Genetic Architecture of Relapsed Pediatric B Cell Precursor Acute Lymphoblastic Leukemia Are Related to the Intensity of Upfront Therapy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 247-247
Author(s):  
Jiangyan Yu ◽  
Esmé Waanders ◽  
Simon V. van Reijmersdal ◽  
Edwin Sonneveld ◽  
Frank N. van Leeuwen ◽  
...  

Abstract B cell precursor acute lymphoblastic leukemia (BCP-ALL) is one of the most common malignancies in children. In the period 1991-2013, the Dutch Childhood Oncology Group (DCOG) has completed three treatment trials for childhood ALL: ALL8, 9 and 10, each protocol with stratifications into risk-groups (details: www.skion.nl). Although the cure rates increased in these subsequent trials, relapses still occurred in a significant number of children. Since consecutive upfront treatment protocols usually change at multiple levels, genomic alterations that are associated with relapse may also be variable, which could provide insight into the biology underlying therapy failure and relapse. In this study, we characterized the genetic architecture of relapsed BCP-ALL patients within the context of these three Dutch upfront protocols. We identified 3 patient groups based on upfront treatment as follows: Group-1: patients treated upfront with high-amounts of corticosteroids (CS) and relatively mild additional chemotherapy (ALL9 NHR/HR); Group-2: patients treated with high-amounts of CS and intensive additional chemotherapy (ALL10 MR); Group-3: patients treated with low-amounts of CS and moderately-intensive additional chemotherapy (ALL8 SR/MR, ALL10 SR). The number of high-risk patients that relapsed after ALL8 HR and ALL10 HR chemotherapy courses was too low to be included for analysis. We determined, at relapse, the presence of copy number alterations and sequence mutations in 21 recurrently affected genes involved in B-cell development, cell cycle regulation and RAS signaling, in 123 patients that relapsed after treatment in group-1 (n=56), group-2 (n=20) and group-3 (n=47). The number of CREBBP mutations in patients that relapsed after treatment according to group-1 (ALL9) was significantly lower compared to the other two groups, whereas B-cell development alterations were most common in patients that relapsed after treatment according to group-1, mainly due to a higher number of IKZF1 alterations (Figure 1). The high number of relapsed patients with leukemic clones carrying IKZF1 alterations in patients treated with high-amounts of CS and relatively mild additional chemotherapy is in line with our recent finding that IKZF1 is a key determinant of GC-induced apoptosis in normal and leukemic B-cells, and that loss of IKZF1 function confers resistance to dexamethasone, the major treatment component in group-1 (Marke et al., submitted). Additionally, in the group-2 patients treated with high-amounts of CS and highly intensive additional chemotherapy, a lower percentage IKZF1-deleted clones was detected at relapse, indicating that more GC-resistant, IKZF1-deleted clones are killed by the intense chemotherapy given in addition to CS in group-2 patients. Similarly, in the group-3 patients relapsing after treatment with lower amounts of CS and moderately-intensive additional chemotherapy, the percentage of surviving IKZF1-deleted clones was lower than in patients treated with high-amounts of CS. Taken together, our data indicate that the genetic architecture of relapsed BCP-ALL patients depends on the upfront treatment and, in addition, that the poor-prognostic feature of IKZF1-deletions may be more prominent in upfront treatment with high-amounts of CS and relatively mild additional chemotherapy. Figure 1. The frequency of genetic alterations in studied genes in patients that relapsed after treatment according to group-1, 2 and 3. Genes were grouped by their corresponding pathways. Group-1: patients treated upfront with high-amounts of CS and relatively mild additional chemotherapy (ALL9 NHR/HR); Group-2: patients treated with high-amounts of CS and intensive additional chemotherapy (ALL10 MR); Group-3: patients treated with low-amounts of CS and moderately-intensive additional chemotherapy (ALL8 SR/MR, ALL10 SR). Asterisk showed significant difference between upfront treatment groups, **p<0.001. Figure 1. The frequency of genetic alterations in studied genes in patients that relapsed after treatment according to group-1, 2 and 3. Genes were grouped by their corresponding pathways. Group-1: patients treated upfront with high-amounts of CS and relatively mild additional chemotherapy (ALL9 NHR/HR); Group-2: patients treated with high-amounts of CS and intensive additional chemotherapy (ALL10 MR); Group-3: patients treated with low-amounts of CS and moderately-intensive additional chemotherapy (ALL8 SR/MR, ALL10 SR). Asterisk showed significant difference between upfront treatment groups, **p<0.001. Disclosures No relevant conflicts of interest to declare.

