Early-life tobacco exposure is causally implicated in aberrant RAG-mediated recombination in childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, yet few environmental risk factors have been identified. We previously found an association between early-life tobacco smoke exposure and frequency of somatic deletions of 8 leukemia driver genes among childhood ALL patients in the California Childhood Leukemia Study. To expand analysis genome-wide and examine potential mechanisms, we conducted tumor whole-genome sequencing in 35 ALL patients, including 18 with high prenatal tobacco exposure and 17 with low exposure as determined by established epigenetic biomarkers. High tobacco exposure patients had significantly more structural variants (P < .001) and deletions (P = .001) genome-wide than low exposure patients. Investigation of off-target RAG recombination revealed that 41% of deletions in the high tobacco exposure patients were putatively RAG-mediated (full RAG motif identified at one or both breakpoints) compared with only 21% in the low exposure group (P = .001). In a multilevel model, deletions in high tobacco exposure patients were 2.44-fold (95% CI:1.13-5.38) more likely to be putatively RAG-mediated than deletions in low exposure patients. No point mutational signatures were associated with prenatal tobacco exposure. Our findings suggest that early-life tobacco smoke exposure may promote leukemogenesis by driving development of somatic deletions in pre-leukemic lymphocytes via off-target RAG recombination.

Skeletal fluorosis: an uncommon cause, yet a rescue treatment?

PURPOSE: Skeletal fluorosis (SF) results from chronic exposure to fluoride (F-) causing excessive aberrantly mineralized brittle bone tissue, fractures, and exostoses. There is no established treatment other than avoiding the source of F-. Still, excess F- can persist in bone for decades after exposure ceases. CASE PRESENTATION: A 50-year-old woman presented with multiple, recurrent, low AQ2 trauma fractures yet high radiologic bone mineral density. Serum F- was elevated, and osteomalacia was documented by non-decalcified transiliac biopsy. She reported intermittently "huffing" a keyboard cleaner containing F- (difluoroethane) for years. Following cessation of her F- exposure, we evaluated the administration of the parathyroid hormone analog, abaloparatide, hoping to increase bone remodeling and diminish her skeletal F- burden. CONCLUSION: Due to the prolonged half-life of F- in bone, SF can cause fracturing long after F- exposure stops. Anabolic therapy approved for osteoporosis, such as abaloparatide, may induce mineralized bone turnover to replace the poorly mineralized osteomalacic bone characteristic of SF and thereby diminish fracture risk. Following abaloparatide treatment for our patient, there was a decrease in bone density as well as a reduction in F- levels.

Adherence to COVID-19 preventive measures among residents in selected townships, Yangon Region, Myanmar: a community-based cross-sectional study.

BACKGROUND: To fight the current coronavirus disease (COVID-19) pandemic, many countries have implemented various mitigation measures to contain the spread of the disease. By engaging with health service providers, the community's participation in adherence to preventive measures is certainly required in the implementation of COVID-19 mitigation strategies. Therefore, this study aimed to assess the level of adherence to COVID-19 preventive measures and its associated factors among the residents, Yangon Region, Myanmar. METHODS: A community-based cross-sectional study was carried out among 636 residents in Yangon Region, Myanmar, from October to December 2021. A multistage non-probability sampling method, purposively selected for three townships in Yangon Region and convenience sampling for 212 participants from each township, was applied and the data were collected by face-to-face interviews using structured and pretested questionnaires. Data were entered, coded, and analyzed using IBM SPSS version 25.0. Simple and multiple logistic regression analysis were performed to identify the significant variables of adherence to COVID-19 preventive measures. RESULTS: As a level of adherence to COVID-19 preventive measures, the proportion of residents who had good adherence was 39.3% (95% CI 35.5-43.2%), moderate adherence was 37.6% (95% CI 33.8-41.5%), and poor adherence was 23.1% (95% CI 19.9-26.6%). The age group of 31-40 years (AOR: 3.13, 95% CI 1.62-6.05), 30 years and younger (AOR: 3.22, 95% CI 1.75-5.92), Burmese ethnicity (AOR: 2.52, 95% CI 1.44-4.39), own business (AOR: 3.19, 95% CI 1.15-8.87), high school education level and below (AOR: 1.64, 95% CI 1.02-2.69), less than 280.90 USD of monthly family income (AOR: 1.51, 95% CI 1.01-2.29), low knowledge about COVID-19 (AOR: 1.90, 95% CI 1.26-2.88) were significantly associated with poor adherence to COVID-19 preventive measures. CONCLUSIONS: In this study, nearly one-fourth of the residents were experiencing poor adherence to COVID-19 preventive measures. Therefore, building up the risk communication through the community using widely used mainstream media, the continuation of disease surveillance and announcement of updated information or advice for the public to increase awareness towards COVID-19, and enforcement to follow the recommended directions and regulations of health institutions are vital to consider for improving the adherence to preventive measures against COVID-19 among the residents.

