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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.

BackgroundAllogeneic hematopoietic stem-cell transplant (allo-HSCT) is a potentially curative therapy for several hematological disorders. Before stem-cell infusion, recipients undergo a conditioning regimen with chemo/radiotherapy and immunosuppressants, requiring the use of antibiotics to treat and prevent infections. This regimen promotes drastic alterations in the recipient’s microbiotas, including the oral microbiota, which have been associated with allo-HSCT complications and poor outcomes. However, long-term longitudinal studies on the oral microbiota of allo-HSCT recipients are scarce and disregard the existence of distinct microbiotas within the oral cavity. Here, we used 16S rRNA gene sequencing to characterize the microbiota dynamics (during and after allo-HSCT) of 31 allo-HSCT recipients at 3 oral sites (gingival crevicular fluid, oral mucosa, and supragingival biofilm).ResultsAnalysis of the oral microbiota dynamics during allo-HSCT revealed a significant decline in bacterial diversity and major shifts in microbiota composition in all oral sites, including blooms of potentially pathogenic genera. These blooms in some cases preceded respiratory infections caused by the blooming genera. We also noticed that differences in microbiota diversity and composition between oral sites were lost during allo-HSCT. Overall, oral microbiotas returned to their preconditioning state after engraftment. However, the ability to recover the initial bacterial composition varied between patients. After stratifying patients based on their ability to recover their preconditioning microbiota composition, we found that recovery of the oral mucosa microbiota composition was not associated with antibiotic usage but was associated with higher preconditioning diversity and earlier reconstitution of normal leukocyte counts. Most notably, oral mucosa microbiota composition recovery was an independent biomarker of better allo-HSCT outcomes.ConclusionWe observed clear patterns of microbiota dysbiosis in all three oral sites during allo-HSCT, however each oral site responded differently to the perturbations associated with allo-HSCT. Oral microbiota injury and recovery patterns were associated with allo-HSCT complications and outcomes. This study highlights the potential clinical impact of the oral microbiota in the allo-HSCT setting and the clinical value of tracking oral microbiota changes during allo-HSCT.

BACKGROUND Oral mucositis (OM) is an important side effect related to allogeneic hematopoietic stem cell transplantation (allo-HSCT), and it has been associated with a significative reduction of quality of life. A negative impact of this toxicity in paediatric patients could result in increased use of parenteral feeding and opioids, longer periods of hospitalization, and a higher risk of systemic infection. AIM To investigate the clinical features and clinical outcomes associated with OM development and severity in hematological cancer paediatric patients undergoing allo-HSCT who underwent professional dental care (PDC) and photobiomodulation (PBM) as prophylactic treatment. DESIGN Medical data and OM presentation were retrieved retrospectively from all patients younger than 18 years who were submitted to allo-HSCT between 2013 and 2016. The incidence of OM was assessed and graded by two oral medicine specialists following the WHO guidelines, and it was correlated with clinical parameters. RESULTS Forty-nine consecutive paediatric patients were included. OM was diagnosed in 73.5% of patients, and in 36.1% of patients, OM was classified as severe. Acute lymphoblastic leukemia as a primary diagnosis and the use of a myeloablative regimen were associated with OM development. The primary diagnosis and use of total body irradiation (TBI) were associated with aggressive OM. Neither the incidence nor the severity of OM affected the overall survival, whereas only the use of a myeloablative regimen and a high body mass index (BMI) were determinants of lower OM-free survival rates. CONCLUSIONS A myeloablative conditioning and a high BMI were observed to be independent prognostic determinants of a lower OMFS rate. The cluster analysis allowed us to outline patient profiles with greater susceptibility to the development and severity of oral mucositis, which seems to be a useful tool to determine the risk of OM in paediatric patients.

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 with 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.

Undifferentiated pleomorphic sarcoma (UPS) is a high-grade neoplasm that is usually located in the extremities and retroperitoneum. In the past, UPS was considered the most common soft tissue sarcoma in adults; due to improvements in diagnostic techniques, most cases have been reclassified as other lineage-specific tumors. Gnathic bones are rarely affected, and the clinicopathological characteristics of this neoplasm when diagnosed in the jaw remain to be better described. In this report, we present a rare case of mandibular UPS affecting an 88-year-old female who demonstrated a painful swelling on the right side of the mandible that was accompanied by a pathological fracture. Microscopic examination revealed a pleomorphic spindle-cell neoplasm with mitotic figures and necrosis. The patient underwent surgery and adjuvant radiotherapy but experienced metastasis after 12 months of follow-up and died. Diagnosis of UPS is challenging, and oral pathologists must be aware of this entity when dealing with aggressive undifferentiated neoplasms.

