Antibodies to S-303 Treated RBC Prepared with the Original Treatment Process (OSRBC) for Pathogen Inactivation Do Not React with RBC Prepared with a Modified S-303 Treatment Process (MSRBC).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 430-430
Author(s):  
Maureen G. Conlan ◽  
George Garratty ◽  
Grace Castro ◽  
Anna Erickson ◽  
Mary Ann Schott ◽  
...  
Keyword(s):  
Blood Donors ◽  
Treatment Process ◽  
Phase Iii ◽  
Antigenic Specificity ◽  
Multiple Time ◽  
Pathogen Inactivation ◽  
Serum Samples ◽  
Phase Iii Trials ◽  
Pre Treatment ◽  
Multiple Time Points

Abstract Background: S-303 (an acridine compound) treatment of RBCs inactivates a broad spectrum of pathogens. Two randomized, controlled Phase III trials of OSRBC to support patients (pts) undergoing cardiovascular surgery (CVS) or with hemoglobinopathies (HB) were in progress when antibodies (Ab) to OSRBC were detected. The specificity of these Ab was determined to be due to residual RBC-bound acridine. The S-303 treatment process was modified in an attempt to reduce immunoreactivity and immunogenicity. MSRBC show reduced RBC-bound S-303 and no reactivity with anti-S-303 Ab. Methods: Retrospective central laboratory testing was performed on all available trial pt serum samples (multiple time points for each pt). Crossmatch (CM) testing (PEG CM) against a minimum of 3 OSRBC units and the paired pre-treatment RBC segment was performed for each sample. CM was defined positive when reactive with any OSRBC, and consistent with anti-S-303 Ab when reactive with all OSRBC, but none of the paired pre-treatment RBC. CM-positive sera were tested for S-303 specificity with a CM inhibition assay using S-303 analogues and also tested for CM reactivity against MSRBC with a gel card CM test. All available baseline sera from trial pts, as well as plasma from 200 healthy blood donors, were also tested by gel card CM against OSRBC and MSRBC to determine prevalence of Ab reactivity to SRBC in absence of prior SRBC exposure. Results: Sera from 8 of 174 (4.6%) pts from both trials showed some CM reactivity with OSRBC. 4 were positive with all ORBC tested; and 4 were inconsistently positive, reactive with some but not all OSRBC. For the 4 pts (2.3%) with consistently positive CM, 3 had OSRBC exposure (HB trial) and 1 had only Control RBC exposure (CVS trial); 3 had positive CM with S-303 specificity. None of these 4 pt sera was CM positive with MSRBC. Only 1 of the other 4 pts with inconsistently positive CM tests had a CM test specific for SRBC (a Control CVS pt); sera from this pt were not reactive with MSRBC. 4 (1.8%) baseline sera from 220 trial pts (205 CVS and 15 HB) were CM-positive with OSRBC; only 2 (0.9%) were CM-positive with all units tested; none was positive with MSRBC. 3 of 200 (1.5%) healthy blood donor plasma were CM-positive with OSRBC; only 2 were positive with all units tested; none was positive with MSRBC. Conclusions: OSRBC were immunogenic in HB pts with prior chronic RBC exposure. Inconsistently positive CM to OSRBC without antigenic specificity for S-303 were detected with some pt sera; these results are under further investigation. Ab to OSRBC was detectable in sera of pts never exposed to S-303 treated RBC. Approximately 1% of pts and healthy blood donors had Ab that reacted with OSRBC. However, no sera with either inconsistent or confirmed CM reactivity to OSRBC were reactive with MSRBC. The MSRBC process eliminated CM reactivity to RBC treated with S-303 and offers the potential for pathogen inactivation treatment of RBC without immunologic reactivity.

scholarly journals Bioinformatics Methods for Learning Radiation-Induced Lung Inflammation from Heterogeneous Retrospective and Prospective Data

2009 ◽  
Vol 2009 ◽  
pp. 1-14 ◽  
Author(s):  
Sarah J. Spencer ◽  
Damian Almiron Bonnin ◽  
Joseph O. Deasy ◽  
Jeffrey D. Bradley ◽  
Issam El Naqa
Keyword(s):  
Multiple Time ◽  
Biological Factors ◽  
Serum Samples ◽  
Prospective Data ◽  
Lung Cancer Patients ◽  
Complex Interactions ◽  
Treatment Conditions ◽  
Dose Volume ◽  
Radiation Induced ◽  
Multiple Time Points

