The Application of Umbilical Cord Blood-derived Platelet Gel for Skin Ulcers Associated With Chronic Graft-Versus-Host Disease in Pediatrics: A Randomized Trial.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative strategy against a variety of malignant and nonmalignant disorders. However, acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) commonly complicate this approach, culminating in substantial morbidities and mortalities. The integumentary system is the preponderant organ involved in cGVHD, and its response to existing treatments, including well-versed immunosuppressants and novel targeted therapies, is not desirable. Despite the rarity, ulcers of sclerotic skin cGVHD are treatment-refractory and associated with significant morbidities and an exaggerated risk of infectious complications. Platelet-rich plasma (PRP) and its derivatives are endowed with growth factors and proangiogenic molecules and hold regenerative potential. This study aimed to assess the safety and efficacy of the application of platelet gel-containing dressing against ulcerative skin cGVHD in pediatric patients. This randomized trial is conducted at the hematopoietic stem cell transplantation unit of the Children's Medical Center Hospital in Tehran, Iran. Twenty-one pediatric patients (aged between 5 and 15 years) were initially enrolled, and 16 met the inclusion criteria. All cases (4 females) were recipients of allo-HSCT who had been complicated with symmetrically or near-symmetrically ulcerative sclerotic skin cGVHD. Fresh umbilical cord blood (UCB) was obtained from healthy donors and underwent centrifugation using a novel PRP preparation kit in a single-step process. Platelet gel was produced by adding thrombin to the isolated buffy coat layer. Two similar ulcers of each patient were randomized to receive either conventional dressing or platelet gels up to 6 times. At each time point evaluation, ulcer size and its relative reduction compared to the basal size were recorded. Included patients received a total of 80 platelet gel-containing dressings. While the mean sizes of randomized ulcers at the beginning of the study were similar, their differences became significant 15 days after the initiation of intervention (P = .019). In addition, the mean reduction in the ulcers' surface area (in comparison to their baseline values) was significantly higher for the intervention arm at all evaluation points (P = .001 for day 5 and P < .001 for subsequent time points). At the end of the trial, the number of ulcers with a more than 50% reduction in size was 14 (87.5%) in the intervention arm (including 6 completely healed ulcers) versus 1 (6.25%, which was not completely healed) in the control arm (P < .001). None of the patients exhibited any localized or systemic treatment-related adverse events. In this study, using a relatively large number of cases, we showed that UCB-derived platelet gel is a safe, feasible, and effective curative approach for skin ulcers of sclerotic skin cGVHD in pediatric patients. Designing upcoming trials on the efficacy of this therapeutic approach for ocular, mucosal, and acute skin GVHD is prudent. Retrospectively registered at the Iranian Registry of Clinical Trials (registration number IRCT20190101042197N1) on August 24, 2020.

Comparison of epidemiologic features between upper and lower limb injuries and risk factors for intensive care unit admission in a university hospital affiliated with the National Trauma Registry of Iran.

PURPOSE: Upper extremity injuries (UEIs) and lower extremity injuries (LEIs) constitute a considerable component of traumas. However, their epidemiologic differences and short-term in-hospital outcomes are not fully elucidated. This study aims to compare such discrepancies in a large-scale study. METHODS: In this retrospective study, all patients with UEIs and/or LEIs hospitalized from 24th July 2016 to 16th May 2020 in Sina Hospital, Tehran, Iran, and registered at the National Trauma Registry of Iran were enrolled in the study. Relevant demographic and clinical characteristics were extracted from the National Trauma Registry of Iran database. Patients were grouped into either UEI or LEI. For those with concomitant UEIs and LEIs, the more severe one based on the abbreviated injury scale was defined as the principal diagnosis. In addition, cases with the abbreviated injury scale > 3 for both UEI and LEI or concomitant injuries to body areas other than the limbs were excluded. Independent samples t-test, Mann-Whitney U test, Chi-square test, quintile regression models, and logistic regression models with "margins" command were used for statistical analyses, as indicated. RESULTS: In this research, 3170 eligible cases were identified. For the LEI group, there was a much higher proportion of male patients (86.7% vs. 82.0%) and higher mean age (years, 42.9 vs. 35.3) compared to the UEI group (both p < 0.001). Patients with an injury severity score (ISS) of 9 - 15 were outnumbered in the LEI group (22.9% vs. 1.6%, p < 0.001), while the proportion of those with an ISS < 9 was higher in the UEI group (98.1% vs. 76.8%, p < 0.001). The multiple logistic regression model showed a statistically significant association between intensive care unit (ICU) admission and ISS (odds ratio (OR) = 4.01 for ISS 9 - 15 vs. ISS <9, 95% confidence interval (CI)|: 3.01 - 5.35; OR = 17.65 for ISS ≥16 vs. ISS < 9, 95% CI: 4.03 - 77.27), age (OR = 1.02, 95% CI: 1.01 - 1.03), cause of injury (OR = 0.27 for blunt trauma vs. road traffic crash, 95% CI: 0.08 - 0.90; OR = 0.49 for cut/stab injuries vs. road traffic crash, 95% CI: 0.28 - 0.84) and body region (OR = 1.65 for lower extremity, 95% CI: 1.19 - 2.29). Having adjusted for other covariates, the odds of ICU admission in patients with LEIs was 1.65 times the odds in patients with UEIs. CONCLUSIONS: Patients with LEIs were older and suffered from more severe injuries. In addition, the age- and ISS-adjusted ICU admission and length of hospital stay were significantly higher in LEI patients. The chance of ICU admission was associated with age, cause of injury, ISS, and body region. The findings of this study can aid in the meticulous selection of ICU-candidate patients. In addition, the role of factors other than ISS and age in ICU admission and prolongation of hospitalization should be addressed by prospective studies.

