IMMU-25. SYNERGY BETWEEN TMZ AND INDIVIDUALIZED MULTIMODAL IMMUNOTHERAPY TO IMPROVE OS OF IDH1 WILD TYPE MGMT PROMOTOR UNMETHYLATED GBM PATIENTS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi97-vi97
Author(s):  
Stefaan Van Gool ◽  
Jennifer Makalowski ◽  
Volker Schirrmacher ◽  
Wilfried Stuecker

Abstract The prognosis of IDH1 wild type MGMT promotor unmethylated (MGMT-p-UM) GBM patients remains poor. Addition of TMZ to radiotherapy shifted the median OS from 11.8 to 12.6 months (Stupp, Lancet Oncol 2019). We retrospectively analysed the value of individualized multimodal immunotherapy (IMI) to improve OS in these patients. Adults with first event of IDH1wt GBM and documented status of MGMT-p-UM, and treated with IMI in the period June 2015 till July 2020, were selected. IMI consisted of 1/ immunogenic cell death (ICD) therapy (NDV injections + modulated electrohyperthermia), 2/ active specific immunotherapy with autologous mature dendritic cells loaded with tumor lysate or ICD therapy-induced serum-derived antigenic extracellular microvesicles and apoptotic bodies (IO-Vac® is an approved advanced therapy medicinal product since 27/05/2015), 3/ modulatory immunotherapy adapted to the patient, and 4/ complementary medicines. Twenty-eight patients (11f, 17m) had a median age of 48y (range 18-69) and a KPI of 90 (50-100). Extent of resection was complete (11), < complete (9) or not documented (8). Seven patients were treated with surgery/radio(chemo)therapy and subsequent IMI (Group-1); 21 patients were treated with radiochemotherapy followed by maintenance TMZ + ICD therapy, followed by DC vaccines (Group-2). Both groups received further maintenance ICD therapy. Age, KPI and extent of resection were not different amongst both groups. PFS was not assessed because of challenges about pseudoprogression. The median OS of group-1 patients was 11m (2y OS: 0%). Surprisingly the median OS of group-2 patients was 18m with 2y OS of 17% (CI95%: +31, -15), which was significantly (Log-rank: p = 0.027) different from group-1. The data suggest that addition of IMI after local therapy on its own has no relevant effect on OS in IDH1 wild type MGMT-p-UM GBM patients, similar to maintenance TMZ. However, the combination of both TMZ + IMI significantly improves median OS.

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi4-vi4
Author(s):  
Stefaan Van Gool ◽  
Jennifer Makalowski ◽  
Wilfried Stuecker

Abstract Multimodal immunotherapy (Newcastle Disease Virus (NDV) + modulated electrohyperthermia + IO-VAC® + immunomodulatory strategies) is an innovative treatment for primary GBM and might prolong overall survival (OS). IO-VAC® consists of DCs loaded with autologous tumor antigens and matured with cytokine cocktail and NDV. We retrospectively reviewed 132 cases of primary GBM. Multimodal immunotherapy was integrated as individualized treatment approach and following different scenario’s in combination with standard treatment in the first line treatment in 71 patients, used at time of first or subsequent relapse as treatment with or without chemotherapy in 61 cases. Median ages were resp. 55 and 53 y. Median KPI at start of immunotherapy was 90 and 80. Median OS for the patients treated with immunotherapy as part of first-line treatment was 20 months with 2-y OS of 40% (CI95%: -13,+13). Median OS for patients treated at time of relapse was 7 months with but still with 18-m OS of 16% (CI95%: -12,+9). Two resp. 1 patients were lost of follow up. A subgroup of 34 GBM patients (10 females) with median age 58y (20–67) was detected, who received NDV + modulated electrohyperthermia during Temozolomide maintenance cycles followed by two IO-VAC® DC vaccinations, and further NDV + modulated electrohyperthermia courses. Median KPI was 70 (60–100). MGMT status was methylated (12), unmethylated (13), unknown (9). Median OS for this subgroup was 23.4 months with 2-year OS of 48% (CI95%: -18,+20). Immunotherapy was feasible without immunotherapy-related side effects of grade III or more. The data suggest that multimodal immunotherapy with IO-VAC® already during and after maintenance chemotherapy, at time of achieved minimal residual disease with local therapy, might help in prolongation of OS. Prolongation of OS in a small group of patients at time of relapse was also demonstrated. IO-VAC® is an approved advanced therapy medicinal product (DE-NW-04-GMP-2015-0030).