Radiotherapy outcomes are determined by complex interactions between physical and biological factors, reflecting both treatment conditions and underlying genetics. Recent advances in radiotherapy and biotechnology provide new opportunities and challenges for predicting radiation-induced toxicities, particularly radiation pneumonitis (RP), in lung cancer patients. In this work, we utilize datamining methods based on machine learning to build a predictive model of lung injury by retrospective analysis of treatment planning archives. In addition, biomarkers for this model are extracted from a prospective clinical trial that collects blood serum samples at multiple time points. We utilize a 3-way proteomics methodology to screen for differentially expressed proteins that are related to RP. Our preliminary results demonstrate that kernel methods can capture nonlinear dose-volume interactions, but fail to address missing biological factors. Our proteomics strategy yielded promising protein candidates, but their role in RP as well as their interactions with dose-volume metrics remain to be determined.

CpG Island Methylation Is a Poor Prognostic Factors in Myelodysplastic Syndrome Patients and Is Reversed by Decitabine Therapy-Results of a Phase III Randomized Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 790-790 ◽  
Author(s):  
Lanlan Shen ◽  
Hagop Kantarjian ◽  
Hussain Saba ◽  
E. Lin ◽  
Don Berry ◽  
...  
Keyword(s):  
Supportive Care ◽  
Cpg Island ◽  
Randomized Study ◽  
Cpg Islands ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Multiple Time ◽  
Cpg Island Methylator Phenotype ◽  
Methylator Phenotype ◽  
Multiple Time Points

Abstract Background. In human neoplasia, aberrant methylation of CpG islands leads to gene silencing, and has an essential role in tumorigenesis through down regulation of tumor suppressor genes. A phase III randomized study comparing a DNA methyltransferase inhibitor; decitabine (DAC) versus supportive care has been completed recently in myelodysplastic syndrome (MDS) patients. The purpose of our study was to determine the prognostic significance of CpG islands methylation in these patients, to test the significance of methylation events in predicting drug response, and to explore the correlation between modulation of DNA methylation and response to DAC. Methods. DNA was extracted from blood and bone marrow of 89 patients before treatment (baseline) and also from a subset of 34 patients at multiple time-points and modified by bisulfite. In this study, we selected 24 CpG islands based on previous studies and ongoing efforts to identify methylated genes by MCA/RDA. For 14 genes, very low levels of methylation were detected in an initial group of 20 MDS patients, and we excluded them from further study. We then analyzed the methylation status of a total of 10 genes in all the samples. Bisulfite-PCR followed by Pyrosequencing was used to analyze DNA methylation levels of each gene. For statistical analysis, methylation levels of each gene were normalized by a Z score method, and each patient was assigned a methylation “score” based on the sum of Z scores for all genes, or a selected group of genes. Samples before and after treatment were available for 20 patients on supportive care (SC) and 14 patients on DAC, and methylation levles at each time point were averaged across the 10 genes. Results. Methylation frequencies of RIL, PGRA, PGRB, Olig2, p15, CDH13, NPM2, ECAD, NOR1 and ER ranged from 7% to 70% in MDS patients at baseline. Methylation levels of all these genes were significantly linked, suggesting concurrent methylation affected by CpG Island Methylator Phenotype (CIMP). There was no association between methylation by Z scores with age, IPSS, or cytogenetics. There was no correlation between baseline methylation and response to DAC therapy. By univariate analysis, methylation was significantly associated with both shortened overall survival and progression-free survival. In multivariate analysis, IPSS score and methylation were independent predictors of progression free survival, and methylation was the only independent predictor of overall survival. Methylation changes were then analyzed for correlation with response in 34 patients (Decitabine arm: 2 CR, 3 PR, 4HI, 4 SD, 1 PD; supportive care arm: 2 HI, 6 SD, 12 PD) at multiple time-points. At the latest available time-point (>4 months at therapy), methylation decreased by 11.2% in patients in DAC but increased by 20.1% in patients in SC. A greater decrease was observed in patients with CR or PR (40.6+/− 15.7%) compared to HI (9.8+/− 13.2%). Methylation increased by 15.4% in patients with SD and 27.2% in patients with PD. Conclusions. Concordant methylation of multiple genes suggests the existence of a CpG island methylator phenotype in MDS. This methylation was associated with poor prognosis and risk of leukemia transformation. Decitabine therapy was associated with reduced methylation over time, which was associated with clinical responses.

