antara setiap faktor klinis, faktor biomolekuler dan faktor terapi dalam hal rata-rata DFS maupun rata-rata OS, namun tidak terdapat pengaruh yang bermakna secara analisis statistik antara faktor terapi (terapi hormon, radioterapi dan terapi target) terhadap DFS dan OS pada pasien kanker payudara usia muda di Kota Padang (p>0,05). Terdapat pengaruh dari pemberian kemoterapi terhadap DFS pada pasien kanker payudara usia muda di Kota Padang (p<0,05). Simpulan: Tidak terdapat hubungan yang bermakna antara faktor klinis dan faktor biomolekuler dengan DFS dan OS, namun terdapat hubungan bermakna antara pemberian kemoterapi dengan DFS dan OS pada penderita KPD usia muda di kota Padang tahun 2008 – 2018.

Risk stratification of patients with locally aggressive differentiated thyroid cancer

2010 ◽  
Vol 49 (03) ◽  
pp. 79-84 ◽  
Author(s):  
J. A. Krämer ◽  
K. W. Schmid ◽  
H. Dralle ◽  
M. Dietlein ◽  
H. Schicha ◽  
...  
Keyword(s):  
Overall Survival ◽  
Thyroid Cancer ◽  
Differentiated Thyroid Cancer ◽  
Staging System ◽  
Nodal Metastasis ◽  
Tnm Staging ◽  
Event Free Survival ◽  
Free Survival ◽  
Kaplan Meier

SummaryThe Multicentre Study Differentiated Thyroid Cancer (MSDS) collective represents a well defined group of patients with locally aggressive thyroid carcinomas (pT4; AJCC/UICC 1997). The aim of the present study was to compare the survival of patients with minimum and extensive extrathyroidal growth according to the new AJCC/UICC TNM staging system 2009. Patients, methods: The followup data of 347 patients were analysed. Patients were reclassified according to the current AJCC/UICC 2009 classification. The event-free and overall survival was evaluated using Kaplan-Meier analysis. In addition, postoperative complications and status of disease were documented. Results: 327 patients were assigned to stage pT3 and 20 patients to stage pT4a, respectively. Median follow-up was 6.1 years (range 0.04–9.8 years). 92.5% of patients reached complete remission. There were 7.8 % recurrences in the thyroid bed, in locoregional lymph nodes and/or in distant sites. The overall survival was >98% both in pT3 and pT4a patients (p = n. s.). In contrast, the event-free survival was significantly less favourable in pT4a patients (p < 0.001). Using multivariate analysis the following parameters were significant predictors of event-free survival: histological tumour type, degree of extrathyroidal extension and nodal metastasis (p < 0.05). Conclusions: The MSDS patients with locally aggressive differentiated thyroid cancer showed an excellent overall survival during a median follow-up of 6.1 years. According to the current AJCC/UICC 2009 classification, pT3 patients with minimal extra thyroidal extension revealed a significantly better event-free survival than pT4a patients with extensive extrathyroidal growth.

Serial cell-free DNA (cfDNA) sampling in advanced pancreatic ductal adenocarcinoma (PDAC) patients may predict therapeutic outcome.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 423-423
Author(s):  
Gehan Botrus ◽  
Yu Fu ◽  
Mohamad Bassam Sonbol ◽  
Leylah Drusbosky ◽  
Daniel H. Ahn ◽  
...  
Keyword(s):  
Overall Survival ◽  
Progression Free Survival ◽  
Ductal Adenocarcinoma ◽  
Rank Test ◽  
First Line ◽  
Free Survival ◽  
Probability Of Survival ◽  
First Line Therapy ◽  
Kaplan Meier ◽  
Next Generation Sequencing Ngs

423 Background: Advanced PDAC remains a deadly disease with a 5-year survival rate of less than 10%. cfDNA - based next generation sequencing (NGS) may identify actionable alterations in patients with PDAC. In this study, we aim to determine the feasibility of utilizing serial cfDNA NGS testing and its potential relevance in predicting therapeutics outcomes. Methods: A total of 23 PDAC patients with PDAC cfDNA isolated from plasma collected at diagnosis and upon disease progression to first line SOC therapy and were analyzed on a 73-74 gene NGS panel (Guardant Health). Changes in molecular profiles from baseline to progression were analyzed for overall survival, progression free survival (PFS), and treatment response. PFS and OS were analyzed using the Kaplan-Meier method and the log-rank test was used to compare the survival of different groups of patients. All p-values were two-sided. Analyses were performed using R (version 3.5.1, R Foundation, Vienna, Austria). Results: In this retrospective study, the 1-year probability of survival was 71% (median 473 days) and the 1-year PFS was 14% (median 212 days). TP53 and KRAS were the most frequently mutated genes identified in baseline samples, with 78% prevalence for each. Patients with clearance of TP53 17% (3/18) patients and/or KRAS 33% (6/18) patients clones after first line therapy significantly increases PFS (p=0.0056 and p=0.037, with HR of 0.087 and 0.32, respectively). However, appearance of TP53 or KRAS alterations upon progression does not significantly affect overall survival or PFS. Conclusions: The preliminary results from this study suggest that cfDNA clearance of TP53 and/or KRAS alterations may predict for improved PFS in PDAC. Confirmation of these findings in larger studies is warranted.

