Search Results (514)

Torque Teno Virus (TTV), a common and genetically diverse component of the human virome, is not linked to any known disease but reflects immune status. Its plasma viral load has shown clinical relevance in solid organ transplant recipients, correlating it with immunosuppression when present at high levels. However, the clinical significance of TTV viral load in hematopoietic stem cell transplantation (HSCT) recipients is less understood. This systematic review aims to evaluate whether plasma TTV DNA load directly correlates with the degree of T-cell immune reconstitution after HSCT, supporting its potential role as a biomarker for immune competence. The study protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews (CRD420251116208) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Twenty-one studies were included. The results showed concordant data about TTV kinetics with peak levels reaching approximately between +90 to +120 days after transplantation. Contradictory results have instead been found for the association of TTV load with immune parameters (lymphocyte counts, viral opportunistic infection, and development of acute graft versus host diseases). Even if a low-risk bias assessment was classified in most studies (67%), it was possible to identify important clinical and methodological differences between them, which might account for the different findings observed. Therefore, future larger studies with standardized protocols are needed to assess whether TTV viral load can serve as a reliable tool for guiding clinical decisions in the context of HSCT. Full article

Background/Objectives: Smoking is linked to an increased risk of pulmonary complications and adverse outcomes following allogeneic hematopoietic cell transplantation (Allo-HCT). Unfortunately, data is rarely correlated with the incidence of GVHD and does not show whether smoking has a negative impact independent from underlying pulmonary comorbidities. Methods: We retrospectively analyzed 407 patients who underwent Allo-HCT between January 2019 and May 2021 and evaluated the impact of smoking history and pre-transplant pulmonary comorbidities on the risk of outcomes including graft-versus-host disease (GVHD), overall survival (OS), and non-relapse mortality (NRM). Results: Patients were divided into the following groups: Group A: smokers with pre-transplant pulmonary comorbidity, 40 pts (9.8%); Group B: non-smokers with pre-transplant pulmonary comorbidity, 71 pts (17.4%); Group C: smokers without pre-transplant pulmonary comorbidity, 105 pts (25.8%); and Group D: non-smokers without pre-transplant pulmonary comorbidity, 191 pts (46.9%). Smokers were also grouped by their smoking history (<10 pack-years (59 pts), 11 to 25 pack-years (50 pts), and >25 pack-years (35 pts)) and by smoking recency: Recent (until Allo-HCT), Former (quit > 1 year ago), and Remote smokers (quit > 10 years ago). Our results showed that Group A demonstrated increased chronic lung GVHD compared to the other groups (p = 0.01). The 3-year OS was lowest in Group A at 45.0%, compared to 70.4%, 62.4%, and 69.4% (p = 0.006), and the NRM was highest at 37.5%, compared to 15.5%, 18.2%, and 14.7% in Groups B, C, and D, respectively (p = 0.001). Smoking recency and higher pack-year dose were associated with worse outcomes. Conclusions: Our study demonstrated the negative synergistic effect of smoking history and pre-transplant pulmonary comorbidities on the incidence of lung GVHD, OS, and NRM. Full article

Mesenchymal stem/stromal cells (MSCs) exhibit broad differentiation capability and strong immunoregulatory potential mediated through intercellular communication and the release of diverse paracrine mediators. They represent a promising but still investigational therapeutic approach for managing complications associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). This review provides an updated synthesis of MSC biology, their bidirectional interaction with immune cells, and their functional contribution to the hematopoietic niche. It also evaluates current clinical evidence regarding the therapeutic roles of MSCs and MSC-derived extracellular vesicles (EVs) in acute and chronic graft-versus-host disease (aGVHD/cGVHD), as well as in poor graft function. Mechanistic insights encompass macrophage polarization toward an anti-inflammatory phenotype, inhibition of dendritic cell maturation, enhancement of regulatory T-cell expansion, and modulation of cytokine signaling pathways. Within the bone marrow milieu, MSCs contribute to stromal restoration and angiogenic repair. Recent phase II/III trials in steroid-refractory (SR)-aGVHD have demonstrated overall response rates ranging from 48 to 71%. Efficacy appears particularly enhanced in pediatric patients and with early MSC administration. Across studies, MSC therapy shows a favorable safety profile; however, heterogeneity in response and inconsistent survival outcomes remain notable limitations. For poor graft function, limited prospective studies indicate hematopoietic recovery following third-party MSC infusions, and combination approaches such as co-administration with thrombopoietin receptor agonists are under investigation. MSC-derived EVs emulate many immunomodulatory effects of their parental cells with a potentially safer profile, though clinical validation remains in its infancy. MSC-oriented interventions hold substantial biological and therapeutic promise, offering a favorable safety margin; however, clinical translation is hindered by product variability, suboptimal engraftment and persistence, and inconsistent efficacy across studies. Future directions should emphasize standardized manufacturing and potency assays, biomarker-driven patient and timing selection, optimized conditioning and dosing strategies, and the systematic appraisal of EV-based or genetically modified MSC products through controlled trials. Full article