Serum cathepsin B (CB) levels are prognostic in chemotherapy-naive patients (pts) with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18036-18036
Author(s):  
J. W. Singer ◽  
F. B. Oldham ◽  
B. Bandstra ◽  
L. Sandalic ◽  
J. Bianco ◽  
...  
Keyword(s):  
Median Survival ◽  
Advanced Nsclc ◽  
Performance Status ◽  
Phase Iii ◽  
Serum Samples ◽  
Protein Levels ◽  
Lysosomal Cysteine Protease ◽  
Phase Iii Trials ◽  
And Performance ◽  
The Impact

18036 Background: CB is an estrogen-influenced lysosomal cysteine protease produced by tumor cells and tumor-associated macrophages; tumor tissue CB protein levels and proteolytic activity are prognostic in NSCLC (Anticancer Res. 2004; 24:4147–61). The prognostic value of serum CB has not previously been evaluated in NSCLC. Here we evaluate the impact of pretreatment CB levels on survival in pts from 2 phase III trials in advanced NSCLC, STELLAR 3 and 4. These trials compared paclitaxel poliglumex (PPX) against commonly used regimens. As the intratumoral metabolic pathway of PPX is characterized by the CB-mediated release of paclitaxel (P) from a polymeric backbone (Ca Chemother Pharm. 2006. Epub ahead of print), correlation of CB levels with PPX efficacy was assessed as well. Methods: Pretreatment serum samples from 450 chemo-naive pts with advanced NSCLC and PS 2 enrolled in STELLAR 3 (P + carboplatin (C) v. PPX + C) (N=315) and STELLAR 4 (vinorelbine or gemcitabine v. PPX) (N=135) were assayed for CB by ELISA (ICON Labs). Values were assessed by quartiles and there was a clear breakpoint at the median. Pts were categorized as high or low CB based on values above or below the median (64 ng/ml). The effect of CB levels on survival was evaluated by log rank for pooled pts from the studies. Results: As detailed in the table , median survival for non-PPX-treated pts was worse if CB was high; in contrast, median survival for PPX-treated pts did not differ by CB level. Pts with high CB receiving PPX showed a trend towards better survival compared to those receiving control regimens. Conclusions: The data suggest that serum CB may be prognostic biomarker for NSCLC. Retrospective analysis suggests a trend towards improved survival in patients with high CB receiving PPX; prospective studies are required to confirm this observation. [Table: see text] No significant financial relationships to disclose.

scholarly journals Long-term Specific IgG Response to SARS-CoV-2 Nucleocapsid Protein in Recovered COVID-19 Patients

2021 ◽  
Author(s):  
Jira Chansaenroj ◽  
Ritthideach Yorsaeng ◽  
Nawarat Posuwan ◽  
Jiratchaya Puenpa ◽  
Nasamon Wanlapakorn ◽  
...  
Keyword(s):  
Symptom Onset ◽  
Multiple Time ◽  
Serum Samples ◽  
Asymptomatic Group ◽  
Seropositivity Rate ◽  
Chemiluminescent Microparticle Immunoassay ◽  
Specific Igg ◽  
Multiple Time Points ◽  
Respiratory Specimens

Abstract This study monitored the long-term immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in patients who had recovered from coronavirus disease (COVID)-19. Anti-nucleocapsid immunoglobulin G (anti-N IgG) titer in serum samples collected at a single (N=302) or multiple time points (N=229) 3–12 months after COVID-19 symptom onset or SARS-CoV-2 detection in respiratory specimens was measured by semiquantitative chemiluminescent microparticle immunoassay. The 531 patients (966 specimens) were classified according to the presence or absence of pneumonia symptoms. Anti‑N IgG was detected in 87.5% of patients (328/375) at 3 months, 38.6% (93/241) at 6 months, 23.7% (49/207) at 9 months, and 26.6% (38/143) at 12 months. The anti-N IgG seropositivity rate was significantly lower at 6, 9, and 12 months than at 3 months (P<0.01) and was higher in the pneumonia group than in the non-pneumonia/asymptomatic group at 6 months (P<0.01), 9 months (P=0.04), and 12 months (P=0.04). The rate started to decline 6–12 months after symptom onset. Anti-N IgG sample/cutoff index was positively correlated with age (r=0.192, P<0.01) but negatively correlated with interval between symptom onset and blood sampling (r=−0.567, P<0.01). These findings can guide vaccine strategies in recovered COVID-19 patients.