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4994-4994
Author(s):  
Nicholas John Kelleher ◽  
David Gallardo ◽  
Salut Brunet ◽  
Pau Montesinos ◽  
Josep-Maria Ribera ◽  
...  

Abstract Background Therapy related acute lymphoblastic leukemia, a subset of secondary acute lymphoblastic leukemia has been estimated as accounting for between 1.2 and 6.9% of all adult acute lymphoblastic leukemia cases. It has been associated with an increased frequency of high risk cytogenetic alterations and with worse clinical outcomes. It has been suggested these patients should be included in high risk treatment protocols. Method In order to evaluate these characteristics in a group of similar patients we contacted centres working within the PETHEMA group to request data on patients diagnosed with ALL asking for clinical information including the presence or absence of previous neoplasia and of previous cytotoxic therapy along with treatment responses and survival data. Results We received information on 429 patients of whom 22 had received cytotoxic therapy for a prior neoplasm.Patients were divided into group 1 with prior cytotoxic therapy, group 2 with prior neoplasia without cytotoxic therapy and group 3 de novo ALL. We found patients in group 3 to be younger than the other two groups Group 1( 55 years) Group 2 (65 years) Group 3 (34 years) (p=0.001). No statistically significant difference was shown for white cell count, cytopenias, CNS involvement, LDH or for B versus T immunophenotype. Nor did our series show a significant difference in the frequencies of high risk cytogenetics between the groups. Figures for complete remission [Group 1- 13 (93%); Group 2- 6 (75%); Group 3-346 (85%) p=0.477] were higher in group 1 therapy related ALL compared with de novo patients without reaching clinical significance. Nor was a statistically significant difference shown for 3 year overall survival [Group 1 (80%); Group 2 (38%); Group 3 (47%) p=0.151] , 3 year event free survival [Group 1 (67%); Group 2 (38%); Group 3 (42%) p=0.24] or for complete remission duration [Group 1 (75%);Group 2 (50%); Group 3 (60%) p=0.462] Conclusion Apart from age, our series did not show an increase in poor risk clinical or cytogenetic features in therapy related ALL patients compared with de novo disease cases and nor was clinical outcome demonstrated to be worse. This would suggest that risk stratification should be carried out using currently recognized parameters without specifically taking into account the status of therapy related disease. Disclosures: No relevant conflicts of interest to declare.


Author(s):  
M. R. Rahman ◽  
M. M. Rahman ◽  
W. E. Wan Khadijah ◽  
R. B. Abdullah

The aim of this study was to enhance the ovulation and subsequent embryo production of equine chorionic gonadotrophin (eCG) superovulated goats by supplementing with human chorionic gonadotrophin (hCG) or gonadotrophin releasing hormone (GnRH). Thirty crossbred donor does were oestrus synchronized using controlled internal drug release (CIDR) device and superovulated using 1500 IU eCG. Then all the donor does were randomly divided into 3 groups. Group 1 were administered 500 IU hCG each at 2 successive days starting from 24 hours after CIDR removal; Group 2 received a single dosage of 20 μg GnRH and Group 3 was control. Ovulation and embryo production responses were evaluated during laparotomy session on Day 7 after CIDR removal. Does in Group 1 showed higher number of CL (10.90) than the Group 2 (1.90) or Group 3 (0.90). The number of ovarian stimulation and number of anovulatory follicles had no significant (P>0.05) differences among the treatment groups. Average number of structure recovered was significantly (P<0.05) higher in Group 1 (3.10) than Group 2 (0.70) or Group 3 (0.00). Moreover, average number of embryo production was higher in Group 1 (0.90) than Group 2 (0.50) and Group 3 (0.00), but no significant difference was observed between Group 1 and Group 2. Results indicated that using hCG hormone would be an effective means for increasing ovulation in eCG superovulated crossbred goats, although it was unable to enhance the embryo number due to increase number of unfertilised ovum.


