A comprehensive comparison and evaluation of surgical techniques for anterior shoulder instability: a Bayesian network meta-analysis.

BACKGROUND: Anterior shoulder instability is a common clinical problem; however, conflicting evidence exists regarding optimal treatment algorithms. We perform a comparative analysis of stabilization techniques used for recurrent anterior shoulder instability to identify the one associated with the lowest rate of recurrent instability. We additionally explore how glenoid bone loss and osseus lesions affect recurrence rates. METHODS: PubMed, MEDLINE, Embase, and Cochrane databases were searched for clinical studies comparing surgical techniques for anterior shoulder instability. Two team members independently assessed all potential studies for eligibility and extracted data. Each included study underwent a risk of bias assessment using the Cochrane risk of bias summary tool. The primary outcome of interest was the rate of recurrent instability, which underwent a Bayesian network meta-analysis. Additional analyses were performed relating to the degree of glenoid bone loss and the presence of osseous lesions. RESULTS: Of 2699 studies screened, 52 studies with 4209 patients were included. Patients who underwent open Latarjet demonstrated the overall lowest rate of recurrent instability [log odds ratio (LOR) 1.93], whereas patients who underwent arthroscopic Bankart repair demonstrated the highest (LOR 2.87). When glenoid bone loss was 10% to 20%, open Latarjet had significantly lower recurrent instability (P = .0016) compared to arthroscopic Bankart repair. When glenoid bone loss increased from 0%-10% to 10%-20%, arthroscopic Bankart repair had a significantly increased rate of recurrence (P = .021). In the presence of an engaging Hill-Sachs lesion, both open Latarjet (P = .01) and arthroscopic Bankart with remplissage (P = .029) had significantly reduced recurrence rates compared to arthroscopic Bankart repair. Finally, regardless of procedure, the presence of a Hill-Sachs or bony Bankart lesion was associated with an increased risk of recurrent instability (r = 0.44, P = .0003, and r = 0.40, P = .006, respectively). CONCLUSION: The open Latarjet has the overall lowest recurrent instability and significantly lower compared to arthroscopic Bankart repair in the setting of increasing glenoid bone loss. Bone loss between 0% and 10% results in similar outcomes across all procedures.

Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Acute Lymphoblastic Leukemia Intercontinental-Berlin-Frankfurt-Münster 2009 Trial.

PURPOSE: The International Berlin-Frankfurt-Münster (BFM) study group conducted a study on pediatric acute lymphoblastic leukemia (ALL). Minimal residual disease (MRD) was assessed using flow cytometry (FCM), and the impact of early intensification and methotrexate (MTX) dose on survival was evaluated. PATIENTS AND METHODS: We included 6,187 patients younger than 19 years. MRD by FCM refined the risk group definition previously used in the ALL intercontinental-BFM 2002 study on the basis of age, WBC count, unfavorable genetic aberrations, and treatment response measured morphologically. Patients at intermediate risk (IR) and high risk (HR) were randomly assigned to protocol augmented protocol I phase B (IB) versus IB regimen. MTX doses of 2 versus 5 g/m2 every 2 weeks, four times, were evaluated in precursor B-cell-ALL (pcB-ALL) IR. RESULTS: The 5-year event-free survival (EFS ± SE) and overall survival (OS ± SE) rates were 75.2% ± 0.6% and 82.6% ± 0.5%, respectively. Their values in risk groups were standard risk (n = 624), 90.7% ± 1.4% and 94.7% ± 1.1%; IR (n = 4,111), 77.9% ± 0.7% and 85.7% ± 0.6%; and HR (n = 1,452), 60.8% ± 1.5% and 68.4% ± 1.4%, respectively. MRD by FCM was available in 82.6% of cases. The 5-year EFS rates in patients randomly assigned to protocol IB (n = 1,669) and augmented IB (n = 1,620) were 73.6% ± 1.2% and 72.8% ± 1.2%, respectively (P = .55), while those in patients receiving MTX doses of 2 g/m2 (n = 1,056) and MTX 5 g/m2 (n = 1,027) were 78.8% ± 1.4% and 78.9% ± 1.4%, respectively (P = .84). CONCLUSION: The MRDs were successfully assessed using FCM. An MTX dose of 2 g/m2 was effective in preventing relapse in non-HR pcB-ALL. Augmented IB showed no advantages over the standard IB.[Media: see text].

Bariatric interventions in obesity treatment and prevention in pediatric acute lymphoblastic leukemia: a systematic review and meta-analysis.