scholarly journals Long-term specific IgG response to SARS-CoV-2 nucleocapsid protein in recovered COVID-19 patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jira Chansaenroj ◽  
Ritthideach Yorsaeng ◽  
Nawarat Posuwan ◽  
Jiratchaya Puenpa ◽  
Nasamon Wanlapakorn ◽  
...  
Keyword(s):  
Symptom Onset ◽  
Multiple Time ◽  
Serum Samples ◽  
Asymptomatic Group ◽  
Seropositivity Rate ◽  
Chemiluminescent Microparticle Immunoassay ◽  
Specific Igg ◽  
Multiple Time Points ◽  
Respiratory Specimens

AbstractThis study monitored the long-term immune response to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection in patients who had recovered from coronavirus disease (COVID)-19. Anti-nucleocapsid immunoglobulin G (anti-N IgG) titer in serum samples collected at a single (N = 302) or multiple time points (N = 229) 3–12 months after COVID-19 symptom onset or SARS-CoV-2 detection in respiratory specimens was measured by semiquantitative chemiluminescent microparticle immunoassay. The 531 patients (966 specimens) were classified according to the presence or absence of pneumonia symptoms. Anti N IgG was detected in 87.5% of patients (328/375) at 3 months, 38.6% (93/241) at 6 months, 23.7% (49/207) at 9 months, and 26.6% (38/143) at 12 months. The anti-N IgG seropositivity rate was significantly lower at 6, 9, and 12 months than at 3 months (P < 0.01) and was higher in the pneumonia group than in the non-pneumonia/asymptomatic group at 6 months (P < 0.01), 9 months (P = 0.04), and 12 months (P = 0.04). The rate started to decline 6–12 months after symptom onset. Anti-N IgG sample/cutoff index was positively correlated with age (r = 0.192, P < 0.01) but negatively correlated with interval between symptom onset and blood sampling (r =  − 0.567, P < 0.01). These findings can guide vaccine strategies in recovered COVID-19 patients.

Relationship between efficacy of denileukin diftitox (Dd) and antibody development in cutaneous T-cell lymphoma (CTCL): An analysis of two phase III studies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19534-e19534
Author(s):  
M. Acosta ◽  
M. Duvic ◽  
A. Lopez-Anaya
Keyword(s):  
Fusion Protein ◽  
Cell Lymphoma ◽  
Phase Iii ◽  
Test Results ◽  
Spearman Correlation ◽  
Serum Samples ◽  
Two Phase ◽  
Antibody Titers ◽  
Pre Treatment ◽  
Phase Iii Studies

e19534 Background: Dd is a novel IL-2 receptor-targeted recombinant fusion protein approved for persistent/recurrent CTCL expressing CD25. The effect of antibody titers on efficacy in CTCL was assessed in 2 phase III studies (11 & 14). Methods: Dd doses were 9 or 18 mcg/kg daily for 5 days, repeating every 21 days, up to 8 courses. Serum samples were collected prior to Dd infusion on day 1 of courses 1, 3, 5, and 7. Immune response to Dd was assessed using 2 enzyme-linked immunoassays: 1 for anti-IL-2 antibody (Ab) and the other for anti-Dd Ab. Immunogenicity data reflect percentage of subjects whose test results were considered positive for antibody to the intact Dd fusion protein. Results: In Study 11, 66% of subjects tested positive for anti-Dd Ab at baseline, possibly due to prior exposure to diphtheria toxin or its vaccine. In both studies, and for both doses, rapid increases in Ab titers were observed in nearly 100% of subjects from courses 1 to 3 (∼650-fold, 11; >=625-fold, 14). After 3 treatment courses, mean Ab levels stabilized and did not change appreciably with time. Pharmacokinetic (PK) parameters (Cmax and AUC) decreased substantially during the same period, but no relationship between Ab formation and clearance was identified. Low Spearman Correlation coefficient values indicated lack of a significant association (i) between the pre-treatment or treatment-related Ab levels and (ii) between PK changes for subjects who responded and subjects who did not respond. Of subjects positive for Ab at baseline, 43% (27/63) and 38% (13/34) responded to treatment, as compared to 50% (16/32) and 54% (7/13) for subjects who had no detectable Ab at baseline in Studies 11 and 14 respectively. There appeared to be higher incidences of response in subjects with lower initial Ab titers. Conclusions: In the studies analyzed, antibody formation in response to Dd exposure did not appear to compromise efficacy for treatment of CTCL. [Table: see text]