BTK (Bruton’s tyrosine kinase) has become a key therapeutic target across several hematologic diseases, beginning with its original use in CLL/SLL. As a central mediator of B-cell receptor signaling and microenvironment interactions, BTK supports survival, proliferation, and trafficking in multiple mature B-cell malignancies (mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, and other indolent/aggressive lymphomas) and in selected immune-mediated conditions such as chronic graft-versus-host disease. Covalent BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) irreversibly bind the C481 residue and have produced high response rates and durable disease control, often replacing chemoimmunotherapy in the relapsed setting and, for some entities, even in the first line. Differences in kinase selectivity lead to different safety profiles: second-generation covalent agents generally maintain efficacy while reducing significant off-target toxicities, especially atrial fibrillation and hypertension. Resistance to covalent BTK inhibitors most commonly develops through BTK C481 substitutions and activating PLCG2 mutations, with other kinase-domain variants increasingly recognized. Non-covalent BTK inhibitors (e.g., pirtobrutinib) bind BTK independently of C481, can overcome classic C481-mediated resistance, and extend BTK pathway targeting into later lines of therapy. Overall, BTK inhibition has evolved into a versatile platform enabling long-term, often chemo-free management strategies. Full article

Background/Objectives: Ocular graft-versus-host disease (oGVHD) is a chronic, immune-mediated complication of allogeneic hematopoietic stem cell transplantation that can progress to corneal ulceration or perforation. These cases are often refractory to standard therapy and present a high risk of graft failure after keratoplasty. We report a case of oGVHD-related corneal perforation successfully managed with a novel amniotic membrane-assisted “envelope” technique during corneal transplantation. Case Report: A 42-year-old man with chronic oGVHD and a full-thickness corneal perforation underwent urgent repair with a lamellar patch graft completely wrapped in cryopreserved amniotic membrane, followed by penetrating keratoplasty (PKP) using an amniotic membrane envelope surrounding the donor lenticule. Results: The amniotic membrane provided a 360° biological barrier that isolated graft antigens from the inflammatory environment while supporting epithelial healing and stromal remodeling. Despite recurrent inflammatory episodes and multiple procedures—including cataract extraction, pars plana vitrectomy, and multilayer amniotic membrane transplantation—the graft remained clear and stable at 12-month follow-up, achieving a best-corrected visual acuity of 20/40. Conclusions: The amniotic membrane envelope technique may represent a valuable adjunct in managing high-risk corneal perforations secondary to oGVHD. By combining immune modulation and regenerative support, this approach can enhance tectonic stability, reduce rejection risk, and promote durable surface recovery, potentially delaying or avoiding keratoprosthesis in refractory cases. Full article

(1) Background: Cutaneous secondary malignant neoplasms are a growing survivorship burden after pediatric cancers and hematopoietic stem cell transplantation (HSCT), yet skin-focused surveillance remains inconsistently implemented. (2) Objective: To synthesize current molecular dermatology insights relevant to prevention, early detection, and treatment of basal cell carcinoma (BCC) in high-risk survivors, while anchoring the discussion in a detailed case of multiple BCCs after childhood acute lymphoblastic leukemia and HSCT. (3) Methods: Narrative review integrating clinical, dermoscopic, molecular, and translational data from recent high-impact studies; case retained in full. (4) Results: Radiation exposure (especially total body irradiation), prior immunosuppression, and persistent immune dysregulation synergize with ultraviolet mutagenesis to create a “field cancerization” state characterized by Hedgehog-pathway activation (Patched1/Smoothened), impaired Deoxyribonucleic Acid damage response, and stromal remodeling. Dermoscopy, when embedded in routine whole-body examinations, markedly improves accuracy for keratinocyte cancers. Chemoprevention (e.g., nicotinamide) and targeted therapies (hedgehog inhibitors; Programmed Death-1 blockade) represent key translational levers for care innovation. (5) Conclusions: Integrating structured dermatologic surveillance with molecularly informed prevention and therapy should be standard in survivorship pathways for hematopoietic stem cell transplantation/Radiotherapy-exposed patients. Full article