The specific shapes of capillaries are associated with worse prognosis in patients with invasive breast cancer.

Angiogenesis is considered essential for tumor progression; however, whether histological counting of blood vessel numbers, expressed as microvessel density (MVD), can be a prognostic factor in breast cancer remains controversial. It has been suggested that the specific morphology of blood vessels such as glomeruloid microvascular proliferation (GMP) is associated with clinical parameters. Here, we aimed to clarify the significance of MVD with revised immunohistochemistry and to identify new blood vessel shapes that predict prognosis in breast cancer. Four hundred and eleven primary breast cancer specimens were collected, and the sections were immunohistochemically stained with CD31 (single staining) and CD31 and Collagen IV (double staining). The prognosis of patients was examined based on the MVD value, and the presence of GMP and other blood vessels with other specific shapes. As a result, high MVD value and the presence of GMP were not associated with worse prognosis. By contrast, patients with deep-curved capillaries surrounding tumor cell nests (C-shaped) or excessively branched capillaries near tumor cell nests showed a significantly poor prognosis. The presence of these capillaries was also correlated with clinicopathological parameters such as Ki-67 index. Thus, the morphology of capillaries rather than MVD can be a better indicator of tumor aggressiveness.

Interprofessional education in antimicrobial stewardship, a collaborative effort.

Introduction: Antimicrobial stewardship (AMS) education and interprofessional collaboration are integral to the success of a stewardship programme. An interactive interprofessional AMS workshop, designed to encourage workplace interprofessional collaboration was piloted in a tertiary hospital. Objectives: To obtain feedback to determine the suitability and sustainability of the AMS workshop. Methods: Feedback was elicited through a predesigned questionnaire containing both open-ended and closed questions on the content and structure of the workshop. Results: The survey had a 70% (n = 16) overall response rate. All participants agreed that the goals of the workshop were met and that the knowledge and skills gained from the workshop would help them in their AMS roles. All participants indicated that the workshop content, and the level at which it was pitched, met their expectations and that it had improved their knowledge and skills. All agreed that they found it advantageous and enjoyed learning as an interprofessional group. Open feedback showed that the workshop was found to be useful and would potentially result in improved patient care, dissemination of knowledge, improved teamwork and organizational culture. Conclusions: The positive feedback and changes made following the workshop demonstrated that a targeted AMS educational workshop adds value to an antimicrobial stewardship programme.

COVID-19 Vaccine Booster Hesitancy among the Elderly in Malaysian Residential Care Homes: A Cross-Sectional Study in Klang Valley.