Evaluation of safety and efficacy of allogeneic adipose tissue-derived mesenchymal stem cells in pediatric bronchiolitis obliterans syndrome (BoS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

BACKGROUND: Allo-HSCT is a definite approach for the management of a wide variety of lethal and debilitating malignant and non-malignant disorders. However, its two main complications, acute and chronic graft-versus-host disease (GVHD), exert significant morbidities and mortalities. BoS, as a manifestation of chronic lung GVHD, is a gruesome complication of allo-HSCT, and for those with steroid-refractory disease, no approved second-line therapies exist. Mesenchymal stem cells (MSCs) exert anti-inflammatory and growth-promoting effects, and their administration against a wide range of inflammatory and neurologic disorders, as well as GVHD, has been associated with promising outcomes. However, literature on the safety and effectiveness of MSC therapy for BoS and pediatric cGVHD is scarce. METHODS: We designed a single-arm trial to administer adipose tissue (AT)-derived MSCs to pediatric patients with refractory BoS after allo-HSCT. AT-MSCs from obese, otherwise healthy donors were cultured in an ISO class 1 clean room and injected into the antecubital vein of eligible patients with a dose of 1 × 106/kg. The primary endpoints included a complete or partial response to therapy [in terms of increased forced expiratory volume in one second (FEV1) values and steroid dose reduction] and its safety profile. RESULTS: Four eligible patients with a median age of 6.5 years were enrolled in the study. Steroid-induced osteoporosis and myopathy were present in three cases. A partial response was evident in three cases after a single injection of AT-MSCs. The treatment was safe and tolerable, and no treatment-related adverse events were noted. Two patients developed manageable COVID-19 infections one and 4 months after AT-MSC injection. After a median follow-up duration of 19 months, all cases are still alive and have had no indications for lung transplantation. CONCLUSIONS: AT-MSCs could be safely administered to our pediatric cases with BoS post-allo-HSCT. Considering their advanced stage of disease, their sub-optimal functional capacity due to steroid-induced complications, and COVID-19 infection post-treatment, we believe that AT-MSC therapy can have possible efficacy in the management of pediatric BoS. The conduction of further studies with larger sample sizes and more frequent injections is prudent for further optimization of AT-MSC therapy against BoS. Trial registration Iranian Registry of Clinical Trials (IRCT), IRCT20201202049568N2. Registered 22 February 2021, https://en.irct.ir/trial/53143 .

Characterization of immune checkpoints expression and lymphocyte densities of iranian breast cancer patients; the co-expression status and clinicopathological associates.