2002 ◽  
Vol 12 (6) ◽  
pp. 749-754 ◽  
Author(s):  
P. Pautier ◽  
C. Genestie ◽  
K. Fizazi ◽  
P. Morice ◽  
C. Mottet ◽  
...  

Uterine sarcomas are an extremely rare event. There is no standard therapy for cases of relapse, although chemotherapy is commonly used. We studied the use of a cisplatin-based chemotherapy regimen for uterine sarcomas with an unusually long follow-up. Thirty-nine women with a median age of 50 years (32–71) entered the study. Histologically, leiomyosarcomas (26), carcinosarcomas (8), and stromal sarcomas (5) were represented. Group 1 consisted of patients undergoing adjuvant therapy (for initial disease, eight patients; for pelvic recurrence, two patients); Group 2 consisted of patients with advanced disease (locoregional after initial local therapy, five patients; local recurrence, six patients) or metastatic disease (stage IV, four patients; recurrence, 14 patients). DECAV therapy consisted of doxorubicin 50 mg/m2 d1, dacarbazine (DTIC) 200 mg/m2/d d1–3, vindesine 2 mg/day d1–2, cisplatin 100 mg/m2 d3, and either cyclophosphamide (CPM) 200 mg/m2/d d1–3 (n = 21), or ifosfamide (IFM) 2 g/m2/d d1–3 with mesna every 4 weeksToxicity included 18 hospital stays for cytopenia (nine patients), including 13 cases of febrile neutropenia. Twenty blood transfusions in 10 patients and 12 platelet transfusions in seven patients were required. One toxicity-related death (hemorrhage) occurred. The overall response rate was 54% (3 complete response, 11 partial response) with a median duration of 13 months (4–36). Median overall survival was 14 month overall, 45 months for Group 1 and 13 months for Group 2. We conclude that the DECAV regimen is clearly active in uterine sarcomas but is too toxic to be recommended routinely.


1974 ◽  
Vol 23 (3) ◽  
pp. 251-257 ◽  
Author(s):  
P. M. Chandler ◽  
V. Krishnapillai

SUMMARYA study was made of the R factors from two multiply drug resistant wild type isolates ofPseudomonas aeruginosafrom a Birmingham hospital (Lowburyet al.1969) from which, in contrast to other strains from the same source (Chandler & Krishnapillai, 1974a), drug resistance was not transferable toEscherichia coliK12 orSalmonella typhimurium. Transfer of drug resistance occurred at a low frequency toShigella flexneri, although drug resistance in this species was subsequently non-transferable.InP. aeruginosathere are several features of these two R factors which distinguish them from the group 1 and 2 R factors described previously (Chandler & Krishnapillai, 1974a). Although coding for resistance to neomycin and tetracycline, they did not express this resistance in two strains ofP. aeruginosaexamined, in contrast to the wild type strains they were isolated in.The control of transfer of the two R factors is different to the group 1 and 2 R factors in that derepression of transfer could be demonstrated following physiological treatments or mutagenesis. The R factors of this third group were compatible with the group 2 R factors, but did not repress their pilus synthesis on the basis of R factor specific phage plating.


Kardiologiia ◽  
2021 ◽  
Vol 61 (4) ◽  
pp. 24-31
Author(s):  
A. S. Postol ◽  
N. M. Neminushchiy ◽  
G. N. Antipov ◽  
A. V. Ivanchenko ◽  
V. V. Lyashenko ◽  
...  