The elderly are considered a high-risk group for severe outcomes and death from COVID-19 infection. Given the emergence of new COVID variants and the immunity provided by vaccines waning over time, booster doses of the vaccine have been advocated for those at risk to stay protected. This study aimed to determine the factors associated with hesitancy toward the second booster of the COVID-19 vaccine among the elderly residing in residential care homes. A cross-sectional study was conducted in 24 residential care homes in the Klang Valley using a face-to-face interview questionnaire. The study population included individuals aged 60 and above who had been fully vaccinated against COVID-19 up to the first booster dose. Second-booster hesitancy was assessed using the Oxford Vaccine Hesitancy Scale with seven items, the aggregate score of which ranges from seven to thirty-five; the higher the score, the greater the level of hesitancy. Multivariate linear regression was employed to determine factors associated with second-booster hesitancy, and a p-value < 0.05 was considered statistically significant. Data from 401 elderly individuals were included for analysis. The mean score of the Oxford Vaccine Hesitancy Scale was 21.6 ± 7.2. Predictors of second booster hesitancy were identified. Age, Indian ethnicity, being a recipient of the Sinovac vaccine as the first COVID-19 booster, experiencing the death of close friends or immediate family members following COVID-19 vaccination, and negative messages (indicating that taking a booster dose is harmful) from caregivers, friends, or family members were found to be associated with an increased second-booster-hesitancy score. Conversely, positive messages (indicating that taking a booster is helpful) from the government and caregivers, friends, or family members were identified as predictors associated with a reduction in the second-booster-hesitancy score. While vaccines effectively combat severe COVID-19, the majority of the elderly hesitate before taking the second booster. Their hesitancy, rooted in the perception of a low self risk and reliance on protection from the initial doses, emphasizes the need for intervention by relevant bodies. Taking into consideration the risk, albeit relatively low, of potentially serious side effects following COVID-19 vaccinations, it is imperative that transparent, appropriate, and positive messaging regarding booster vaccines, particularly in the context of the elderly from residential care homes, be available. Encouraging this high-risk group to embrace the second booster aligns with the goal of maximizing protection within the vulnerable elderly population.

Culturally adapted training for community volunteers to improve their knowledge, attitude and practice regarding non-communicable diseases in Vietnam.

BACKGROUND: The burden of non-communicable diseases is becoming unmanageable by primary healthcare facilities in low- and middle-income countries. Community-based approaches are promising for supporting healthcare facilities. In Vietnam, community health volunteers are trained in providing health promotion and screening in a culturally adapted training. This study aims to assess the change in knowledge, attitude and practice regarding NCD prevention and management after a culturally adapted training, and the potential mechanisms leading to this change. METHODS: The Knowledge Attitude and Practice survey was assessed before and after an initial training, and before and after a refresher training (n = 37). We used a focus group discussion with community health volunteers (n = 8) to map potential mechanisms of the training and applying learned knowledge in practice. Data were collected in the districts Le Chan and An Duong of Hai Phong, Vietnam, in November 2021 and May 2022. RESULTS: We found that knowledge increased after training (mean = 5.54, 95%-confidence interval = 4.35 to 6.74), whereas attitude and practice did not improve. Next, knowledge decreased over time (m=-12.27;-14.40 to -10.11) and did not fully recover after a refresher training (m=-1.78;-3.22 to -0.35). As potential mechanisms for change, we identified the use of varying learning methods, enough breaks, efficient coordination of time located for theory and practice, handout materials, large group size and difficulty in applying a digital application for screening results. CONCLUSION: Culturally adapted trainings can improve knowledge among community health volunteers which is important for the support of primary healthcare in low- and middle-income countries. Using a digital screening application can be a barrier for the improvement of knowledge, attitude and practice and we suggest using an intergenerational or age-friendly approach, with the supervision of primary healthcare professionals. Future research on behavioral change should include additional components such as self-efficacy and interrelationships between individuals.

Real-world experience with ruxolitinib therapy for steroid-refractory acute graft versus host disease.

Acute graft versus host disease (aGVHD) is a complication of allogeneic hematopoietic stem cell transplant (HCT) and is associated with significant morbidity and mortality. Steroid refractory aGVHD (SR-aGVHD) carries a particularly grim prognosis. Ruxolitinib has shown promise for treatment of SR-aGVHD in a phase 3 trial; however, safety and efficacy data outside of the clinical trial setting is lacking. We performed a multicenter retrospective study to examine the response to ruxolitinib and its efficacy in patients with SR-aGVHD. We included 59 patients treated with ruxolitinib for SR-aGVHD between 2015 and 2022. Of these 59 patients, 36 patients (61.0%) achieved a complete (CR) or partial response (PR) at 28 days, while 31 patients (52.5%) obtained a CR/PR at day 56. Patients that achieved a CR or PR at day 28 had a higher rate of overall survival (OS; 69.2%), compared with patients that did not (31.6%; p = 0.037). OS at 12 months was 41.5%, with a median OS duration of 5.3 months. Failure free survival (FFS) at 12 months was 29.1%, with a median FFS of 2.6 months. Overall, this real-world experience data support ruxolitinib as the standard of care for SR-aGVHD in a non-controlled trial population.