On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2024 Annual Conference. The conference was held on 1–3 May 2024 in beautiful Victoria, British Columbia, at the Victoria Conference Centre, and attracted 293 in-person delegates and five virtual attendees. Several plenary sessions were held on topics such as gene therapy for hemoglobin disorders, optimizing donor selection, graft-versus-host disease (GvHD) strategies, collaborative care, survivorship, graft failure, and CAR-T therapy. Poster authors presented their work during a lively and engaging networking reception on Thursday, 2 May, and oral abstract authors were featured during the oral abstract session in the afternoon of Friday, 3 May 2024. Forty-nine (49) abstracts were selected for presentation as posters and six (6) as oral presentations. Abstracts were submitted within four categories: (1) Basic/Translational Sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support. The top six (6) abstract authors were invited to give an oral presentation, and the top four (4) poster abstracts were selected to receive an award. All of these were marked as “Award Recipient” within the relevant category. Three abstracts were determined by the peer review panel to be inappropriate for this conference and were not invited to present at the conference, and two authors withdrew their abstract; therefore, five abstract numbers are missing from the list. We congratulate all the 2024 abstract presenters on their research and contributions to the field. Full article

Chimeric antigen receptor (CAR)-based immunotherapy has shown considerable promise in cancer treatment by redirecting immune effector cells to recognize and eliminate tumor cells in an antigen-specific manner. While CAR-T cells bearing tumor-specific CARs have shown remarkable success in treating some hematological malignancies, their clinical application is limited by cytokine release syndrome, neurotoxicity, and graft-versus-host disease. In contrast, CAR–natural killer (NK) cells retain their multiple forms of natural anti-tumor capabilities without the pathological side effects and are compatible with allogeneic “off-the-shelf” application by not requiring prior activation signaling. Despite CAR-NK therapies showing promising results in hematological malignancies, they remain limited as effector cells against solid tumors. This is primarily due to the complex, immunosuppressive tumor microenvironment (TME), characterized by hypoxia, nutrient depletion, lactate-induced acidosis, and inhibitory soluble factors. Collectively, these significantly impair NK cell functionality. This review examines challenges faced by CAR-NK therapy in combating solid tumors and outlines strategies to reduce them. Barriers include tumor antigen heterogeneity, immune escape, trogocytosis-mediated fratricide, rigid structural and metabolic barriers in the TME, immunosuppressive factors, and defective homing and cell persistence of CAR-NK cells. We also emphasize the impact of combining other complementary immunotherapies (e.g., multi-specific immune engagers and immunomodulatory agents) that further strengthen CAR-NK efficacy. Finally, we highlight critical research gaps in CAR-NK therapy and propose that cutting-edge technologies are required for successful clinical translation in solid tumor treatment. Full article

Adoptive cellular therapy with donor-derived T cells has always been an attractive strategy after allogeneic hematopoietic stem cell transplantation (allo-HSCT) to reduce the risk of relapse in acute myeloid and lymphoid leukemias. Donor lymphocyte infusion (DLI) is still the best-established option, especially in the preemptive phase when measurable residual disease (MRD) becomes positive and in the prophylactic setting—when MRD is not detectable. However, the clinical benefit of DLI is counterbalanced by the possible onset of graft-versus-host disease (GvHD), which continues to restrict its wide application. To address this challenge, several alternative cell-based strategies have been developed. One of these is represented by cytokine-induced killer (CIK) cells, generated from donor peripheral blood mononuclear cells through stimulation with anti-CD3 antibodies, interferon-γ, and interleukin-2. These cells are characterized by a hybrid phenotype, combining T-cell functions with natural killer-like properties, and exhibit antitumor activity in an MHC-unrestricted manner. CIK cells are generally well tolerated and associated with low toxicity but their efficacy is so far modest. Based on the experience of CAR-T in the treatment of B-cell lymphoid disease, CIK cells have been engineered with chimeric antigen receptors (CAR) developing the CARCIK cells. This novel cellular strategy represents a promising approach in the treatment of acute myeloid and lymphoid leukemia relapsed post-allo-HSCT. This review provides an overview of the current CAR-CIK experiences in the setting of acute leukemias and outlines future directions for their clinical translation. Full article

