Long-term outcome after a treosulfan-based conditioning regimen for patients with acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for patients with acute myeloid leukemia (AML). However, post-HCT relapse and regimen-related toxicity remain significant barriers to long-term survival. In recent years, new conditioning regimens have been explored to improve transplantation outcomes in patients with AML. Treosulfan combines a potent immunosuppressive and antileukemic effect with a low toxicity profile. METHODS: To investigate the role of treosulfan-based conditioning, the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party performed a registry analysis of 520 adult patients with AML who received treosulfan-based conditioning and underwent HCT between 2000 and 2012, including 225 patients in first complete remission, 107 in second or later complete remission, and 188 with active/advanced disease 188 (88 with primary refractory disease). The median patient age was 57 years (range, 20-73 years). Donors were human leukocyte antigen-identical siblings (n = 187), unrelated donors (n = 235), or mismatched related donors (n = 98). Conditioning regimens included treosulfan (42 g/m2 [n = 396], 36 g/m2 [n = 109], or 30 g/ m2 [n = 15]) with fludarabine or alkylating agents followed by infusion of hematopoietic stem cells (bone marrow, n = 52; peripheral blood, n = 468). RESULTS: At a median follow-up of 61 months, the 5-year overall survival, leukemia-free survival, relapse incidence, and nonrelapse mortality rates were 38%, 33%, 42%, and 25%, respectively. The incidence of grade II-IV acute and chronic graft-versus-host disease was 24% (grade III-V, 11%) and 38%, respectively. Only 11 patients (2%) developed veno-occlusive disease, with two deaths (0.4%) from veno-occlusive disease. CONCLUSIONS: Treosulfan-based conditioning regimens provide an acceptable long-term survival with favorable nonrelapse mortality and a very low risk of veno-occlusive disease. Further studies are needed to optimize the treosulfan-based conditioning regimen for patients with AML

Measurable residual disease, FLT3-ITD mutation, and disease status have independent prognostic influence on outcome of allogeneic stem cell transplantation in NPM1-mutated acute myeloid leukemia

Nucleophosmin-1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3-internal tandem duplication (FLT3-ITD). Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified 1572 adult (age &gt;= 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or second complete remission (CR2:22%) who were transplanted from matched sibling donors (30.8%) or unrelated donors (57.4%) between 2007 and 2019 at EBMT participating centers. Median follow-up for survivors was 23.7 months. FLT3-ITD was present in 69.3% of patients and 39.2% had detectable minimal/measurable residual disease (MRD) at transplant. In multivariate analysis, relapse incidence (RI) and leukemia-free survival (LFS) were negatively affected by concomitant FLT3-ITD mutation (HR 1.66 p = 0.0001, and HR 1.53, p &lt; 0.0001, respectively), MRD positivity at transplant (HR 2.18, p &lt; 10(-5) and HR 1.71, p &lt; 10(-5), respectively), and transplant in CR2 (HR 1.36, p = 0.026, and HR 1.26, p = 0.033, respectively), but positively affected by Karnofsky score &gt;= 90 (HR 0.74, p = 0.012, and HR 0.7, p = 0.0002, respectively). Overall survival (OS) was also negatively influenced by concomitant FLT3-ITD (HR 1.6, p = 0.0001), MRD positivity at transplant (HR 1.61, p &lt; 10(-5)), and older age (HR 1.22 per 10 years, p &lt; 0.0001), but positively affected by matched sibling donor (unrelated donor: HR 1.35, p = 0.012; haploidentical donor: HR 1.45, p = 0.037) and Karnofsky score &gt;= 90 (HR 0.73, p = 0.004). These results highlight the independent and significant role of FLT3-ITD, MRD status, and disease status on posttransplant outcomes in patients with NPM1-mutated AML allowing physicians to identify patients at risk of relapse who may benefit from posttransplant prophylactic interventions.</p

Drivers of diversification and pluriactivity among smallholder farmers—evidence from Nigeria

Diversification and pluriactivity have become a norm among farm business owners (FBOs) due to persistent low farm income. This study applies the resource-based theory to examine drivers of diversification and livelihood income-oriented towards a sustainable livelihood. Our framework develops hypotheses about the impact of internal and external resources on livelihood choices at the household level. We use a survey of 480 rural Nigerian farmers (agripreneurs), applying a Multivariate Tobit to test our framework. We find that education plays the most significant role in all types of employment options. The more FBOs are educated, the more the likelihood that they will choose non-farm or wage employment. This study revealed that while the agriculture sector’s share of rural employment is declining, non-farm is on the increase. More so, there is a decline in farming among the young generation, marital status bias and gender influence in resource allocation. The socioeconomic (income and food security) and socio-cultural (employment and rural-urban migration) implications of rural sustainability linked to UN Development Goals have been highlighted and analysed in this article