BACKGROUND: Breast malignancies are now the most common and deadliest type of neoplasms among women worldwide. Novel therapeutic approaches are needed to combat advanced stages of breast cancer. In this study, we aimed to investigate the expression and co-expression status of three immune checkpoints (PD-1, PD-L1, and LAG-3), as well as tumor-infiltrating lymphocytes (TIL) scores, and to further establish their potential correlations with clinicopathologic features. METHODS: We performed a retrospective study on 361 pathologic samples of breast cancer. Immunohistochemistry was performed to assess the status of the immune checkpoint markers, and H&E staining was used to score TILs. The correlations of the immune checkpoint markers of tumor cells and tumor-associated immune cells and TIL scores with clinicopathological characteristics were analyzed. RESULTS: Out of 361 assessed samples, LAG-3 was positive in 51%, while IC PD-L1 and TC PD-L1 were detectable in 36% and 8.9%, respectively. Moreover, both IC PD-L1 and LAG-3 stained positively in 24.4% of samples. IC PD-L1 expression was significantly higher in tumors with higher nuclear, mitotic, and overall grades and tubule formation. In addition, TC PD-L1 and LAG-3 exhibited a similar trend for higher overall grading. Tumors with positive estrogen- and progesterone-receptor (ER and PR) expression had significantly lower IC PD-L1 and TC PD-L1 staining, while LAG-3 positivity was more prevalent in HER2 positive samples. Tumors that were positive for these biomarkers had significantly higher Ki-67 scores. LAG-3 expression showed significant correlations with PD-1 and IC PD-L1 expression. Besides, the co-expression of LAG-3 and IC PD-L1 was significantly more encountered in luminal B and triple-negative subtypes, compared to the luminal A subtype. Regarding TILs, their scoring was significantly higher in ER and PR negative and HER2 positive samples. Intriguingly, samples with positive staining for LAG-3, IC PD-L1, and TC PD-L1 had significantly higher TIL scorings. CONCLUSIONS: Immune checkpoints show differentially different levels of expression in certain molecular subtypes of breast cancer. Moreover, they reveal a meaningful correlation with each other, proliferation indices, and histologic grades. Finally, a sizable proportion of breast cancers co-express PD-L1 and LAG-3, which will make them appropriate targets for future combined ICIs.

Ocular graft-versus-host disease (oGVHD): From A to Z.

Allogeneic hematopoietic stem cell transplantation is a definitive therapy for a variety of disorders. One of the complications is acute graft-versus-host disease (aGVHD), which has a high mortality rate. Patients can also develop chronic graft-versus-host disease (cGVHD), a more indolent yet afflicting condition that affects up to 70% of patients. Ocular involvement (oGVHD) is one of the most prevalent presentations of cGVHD and can manifest as dry eye disease, meibomian gland dysfunction, keratitis, and conjunctivitis. Early recognition of ocular involvement using regular clinical assessments as well as robust biomarkers can aid in better management and prevention. Currently, the therapeutic strategies for the management of cGVHD, and oGVHD in particular, have mainly focused on the control of symptoms. There is an unmet need for translating the preclinical and molecular understandings of oGVHD into clinical practice. Herein, we have comprehensively reviewed the pathophysiology, pathologic features, and clinical characteristics of oGVHD and summarized the therapeutic landscape available to combat it. We also discuss the direction of future research regarding a more directed delineation of pathophysiologic underpinnings of oGVHD and the development of preventive interventions.

Effective factors of improved helmet use in motorcyclists: a systematic review.

BACKGROUND: Road traffic injuries (RTI) are one of the most prominent causes of morbidity and mortality, especially among children and young adults. Motorcycle crashes constitute a significant part of RTIs. Policymakers believe that safety helmets are the single most important protection against motorcycle-related injuries. However, motorcyclists are not wearing helmets at desirable rates. This study systematically investigated factors that are positively associated with helmet usage among two-wheeled motorcycle riders. METHODS: We performed a systematic search on PubMed, Scopus, Web of Science, Embase, and Cochrane library with relevant keywords. No language, date of publication, or methodological restrictions were applied. All the articles that had evaluated the factors associated with helmet-wearing behavior and were published before December 31, 2021, were included in our study and underwent data extraction. We assessed the quality of the included articles using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for observational studies. RESULTS: A total of 50 articles were included. Most evidence suggests that helmet usage is more common among drivers (compared to passengers), women, middle-aged adults, those with higher educations, married individuals, license holders, and helmet owners. Moreover, the helmet usage rate is higher on highways and central city roads and during mornings and weekdays. Travelers of longer distances, more frequent users, and riders of motorcycles with larger engines use safety helmets more commonly. Non-helmet-using drivers seem to have acceptable awareness of mandatory helmet laws and knowledge about their protective role against head injuries. Importantly, complaint about helmet discomfort is somehow common among helmet-using drivers. CONCLUSIONS: To enhance helmet usage, policymakers should emphasize the vulnerability of passengers and children to RTIs, and that fatal crashes occur on low-capacity roads and during cruising at low speeds. Monitoring by police should expand to late hours of the day, weekends, and lower capacity and less-trafficked roads. Aiming to enhance the acceptance of other law-abiding behaviors (e.g., wearing seat belts, riding within the speed limits, etc.), especially among youth and young adults, will enhance the prevalence of helmet-wearing behavior among motorcycle riders. Interventions should put their focus on improving the attitudes of riders regarding safety helmets, as there is acceptable knowledge of their benefits.