Introduction: Allogeneic penetrating limbo-keratoplasty (limbo-PK) is one of the surgical methods for the treatment of limbal stem cell deficiency (LSCD). We report real-life results on different entities. Methods: Patients treated with limbo-PK at the Department of Ophthalmology of the University Medical Center Mainz were evaluated retrospectively. The primary endpoint was the epithelialization of the graft one year postoperatively. In addition, the postoperative best corrected visual acuity (BCVA), ocular concomitant diseases, drug treatment, and the need for further eye surgery postoperatively were examined. Results: We included 14 eyes of 13 patients (4 female) aged 59.8 ± 14.1 years who underwent limbo-PK between 2020 and 2024. Indications for limbo-PK included chemical burns (n = 4), blast injuries (n = 4), thermal burns (n = 2), trauma (n = 1) graft-versus-host disease (n = 1), and ectrodactyly-ectodermal dysplasia (EEC) (n = 1). The mean preoperative BCVA was 2.2 ± 0.6 logMAR (range: light perception to 0.7 logMAR). Four limbo-PK-grafts were HLA-typed. All limbo-PKs were combined with amniotic membrane transplantation; three with cataract surgery and one with tarsorrhaphy. Postoperatively, all patients received local immunosuppression, and 12 (85.7%) received additional systemic immunosuppression. At one-year follow-up mean BCVA increased to 1.0 ± 0.7 logMAR (range: 2.3 to 0.1, p-value = 0.03) and 11 of 14 eyes showed a functional graft with closed epithelium. In the further postoperative course, four patients needed a further Limbo-PK due to graft failure (n = 2), immune graft rejection after stopping local immunosuppressive therapy (n = 1) and perforation of the graft in a severe case of GvHd (n = 1). Conclusions: Limbo-PK is an effective surgical method for the treatment of LSCD. In our study cohort, we observed a significant improvement in mean BCVA one year postoperatively, with a functional, epithelialized graft achieved in 11 of 14 eyes. Full article

Background: Haploidentical hematopoietic cell transplantations (haplo-HCTs) with post-transplant cyclophosphamide (PT-Cy) are standard practice, but complications causing morbidity and mortality are not well described. Methods: The aim of this prospective non-interventional multicenter study was to document frequency of potential non-infectious and infection-related complications and main transplant outcomes after the first unmanipulated haplo-HCT with PT-Cy between 2017 and 2019 in 129 adult patients with hematological malignancies. The median follow-up was 37.3 months [95% CI: 34.3–39.7]. Results: The cumulative incidence (CI) of acute graft versus host disease (aGvHD) at day +100 was 22.4% grade II-IV [95% CI: 15.5–30.1] and 8.8% grade III-IV [95% CI: 4.6–14.6], respectively. The cumulative incidence of chronic GvHD (cGvHD) at 24 months was 25.8% [95% CI: 18.5–33.6]; extensive cGvHD was 10.9% [95% CI: 6.3–17.1], respectively. The most frequent non-infectious complications for the whole study population were mucositis—37.5% (n = 48); renal insufficiency—18% (n = 23); and cardiovascular complications—10.9% (n = 14). The following infection-related complications were diagnosed: bacterial in 84 (65.1%), viral in 66 (51.6%), and fungal in 24 (18.6%) recipients. Two-year OS was 58.1% [95% CI: 50.2–67.3]; NRM—27.1% [95% CI: 19.7–35]; PFS—50.4% [95% CI: 42.5–59.8]; and GRFS—38.8% [95% CI: 31.2–48.1]. About 50% of all deaths were directly caused by infection or infection-related conditions. Conclusions: Disease remission status at transplant significantly affected PFS, chronic GvHD, and GRFS. Although clinical applications of haplo-HCT with PTCy are widespread, the study confirms the need to reduce infection-related mortality after this type of GvHD prophylaxis. Full article

Background/Objectives: Myeloid sarcoma (MS) is a rare extramedullary manifestation of myeloid blasts, with limited systematic data, particularly regarding molecular (NGS) concordance between MS tissue and bone marrow. We hypothesized that clonal heterogeneity may exist between these sites due to their distinct biological environments. Methods: We conducted a systematic review and meta-analysis of 85 studies encompassing 7241 MS patients, to evaluate clinical characteristics, mutational profiles, treatment patterns, and outcomes. Mutational concordance or discordance between MS and bone marrow was assessed in a subset of 112 patients. Results: Male predominance (59%) and skin/soft tissue localization (31%) were most common. NPM1 (25%) and FLT3 (20%) were the most frequently reported mutations. Among 112 patients with paired sequencing, 56% showed discordance in mutational profiles. NPM1 was significantly enriched in MS sites compared to bone marrow (35% vs. 21%, p = 0.02) and was associated with skin involvement. Discordance was more frequent in isolated and secondary MS. Venetoclax with hypomethylating agents achieved a 44% response rate, mainly in secondary MS. Post-transplant isolated extramedullary relapse occurred in 46% of relapsed patients and was linked to high rates of graft-versus-host disease. The pooled median overall survival was 12.8 months. Conclusions: MS demonstrates significant molecular heterogeneity. Routine site-specific NGS profiling may guide targeted therapy in this rare disease. Full article

