MRD-Based Therapeutic Decisions in Genetically Defined Subsets of Adolescents and Young Adult Philadelphia-Negative ALL.
Ontology highlight
ABSTRACT:
SUBMITTER: Tosi M
PROVIDER: S-EPMC8123823 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Importance:The incidence of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adolescent and young adult (AYA) patients (age range, 15-39 years) in the United States is increasing at a greater rate than in younger or older persons. Their optimal treatment has been increasingly debated as pediatric regimens have become more widely used in the age group. This review compares the basic features of pediatric and adult chemotherapy regimens for ALL and LBL, recognizes and describes the challenges of the pediatric regimen, and suggests strategies to facilitate its adoption for AYAs with ALL and LBL. Observations:All but 2 of 25 published comparisons of outcomes with pediatric and adult regimens for ALL and LBL in AYAs and 1 meta-analysis favor the pediatric regimen. After more than a half-century of clinical trials of the pediatric regimens, including at least 160 phase 3 trials in the United States, the pediatric regimens have become far more complex than most adult regimens. Asparaginase, a critical component of the pediatric regimens, is more difficult to administer to AYAs (and older patients) but nonetheless has a favorable benefit to toxicity ratio for AYAs. A dramatic reduction in outcome of ALL and LBL during the AYA years (the "survival cliff") is coincident with similar reductions in proportions of AYAs referred to academic centers and enrolled on clinical trials (the "accrual cliff" and "referral cliff"). Conclusions and Relevance:The accumulating data increasingly support treating AYAs with ALL and LBL with a pediatric-inspired regimen or an approved institutional or national clinical trial tailored for this patient group. A need to develop clinical trials specifically for AYAs and to encourage their participation is paramount, with a goal to improve both the quantity and quality of survival.
| S-EPMC7534395 | biostudies-literature
Project description:Pancreatic cancer is the fourth cause of death from cancer in the western world. Majority of patients present with advanced unresectable disease responding poorly to most chemotherapeutic agents. Chemotherapy for pancreatic cancer might be improved by adjusting it to individual genetic profiles. We attempt to identify genetic predictors of chemosensitivity to broad classes of anticancer drugs.Using a panel of genetically defined human pancreatic cancer cell lines, we tested gemcitabine (antimetabolite), docetaxel (antimicrotubule), mitomycin C (MMC; alkylating), irinotecan (topoisomerase I inhibitor), cisplatin (crosslinking), KU0058948 (Parp1 inhibitor), triptolide (terpenoid drug), and artemisinin (control).All pancreatic cancer cell lines were sensitive to triptolide and docetaxel. Most pancreatic cancer cells were also sensitive to gemcitabine and MMC. The vast majority of pancreatic cancer cell lines were insensitive to cisplatin, irinotecan, and a Parp1 inhibitor. However, individual cell lines were often sensitive to these compounds in unique ways. We found that DPC4/SMAD4 inactivation sensitized pancreatic cancer cells to cisplatin and irinotecan by 2- to 4-fold, but they were modestly less sensitive to gemcitabine. Pancreatic cancer cells were all sensitive to triptolide and 18% were sensitive to the Parp1 inhibitor. P16/CDKN2A-inactivated pancreatic cancer cells were 3- to 4-fold less sensitive to gemcitabine and MMC.Chemosensitivity of pancreatic cancer cells correlated with some specific genetic profiles. These results support the hypothesis that genetic subsets of pancreatic cancer exist, and these genetic backgrounds may permit one to personalize the chemotherapy of pancreatic cancer in the future. Further work will need to confirm these responses and determine their magnitude in vivo.
| S-EPMC3513499 | biostudies-literature
Project description:Evaluation of minimal residual disease (MRD) during first-line treatment and after salvage therapy is part of the standard management of acute lymphoblastic leukemia (ALL). Persistent or recurrent MRD is one of the most relevant prognostic factors and identifies a group of patients with resistance to standard chemotherapy. These patients have a high risk of relapse despite continued first-line therapy. Although stem cell transplantation (SCT) is an appropriate strategy, patients with high MRD show an increased relapse rate even after SCT. Approximately one-quarter of adult ALL patients develop an MRD failure, defined as MRD above 0.01% after standard induction and consolidation. The best time point and level of MRD for treatment modification are matters of debate. In order to eradicate MRD and thereby improve chances for a cure, new targeted compounds with different mechanisms of action compared to chemotherapy are being utilized. These compounds include monoclonal antibodies, chimeric antigen receptor T cells, and molecular targeted compounds. Essential factors for decision-making, available compounds, and follow-up therapies are discussed.
