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IMPORTANCE: The oral cavity is the ultimate doorway for microbes entering the human body. We analyzed oral microbiota dynamics in allogeneic hematopoietic stem-cell transplant recipients and showed that microbiota injury and recovery patterns were highly informative on transplant complications and outcomes. Our results highlight the importance of tracking the recipient's microbiota changes during allogeneic hematopoietic stem-cell transplant to improve our understanding of its biology, safety, and efficacy.

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BACKGROUND: Steroid-refractory acute graft-vs.-host disease (SR-aGVHD) is a complication of allogeneic hematopoietic stem cell transplantation with a dismal prognosis and for which there is no consensus-based second-line therapy. Ruxolitinib is not easily accessible in many countries. A possible therapy is the administration of mesenchymal stromal cells (MSCs). METHODS: In this retrospective study, 52 patients with severe SR-aGVHD were treated with MSCs from umbilical cord (UC-MSCs) in nine institutions. RESULTS: The median (range) age was 12.5 (0.3-65) years and the mean ± SD dose (×106/kg) was 4.73 ± 1.3 per infusion (median of four infusions). Overall (OR) and complete response (CR) rates on day 28 were 63.5% and 36.6%, respectively. Children (n = 35) had better OR (71.5% vs. 47.1%, p = 0.12), CR (48.6% vs. 11.8%, p = 0.03), overall survival (p = 0.0006), and relapse-free survival (p = 0.0014) than adults (n = 17). Acute adverse events (all of them mild or moderate) were detected in 32.7% of patients, with no significant difference in children and adult groups (p = 1.0). CONCLUSIONS: UC-MSCs are a feasible alternative therapy for SR-aGVHD, especially in children. The safety profile is favorable.

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BACKGROUND: Allogeneic hematopoietic stem cell transplant (allo-HSCT) is used to treat several hematological diseases, but immunosuppression during allo-HSCT facilitates opportunistic microbial growth in tissues, such as actinomycosis. An effective diagnosis of opportunistic diseases is essential for correct management of the disease and preservation of the immunosuppressed patient's life. CASE DESCRIPTION: A 57-year-old female patient was diagnosed with extranodal nasal type NK/T cell lymphoma and underwent curative treatment with allo-HSCT. Twenty-one days after the last clinical follow-up, the patient presented a necrotizing lesion in the papilla region between the first and second molars of the second quadrant. Histopathological analysis showed the presence of a bacterial cluster consistent with Actinomyces infection, and a dense lymphoid infiltrate was also observed. Immunohistochemistry for CD20, CD3, and CD56 was performed to exclude the possibility of the recurrence of extranodal NK/T cell lymphoma. Oral microbiota profiling showed a huge increase in the abundance of Actinomyces bacteria in the subgingival region three weeks prior to appearance of the lesion. CONCLUSIONS: Opportunistic infections with an unusual clinical appearance are confounding factors in therapeutic decision-making. We present for the first time a case of actinomycosis in the gingival papilla region following allo-HSCT. We also highlight how microbiota profiling through next-generation sequencing could be used to anticipate bacterial infection diagnosis.

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Oral mucositis (OM) is a complex acute cytotoxicity of antineoplastic treatment that affects 40-85% of patients undergoing hematopoietic stem-cell transplantation. OM is associated with prolonged hospitalization, increased extensive pharmacotherapy, need for parenteral nutrition, and elevated treatment costs. As OM onset relates to the mucosal microenvironment status, with a particular role for microbiota-driven inflammation, we aimed to investigate whether the oral mucosa microbiota was associated with the clinical course of OM in patients undergoing allogeneic hematopoietic stem-cell transplantation. We collected oral mucosa samples from 30 patients and analyzed the oral mucosa microbiota by 16S rRNA sequencing. A total of 13 patients (43%) developed ulcerative OM. We observed that specific taxa were associated with oral mucositis grade and time to oral mucositis healing. Porphyromonas relative abundance at preconditioning was positively correlated with ulcerative OM grade (Spearman ρ = 0.61, P = 0.028) and higher Lactobacillus relative abundance at ulcerative OM onset was associated with shortened ulcerative OM duration (P = 0.032). Additionally, we generated a machine-learning-based bacterial signature that uses pre-treatment microbial profiles to predict whether a patient will develop OM during treatment. Our findings suggest that further research should focus on host-microbiome interactions to better prevent and treat OM.