Background: The aim of this study was to investigate the effects of chronic graft-versus-host disease (cGVHD) and its treatment with cyclosporine and extracorporeal photopheresis (ECP) on salivary caries risk factors. Methods: In this exploratory single-centre cross-sectional pilot study, saliva samples from 22 cGVHD patients were analysed for flow rate, pH, buffering capacity, and counts of Streptococcus mutans and Lactobacillus. A detailed dental examination assessed plaque, carious lesions, and their progression. Caries risk was determined based on general health and diet questionnaires and clinical findings. Results: Patients receiving a combination of cyclosporine and ECP had significantly fewer carious teeth, affected tooth surfaces, and non-cavitated carious lesions compared with those treated with ECP alone (Bonferroni test, p = 0.004, p = 0.002, and p < 0.001, respectively). Patients treated with ECP had more carious teeth and affected surfaces than those who did not receive either ECP or cyclosporine (p = 0.008 and p = 0.002), whereas patients treated with cyclosporine only had more non-cavitated lesions than those receiving both cyclosporine and ECP (p < 0.001). A negative correlation was observed between cyclosporine dose and stimulated salivary flow (R = −0.672, p = 0.0486), and a positive correlation between cyclosporine dose and caries risk (R = 0.640, p = 0.0461). Conclusions: The disease and its treatment were associated with reduced salivary flow and increased caries risk. Patients’ oral health should be monitored regularly and managed with care to prevent further deterioration. Full article

Fecal microbiota transplantation (FMT) is a therapeutic strategy designed to modify and enrich the recipient’s gut microbiota by administering processed donor stool, with the goal of treating dysbiosis and related conditions. In 2013, the United States Food and Drug Administration (FDA) approved FMT for recurrent Clostridioides difficile infection (rCDI). Since then, its use has been proposed and investigated in several other disorders characterized by gut microbiota imbalance and altered host–microbiota interactions, including inflammatory bowel disease (IBD), immune checkpoint inhibitor-induced colitis (ICI-iC), and gastrointestinal graft-versus-host disease (GI-GVHD). This review aims to highlight the commonalities among these conditions, the pathophysiological mechanisms that support the rationale for FMT, and emerging evidence from clinical studies. Although available studies are heterogeneous, FMT is a rapidly evolving field of research with promising potential to treat IBD and improve outcomes following oncological immunotherapy and allogenic stem cell transplantation. With further validation, FMT could become an important approach in managing immune-mediated gastrointestinal diseases. Full article

The cannabidiol (CBD)-rich cannabis extract CAN296 shows anti-inflammatory and anticancer activity relevant to oral lichen planus (OLP), oral graft-versus-host disease (oGVHD), and oral squamous cell carcinoma (OSCC), but its high lipophilicity limits aqueous dispersion. This study developed a stable Tween-based nanoemulsion optimized for oral mucosal delivery. Ethanol-dissolved CAN296 was nanoemulsified using a 1% Tween/Span system. Physical stability was visually assessed; droplet size and morphology were examined by dynamic light scattering (DLS) and transmission electron microscopy (TEM); and wettability was measured by static contact angle (SCA). Additional evaluations included temperature stability (25 °C vs. 4 °C), in vitro release using a dialysis membrane, and scanning electron microscopy (SEM) of membrane-associated droplets. Nanoemulsions with ≥80% Tween 80 incorporated CAN296 up to 800 µg/mL, clear at 400 µg/mL, and uniformly turbid at 800 µg/mL. DLS and TEM confirmed spherical nanoscale droplets, and SCA indicated favorable cohesion and wettability. Stability was maintained for 30 days at 4 °C. Dialysis studies demonstrated strong membrane association with limited diffusion, supported by SEM visualization of membrane-bound droplets. The Tween-dominant (≥80%) nanoemulsion stably incorporated CAN296 up to 800 µg/mL, demonstrated nanoscale uniformity, improved 4 °C stability, and strong membrane retention under static conditions, suggesting potential for localized oral delivery. Full article