Role of Immunotherapy in Sarcomas.

Sarcomas are a group of malignancies of mesenchymal origin with a plethora of subtypes. Given the sheer heterogeneity of various subtypes and the rarity of the disease, the management of sarcomas has been challenging, with poor patient outcomes. Surgery, radiation therapy and chemotherapy have remained the backbone of treatment in patients with sarcoma. The introduction of immunotherapy has revolutionized the treatment of various solid and hematological malignancies. In this review, we discuss the basics of immunotherapy and the immune microenvironment in sarcomas; various modalities of immunotherapy, like immune checkpoint blockade, oncolytic viruses, cancer-targeted antibodies, vaccine therapy; and adoptive cell therapies like CAR T-cell therapy, T-cell therapy, and TCR therapy.

Prenatal exposure to environmental heavy metals and newborn telomere length: A systematic review and meta-analysis.

Exposure to environmental heavy metals is associated with telomere length (TL) alteration. Available information regarding the effect of prenatal exposure to environmental pollutants on newborn TL is controversial. The aim of this study is to systematically review and conduct a meta-analysis of the existing epidemiological studies on the associations between prenatal metal exposure and newborn TL. A comprehensive literature search was performed using the online databases of PubMed, Web of Science, and ScienceDirect from their inception to December 1, 2023. Thirteen eligible studies were included from the overall initial identification of 3559 records. The effect size was expressed as standardized beta coefficients with 95% confidence intervals (CIs) by the restricted maximum-likelihood approach with a weighted random-effects model. Prenatal exposure to environmental heavy metals was associated with a shorter newborn TL (standardized beta = -0.04; 95% CI: -0.08, 0.00; p = 0.05). Subgroup analysis showed that prenatal exposure to cadmium was significantly, negatively associated with TL in newborns (standardized beta = -0.05; 95% CI: -0.10, -0.01; p = 0.021). Heavy metal exposure during the third trimester was significantly associated with a shorter TL in newborns (standardized beta = -0.05; 95% CI: -0.11, -0.01; p = 0.045). No significant association was found between the newborn's sex and exposure sample type. This study provides evidence for the negative effect of prenatal exposure to heavy metals on newborn TL. In particular, cadmium exposure and exposure during the third trimester of pregnancy are critical factors associated with heavy metal-induced TL shortening.

A cell-and-plasma numerical model reveals hemodynamic stress and flow adaptation in zebrafish microvessels after morphological alteration.

The development of a functional cardiovascular system ensures a sustainable oxygen, nutrient and hormone delivery system for successful embryonic development and homeostasis in adulthood. While early vessels are formed by biochemical signaling and genetic programming, the onset of blood flow provides mechanical cues that participate in vascular remodeling of the embryonic vascular system. The zebrafish is a prolific animal model for studying the quantitative relationship between blood flow and vascular morphogenesis due to a combination of favorable factors including blood flow visualization in optically transparent larvae. In this study, we have developed a cell-and-plasma blood transport model using computational fluid dynamics (CFD) to understand how red blood cell (RBC) partitioning affect lumen wall shear stress (WSS) and blood pressure in zebrafish trunk blood vascular networks with altered rheology and morphology. By performing live imaging of embryos with reduced hematocrit, we discovered that cardiac output and caudal artery flow rates were maintained. These adaptation trends were recapitulated in our CFD models, which showed reduction in network WSS via viscosity reduction in the caudal artery/vein and via pressure gradient weakening in the intersegmental vessels (ISVs). Embryos with experimentally reduced lumen diameter showed reduced cardiac output and caudal artery flow rate. Factoring in this trend into our CFD models, simulations highlighted that lumen diameter reduction increased vessel WSS but this increase was mitigated by flow reduction due to the adaptive network pressure gradient weakening. Additionally, hypothetical network CFD models with different vessel lumen diameter distribution characteristics indicated the significance of axial variation in lumen diameter and cross-sectional shape for establishing physiological WSS gradients along ISVs. In summary, our work demonstrates how both experiment-driven and hypothetical CFD modeling can be employed for the study of blood flow physiology during vascular remodeling.