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Intestinal microbiota (IM) diversity and composition regulates host immunity and affects outcomes after allogeneic stem cell transplantation (allo-HSCT). We evaluated if the oral mucosa microbiota (OM) could impact the outcomes in patients who underwent allo-HSCT. Samples from the oral mucosa of 30 patients were collected at three time points: before the conditioning regimen, at aplasia, and at engraftment. We analyzed the associations of OM diversity and composition with allo-HSCT outcomes. Lower OM diversity at preconditioning was associated with a higher risk of relapse at 3 years (68% versus 33%, respectively; P = 0.04). Dominance (relative abundance ≥ 30%) by a single genus at preconditioning was also associated with a higher risk of relapse (63% versus 36% at 3 years, respectively; P = 0.04), as well as worse progression-free survival (PFS; 19% versus 55%, respectively; P = 0.01), and overall survival (OS) at 3 years (38% versus 81%, respectively; P = 0.02). In our study we observed that OM dysbiosis is associated with a higher risk of relapse and worse survival after allo-HSCT.

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Acute graft-versus-host disease (aGVHD) is one of the major causes of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recently, aGVHD onset was linked to intestinal microbiota (IM) dysbiosis. However, other bacterial-rich gastrointestinal sites, such as the mouth, which hosts several distinctive microbiotas, may also impact the risk of GVHD. The dental biofilm microbiota (DBM) is highly diverse and, like the IM, interacts with host cells and modulates immune homeostasis. We characterized changes in the DBM of patients during allo-HSCT and evaluated whether the DBM could be associated with the risk of aGVHD. DBM dysbiosis during allo-HSCT was marked by a gradual loss of bacterial diversity and changes in DBM genera composition, with commensal genera reductions and potentially pathogenic bacteria overgrowths. High Streptococcus and high Corynebacterium relative abundance at preconditioning were associated with a higher risk of aGVHD (67% vs. 33%; HR = 2.89, P = 0.04 and 73% vs. 37%; HR = 2.74, P = 0.04, respectively), while high Veillonella relative abundance was associated with a lower risk of aGVHD (27% vs. 73%; HR = 0.24, P < 0.01). Enterococcus faecalis bloom during allo-HSCT was observed in 17% of allo-HSCT recipients and was associated with a higher risk of aGVHD (100% vs. 40%; HR = 4.07, P < 0.001) and severe aGVHD (60% vs. 12%; HR = 6.82, P = 0.01). To the best of our knowledge, this is the first study demonstrating that DBM dysbiosis is associated with the aGVHD risk after allo-HSCT.

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BACKGROUND: Malnutrition is a common finding in allogeneic hematopoietic stem cell transplantation (alloHSCT) patients, and there is some evidence that malnutrition might negatively affect the transplant outcomes. METHOD: We performed a retrospective study with 148 patients aged 18-75 years, who underwent alloHSCT between 2011 and 2017. Patients were classified according to the body mass index (BMI) and the Subjective Global Assessment (SGA). The SGA was assessed on the day of hospitalization for the transplant, and classifies patients into three groups: A (well-nourished), B (moderately malnourished) and C (severely malnourished). RESULTS: The SGA classified 49 (33%) patients as well-nourished, 54 (37%) as moderately malnourished, and 45 (30%) as severely malnourished. SGA-C was also associated with severe acute graft versus host disease (aGVHD) with a cumulative incidence (CI) of 31% vs. a CI of 14% for combined well-nourished or moderately malnourished group (SGA-A or -B, P = 0.017). In multivariate analysis, SGA-C compared to SGA-A or -B, remained as an independent risk factor for aGVHD (hazard ratio - HR 1.68, 95% confidence interval - 95% CI 1.02-2.74), and nonrelapse mortality (NRM - HR 3.63, 95% CI 1.76-7.46), worse progression free survival (HR 2.12, 95% CI 1.25-3.60), and worse overall survival (HR 3.27, 95% CI 1.90-5.64). CONCLUSION: Malnutrition increases the risk of aGVHD and NRM and has a negative impact on survival.