scholarly journals Prognostic Significance of FOXO3 in Pediatric Acute Myeloid Leukemia (AML) Patients Treated with Bortezomib Addition to Standard Therapy: Results from a Children's Oncology Group Phase 3 Clinical Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2676-2676
Author(s):  
Anneke D. van Dijk ◽  
Peter P. Ruvolo ◽  
Fieke W Hoff ◽  
Yihua Qiu ◽  
Alan S Gamis ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Oncology Group ◽  
Event Free Survival ◽  
Phase 3 ◽  
Free Survival ◽  
Prognostic Effect ◽  
The Poor ◽  
Kaplan Meier ◽  
Pediatric Aml

The proteasome degrades unneeded and damaged proteins. Tumor cells highly depend on increased protein production and their degradation suggesting that malignant cells with a high proliferation index will be more sensitive to proteasome inhibition. The addition of the proteasome inhibitor Bortezomib (Velcade, 'BTZ') to standard pediatric AML chemotherapy (cytarabine, daunorubicin and etoposide, 'ADE') depleted leukemia-initiating cells in a phase 2 clinical trial in pediatric AML (pedi-AML) patients. A randomized phase 3 clinical trial was then conducted by the Children's Oncology Group (COG) comparing ADE and ADE+BTZ treatment regimes in pedi-AML (AAML1031). To determine if there were specific protein expression profiles that correlated with response to BTZ-containing chemotherapy, we analyzed key components of the proteome of pedi-AML that participated in the trial using reverse phase protein arrays (RPPA). RPPA-based expression of 293 validated antibodies was tested in 500 leukemia samples and compared to expression in CD34+ samples from healthy individuals (n=30). Among all proteins, FOXO3 expression was identified as the protein with the highest influence on outcome in the ADE group. The expression of FOXO3 was prognostic for event-free survival (EFS) in both univariate (HR = 0.56, 95% CI = 0.34-0.90, P = 0.017) and multivariate (HR = 0.55, 95% CI = 0.34-0.88, P = 0.013) analysis. All patients were divided into two clusters (low and high) based on their FOXO3 expression level using median FOXO3 expression in normal CD34+. Kaplan-Meier survival analysis showed poor OS (3 year OS 65.3% vs. 73.9%, P = 0.03) and EFS (3 year EFS, 42.8% vs. 55%, P = 0.01) in low FOXO3 expressors (n=119) compared to patients with high FOXO3 expression (n=291) (fig. 1A). Notably, the poor prognostic effect of low FOXO3 for OS was seen in ADE (3 year OS 60% vs. 72.3%, P = 0.03), but not in ADE-BTZ (3 year OS 70.3% vs. 75.3%, P = 0.23) (fig. 1B). This suggests that in particular patients with low FOXO3 may be eligible candidates for BTZ-addition. To validate our findings, we performed knockdown (KD) of FOXO3 using a short hairpin approach in OCI-AML3 (p53WT) and THP-1 (p53null) cell lines. KD FOXO3 in OCI-AML3 had a short-term growth advantage compared to controls (Day 4, P = 0.004), but not KD FOXO3 THP-1 cells suggesting a role for p53 in the FOXO3 functional pathway. KD FOXO3 cells were more resistant to doxorubicin and etoposide combination therapy than controls (P = 0.04), confirming our clinical observations. Since therapeutic regimes in AML are currently shifting towards Bcl-2 inhibition by Venetoclax (ABT-199, 'ABT'), we were eager to test whether BTZ and ABT could act in synergy, and if this is related to FOXO3 expression. Single low dose BTZ and ABT did not reduce cell numbers after 3 days, but were effective when used in combination (<12% survival, P < 0.001) in OCI-AML3 and THP-1. Although cell counts were lower regardless FOXO3 status in both cell lines, flow cytometry analysis using Annexin V staining revealed significant more apoptosis in KD FOXO3 THP-1 compared to controls. Using RPPA-based profiling, we identified a cluster of pedi-AMLs that benefitted from BTZ-addition to standard therapy. We hypothesize that AML patients with low FOXO3 levels have less activation of their apoptotic transcriptional programs and that this subgroup may benefit from proteasome blockage to prevent FOXO3 proteasomal degradation. The use of FOXO3 as potential biomarker may identify a prognostically adverse cluster in pedi-AML that could stratify patients for ADE+BTZ therapy. Patients with low FOXO3 expression may potentially benefit from ADE+BTZ in combination with ABT, a novel and promising combination approach in AML that warrants further investigation. Figure 1. A. Kaplan meier analysis comparing overall survival (OS) and event-free survival (EFS) between low (n=119, blue) and high (n=291, red) FOXO3 expression in pedi-AML patients. Children with low FOXO3 had significantly poorer OS (P = 0.033, Wilcoxon) and EFS (P = 0.011, Wilcoxon). B. Overall survival between ADE (solid) and ADE+BTZ (dashed) treated patients based on low (blue) or high (red) FOXO3 protein expression. The poor prognostic effect of FOXO3 is present in ADE, but not in ADE+BTZ treated patients (P = 0.028, Wilcoxon). Figure 1 Disclosures No relevant conflicts of interest to declare.

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