VASA ◽  
2020 ◽  
Vol 49 (4) ◽  
pp. 281-284
Author(s):  
Atıf Yolgosteren ◽  
Gencehan Kumtepe ◽  
Melda Payaslioglu ◽  
Cuneyt Ozakin

Summary. Background: Prosthetic vascular graft infection (PVGI) is a complication with high mortality. Cyanoacrylate (CA) is an adhesive which has been used in a number of surgical procedures. In this in-vivo study, we aimed to evaluate the relationship between PVGI and CA. Materials and methods: Thirty-two rats were equally divided into four groups. Pouch was formed on back of rats until deep fascia. In group 1, vascular graft with polyethyleneterephthalate (PET) was placed into pouch. In group 2, MRSA strain with a density of 1 ml 0.5 MacFarland was injected into pouch. In group 3, 1 cm 2 vascular graft with PET piece was placed into pouch and MRSA strain with a density of 1 ml 0.5 MacFarland was injected. In group 4, 1 cm 2 vascular graft with PET piece impregnated with N-butyl cyanoacrylate-based adhesive was placed and MRSA strain with a density of 1 ml 0.5 MacFarland was injected. All rats were scarified in 96th hour, culture samples were taken where intervention was performed and were evaluated microbiologically. Bacteria reproducing in each group were numerically evaluated based on colony-forming unit (CFU/ml) and compared by taking their average. Results: MRSA reproduction of 0 CFU/ml in group 1, of 1410 CFU/ml in group 2, of 180 200 CFU/ml in group 3 and of 625 300 CFU/ml in group 4 was present. A statistically significant difference was present between group 1 and group 4 (p < 0.01), between group 2 and group 4 (p < 0.01), between group 3 and group 4 (p < 0.05). In terms of reproduction, no statistically significant difference was found in group 1, group 2, group 3 in themselves. Conclusions: We observed that the rate of infection increased in the cyanoacyrylate group where cyanoacrylate was used. We think that surgeon should be more careful in using CA in vascular surgery.


2021 ◽  
Vol 28 (3) ◽  
pp. 328-338
Author(s):  
Ogbutor Udoji Godsday ◽  
Nwangwa Eze Kingsley ◽  
Nwogueze Bartholomew Chukwuebuka ◽  
Chukwuemeka Ephraim ◽  
Ezunu Emmanuel ◽  
...  