| S-EPMC8824253 | biostudies-literature
Project description:Background/aimsRecent changes in the diagnostic criteria for myeloproliferative neoplasms (MPNs) and increasing patient numbers necessitate updating of the data on vascular events in patients with such disorders.MethodsIn this single-center study, thrombotic and hemorrhagic events were retrospectively analyzed in patients diagnosed with essential thrombocythemia (ET), polycythemia vera (PV) prefibrotic/early primary myelofibrosis (pre-PMF), or PMF, based on the 2016 World Health Organization diagnostic criteria.ResultsOf a total of 335 consecutive patients (139 ET, 42 pre-PMF, 124 PV, and 30 PMF patients; 192 males and 143 females) of median age 64 years (range, 15 to 91), 112 (33.4%) experienced a total of 126 thrombotic events before diagnosis, at the time of diagnosis, or during follow-up over a median of 4.6 years (range, 0.1 to 26.5). Cerebrovascular thrombosis (18.8%) was the most common initial event, followed by coronary heart disease (10.1%) and splanchnic (1.5%) and peripheral thrombosis (1.5%). Arterial thrombosis was more common than venous thrombosis (31.3% vs. 2.1%, respectively; p = 0.001). Thrombosis was most frequent in PV patients (39.5%), followed by patients with pre-PMF (38.1%), ET (30.9%), and PMF (13.3%). Of the 112 patients who experienced thromboses, 53 (47%) and 39 (33.9%) had thrombotic events before and at the time of MPN diagnosis, respectively. Twenty-seven patients (8.1%) experienced 29 hemorrhagic events, of which gastrointestinal bleeding (n = 20) was the most common.ConclusionMost thrombotic events occurred before or at the time of diagnosis, and the prevalence of arterial thrombosis was markedly higher than that of venous thrombosis in patients with MPN.
| S-EPMC8435504 | biostudies-literature
Project description:The striosome compartment within the dorsal striatum has been implicated in reinforcement learning and regulation of motivation, but how striosomal neurons contribute to these functions remains elusive. Here, we show that a genetically identified striosomal population, which expresses the Teashirt family zinc finger 1 (Tshz1) and belongs to the direct pathway, drives negative reinforcement and is essential for aversive learning in mice. Contrasting a "conventional" striosomal direct pathway, the Tshz1 neurons cause aversion, movement suppression, and negative reinforcement once activated, and they receive a distinct set of synaptic inputs. These neurons are predominantly excited by punishment rather than reward and represent the anticipation of punishment or the motivation for avoidance. Furthermore, inhibiting these neurons impairs punishment-based learning without affecting reward learning or movement. These results establish a major role of striosomal neurons in behaviors reinforced by punishment and moreover uncover functions of the direct pathway unaccounted for in classic models.
| S-EPMC8605319 | biostudies-literature
Project description:BackgroundPediatric-based or -inspired trials have improved the prognosis of adolescents and young adults (AYA) with Philadelphia chromosome-negative (Ph-neg) acute lymphoblastic leukemia (ALL).MethodsThis study reports the results of treatment of the ALLRE08 trial, a full pediatric trial for AYA aged 15-30 years with standard-risk (SR) ALL.ResultsFrom 2008 to 2018, 89 patients (38 adolescents [15-18 years] and 51 young adults [YA, 19-30 years], median age: 20 [15-29] years) were enrolled in the ALLRE08 trial. The complete response (CR) was 95%. Twenty-two patients were transferred to a high-risk (HR) protocol because of poor marrow response on day 14 (n = 20) or high-level of end-induction minimal residual response (MRD ≥ 0.25%, n = 2). Cumulative incidence of relapse (CIR) at 5 years was 35% (95%CI: 23%-47%), with significant differences between adolescents and YA: 13% (4%-28%) vs 52% (34%-67%), P = .012. No treatment-related mortality was observed in 66/66 patients following the ALLRE08 trial vs 3/23 patients moved to a HR trial. The estimated 5-year overall survival (OS) was 74% (95%CI: 63%-85%), with significantly higher rates for adolescents vs YA: 87% (95%CI: 74%-100%) vs 63% (46%-80%), P = .021. Although CIR or OS were lower in patients who were transferred to a HR trial, the differences were not statistically significant (CIR: 34% [21%-47%] vs 37% [14%-61%]; OS: 78% [66%-90%] vs 61% [31%;91%]).ConclusionA full pediatric trial is feasible and effective for AYA with Ph-neg, SR-ALL, with better results for adolescents than for YA. Outcome of patients with poor early response rescued with a HR trial was not significantly inferior.
| S-EPMC7131850 | biostudies-literature
Project description:The objective of this study was to characterize and compare muscle histopathological findings in 3 different genetic motor neuron disorders. We retrospectively re-assessed muscle biopsy findings in 23 patients with autosomal dominant lower motor neuron disease caused by p.G66V mutation in CHCHD10 (SMAJ), 10 X-linked spinal and bulbar muscular atrophy (SBMA) and 11 autosomal dominant c9orf72-mutated amyotrophic lateral sclerosis (c9ALS) patients. Distinct large fiber type grouping consisting of non-atrophic type IIA muscle fibers were 100% specific for the late-onset spinal muscular atrophies (SMAJ and SBMA) and were never observed in c9ALS. Common, but less specific findings included small groups of highly atrophic rounded type IIA fibers in SMAJ/SBMA, whereas in c9ALS, small group atrophies consisting of small-caliber angular fibers involving both fiber types were more characteristic. We also show that in the 2 slowly progressive motor neuron disorders (SMAJ and SBMA) the initial neurogenic features are often confused with considerable secondary "myopathic" changes at later disease stages, such as rimmed vacuoles, myofibrillar aggregates and numerous fibers reactive for fetal myosin heavy chain (dMyHC) antibodies. Based on our findings, muscle biopsy may be valuable in the diagnostic work-up of suspected motor neuron disorders in order to avoid a false ALS diagnosis in patients without clear findings of upper motor neuron lesions.