Evaluation of the absolute lymphocyte count as a biomarker for melanoma patients treated with the commercially available dose of ipilimumab (3mg/kg).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8575-8575 ◽  
Author(s):  
Michael Andrew Postow ◽  
Jianda Yuan ◽  
Katherine Panageas ◽  
Kita Bogatch ◽  
Margaret Callahan ◽  
...  
Keyword(s):  
Survival Data ◽  
Lymphocyte Count ◽  
Preliminary Finding ◽  
Absolute Lymphocyte Count ◽  
Phase Iii ◽  
Cancer Center ◽  
Karnofsky Performance Score ◽  
Phase Iii Trials ◽  
Pre Treatment

8575 Background: Ipilimumab (ipi) has demonstrated an overall survival (OS) benefit in 2 phase III trials. Only ~30% of patients (pts) achieve clinical benefit, and factors that determine which pts benefit are unclear. For pts treated with 10mg/kg of ipi, we previously reported that an absolute lymphocyte count (ALC) ≥1000/μL prior to dose 3 [week (wk) 7] was associated with improved OS. Since the mean increase in ALC during ipi treatment correlates with dose, we investigated if ALC is also associated with improved OS at 3mg/kg, the currently FDA approved, commercially available dose. Methods: In an IRB-approved analysis, we evaluated landmark survival data from 137 pts treated with 3mg/kg of ipi at Memorial Sloan-Kettering Cancer Center. 67 pts were treated on an expanded access protocol (CA 184-045). 70 pts were treated per FDA approval (commercial ipi) with 4 standard induction doses. These 2 groups were analyzed separately because some pts in CA 184-045 received re-induction ipi. ALC was determined at first ipi dose (baseline, wk 1) and at subsequent doses (wks 4, 7, and 10). Results: Pts treated with 3mg/kg on CA 184-045 with a wk 7 (prior to dose 3) ALC ≥1000/µL had significantly improved OS compared to pts with an ALC at wk 7 <1000/μL (Median OS: not reached vs. 4.24 mos, p<0.001). This OS difference was also seen for pts treated with commercial ipi (Median OS: not reached vs. 4.44 mos, p<0.01). This difference remained significant in a multivariable model accounting for Karnofsky performance score, LDH, M-stage, and number of prior therapies for pts in the CA 184-045 group and commercial ipi group (p=0.01 and p=0.05, respectively). Baseline ALC ≥1000/µL was associated with improved OS (p=0.02) for pts in the commercial ipi group, though follow-up is limited. Conclusions: At the FDA approved dose of ipi, 3mg/kg, ALC at wk 7 remains significantly associated with improved OS. Our preliminary finding of improved OS for pts treated with commercial ipi whose pre-treatment baseline ALC ≥1000/µL deserves confirmation with longer follow-up and prospective validation. Baseline or on treatment ALC may be a marker of overall prognosis, regardless of therapy.

A nomogram predicting survival of patients (pts) with metastatic or unresectable urothelial cancer (UC) treated with cisplatin-based chemotherapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5055-5055 ◽  
Author(s):  
D. F. Bajorin ◽  
I. Ostrovnaya ◽  
A. Iasonos ◽  
M. I. Milowsky ◽  
M. Boyle ◽  
...  
Keyword(s):  
Median Survival ◽  
Phase Ii ◽  
Cox Model ◽  
Performance Status ◽  
Phase Iii ◽  
Poor Performance Status ◽  
Long Term Outcome ◽  
Phase Ii Studies ◽  
Phase Iii Trials ◽  
Pre Treatment