Aim      Analysis of responses of cardioverter-defibrillators implanted in patients with cardiomyopathies (CMPs) of various origins and a high risk of sudden cardiac death (SCD) to assess the effectiveness of a modern strategy for primary prevention of SCD.Material and methods  In the Federal Center for High Medical Technologies in Kaliningrad from 2014 through 2018, implantable cardioverter-defibrillators (ICD) and cardiac resynchronization therapy defibrillators (CRT-D) were installed in 165 patients. Major indications for device implantation in these patients included left ventricular (LV) systolic dysfunction with ejection fraction (EF) ≤35 %; chronic heart failure (CHF) consistent with the New York Heart Association (NYHA) functional class (FC) II-III (IV for CRT-D) without previous episodes of life-threatening ventricular arrhythmias, circulatory arrest and resuscitation, which was consistent with the current international strategy for primary prevention of SCD. The study patients were divided into two groups based on the CMP origin; group 1 included 101 (61.2 %) patients with CMP of ischemic origin (ICMP) and group 2 consisted of 64 (38.8 %) patients with CMP of non-ischemic origin (NCMP). Information about arrhythmic episodes and device activation was retrieved from the device electronic memory during visits of patients to the clinic and was also transmitted to the clinic by a remote monitoring system. This information was studied and evaluated for the validity and effectiveness of the device triggering. If necessary, the parameters of detection and treatment were adjusted taking into account the obtained information. Information was analyzed and statistically processed with the SPSS Statistics 20.0 software.Results The patients were followed up for 28.3 ± 15.6 months, during which the devices delivered therapy to 55 (33.3%) patients of the entire group. In the ICMP group, the devices were activated in 44 (26.7 %) patients and in the NCMP group, the devices were activated in 11 (6.7 %) patients. In group 1 (ICMP), appropriate triggering was observed in 33 (20.0%) patients and inappropriate triggering was observed in 11 (6.7%) patients. In group 2 (NCMP), appropriate triggering was observed in 2 (1.2 %) patients and inappropriate triggering was observed in 9 (5.5 %) patients. The main cause of inappropriate triggering was atrial fibrillation (AF). 17 (10.3 %) patients with ICMP had sustained ventricular tachycardia (VT), which did not reach the detection frequency for ICD therapy; these VTs were only detected by devices and terminated spontaneously. Intragroup differences in the number of patients who received an appropriate treatment were statistically significant: 33 (32.6 %) in the ICMP group vs. 2 (3.1 %) in the NCMP group (р<0.006). Differences in the number of patients who received an inappropriate treatment were not statistically significant although their number was greater in the NCMP group than in the ICMP group (9 (14.1 %) vs. 11 (10.9 %), р>0.05).Conclusion      A higher requirement for the ICD treatment was revealed in patients with ICMP compared to patients with NCMP. The low demand for the ICD treatment in patients with NCMP and the more frequent inappropriate actuation of the devices in this patient group due to AF allow a conclusion that the criteria for primary prevention of SCD with ICD (LV EF ≤35% and clinically significant CHF) are not equally effective indications for ICD implantation in patients with ICMP and NCMP. It can be assumed that life-threatening ventricular arrhythmias are evident in patients with NCMP before the development of hemodynamically significant LV dysfunction and CHF, which warrants further research in this direction. 


2020 ◽  
pp. 130-136
Author(s):  
L. Yu. Karakhalis ◽  
Yu. S. Ponomareva ◽  
N. S. Ivantsiv

Introduction: to investigate the possibility of using clindamycin and butaconazole in local therapy of moderate and severe dysbiosis in patients during the menopausal transition (early and late).Materials and methods: 107 women were examined. They were divided into two groups depending on their complains: the patients of group 1 (49.5%) had an early transition to menopause (44.7 ± 2.3 years); the patients of group 2 (50.5%) corresponded to a late transition to menopause (49.1 ± 1.5 years). The complains were evaluated. The levels of hormones (FSH, AMH, Inhibin B, estradiol) were determined. A study of the vaginal biotope was conducted by PCR ‘Femoflor 8. Statistical studies were conducted in the environment of STATISTICA 10 package (Tibco, USA). The difference in average values was considered statistically significant for p<0.05. Results: vegetative-vascular disorders were typically for patient in group 2 and detected in 74.1%. Mucosal dryness was 5.2 times more common in patients 2 group, as was dyspareunia (5.5 times more often), dysuria (14 times more often), itching in the vagina (3.5 times more often), discomfort (3.4 times often). All patient in group 2, and 51% of patient in group 1 had moderate and severe dysbiosis on the background of hypoestrogenia.Conclusion: The period of menopausal transition is characterized as a abnormalities of the vaginal biotope due to the activation of aerobes, anaerobes, and fungi of the genus Candida, and estrogen deficiency, that is more pronounced in patients with a late transition to menopause. Combined approach to the therapy these disorders allows to level out the clinical manifestation due to the consistent use of Clindacin B prolong and Ovipol Clio, but also improve the quality of life by individually selecting the duration estradiol therapy.