Decline in normal physiological pulmonary function has been attributed to premorbid conditions such as prehypertension. Research evidence suggests that physical activity reduces age-related decline in pulmonary function and improves the efficiency of the lungs in prehypertensive patients. However, there is a scarcity of data evidence relating to isometric exercise and pulmonary function. Furthermore, the interrelationship between the intensity and duration of isometric exercise and pulmonary function in these patients is still uncertain. Therefore, this study was undertaken to investigate the effect of isometric handgrip exercise on pulmonary function capacity in adults with prehypertension. To determine the effectiveness of isometric handgrip exercise on pulmonary function capacity in adults with prehypertension. A quasi experiment using a pre- and post-exercise method was carried out in two out-patients hospital settings. The sample comprised 192 sedentary pre-hypertensive subjects, aged between 30–50 years, that were randomly distributed into three groups of 64 participants each. The subjects performed, for 24 consecutive days, an isometric handgrip exercise at 30% Maximum Voluntary Contraction (M.V.C.). At the end of the 24 days, group one (GP1) discontinued, while group two (GP2) continued the exercise protocol for another 24 consecutive days and group three (GP3) continued with the exercise protocol for another 24 consecutive days but at 50% M.V.C. Determinants of lung function (outcomes) were Forced Expiratory Volume in 1 s (FEV1), Forced Vital Capacity (FVC), FEV1/FVC Ratio and Peak Expiratory Flow Rate (PEFR). The study shows that there was no statistically significant difference in the pre- and post-exercise outcomes for FEV1, FVC, FEV1/FVC Ratio and PEFR after 24 days for group 1. In group 2, there was a statistically significant difference in the FVC [(mean = 0.12 ± 0.12), (p = 0.002)], FEV1 [(mean = 0.15 ± 0.17), (p = 0.003)] and PEF [(mean = 0.85 ± 0.35), (p = 0.001)] after 48 days. In group 3, there was a statistically significant difference (p = 0.001) in all the outcomes assessed after 48 days. There was a between groups difference in favour of group 2 compared with group 1 for outcomes of FEV1 [(mean = 0.142 ± 0.68), (p = 0.005)] and PEF [(mean = 0.83 ± 0.19), (p = 0.0031)]. There was statistically significant difference in favour of group 3 compared to group 2, by increasing the exercise intensity from 30% to 50% M.V.C., for outcomes of FVC [mean change = 0.10 ± 0.052), (p = 0.005)], FEV1/FVC [mean change = 3.18 ± 0.75), (p = 0.017)] and PEF [(mean change = 0.86 ± 0.35), (p = 0.001)] after 48 days. Isometric handgrip exercise (after 48 days at 30% to 50% M.V.C.) improves outcomes of pulmonary function capacity in adults with prehypertension. Meanwhile, duration and/or increase in intensity of the isometric effort significantly contributed to the affects attained.


Arthroplasty ◽  
2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Zhijie Chen ◽  
Kaizhe Chen ◽  
Yufei Yan ◽  
Jianmin Feng ◽  
Yi Wang ◽  
...  

Abstract Objective To evaluate the effect of medial posterior tibial slope (PTS) on mid-term postoperative range of motion (ROM) and functional improvement of the knee after medial unicompartmental knee arthroplasty (UKA). Methods Medical records of 113 patients who had undergone 124 medial UKAs between April 2009 through April 2014 were reviewed retrospectively. The mean follow-up lasted 7.6 years (range, 6.2–11.2 years). Collected were demographic data, including gender, age, height, weight of the patients. Anteroposterior (AP) and lateral knee radiographs of the operated knees were available in all patients. The knee function was evaluated during office follow-up or hospital stay. Meanwhile, postoperative PTS, ROM, maximal knee flexion and Hospital for Special Surgery (HSS) knee score (pre−/postoperative) of the operated side were measured and assessed. According to the size of the PTS, patients were divided into 3 groups: group 1 (<4°), group 2 (4° ~ 7°) and group 3 (>7°). The association between PTS and the knee function was investigated. Results In our cohort, the average PTS was 2.7° ± 0.6° in group 1, 5.6° ± 0.9° in group 2 and 8.7° ± 1.2° in group 3. Pairwise comparisons showed significant differences among them (p < 0.01). The average maximal flexion range of postoperative knees in each group was 112.4° ± 5.6°, 116.4° ± 7.2°, and 117.5° ± 6.1°, respectively, with significant difference found between group 1 and group 2 (p < 0.05), and between group 1 and group 3 (p < 0.05). However, the gender, age, and body mass index (BMI) did not differ between three groups and there was no significant difference between groups in terms of pre−/postoperative HSS scores or postoperative knee ROM. Conclusion A mid-term follow-up showed that an appropriate PTS (4° ~ 7°) can help improve the postoperative flexion of knee. On the other hand, too small a PTS could lead to limited postoperative knee flexion. Therefore, the PTS less than 4° should be avoided during medial UKA.