Comparison of Promoter Hypermethylation Pattern in Salivary Rinses Collected with and without an Exfoliating Brush from Patients with HNSCC

Background: Salivary rinses have been recently proposed as a valuable resource for the development of epigenetic biomarkers for detection and monitoring of head and neck squamous cell carcinoma (HNSCC). Both salivary rinses collected with and without an exfoliating brush from patients with HNSCC are used in detection of promoter hypermethylation, yet their correlation of promoter hypermethylation has not been evaluated. This study was to evaluate the concordance of promoter hypermethylation between salivary rinses collected with and without an exfoliating brush from patients with HNSCC. Methodolgy: 57 paired salivary rinses collected with or without an exfoliating brush from identical HNSCC patients were evaluated for promoter hypermethylation status using Quantitative Methylation-Specific PCR. Target tumor suppressor gene promoter regions were selected based on our previous studies describing a panel for HNSCC screening an

The European Society for Blood and Marrow Transplantation (EBMT) consensus recommendations for donor selection in haploidentical hematopoietic cell transplantation

The number of HLA-haploidentical hematopoietic cell transplants continues to increase worldwide due to recent improvements in outcomes, allowing more patients with hematological malignancies and non-malignant disorders to benefit from this procedure and have a chance to cure their disease. Despite these encouraging results, questions remain as multiple donors are usually available for transplantation, and choosing the best HLA-haploidentical donor for transplantation remains a challenge. Several approaches to haploidentical transplantation have&nbsp;been developed over time and, based on the graft received, can be grouped as follows: T-cell depleted haploidentical transplants, either complete or partial, or with&nbsp;T-cell replete grafts, performed with post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, or G-CSF-primed bone marrow graft and enhanced GVHD prophylaxis. Carefully selecting the donor can help optimize transplant outcomes for recipients of haploidentical donor transplants. Variables usually considered in the donor selection include presence of donor-specific antibodies in the recipient, donor age, donor/recipient gender and ABO combinations, and immunogenic variables, such as natural killer cell alloreactivity or KIR haplotype. Here we provide a comprehensive review of available evidence for selecting haploidentical donors for transplantation, and summarize the recommendations from the European Society for Blood and Marrow Transplantation (EBMT) on donor selection for different transplant platforms

Investigating off-Hugoniot states using multi-layer ring-up targets

Laser compression has long been used as a method to study solids at high pressure. This is commonly achieved by sandwiching a sample between two diamond anvils and using a ramped laser pulse to slowly compress the sample, while keeping it cool enough to stay below the melt curve. We demonstrate a different approach, using a multilayer ‘ring up’ target whereby laser-ablation pressure compresses Pb up to 150 GPa while keeping it solid, over two times as high in pressure than where it would shock melt on the Hugoniot. We find that the efficiency of this approach compares favourably with the commonly used diamond sandwich technique and could be important for new facilities located at XFELs and synchrotrons which often have higher repetition rate, lower energy lasers which limits the achievable pressures that can be reached

Effect of Mitomycin - C and Triamcinolone on Preventing Urethral Strictures

Urethral stricture is a common disease with high recurrence rate. Several manipulations were defined to prevent the recurrence but the results were disappointing. This study aimed to evaluate the efficacy of triamcinolone and mitomycin-C on urethral stricture formation and their effect on inhibition of urethral fibrosis. A total of 24 New Zealand rabbits were divided into 3 groups. Urethras of rabbits were traumatized with pediatric resectoscope. Resection area was irrigated with 10mL saline, swapped with a cotton wool soaked with 0.5mg/mL MMC and injected by 40mg triamcinolone in groups 1, 2 and 3 respectively. Retrograde urethrogram was performed at 28th day of procedure and the urethra was removed for histopathologic evaluation. There were significant differences in urethral diameters and in lumen reduction rate between the control and study groups (p< 0.001). Compared to control group, all treatment groups showed mild fibrosis, less collagen bundle irregularity, and lower numbers of fibroblasts (p= 0.003). The Tunnel assay showed that the number of apoptotic cells in the submucosal connective tissue was quantitatively higher in control groups (p= 0.034). In the view of efficacy and safety, MMC and triamcinolone have the potential to replace the use of stents, clean intermittent catheterization, or long term catheters following internal urethrotomy. There were no statistically significant differences between two agents in terms of preventing urethral stricture formation in the present study. Mitomycin C and triamcinolone decreased the recurrence rates of urethral stricture