Introduction of a modified single stage reconstruction technique of male penopubic epispadias.

OBJECTIVE: To represent the long-term outcomes of our modified single-stage technique for the reconstruction of isolated penopubic epispadias in male patients. PATIENTS AND METHODS: Data from 113 patients were obtained from bladder-exstrophy-epispadias database of our tertiary center. A total of seven boys with isolated penopubic epispadias with no prior history of surgery and any other anomaly underwent our modified surgical approach from February 1997 to September 2019. The mean ± SD age at surgery was 6.5 ± 2.4 years. Volitional voiding status and cosmetic appearance were evaluated at each follow-up interval. Postoperative follow-up was performed at quarterly intervals in the first year and once a year in subsequent years. RESULTS: The mean ± SD of follow-up was 8.5 ± 6 years. All boys who were incontinent achieved urinary control and the ability of normal transurethral micturition following the surgery. Four boys became completely dry, and the other three attained social dryness. Postoperative mean (SD) bladder capacity was significantly increased from 54.5 (11) to 124 (40.0) within 6 months, and to 194 (47.5) at 18 months after surgery. Dorsal curvature has been resolved in all cases, and no postoperative complications were noted except for surgical site infection in one patient treated with antibiotics and bilateral vesicourethral reflux resolved after injection of bulking agents. Four patients had normal erectile function and ejaculation, while the others have not reached puberty yet. Moreover, none of the patients developed urethrocutaneous fistula, stricture, or penile ischemia. CONCLUSION: The present findings suggest the safety and effectiveness of the combination of single-stage urethro-genitoplasty, bladder neck plication, and fat pad pedicled flap in management of boys with isolated penopubic epispadias that can lead to the achievement of urinary control, acceptable sexual function, and cosmetically satisfactory genitalia. Minimal morbidity, low complication rate, and promising outcomes are essential factors, supporting the notion of introducing this technique as a valid option for management of this entity.

Cognitive appraisals of disability in persons with traumatic spinal cord injury: a scoping review.

STUDY DESIGN: Scoping review. OBJECTIVES: To describe the meaning of cognitive appraisals, their relation with outcome. measures, and adapted appraisal scales after Spinal Cord Injury (SCI) in the existing literature. METHODS: This review was performed according to the Arksey and O'Malley (2005) framework that consisted of five steps: setting the review question, searching the literature, selecting and classifying the studies, charting the data, and summarizing the results. Published articles from 1990 to 16 May 2020 related to cognitive appraisal, persons with traumatic SCI (TSCI), and persons older than 18 years were identified by searching by key terms in four databases (PubMed, Web of Science, Scopus, and Embase). RESULTS: The included studies (n = 26) were categorized into three categories. Categories focused on the meanings of cognitive appraisals following TSCI (i.e., appraisals being complex and context-related, or in general definition how persons with TSCI interpret their disability and how they evaluate the resources available to respond to it), the relationship between cognitive appraisals and physical/psychological/social/ outcomes, and appraisals of disability (including the use of appraisals as a predictor of subsequent positive or negative consequences). CONCLUSIONS: The results demonstrated that a cognitive appraisal of TSCI is critical to longer-term rehabilitation outcomes. A combination of physical and psychological-based interventions can help to modify negative or dysfunctional appraisals. Cognitive appraisal in TSCI seems to vary from person to person. To predict it and develop a rehabilitation plan, future research needs to focus on the relationship between cognitive appraisal and person-related factors, including demographic characteristics.

Barriers and factors associated with the use of helmets by Motorcyclists: A scoping review.

Road Traffic Injuries (RTIs) have imposed a great global burden on public health. Motorcyclists and pedestrians comprise the most significant proportion of this burden. Several studies have demonstrated a link between helmet wearing and a decline in the impact of RTIs in motorcyclists. In this study, we aimed to review the barriers to helmet utilization by motorcyclists. This scoping review has been conducted in accordance with the guidelines for the systematic review of observational studies and the PRISMA Checklist. The search was conducted by using related keywords in EMBASE, PubMed, Scopus, and Cochrane Library. Four independent reviewers carried out the screening. The main outcomes of interest were barriers to helmet usage among motorcyclists, drawn from the finally included studies. Fifty-three records were selected for data extraction. According to these reports, the barriers and factors associated with helmet usage among motorcyclists were categorized into five entities as: legislations/enforcement strategies, helmet disadvantages (discomfort, visual/auditory blockage, and thermal dysregulation), risky behaviors (riding while drunk or high on drugs), sex and/or age factors, and the location and time of the injury event (rural vs. urban locations, day vs. night riding). From the perspective of policymakers, the findings of this review are of utmost importance and could be used in addressing the challenge of inadequate compliance with helmet use.