2021 ◽  
pp. 1-7
Author(s):  
Emre Erdem ◽  
Ahmet Karatas ◽  
Tevfik Ecder

<b><i>Introduction:</i></b> The effect of high serum ferritin levels on long-term mortality in hemodialysis patients is unknown. The relationship between serum ferritin levels and 5-year all-cause mortality in hemodialysis patients was investigated in this study. <b><i>Methods:</i></b> A total of 173 prevalent hemodialysis patients were included in this study. The patients were followed for up to 5 years and divided into 3 groups according to time-averaged serum ferritin levels (group 1: serum ferritin &#x3c;800 ng/mL, group 2: serum ferritin 800–1,500 ng/mL, and group 3: serum ferritin &#x3e;1,500 ng/mL). Along with the serum ferritin levels, other clinical and laboratory variables that may affect mortality were also included in the Cox proportional-hazards regression analysis. <b><i>Results:</i></b> Eighty-one (47%) patients died during the 5-year follow-up period. The median follow-up time was 38 (17.5–60) months. The 5-year survival rates of groups 1, 2, and 3 were 44, 64, and 27%, respectively. In group 3, the survival was lower than in groups 1 and 2 (log-rank test, <i>p</i> = 0.002). In group 1, the mortality was significantly lower than in group 3 (HR [95% CI]: 0.16 [0.05–0.49]; <i>p</i> = 0.001). In group 2, the mortality was also lower than in group 3 (HR [95% CI]: 0.32 [0.12–0.88]; <i>p</i> = 0.026). No significant difference in mortality between groups 1 and 2 was found (HR [95% CI]: 0.49 [0.23–1.04]; <i>p</i> = 0.063). <b><i>Conclusion:</i></b> Time-averaged serum ferritin levels &#x3e;1,500 ng/mL in hemodialysis patients are associated with an increased 5-year all-cause mortality risk.


2019 ◽  
Vol 71 (1) ◽  
Author(s):  
Mohamed MesbahTahaHassanin ◽  
Ahmad ShafieAmmar ◽  
Radwa M. Abdullah ◽  
Mohammad Hassan Khedr

Abstract Background Right ventricular apical pacing with the resultant left ventricular dyssynchrony often leads to depressed systolic function and heart failure. This study aimed at investigating the relation between various septal locations guided by ECG and fluoroscopy and the intermediate term functional capacity of the patients. Results Fifty patients who received a single lead pacemaker with assumed > 90% pacemaker dependency. Patients were randomized according to RV pacing site RV into group 1 “high septum” (n = 15), group 2 “mid septum” (n = 25), and group 3 “low septum” (n = 10) using QRS vector and duration as well as fluoroscopic parameters. Their clinical status was assessed 6 months after device implementation using 6-min walk test (6MWT). The study showed that paced QRS complex duration itself has no significant difference between the different septal pacing locations (P-value 0.675), although its combination with the paced QRS complex vector can signify the optimal pacing site and 6MWT showed a significant difference among the groups in favor of group 1; group 1 (413.3 ± 148.5), group 2 (359.8 ± 124.6), and group 3 (276.0 ± 98.5) P value 0.04. Conclusion There was a significant difference found between the three septal pacing sites concerning the patient functional capacity with superiority of high septal location. By contrast, different septal sites showed no significant difference of the paced QRS complex duration. To optimize the pacing site in the septum, assessment of the paced QRS vector in leads I and III is of a great benefit especially when combined with paced QRS complex duration assessment.


2016 ◽  
Vol 10 (02) ◽  
pp. 220-224 ◽  
Author(s):  
Emre Bayram ◽  
Huda Melike Bayram