5055 Background: Cisplatin-based chemotherapy is the standard of care for pts with metastatic or unresectable UC with phase III studies reporting median survivals of 12–15 months. Even more survival variation exists in phase II studies and this disparity is most frequently due to prognostic factors and not individual regimens. Thus, better tools are needed to predict survival both for individual pts and to balance phase III trials. Nomograms have utility in predicting short- and long-term outcome in muscle-invasive UC treated by surgery but they have not been explored in more advanced UC. Methods: We identified 308 pts with metastatic and/or unresectable UC treated on prospective phase II MSKCC protocols of cisplatin-based therapy containing 3–5 total chemotherapy agents. 203 pts received methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), 45 had ifosfamide, paclitaxel and cisplatin (ITP) and 60 pts received doxorubicin plus gemcitabine (AG) followed by ITP (AG-ITP). Survival distributions were compared across trials. Pre-treatment characteristics were then assessed for impact on survival and a nomogram from a fitted Cox model was created to predict 1-yr, 2-yr, 5-yr and median survival. Results: No difference in median survivals were seen among the 3 regimens; median survival was 14.8 months for MVAC, 18.0 months for ITP and 16.1 months for AG- ITP (p=NS). Median survival for all pts was 12.99 months; 268 pts died and 40 pts were censored. 288 pts had all pre-treatment data. Characteristics most associated with survival included visceral metastases (present versus absent, p=.00001) and Karnofsky poor performance status (≥ 80 versus < 80, p= .0005) followed by hemoglobin (normal versus < normal, p=.01) and albumin (actual values, p<.02). These characteristics were then used to construct a nomogram utilizing all 4 factors to predict probabilities of 1-yr, 2-yr, and 5-yr survival. Conclusions: The number and sequence of drugs utilized in cisplatin-based chemotherapy did not substantially impact survival of pts with advanced UC. A nomogram of pre-treatment clinical factors can predict probability of pt survival at 1 yr, 2yrs, and 5 yrs. This nomogram may also be useful to balance treatment arms in phase III trials. No significant financial relationships to disclose.

EXTRA Trial-Evaluation of capecitabine treatment with radiotherapy (RT) in anal cancer: Preliminary results on toxicity and outcome

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14085-14085
Author(s):  
R. Glynne-Jones ◽  
H. Meadows ◽  
S. Wan
Keyword(s):  
Chest Pain ◽  
Anal Carcinoma ◽  
Complete Response ◽  
Early Response ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
End Of Treatment ◽  
Phase Iii Trials ◽  
Pre Treatment ◽  
Grade 3

14085 Background: Phase III trials have shown RT + 5-Fluorouracil (5-FU) + mitomycinC (MMC) as the standard treatment for patients with epidermoid anal carcinoma. The objective of this trial is to determine if capecitabine in combination with MMC has a similar outcome in terms of complete response (CR) rate and toxicity to a 5-day infusion of 5-FU. Capecitabine is a rational alternative to 5-FU as these cancers express high levels of thymidine phosphoralase. Methods: Main eligibility criteria are histologically proven anal carcinoma (epidermoid, squamous, basaloid), fit to receive capecitabine and MMC and ineligible for the ongoing phase III UK trial, ACT II. Exclusion criteria include complete local excision, prior chemoradiation, uncontrolled cardiovascular disease and known HIV+ve. All patients receive: 50.4Gy in 28F(RT) and capecitabine 1650mg/m2/day on each RT treatment day (M-F) over 6 weeks. In addition patients receive MMC 12mg/m2, day 1 only. Assessment of response is by CT scan at 4 wks post chemoradiation. Results: To date 18/30 patients have been registered. Pre-treatment characteristics are: median age 59 yrs (44–85); 7 male, 11 female; 13 Canal, 5 Margin; 5T1, 4T2, 6T3, 2T4, 1Tx; 4N+ve, 13N-ve, 1Nx. Data on 14 evaluable pts are presented here. RT compliance: 12 pts completed planned treatment, treatment was interrupted in 2 cases (chest pain 1; machine breakdown 1). Chemotherapy compliance: 10 pts completed protocol treatment, in 3 pts chemotherapy was affected due to toxicity (1 dose reduced, 2 stopped early 1 due to chest pain and 1 due to grade 3 skin and diarrhoea). One patient decided to stop treatment. Grade 3 toxicity was reported in 2 pts during treatment: dyspnoea 1, diarrhoea 1. Four weeks post chemoradition, 10 had CR, 3 had partial response and 1 pt was not assessable. Thirteen pts are alive and disease free at a median follow-up of 6 months (range 1 -13). One pt has relapsed in an inguinal node 9 months after the end of treatment following a previous CR. Conclusions: This early information suggests that this regimen can be given without interruption and with acceptable toxicity. The early response data is encouraging and the trial aims to reach target accrual by Summer 2006. Educational grant provided by Roche pharmaceuticals. [Table: see text]