MCM6 versus Ki-67 in diagnosis of luminal molecular subtypes of breast cancers.

BACKGROUND: Currently, breast cancers are divided into four major molecular subtypes. The distinction between the luminal A and luminal B subtypes is mainly based on the cellular proliferation indices and is assessed by the Ki-67 scoring. Due to the limitations in the assessment and expression of Ki-67, we hypothesized that minichromosome maintenance protein 6 (MCM6) might be taken as a surrogate marker to differentiate molecular subtypes and aid in more precise grading of tumors. METHODS: We performed a retrospective, cross-sectional study on 124 samples of breast cancer and 40 samples of normal breast tissue. Relevant clinical information was retrieved from the Cancer Institute database. RESULTS: MCM6 could discriminate between various categories of histologic grades, tubule formation, mitotic indices, and nuclear pleomorphism (P = 0.002 for tubule formation and P < 0.001 for other). Moreover, the MCM6 score exhibited a significant correlation with the mitotic count (P < 0.001). However, the Ki-67 score could not discriminate subgroups of the mitotic index and nuclear pleomorphism. Compared to the luminal A subtype, luminal B exhibited a higher MCM6 score (P = 0.01). Besides, MCM6 scores were higher for certain subtypes with more aggressive behaviors, such as hormone receptor (HR)-negative disease, and human epidermal growth factor receptor 2 (HER2)-enriched and triple-negative breast cancers, as there was a significantly higher MCM6 mean score in the HR-negative in comparison to the luminal breast cancers (P < 0.001). Similarly, higher MCM6 scores were observed among samples with more advanced nuclear grades, tubule formation, and overall grades. CONCLUSION: MCM6 can differentiate luminal A and luminal B subtypes and is correlated with mitotic counts. However, this study was unable to prove the superiority of MCM6 in differentiating between molecular subtypes compared to the Ki-67 score. Nevertheless, in our study, MCM6 was superior to Ki-67 in exhibiting correlations with the mitotic grade, tubule formation, and nuclear grades. More studies are needed to standardize its assessment methods, determine more robust cut-off values, and evaluate its associations with prognostic features of breast cancer.

Resistance mechanisms to programmed cell death protein 1 and programmed death ligand 1 inhibitors.

Introduction: In the past few years, administrating monoclonal humanized antibodies, namely checkpoint inhibitors, against programmed cell death protein 1 (PD-1), and its ligand (PD-L1), has yielded reassuring tumor regression rates. Anti-PD-1/PD-L1 checkpoint inhibitors disrupt the engagement of PD-1 on T-cells and their ligands on tumor or other target cells and reactivate the tumor-specific T infiltrating lymphocytes (TILs), which are mostly in a state of anergy before the PD-1/PD-L1 blockade. However, a limited number of patients initially respond, and the others show a primary (innate) resistance. Moreover, the rate of relapse and tumor progression after a partial, or even complete response (secondary or acquired resistance) is relatively considerable.Areas covered: This paper presents a comprehensive discussion on the mechanisms of primary and secondary resistance to PD-1/PD-L1 blockade. Loss of T-cell infiltration or T-cell exclusion, lack of PD-L1 or PD-1 expression, and also lack of tumor immunogenicity are among the most important mechanisms, and also biomarkers of resistance in patients undergoing PD-1/PD-L1 blockade. Several somatic mutations in tumors are known to be related to at least one of the resistance mechanisms.Expert opinion: Identification of the novel resistance mechanisms suggests further combinatorial therapies to tackle primary and secondary resistance to PD-1/PD-L1 blockade.

Importance of TNF-alpha and its alterations in the development of cancers.

TNF-alpha is involved in many physiologic and pathologic cellular pathways, including cellular proliferation, differentiation, and death, regulation of immunologic reactions to different cells and molecules, local and vascular invasion of neoplasms, and destruction of tumor vasculature. It is obvious that because of integrated functions of TNF-alpha inside different physiologic systems, it cannot be used as a single-agent therapy for neoplasms; however, long-term investigation of its different cellular pathways has led to recognition of a variety of subsequent molecules with more specific interactions, and therefore, might be suitable as prognostic and therapeutic factors for neoplasms. Here, we will review different aspects of the TNF-alpha as a cytokine involved in both physiologic functions of cells and pathologic abnormalities, most importantly, cancers.