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ABSTRACT Objective: To investigate, in a large prospective multicenter study, whether 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography is sufficiently accurate to identify clinically important bone marrow involvement by Hodgkin's lymphoma to replace routine bone marrow biopsy in a developing tropical country. Methods: Patients newly diagnosed with Hodgkin's lymphoma were recruited from six cancer centers in Brazil. All were staged by the results of positron emission tomography/computed tomography that were centrally reviewed and by iliac crest bone marrow biopsy. Patients were classified as having marrow disease if they had lymphoma identified by marrow biopsy histology or had focal 2-[18F]-fluoro-2-deoxy-D-glucose marrow uptake that resolved following chemotherapy. Results: A total of 246 participants were recruited from six different centers and 62 (25.2%) were judged to have Hodgkin's lymphoma in the bone marrow. Positron emission tomography and biopsies were concordant in 206 patients (83%). Positron emission tomography correctly identified marrow disease in 59/62 patients (95.1%) and marrow biopsy in 25/62 patients (40.3%). In 22/62 (35.4%) patients, the two techniques were concordant in the diagnosis of marrow involvement. Of the forty discordant results, positron emission tomography found bone marrow involvement in 37 patients, upstaging 22 to stage IV and having an impact on therapeutic decision in nine cases given their reallocation from early to advanced stage. Three false negative positron emission tomography results were obtained with bone marrow biopsy giving positive findings. All three cases were classified as stage IV regardless of bone marrow findings implying no modification in the clinical management. The sensitivity, specificity and accuracy of positron emission tomography for detecting bone marrow disease were 95%, 100% and 98% and for bone marrow biopsy they were 40%, 100% and 84%, respectively. Conclusion: We conclude that positron emission tomography can replace marrow biopsy in Brazilian patients with Hodgkin's lymphoma without compromising clinical management.

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OBJECTIVE: To investigate, in a large prospective multicenter study, whether 2-[18F]-fluoro-2-deoxy-d-glucose-positron emission tomography is sufficiently accurate to identify clinically important bone marrow involvement by Hodgkin's lymphoma to replace routine bone marrow biopsy in a developing tropical country. METHODS: Patients newly diagnosed with Hodgkin's lymphoma were recruited from six cancer centers in Brazil. All were staged by the results of positron emission tomography/computed tomography that were centrally reviewed and by iliac crest bone marrow biopsy. Patients were classified as having marrow disease if they had lymphoma identified by marrow biopsy histology or had focal 2-[18F]-fluoro-2-deoxy-d-glucose marrow uptake that resolved following chemotherapy. RESULTS: A total of 246 participants were recruited from six different centers and 62 (25.2%) were judged to have Hodgkin's lymphoma in the bone marrow. Positron emission tomography and biopsies were concordant in 206 patients (83%). Positron emission tomography correctly identified marrow disease in 59/62 patients (95.1%) and marrow biopsy in 25/62 patients (40.3%). In 22/62 (35.4%) patients, the two techniques were concordant in the diagnosis of marrow involvement. Of the forty discordant results, positron emission tomography found bone marrow involvement in 37 patients, upstaging 22 to stage IV and having an impact on therapeutic decision in nine cases given their reallocation from early to advanced stage. Three false negative positron emission tomography results were obtained with bone marrow biopsy giving positive findings. All three cases were classified as stage IV regardless of bone marrow findings implying no modification in the clinical management. The sensitivity, specificity and accuracy of positron emission tomography for detecting bone marrow disease were 95%, 100% and 98% and for bone marrow biopsy they were 40%, 100% and 84%, respectively. CONCLUSION: We conclude that positron emission tomography can replace marrow biopsy in Brazilian patients with Hodgkin's lymphoma without compromising clinical management.