A systematic review of neglected tropical diseases (NTDs) in Myanmar.

BACKGROUND: Neglected tropical diseases (NTDs) affect most impoverished communities in developing countries, like Myanmar in Southeast Asia. NTDs have been understudied and underreported in Myanmar. METHODS: A systematic review of published and grey literature (1900-2023) on neglected tropical diseases (NTDs) in Myanmar was conducted. The literature search included five international databases: PubMed, EMBASE, Ovid Global Health, and Web of Science Core Collection and one national database: the Myanmar Central Biomedical Library (locally published papers and grey literature). The selection criteria included articles with all types of study designs of current or previous infections conducted in humans, that reported NTDs, recognised by WHO, US CDC, and listed in PLoS NTDs. We included melioidosis and rickettsioses which we consider also meet the definition of an NTD. RESULTS: A total of 5941 records were retrieved and screened, of which, 672 (11%) met the selection criteria and were included in this review. Of the included articles, 449 (65%) were published after 2000 and 369 (55%) were from two regions (Yangon and Mandalay) of Myanmar. Of the included articles, 238 (35%) reported bacterial NTDs, 212 (32%) viral NTDs, 153 (23%) helminth NTDs, 25 (4%) protozoal NTDs and 39 (6%) reported more than one aetiology. Based on reported frequency in descending order, the bacterial NTDs were leprosy, Escherichia coli enteritis, salmonellosis, cholera, shigellosis, melioidosis, leptospirosis and rickettsioses; the viral NTDs were dengue, chikungunya and Japanese encephalitis virus (JEV) infection; the protozoal NTDs were amoebiasis, giardiasis and leishmaniasis, and the helminth NTDs were ascariasis, trichuriasis, hookworm disease, filariasis and strongyloidiasis. CONCLUSION: This review summarises NTDs reported in Myanmar over the past 100 years. The findings suggest that most NTDs are likely to be under reported, especially from the majority of the country which is far from academic centres. Research capacity building together with strengthening of laboratory systems would lead to better understanding of the true burden of NTDs in Myanmar. TRIAL REGISTRATION: PROSPERO registration ID: CRD42018092627.

Antimicrobial resistance and antimicrobial stewardship in South Africa: a survey of healthcare workers in academic and nonacademic hospitals.

Objective: Antimicrobial stewardship programmes (ASPs) facilitate appropriate antimicrobial use and require contextualization for optimal functioning. We aimed to investigate perceptions of and antimicrobial resistance (AMR) and ASPs among healthcare workers in academic and nonacademic hospitals. Design: Cross-sectional survey. Setting: Three academic (Charlotte Maxeke Johannesburg Academic, Inkosi Albert Luthuli, Tygerberg) and three nonacademic hospitals (Leratong, Prince Mshiyeni Memorial, and Paarl) in South Africa from January to June 2022. Participants: Doctors, nurses, and pharmacists. Methods: Voluntary questionnaire using Google Forms, encompassing AMR, ASPs, and selected discipline-specific components. Results: Participants comprised 79 doctors (50 academic), 178 nurses (169 academic), and 21 pharmacists (18 academic) and were female predominant. AMR was a problem in academic hospitals (74.7% vs 51.2%, p 0.004); 73.5% overall reported inappropriate antimicrobial use as a major contributor. Adequate education on antimicrobials occurred in only 36.4% overall. Microbiological testing guided therapy more often in nonacademic settings (80.0% vs 50.2%, p <0.001). In both settings, antimicrobial availability drove selection in 48.2%. Overall, ASPs improved patient care (89.8%) and reduced antimicrobial use (86.9%), although felt to override prescriber autonomy in academic settings (29.4% vs 7.5%, p 0.007), mainly among nurses. Only 50.2% reported successful local ASPs. A minority of pharmacists (20.0%) reported sufficient hospital support for ASPs. Education, involvement of infection control staff, and inclusion of nurses in ASPs were most impactful on AMR. Conclusion: Selected healthcare worker perspectives differ by category and setting and can be targeted to improve ASPs. Further studies should target a higher number of clinical staff in both settings.