| S-EPMC4801364 | biostudies-literature
Project description:Cannabis use in youth is rising and has been linked to deficits in cognitive functioning. However, cognitive findings have primarily been based on small samples of users seeking treatment, and few studies have evaluated cognition in occasional cannabis users. Here, we examined 4,568 adolescents and young adults (ages 14-21 years) drawn from the Philadelphia Neurodevelopmental Cohort, a prospective, population-based study. Participants were classified as cannabis Non-Users (n = 3,401), Occasional Users (twice per week or less; n = 940), or Frequent Users (>3 times per week; n = 227). Mixed-model analyses examined main effects of cannabis use and interactions between age and cannabis use on cognitive functioning. There was a significant interaction between cannabis group and age such that adolescent (but not young adult) Frequent Users performed worse than Non-Users on measures of executive control (p = .002). Earlier age of cannabis use was associated with worse performance in executive control in Occasional Users (p = .04). Unexpectedly, Occasional Users exhibited better executive control, memory, and social cognition than Non-Users (ps < .05). Although mild executive control deficits in adolescent frequent users and a relation between early cannabis initiation and cognitive performance are partially consistent with prior research, cognitive deficits were not found in other hypothesized domains in this community-based sample. Moreover, occasional cannabis users displayed equivalent or even slightly better executive control, social-cognitive, and memory abilities compared with nonusers, suggesting complex relationships between cannabis use and cognition in youth. Longitudinal studies with community samples are needed to identify variables affecting risk and resilience to cognitive deficits associated with cannabis. (PsycINFO Database Record
| S-EPMC5468477 | biostudies-literature
Project description:The majority of adult patients affected by B-cell acute lymphoblastic leukemia (B-ALL) will relapse after an initial response, while approximately 20% will display primary resistant disease. Patients suffering from relapsed/refractory B-ALL have a very poor outcome. Allogeneic hematopoietic cell transplantation (HCT) still represents the only curative approach, but is not so frequently feasible, because of patient's fitness, donor availability, and the ability to achieve a remission prior to HCT. The estimated remission rates with conventional cytotoxic agents are around 30%, but they are short-lived. These disappointing results led to the introduction of new immunologic-based treatments-blinatumomab and inotuzumab. They produced a substantial improvement in terms of response rates, with the ability, in most cases, to induce a minimal residual disease (MRD)-negative status. Similarly, T cells engineered to express a CD19-specific chimeric antigen receptor (CAR-T) have yielded sensational results among patients with relapsed/refractory B-ALL, with unexpectedly high MRD-negative complete remissions rates. However, the first studies looking at long-term outcomes after CAR-T infusions told us that a significant fraction of such responses are not durable, and may benefit from a consolidation approach such as an allogeneic HCT.
| S-EPMC8432388 | biostudies-literature
Project description:Pediatric regimens have improved outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL). However, results remain inferior to children with ALL. The Australasian Leukaemia and Lymphoma Group (ALLG) ALL06 study (anzctr.org.au/ACTRN12611000814976) was designed to assess whether a pediatric ALL regimen (Australian and New Zealand Children's Haematology and Oncology Group [ANZCHOG] Study 8) could be administered to patients aged 15 to 39 years in a comparable time frame to children as assessed by the proportion of patients completing induction/consolidation and commencing the next phase of therapy (protocol M or high-risk [HR] treatment) by day 94. Minimal residual disease (MRD) response stratified patients to HR treatment and transplantation. From 2012 to 2018, a total of 86 patients were enrolled; 82 were eligible. Median age was 22 years (range, 16-38 years). Induction/consolidation was equally deliverable in ALL06 as in Study 8. In ALL06, 41.5% (95% confidence interval [CI], 30.7-52.9) commenced protocol M or HR therapy by day 94 vs 39.3% in Study 8 (P = .77). Median time to protocol M/HR treatment was 96 days (interquartile range, 87.5-103 days) in ALL06 vs 98 days in Study 8 (P = .80). Induction mortality was 3.6%. With a median follow-up of 44 months (1-96 months), estimated 3-year disease-free survival was 72.8% (95% CI, 62.8-82.7), and estimated 3-year overall survival was 74.9% (95% CI, 65.3-84.5). End induction/consolidation MRD negativity rate was 58.6%. Body mass index ≥30 kg/m2 and day 79 MRD positivity were associated with poorer disease-free survival and overall survival. Pediatric therapy was safe and as deliverable in AYA patients as in children with ALL. Intolerance of pediatric ALL induction/consolidation is not a major contributor to inferior outcomes in AYA ALL.
| S-EPMC8714725 | biostudies-literature