Most children are surviving acute lymphoblastic leukemia (ALL) today. Yet, the emergence of cardiometabolic comorbidities in this population may impact long-term outcomes including the quality of life and lifespan. Obesity is a major driver of cardiometabolic disorders in the general population, and in ALL patients it is associated with increased risk of hypertension, dysglycemia, and febrile neutropenia when compared with lean ALL patients undergoing therapy. This systematic review aims to assess the current evidence for bariatric interventions to manage obesity in children with ALL. The primary outcome for this systematic review was the change in BMI z-score with implementation of the interventions studied. Literature searches were conducted in several databases. Ten publications addressing the study question were included in this review, and five studies were used in the meta-analysis to assess the impact of the bariatric interventions on obesity. The BMI z-score did not change significantly with the interventions. However, the quality of evidence was low, which precluded the recommendation of their use. In conclusion, prospective, rigorous, adequately powered, and high-quality longitudinal studies are urgently needed to deliver effective lifestyle interventions to children with ALL to treat and prevent obesity. These interventions, if successful, may improves cardiometabolic health outcomes and enhance the quality of life and life expectancy in children with ALL.

Geographical Distribution, Incidence, Malignancies, and Outcome of 136 Eastern Slavic Patients With Nijmegen Breakage Syndrome and NBN Founder Variant c.657_661del5.

Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to lymphoid malignancies. The majority of NBS patients are identified with a homozygous five base pair deletion in the Nibrin (NBN) gene (c.657_661del5, p.K219fsX19) with a founder effect observed in Caucasian European populations, especially of Slavic origin. We present here an analysis of a cohort of 136 NBS patients of Eastern Slav origin across Belarus, Ukraine, Russia, and Latvia with a focus on understanding the geographic distribution, incidence of malignancy, and treatment outcomes of this cohort. Our analysis shows that Belarus had the highest prevalence of NBS (2.3 per 1,000,000), followed by Ukraine (1.3 per 1,000,000), and Russia (0.7 per 1,000,000). Of note, the highest concentration of NBS cases was observed in the western regions of Belarus and Ukraine, where NBS prevalence exceeds 20 cases per 1,000,000 people, suggesting the presence of an "Eastern Slavic NBS hot spot." The median age at diagnosis of this cohort ranged from 4 to 5 years, and delay in diagnosis was more pervasive in smaller cities and rural regions. A total of 62 (45%) patients developed malignancies, more commonly in males than females (55.2 vs. 34.2%; p=0.017). In 27 patients, NBS was diagnosed following the onset of malignancies (mean age: 8 years). Malignancies were mostly of lymphoid origin and predominantly non-Hodgkin lymphoma (NHL) (n=42, 68%); 38% of patients had diffuse large B-cell lymphoma. The 20-year overall survival rate of patients with malignancy was 24%. However, females with cancer experienced poorer event-free survival rates than males (16.6% vs. 46.8%, p=0.036). Of 136 NBS patients, 13 underwent hematopoietic stem cell transplantation (HSCT) with an overall survival of 3.5 years following treatment (range: 1 to 14 years). Indications for HSCT included malignancy (n=7) and immunodeficiency (n=6). Overall, 9% of patients in this cohort reached adulthood. Adult survivors reported diminished quality of life with significant physical and cognitive impairments. Our study highlights the need to improve timely diagnosis and clinical management of NBS among Eastern Slavs. Genetic counseling and screening should be offered to individuals with a family history of NBS, especially in hot spot regions.

Clinical Impact of Additional Cytogenetic Aberrations, cKIT and RAS Mutations, and Treatment Elements in Pediatric t(8;21)-AML: Results From an International Retrospective Study by the International Berlin-Frankfurt-Münster Study Group.