ABSTRACT Objective: The purpose of this study was to evaluate fracture resistance of teeth with immature apices treated with coronal placement of mineral trioxide aggregate (MTA), bioaggregate (BA), and Biodentine. Materials and Methods: Forty-one freshly extracted, single-rooted human premolar teeth were used for the study. At first, the root length was standardized to 9 mm. The crown-down technique was used for the preparation of the root canals using the rotary ProTaper system (Dentsply Maillefer, Ballaigues, Switzerland) of F3 (30). Peeso reamer no. 6 was stepped out from the apex to simulate an incompletely formed root. The prepared roots were randomly assigned to one control (n = 5) and three experimental (n = 12) groups, as described below. Group 1: White MTA (Angelus, Londrina, Brazil) was prepared as per the manufacturer's instructions and compacted into the root canal using MAP system (Dentsply Maillefer, Ballaigues, Switzerland) and condensed by pluggers (Angelus, Londrina, Brazil). Group 2: The canals were filled with DiaRoot-BA (DiaDent Group International, Canada). Group 3: Biodentine (Septodont, Saint Maur des Fosses, France) solution was mixed with the capsule powder and condensed using pluggers. Instron was used to determine the maximum horizontal load to fracture the tooth, placing the tip 3 mm incisal to the cementoenamel junction. Mean values of the fracture strength were compared by ANOVA followed by a post hoc test. P < 0.05 was considered statistically significant. Results: No significant difference was observed among the MTA, BA, and biodentine experimental groups. Conclusion: All the three materials tested, may be used as effective strengthening agents for immature teeth.


2018 ◽  
Vol 24 (1) ◽  
pp. 37
Author(s):  
Annisa Trissatharra ◽  
Sri Ratna Dwiningsih ◽  
Ratna Sofaria Munir

Objectives: To identify the effect of monoclonal antibody bZP3 at ovarian follicles that undergo atresia and diameter of various ovarian follicles.Materials and Methods: This is a true experimental research with post only control group design. Samples were 36 female mices (Mus musculus) which is divided into 6 groups, there are 3 control groups (group 1, 2, and 3) injected by Phospatase Buffer Saline (PBS) 50µl and 3 treatment groups (group 4, 5, and 6) injected by Mab bZP3 50µl. Group 1 and 4 terminated at 5th day, group 2 and 5 terminated at 10th day, and group 3 and 6 terminated at 20th day. Evaluation of atretic ovarian follicles and diameter of ovarian follicles performed by hematoxylin eosin (HE) and the data processed by parametric statistic.Results: There are no significant in different among groups in the aspect of atretic follicles and diameter of folicles (p>0.05), but descriptively, number of follicles undergo atresia of the follicle primary, secondary, and tertiary treatment group was higher than the control group, except on the 20th day of observation time.Conclusion: administration of Mab bZP3 had no effect to amount of atretic follicles and diameter of folicles during observation time.


2012 ◽  
Vol 27 (1) ◽  
pp. 82-87 ◽  
Author(s):  
Adelina Maria da Silva ◽  
Wilson Machado de Souza ◽  
Nair Trevizan Machado de Souza ◽  
Marion Burkhardt de Koivisto ◽  
Patrícia de Athayde Barnabé ◽  
...  

PURPOSE: To evaluate bone healing in the extraction socket of the feline mandibular canine tooth after grafting. METHODS: Eighteen adult cats were submitted to unilateral extraction of mandibular canine tooth and divided into three groups. In group 1 (n=6), control, the extraction socket was left empty. In group 2 (n=6), the extraction socket was filled with autogenous cancelous bone from the iliac crest and in group 3 (n=6), with cortical bone chips from the iliac crest. Cats were euthanized at 6 weeks postoperative. RESULTS: Immediate postoperative radiographs in dorsoventral view showed a radiolucent area at the extraction wound. A decreased radiolucency was observed on the radiographs taken at 6 weeks postoperative. Histological examination showed formation of woven bone within the extraction socket. The percentage of newly formed bone within the extraction socket, measured by the histometry, showed no statistically significant difference among the values of the three groups (Kruskal-Wallis'test p>0.05) (group 1: 52.54 ± 15.46, group 2: 50.51 ± 5.01, group 3: 51.85 ± 9.52). CONCLUSION: The bone regeneration observed in the extraction sockets filled with autogenous cancellous bone or autogenous cortical bone chips was similar to that observed in the control sites, given an observation period of 6 weeks after extraction of the mandibular canine tooth.


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