Group B streptococcus in the Northern Territory in 2023: clindamycin down but not out.

Group B streptococcus (GBS) is a significant cause of perinatal morbidity and mortality; prophylactic antibiotics in the obstetric population can mitigate the risk of neonatal infection. The antibiotic of choice is penicillin; however, in women who have a penicillin hypersensitivity, clindamycin is the preferred agent. Worldwide resistance to clindamycin is rising in GBS isolates. In the Top End of the Northern Territory of Australia, we reviewed 113 GBS isolates in 2023. These GBS isolates revealed a 30% resistance to clindamycin. This rate has considerably increased since the Australia-wide survey published in 2011 where GBS resistance to clindamycin was quoted at 4.2%. As a result of this study, we are advocating for a change in practice in patients with known GBS resistance with penicillin hypersensitivity.

Epigenomic signature of major congenital heart defects in newborns with Down syndrome.

BACKGROUND: Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs. METHODS: We used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples. RESULTS: We found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples. CONCLUSIONS: A sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.

Mother's Dietary Diversity and Underweight among Under-five Rural Children in Three Major Agro-climatic Zones, Myanmar.

Background: Children's growth is essential to nutritional status and population health. In 2015, 18.9% of under-five children in Myanmar were underweight, and only 25% of 6-23-month-old children had the minimum dietary diversity (MDD). Objectives: We conducted this study to assess the association between mother's dietary diversity score (DDS) and underweight among under-five children. Materials and Methods: This study analyzed data from the "Livelihood and Food Security Survey," a cross-sectional study conducted in 2016 in rural areas in Chin State, Magway, and Ayeyarwady regions. It included 2029 under-five children and used underweight as an outcome variable. We calculated DDSs for mothers of under-five children using the MDD-women methodology. The prevalence of underweight and MDD were estimated. A multivariable binary logistic regression analysis estimated odds ratios and 95% confidence intervals (CIs). Results: The overall prevalence of underweight was 26.3% (95% CI: 23.4, 29.3), and that of the mother with a MDD score was 29.2% (95% CI: 26.0, 32.8). Multivariable binary logistic regression analysis showed that the prevalence of underweight in children was higher if maternal MDD was not met (adjusted odds ratio = 1.41; 95% CI: 1.05, 1.89). Conclusions: The children's age, types of toilets, and region were independent predictors of being underweight. Underweight among under-five children and diverse food consumption among their mothers are critical public health challenges in rural Myanmar that require urgent action. Nutrition education for rural communities should focus on feeding children with locally available diverse foods.

Propensity Score Matching Analysis Comparing the Efficacy and Steroid Tapering Benefit of Extracorporeal Photopheresis to Best Available Therapy in Third-Line or Beyond Treatment for Chronic GvHD.

Graft-versus host disease (GVHD) is one of the major limitations to allogeneic hematopoietic stem cell transplantation (HCT). Although corticosteroids with calcineurin inhibitors are established first line-therapy for chronic graft-versus-host disease (cGVHD), approximately one-half of cGVHD patients are refractory to corticosteroid therapy. The goal of the present study was to compare treatment outcomes of patients treated with extracorporeal photopheresis (ECP) and best available therapy (BAT) as third-line or beyond treatment for cGVHD. Using propensity score matching (PSM), treatment outcomes were compared between ECP-treated patients (n = 74) and a historical cohort of cGVHD patients treated with BAT (n = 132). By adjusting for unbalanced risk factors between the groups, including GVHD severity at the start of therapy, acute GVHD history, and baseline corticosteroid dose, 62 patients were balanced and selected for PSM. In the PSM cohort, the ECP group showed a 12-month failure-free survival (FFS) rate of 70.1% versus 32.5% in the BAT group (P < .0001; hazard rate [HR], .214), and 93.1% 12 months' overall survival (OS) rate of 93.1% versus 68.1% in the BAT group (P = .0249; HR, .3811); multivariate analysis confirmed ECP's superior FFS and OS compared with BAT. Generalized linear model analysis showed faster tapering of corticosteroids and higher rates of prednisone discontinuation in the ECP versus BAT PSM groups in the first 6 months. The ECP group also had a higher percentage of prednisone discontinuation, by 6% at month 0, by 14.9% at month 3, and by 22.5% at month 6. The current study demonstrates superior FFS, OS, and steroid tapering efficacy for ECP compared with BAT as third-line therapy or beyond in cGVHD patients.