A Modified Process for Preparation of Pathogen Inactivated RBC Using S-303 in Multiple Additive Solutions Maintains RBC Function and Reduces Immunologic Activity.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 943-943
Author(s):  
A.C. Erickson ◽  
V.A. Lee ◽  
M.A. Schott ◽  
G.M. Castro ◽  
T. Peterson ◽  
...  
Keyword(s):  
Post Treatment ◽  
Phase Iii ◽  
Extracellular Potassium ◽  
Pathogen Inactivation ◽  
Phase I Clinical Trials ◽  
Original Process ◽  
Atp Levels ◽  
Pre Treatment ◽  
Immunologic Activity

Abstract Background: Treatment of RBC with S-303 (acridine derivative) inactivates pathogens and leukocytes. The original process for S-303 treatment of RBC (oSRBC) for pathogen inactivation (PI) used 0.2mM S-303 and 2mM glutathione (GSH). Two randomized, controlled Phase III trials were voluntarily discontinued when antibodies, specific to residual acridine on oSRBC, were detected in 2 patients. Following this observation, a modified PI process using 0.2mM S-303 and 20mM GSH (mSRBC) was developed to reduce S-303 binding to the RBC surface which inactivates a broad spectrum of pathogens and maintains good RBC function. Aims: This study was designed to demonstrate the reduction in binding of S-303 to the RBC surface and preservation of in vitro RBC function with MSRBC in preparation for Phase I clinical trials. Methods: Leukoreduced RBC were prepared in Erythrosol, AS-3, AS-5, SAG-M or PAGGS-M additive solution. mSRBC were treated with 20mM GSH, pH 9.0, plus 0.2mM S-303 and incubated for 20 hours at RT. Post-treatment binding of S-303 to the RBC surface was assessed by gel agglutination test using a mouse monoclonal antibody specific to acridine. In vitro function was assayed pre- and 20 hours post-treatment, and weekly for 35 days (d) of storage. Parameters assessed for in vitro RBC function include intracellular ATP, 2,3-DPG, hemolysis, and extracellular potassium, glucose and lactate. Results: No agglutination was detected by gel column for mSRBC compared to 4+ readings for oSRBC indicating a reduction in S-303 bound to the RBC surface. While S-303 treatment results in higher initial ATP levels compared to pre-treatment, the mSRBC ATP level is maintained throughout 35d of storage. At 35d, oSRBC displayed glucose and lactate concentrations comparable to control RBC. In contrast, mSRBC had lower glucose and higher lactate concentrations than control RBC, consistent with observed higher ATP levels from increased glucose metabolism. After 35d of storage, hemolysis for oSRBC, Erythrosol mSRBC, AS-5 mSRBC, SAG-M mSRBC, and PAGGS-M mSRBC was comparable to controls whereas AS-3 mSRBC hemolysis was similar with the exception of 1 donor in AS-3 that showed a higher hemolysis level. Extracellular potassium levels were unaffected by oSRBC and mSRBC treatment. Conclusion: A modified PI process has been developed for RBC that significantly reduces S-303 bound to the RBC surface compared to the original process while retaining the critical RBC functions. The reduction in bound S-303 offers the potential for PI treatment for RBC without immunologic reactivity. ATP (μmol/g Hb) % Hemolysis GAT Mean (SD) Mean (SD) oSRBC t=0 3.9 (0.2) 0.1 (0.0) t=20h 4.8 (0.3) 0.2 (0.0) 4+ 35 day 2.6 (0.4) 0.4 (0.0) mSRBC Erythrosol t=0 3.4 (0.2) 0.1 (0.0) t=20h 5.7 (0.1) 0.1 (0.0) 0 35 day 3.8 (0.2) 0.1 (0.0) mSRBC AS-3 t=0 3.4 (0.5) 0.2 (0.1) t=20h 6.2 (0.4) 0.3 (0.1) 0 35 day 3.7 (0.4) 0.7 (0.8) mSRBC AS-5 t=0 3.3 (0.2) 0.1 (0.1) t=20h 5.4 (0.7) 0.3 (0.4) 0 35 day 3.3 (0.4) 0.5 (0.3) mSRBC SAG-M t=0 3.1 0.0 t=20h 5.0 0.0 0 35 day in progress in progress mSRBC PAGGS-M t=0 3.1 0.0 t=20h 5.1 0.0 0 35 day in progress in progress

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