2019 ◽  
Vol 18 (3) ◽  
pp. 262-268 ◽  
Author(s):  
Vladimíra Fejfarová ◽  
Hana Tibenská ◽  
Jitka Niklová ◽  
Robert Bém ◽  
Michal Dubský ◽  
...  

Infections caused by Pseudomonas sp are difficult to resolve by antibiotics (ATBs) and local therapy. The aim of our pilot study was to assess the effect of different local agents—particularly acidifying solutions—on the healing of diabetic foot ulcers (DFUs), eradication of pathogens, and economic costs related to DFU therapy. In this case study, we monitored 32 DFU patients infected by Pseudomonas species. Patients were divided into 2 groups according to the local therapy provided: group 1 (n = 15)—modern local treatment; group 2 (n = 17)—acidifying antiseptic solutions. The study groups differed only with regard to ATB usage prior to enrolment in the study ( P = .004), but did not differ with regard to age, diabetes control, peripheral arterial disease, or microcirculation status. During the follow-up period, DFUs healed in 20% of cases in group 1, but there were no cases of healing in group 2 (NS). The length of ATB therapy, the number of new osteomyelitis, lower limb amputations, and the changes of DFUs status/proportions did not differ significantly between study groups. Pseudomonas was eradicated in 67% of cases in group 1 and in 65% of cases in group 2. The local treatment given to group 2 patients was associated with lower costs ( P < .0001). Conclusion. Acidifying agents had the same effect as modern healing agents on wound healing, the number of amputations, and the eradication of Pseudomonas. Moreover, therapy performed using acidifying solutions proved in our pilot study markedly cheaper.


2020 ◽  
Vol 21 (6) ◽  
pp. 403-410
Author(s):  
Apichaya Puangpetch ◽  
Rawiporn Tiyasirichokchai ◽  
Samart Pakakasama ◽  
Supaporn Wiwattanakul ◽  
Usanarat Anurathapan ◽  
...  

Aim: 6-Mercaptopurine (6MP) is key to the treatment of acute lymphoblastic leukemia (ALL) as part of maintenance therapy. NUDT15 was identified as a novel thiopurine regulator conferring 6MP sensitivity. The aim of this study was to evaluate the influence of NUDT15 variants on 6MP-induced neutropenia in Thai children with ALL. Materials & methodology: Genotyping of NUDT15 (c.415C>T; rs116855232) and c.36_37insGGAGTC; rs554405994) was performed by Sanger sequencing in 100 patients with ALL. Patients were classified into wild-type (group 1), heterozygous variant (group 2) and homozygous variant (group 3). Clinical and laboratory features during the first 6 months of maintenance therapy were investigated. Therapy-induced neutropenia was observed in 31 patients during the weeks 1–8 (early myelotoxicity), while therapy-induced neutropenia was observed in 47 patients during the weeks 9–24 (late myelotoxicity). Results: There were 85 wild-type patients, 14 heterozygous variant patients and one homozygous variant patient. NUDT15 variants were associated with neutropenia as compared with wild-type (odds ratio: 17.862; 95% CI: 4.198–75.992, padj = 9.5 × 10-5). Multivariate analysis showed that the low-risk group was associated with neutropenia (p = 0.014) in the first 8 weeks of 6MP therapy. Group 2 and group 3 patients had significantly lower absolute neutrophil counts compared with group 1. The adjusted dose during the first 6 months of maintenance therapy with NUDT15 genotype group 1, 2 and 3 were 50, 36.6 and 12.5 mg/m2/day, respectively. Conclusion: Taken together, our results indicate NUDT15 variants may cause neutropenia, and the 6MP dosage should be considered in patients according to the NUDT15 variants to inform personalized 6MP therapy.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2046-2046
Author(s):  
Yang Liu ◽  
Margie Richardson ◽  
Kwanza Warren ◽  
Myla S. Strawderman ◽  
Nimish Mohile ◽  
...  