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Mucormycosis is an invasive fungal disease caused by fungi from the Mucorales order that are found in the soil and decaying organic debris. Mucormycosis has been reported to be the third most common fungal disease in stem cell transplanted patients. The fungi have a tendency for vascular invasion, resulting in thrombi development, which decreases blood supply and leads to extensive tissue necrosis. Here, the authors present a patient of mucormycosis affecting the soft palate, oropharynx, and hypopharynx in a type II diabetic male patient who underwent allogeneic stem cell transplantation, and the authors further review the literature on oral mucormycosis for the last 10 years.

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We report the case of a cord blood haematopoietic stem cell transplant recipient who was vaccinated for Yellow Fever (YF) 7 days before initiating chemotherapy and had persistent YF antibodies more than 3 years after vaccination. Since the stem cell donor was never exposed to wild YF or to the YF vaccine, and our patient was not exposed to YF or revaccinated, this finding strongly suggests the persistence of recipient immunity. We briefly discuss potential consequences of incomplete elimination of recipient's leukocytes following existing haematopoietic cancer treatments.

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BACKGROUND: Human herpesviruses may cause severe complications after allogeneic hematopoietic stem cell transplantation (HSCT). However, the impact of some of these infections on transplant outcomes is still unclear. A prospective survey on the incidence and clinical features of herpesviruses infections after HSCT has not yet been conducted in Brazilian patients, and the impact of these infections on HSCT outcome remains unclear. METHODS: We prospectively analyzed the incidence of infection of the eight human herpesviruses simultaneously in 1 045 peripheral blood samples from 98 allogeneic HSCT recipients. Samples were collected weekly starting at the time of transplant until day +100. All herpesviruses were screened and quantified in plasma by quantitative real-time polymerase chain reaction. Median follow up time was 24 months. RESULTS: The incidences of infection for each herpesvirus were as follows: cytomegalovirus (CMV), 44%; human herpesvirus [HHV] 6, 18%; HHV8, 6%; Epstein-Barr virus, 3%; herpes simplex virus 1, 3%; varicella zoster virus, 3%; HHV7, 2%; and herpes simplex virus 2, 1%. The CMV infection was significantly more frequent among adults and was associated with a higher risk of developing acute graft-versus-host disease. The HHV6 infection was significantly more frequent after umbilical cord blood transplant and was associated with an increased risk of platelet engraftment failure. There was no significant impact of these infections on the other transplant outcomes. CONCLUSIONS: Herpesviruses infections were uncommon after HSCT, except for CMV and HHV6, which, although relatively frequent, had no clinically relevant impact on the outcomes.

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Human herpesvirus 6 (HHV-6) may cause severe complications after haematopoietic stem cell transplantation (HSCT). Monitoring this virus and providing precise, rapid and early diagnosis of related clinical diseases, constitute essential measures to improve outcomes. A prospective survey on the incidence and clinical features of HHV-6 infections after HSCT has not yet been conducted in Brazilian patients and the impact of this infection on HSCT outcome remains unclear. A rapid test based on real-time quantitative polymerase chain reaction (qPCR) has been optimised to screen and quantify clinical samples for HHV-6. The detection step was based on reaction with TaqMan® hydrolysis probes. A set of previously described primers and probes have been tested to evaluate efficiency, sensitivity and reproducibility. The target efficiency range was 91.4% with linearity ranging from 10-106 copies/reaction and a limit of detection of five copies/reaction or 250 copies/mL of plasma. The qPCR assay developed in the present study was simple, rapid and sensitive, allowing the detection of a wide range of HHV-6 loads. In conclusion, this test may be useful as a practical tool to help elucidate the clinical relevance of HHV-6 infection and reactivation in different scenarios and to determine the need for surveillance.

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