Comparison of Methods for Detection of Blastocystis Infection in Routinely Submitted Stool Samples, and also in IBS/IBD Patients in Ankara, Turkey

BACKGROUND: This study compared diagnostic methods for identifying Blastocystis in stool samples, and evaluated the frequency of detection of Blastocystis in patients with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). RESULTS AND DISCUSSION: From a set of 105 stool specimens submitted for routine parasitological analysis, 30 were identified as positive for Blastocystis by the culture method. From that group of 30 positives, Lugol's stain, trichrome staining, and an immunofluorescence assay identified 11, 15, and 26 samples as positive respectively. Using culture as a standard, the sensitivity of Lugol's stain was 36.7%, trichrome staining was 50%, and the IFA stain was 86.7%. The specificity of Lugol's stain was 91%, trichrome staining was 100%, and the IFA stain was 97.3%. In the group of 27 IBS and IBD patients, using all methods combined, we detected Blastocystis in 67% (18/27) of the patients. Blastocystis was detected in 33% (2/6) of IBD patients and 76% (16/21) of IBS patients. For comparison, trichrome staining alone, the method most frequently used in many countries, would have only identified Blastocystis infection in 29% (6/21) of the IBS patients. No parasitic co-infections were identified in the IBS/IBD patients. Most Blastocystis-positive IBS/IBD patients were over 36 with an average length of illness of 4.9 years. CONCLUSIONS: Most IBS patients in this study were infected with Blastocystis. IFA staining may be a useful alternative to stool culture, especially if stool specimens have been chemically preserved

Clinical applications of donor lymphocyte infusion from an HLA-haploidentical donor: consensus recommendations from the Acute Leukemia Working Party of the EBMT

Donor lymphocyte infusion has been used in the management of relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. It can eradicate minimal residual disease or be used to rescue a hematologic relapse, being able to induce durable remissions in a subset of patients. With the increased use of haploidentical hematopoietic cell transplantation, there is renewed interest in the use of donor lymphocytes to either treat or prevent disease relapse post transplant. Published retrospective and small prospective studies have shown encouraging results with therapeutic donor lymphocyte infusion in different haploidentical transplantation platforms. In this consensus paper, finalized on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use of donor lymphocyte infusion from haploidentical donor, and provide recommendations on its therapeutic, pre-emptive and prophylactic use in clinical practice

Suppression of Radiation-Induced Salivary Gland Dysfunction by IGF-1

Radiation is a primary or secondary therapeutic modality for treatment of head and neck cancer. A common side effect of irradiation to the neck and neck region is xerostomia caused by salivary gland dysfunction. Approximately 40,000 new cases of xerostomia result from radiation treatment in the United States each year. The ensuing salivary gland hypofunction results in significant morbidity and diminishes the effectiveness of anti-cancer therapies as well as the quality of life for these patients. Previous studies in a rat model have shown no correlation between induction of apoptosis in the salivary gland and either the immediate or chronic decrease in salivary function following gamma-radiation treatment.A significant level of apoptosis can be detected in the salivary glands of FVB mice following gamma-radiation treatment of the head and neck and this apoptosis is suppressed in transgenic mice expressing an activated mutant of Akt (myr-Akt1). Importantly, this suppression of apoptosis in myr-Akt1 mice preserves salivary function, as measured by saliva output, three and thirty days after gamma-radiation treatment. In order to translate these studies into a preclinal model we found that intravenous injection of IGF1 stimulated activation of endogenous Akt in the salivary glands in vivo. A single injection of IGF1 prior to exposure to gamma-radiation diminishes salivary acinar cell apoptosis and completely preserves salivary gland function three and thirty days following irradiation.These studies suggest that apoptosis of salivary acinar cells underlies salivary gland hypofunction occurring secondary to radiation of the head and neck region. Targeted delivery of IGF1 to the salivary gland of patients receiving head and neck irradiation may be useful in reducing or eliminating xerostomia and restoring quality of life to these patients