2046 Background: Recent clinical trials have shown that adding tumor treating fields (TTF) to the Stupp protocol (SP) has increased survival after glioblastoma (GBM) diagnosis. However, whether this regimen improves population-based survival for patients with GBM remains unknown. Methods: We retrospectively identified adult patients with newly diagnosed GBM treated at our institution from January 2000 to July 2017 (n = 438, median age: 63 years).We grouped patients into three time periods for comparison: 2000-2004 (group 1, prior to SP), 2005-2013 (group 2, SP) and 2014-2017 (group 3, adding TTF to SP). The Kaplan-Meier method was used to estimate survival. Statistical analysis included unadjusted group comparisons by Chi-square and Log-rank tests and adjusted group comparisons using logistic and Cox models. Results: Thirty-seven percent (43/117) of patients with GBM in group 3 received TTF with SP therapy; when compared to those who received SP only, these patients had significant improvements in 6-month and 1-year overall survival (OS) rates (100.0% vs. 82.4%, p < 0.01; 86.0% vs. 66.2%, p < 0.05, respectively) (unadjusted for prognostic factors including sex, age, KPS and extent of resection) and an increased trend of median OS (479.0 vs. 448 days, p = 0.269). However, after adjusting for those prognostic factors, we didn’t find a statistically better survival for patients treated with TTF (OR: 6.156, p = 0.097, OR: 2.102, p = 0.185, respectively). Furthermore, multivariate Cox proportion hazards model after adjusting for those prognostic factors showed no significant survival benefits for patients treated with TTF and SP compared to those treated with SP only (HR = 0.797, p = 0.648). In addition, we didn’t find significant increases of 6-month, 1-year survival rates and median OS for patients in group 3 when compared to those in group 2 who had seen increased trends of survival trends when compared to those in group 1. Conclusions: Although adding TTF to SP appeared to benefit patients with GBM, this effect might be due to selection bias, e.g., TTF was offered to those patients with better prognostic factors. Ascertaining the long-term benefits of TTF requires further investigation.


1999 ◽  
Vol 89 (2) ◽  
pp. 182-188 ◽  
Author(s):  
Robert L. Bowden ◽  
John F. Leslie

We developed a method for inducing sexual outcrosses in the homothallic Ascomycete fungus Gibberella zeae (anamorph: Fusarium graminearum). Strains were marked with different nitrate nonutilizing (nit) mutations, and vegetative compatibility groups served as additional markers in some crosses. Strains with complementary nit mutations were cocultured on carrot agar plates. Ascospores from individual perithecia were plated on a minimal medium (MM) containing nitrate as the sole nitrogen source. Crosses between different nit mutants segregated in expected ratios (3:1 nit-:nit+) from heterozygous perithecia. Analysis of vegetative compatibility groups of progeny of two crosses indicated two and three vegetative incompatibility (vic) genes segregating, respectively. For rapid testing of sexual recombination between nit mutants, perithecia were inverted over MM to deposit actively discharged ascospores. Development of proto-trophic wild-type colonies was taken as evidence of sexual recombination. Strains of G. zeae group 2 from Japan, Nepal, and South Africa, and from Indiana, Kansas, and Ohio in the United States were sexually interfertile. Four group 1 strains were not interfertile among themselves or with seven group 2 strains. Attempts to cross G. zeae with representatives of F. acuminatum, F. avenaceum, F. culmorum, F. crookwellense, F. oxysporum, and three mating populations of G. fujikuroi were not successful.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xue Zhao ◽  
Shishanthi Jayarathna ◽  
Helle Turesson ◽  
Ann-Sofie Fält ◽  
Gustav Nestor ◽  
...  

AbstractDNA-free genome editing was used to induce mutations in one or two branching enzyme genes (Sbe) in tetraploid potato to develop starch with an increased amylose ratio and elongated amylopectin chains. By using ribonucleoprotein (RNP) transfection of potato protoplasts, a mutation frequency up to 72% was achieved. The large variation of mutations was grouped as follows: Group 1 lines with all alleles of Sbe1 mutated, Group 2 lines with all alleles of Sbe1 as well as two to three alleles of Sbe2 mutated and Group 3 lines having all alleles of both genes mutated. Starch from lines in Group 3 was found to be essentially free of amylopectin with no detectable branching and a chain length (CL) distribution where not only the major amylopectin fraction but also the shortest amylose chains were lost. Surprisingly, the starch still formed granules in a low-ordered crystalline structure. Starch from lines of Group 2 had an increased CL with a higher proportion of intermediate-sized chains, an altered granule phenotype but a crystalline structure in the granules similar to wild-type starch. Minor changes in CL could also be detected for the Group 1 starches when studied at a higher resolution.


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