PURPOSE: This retrospective cohort study aimed to determine the predictive relevance of clinical characteristics, additional cytogenetic aberrations, and cKIT and RAS mutations, as well as to evaluate whether specific treatment elements were associated with outcomes in pediatric t(8;21)-positive patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: Karyotypes of 916 pediatric patients with t(8;21)-AML were reviewed for the presence of additional cytogenetic aberrations, and 228 samples were screened for presence of cKIT and RAS mutations. Multivariable regression models were used to assess the relevance of anthracyclines, cytarabine, and etoposide during induction and overall treatment. End points were the probability of achieving complete remission, cumulative incidence of relapse (CIR), probability of event-free survival, and probability of overall survival. RESULTS: Of 838 patients included in final analyses, 92% achieved complete remission. The 5-year overall survival, event-free survival, and CIR were 74%, 58%, and 26%, respectively. cKIT mutations and RAS mutations were not significantly associated with outcome. Patients with deletions of chromosome arm 9q [del(9q); n = 104] had a lower probability of complete remission (P = .01). Gain of chromosome 4 (+4; n = 21) was associated with inferior CIR and survival (P < .01). Anthracycline doses greater than 150 mg/m(2) and etoposide doses greater than 500 mg/m(2) in the first induction course and high-dose cytarabine 3 g/m(2) during induction were associated with better outcomes on various end points. Cumulative doses of cytarabine greater than 30 g/m(2) and etoposide greater than 1,500 mg/m(2) were associated with lower CIR rates and better probability of event-free survival. CONCLUSION: Pediatric patients with t(8;21)-AML and additional del(9q) or additional +4 might not be considered at good risk. Patients with t(8;21)-AML likely benefit from protocols that have high doses of anthracyclines, etoposide, and cytarabine during induction, as well as from protocols comprising cumulative high doses of cytarabine and etoposide.

Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002.

PURPOSE: From 2002 to 2007, the International Berlin-Frankfurt-Münster Study Group conducted a prospective randomized clinical trial (ALL IC-BFM 2002) for the management of childhood acute lymphoblastic leukemia (ALL) in 15 countries on three continents. The aim of this trial was to explore the impact of differential delayed intensification (DI) on outcome in all risk groups. PATIENTS AND METHODS: For this trial, 5,060 eligible patients were divided into three risk groups according to age, WBC, early treatment response, and unfavorable genetic aberrations. DI was randomized as follows: standard risk (SR), two 4-week intensive elements (protocol III) versus one 7-week protocol II; intermediate risk (IR), protocol III × 3 versus protocol II × 1; high risk (HR), protocol III × 3 versus either protocol II × 2 (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP] option), or 3 HR blocks plus single protocol II (Berlin-Frankfurt-Münster [BFM] option). RESULTS: At 5 years, the probabilities of event-free survival and survival were 74% (± 1%) and 82% (± 1%) for all 5,060 eligible patients, 81% and 90% for the SR (n = 1,564), 75% and 83% for the IR (n = 2,650), and 55% and 62% for the HR (n = 846) groups, respectively. No improvement was accomplished by more intense and/or prolonged DI. CONCLUSION: The ALL IC-BFM 2002 trial is a good example of international collaboration in pediatric oncology. A wide platform of countries able to run randomized studies in ALL has been established. Although the alternative DI did not improve outcome compared with standard treatment and the overall results are worse than those achieved by longer established leukemia groups, the national results have generally improved.

Combination of a selective activator of the glucocorticoid receptor Compound A with a proteasome inhibitor as a novel strategy for chemotherapy of hematologic malignancies.

Glucocorticoids are widely used for the treatment of hematological malignancies; however, their chronic use results in numerous metabolic side effects. Thus, the development of selective glucocorticoid receptor (GR) activators (SEGRA) with improved therapeutic index is important. GR regulates gene expression via (1) transactivation that requires GR homodimer binding to gene promoters and is linked to side effects and (2) transrepression-mediated via negative GR interaction with other transcription factors. Novel GR modulator Compound A (CpdA) prevents GR dimerization, retains glucocorticoid anti-inflammatory activity and has fewer side effects compared with glucocorticoids in vivo. Here we tested CpdA anticancer activity in human T- and B-lymphoma and multiple myeloma cells expressing GR and their counterparts with silenced GR. We found that CpdA in GR-dependent manner strongly inhibited growth and viability of human T-, B-lymphoma and multiple myeloma cells. Furthermore, primary leukemia cell cultures from T-ALL patients appeared to be equally sensitive to glucocorticoid dexamethasone and CpdA. It is known that GR expression is controlled by proteasome. We showed that pretreatment of lymphoma CEM and NCEB cells with proteasome-inhibitor Bortezomib resulted in GR accumulation and enhanced ligand properties of CpdA, shifting GR activity toward transrepression evaluated by inhibition of NFкB and AP-1 transcription factors. We also revealed remarkable GR-dependent cooperation between CpdA and Bortezomib in suppressing growth and survival of T- and B-lymphoma and multiple myeloma MM.1S cells. Overall, our data provide the rationale for novel GR-based therapy for hematological malignancies based on combination of SEGRA with proteasome inhibitors.