Single centre retrospective analysis of extracorporeal photopheresis (ECP) therapy in patients heavily pre-treated for chronic graft-versus-host disease (cGvHD) with steroid failure.

BACKGROUND: Extracorporeal photopheresis (ECP) is recommended as a second- or later-line therapy for chronic GvHD (cGvHD). Benefits include reasonable response with avoidance of intense systemic immunosuppression, which can translate into lowering the risk of systemic toxicity and opportunistic infection. METHODS: We evaluated 75 patients treated with ECP for cGvHD from 2007 to 2021 at Princess Margaret Cancer Centre, and analyzed overall response rate (ORR) and clinical benefit (CB) at 3, 6 and 12 months plus other long-term treatment outcomes. RESULTS: With a median follow-up of 72 months, a gradual increase in ORR was noted over time: 21% (16 out of 75 patients), 57% (36/63) and 70% (32/46) at month 3, 6 and 12, respectively. Gradual increase in CB was also observed over time with CB rate of 23% (17/75), 62% (39/63), and 76% (35/46) at months 3, 6 and 12, respectively. A total of 27 failures (36%) were noted, due to: 1) ECP resistance requiring switch to other therapy (n = 14, 19%), 2) non-relapse mortality (n = 10, 13%), 3) relapse of primary disease (n = 1, 1%) or 4) ECP procedure-related complication (n = 1, 1%, line infection), with 20 deaths (27%) observed. Failure-free survival (FFS) and overall survival (OS) rates were 68.3% and 85.9% at 12 months, respectively. After starting ECP, the proportions of patients who completely discontinued steroids were 17%, 32%, and 64% at months 3, 6 and 12, respectively. CONCLUSION: ECP is an effective treatment option for heavily pre-treated cGvHD patients.

A Single-center, Real-world Experience of Chronic GVHD Treatment Using Ibrutinib, Imatinib, and Ruxolitinib and its Treatment Outcomes.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is a common cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Tyrosine kinase inhibitors (TKIs), including ruxolitinib, imatinib, and ibrutinib, have shown promising efficacy in cGVHD treatment. METHOD: A total of 43 patients who developed cGVHD and received at least one line of TKI therapy for cGVHD treatment were evaluated retrospectively. The overall response, clinical benefit (CB), corticosteroid dose reduction, failure-free survival (FFS), and overall survival (OS) were assessed. RESULT: A total of 62 lines of TKI therapy were evaluated, including ruxolitinib (n = 18), ibrutinib (n = 13), and imatinib (n = 31). With a 12-month median follow-up duration, 19/58 (32.8%), 20/41 (48.7%), and 17/29 (58.6%) responded to TKI therapy at 3, 6, and 12 months, respectively. The CB was observed in 80% of patients over time, allowing prednisone dose reduction in all 3 TKIs. The FFS rate at 12 months was higher in the imatinib (71%) and ruxolitinib groups (67%) than in the ibrutinib group (46%), while the OS rate at 12 months was similar among the three groups at 96%-100% in patients. In the sclerotic GVHD patient subgroup (n = 39), the overall response rate gradually increased over time. Ruxolitinib appeared to be as effective as imatinib and gradually improved the photographic range of motion score in sclerotic GVHD patients. CONCLUSION: TKI drugs ruxolitinib, imatinib, and Ibrutinib are effective and feasible for cGVHD treatment. Ruxolitinib is as effective as imatinib for sclerotic GVHD.