This study was performed to characterise oral shedding of herpesviruses in patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) and to investigate its relationship with oral mucositis (OM). PCR and enzymatic digestion were conducted to identify oral shedding of herpesviruses and its correlation with OM development in 31 patients. The samples were collected at three sites in the oral cavity and at 5 times during follow-up; two additional collections were made from patients who developed ulcerative OM. HSV-1, EBV, CMV, HHV-6A, HHV-6B, and HHV-7 were detected in 4.97%, 16.02%, 4.41%, 2.20%, 3.31%, and 68% of the oral mucosal samples, respectively; 4.41%, 16.57%, 5.52%, 2.20%, 5.52%, and 63.53% of supragingival samples, respectively, and 4.41%, 18.23%, 2.76%, 1.65%, 2.75%, and 35.91% of subgingival samples, respectively. OM was diagnosed in 13 patients. The presence of HHV-7 in C1 (oral mucosa: p = 0.032) and C2 (supragingival: p = 0.009; subgingival: p = 0.002) was significantly increased in patients who developed OM, and patients exhibiting HHV-7 shedding in the oral cavity were 3.32-fold more likely to develop OM. Patients who developed OM showed higher HHV-7 shedding in the oral cavity at nadir (immediately prior to OM development), suggesting modifications to the inflammatory microenvironment. HHV-7 may be involved in oral dysbiosis in HSCT-related OM; enhanced understanding of its role in the pathogenesis of OM may lead to the development of strategies for managing and preventing this common side effect of alloHSCT.

Objectives To characterise the oral shedding of herpes viruses in patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) and investigate its relationship with clinical outcomes. Materials and methods Polymerase chain reaction and enzymatic digestion were performed to identify the oral shedding of the members of the Herpesviridae family in 31 patients. The samples were collected from the oral cavity at five timestamps. Results The presence of each herpesvirus in the oral cavity was observed in 3.2%, 12.9%, 19.3%, 32.2%, 54.8%, and 93.5% patients for human herpesvirus (HHV)-6A, herpes simplex virus-1, HHV-6B, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and HHV-7, respectively. Oral shedding of herpes virus was not uncommon after alloHSCT. There was a statistically significant association between the EBV and CMV oral shedding at C1 and the cumulative incidence of acute graft versus host disease (aGVHD). The results suggested that the presence of HSV-1 at C2 was related to a relapse. The HHV-7 oral shedding at C2 suggests a possible link between relapse, progression-free survival, and overall survival of the patients. Conclusions Patients who developed aGVHD showed higher CMV and EBV shedding in the oral cavity at aplasia, suggesting modifications to the pattern of immune cell response and inflammatory microenvironment.

Background: Intestinal microbiota (IM) diversity and composition regulates host immunity and affects outcomes after allogeneic stem cell transplantation (allo-HSCT). Methods: We evaluated how the oral mucosa microbiota (OM) impacts 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, at aplasia, and at engraftment. We analyzed the associations of OM diversity and composition with allo-HSCT outcomes. Results: Higher OM diversity at preconditioning was associated with a lower risk of relapse in 3 years (33% versus 68%, respectively; P = 0.04). Dominance (relative abundance ≥30%) by a single genus at preconditioning was associated with a higher risk of relapse (63% versus 36%, respectively; P = 0.04), worse progression-free survival (PFS; 19% versus 55%, respectively; P = 0.01), and poorer overall survival (OS) at 3 years (38% versus 81%, respectively; P= 0.02). Conclusion: The presence of Solobacterium at preconditioning was associated with a lower risk of relapse (9% versus 56%, respectively; P = 0.04). This is the first study to address the relationship between OM and clinical outcomes after allo-HSCT.

The Numb Chin Syndrome (NCS) is defined as facial and oral numbness restricted to the mental nerve’s distribution involving the lower lip, skin of the chin, or gingiva of the lower anterior teeth. Hypoesthesia can occur unilaterally or bilaterally. Although this syndrome is rare, its importance is related to the fact that it represents the clinical manifestations of malignant diseases. Breast cancer and non-Hodgkin lymphoma are the most common cause of NCS. The patient, a 58-year-old woman, treated for a Burkitt Lymphoma (BL) nine years ago, described a two-week history of change in sensitivity and pain in the chin region, without relief with the use of analgesics. She had no headache, speech disturbance, dysphagia, visual disturbance, or other neurological symptoms. No surgical intervention has been performed recently. The intraoral examination revealed a healthy oral mucosa and a small area adjacent to the right mental nerve region that was uncomfortable to palpation. No changes were found in the bone trabeculae at cone-beam computed tomography. The contrasted magnetic resonance features made it possible to identify a change in the mandibular body extending to the entire right side, coinciding with the patient’s complaint, indicating a probable mandibular medullary invasion. The patient was submitted to a biopsy to rule out a possible recurrence of BL. The microscopic findings were consistent with the diagnosis of BL. The present report described a very unusual presentation of late recurrent BL nine years after the first treatment, which manifested as an NCS.

Oral positioning radiotherapy stents are devices that protect healthy structures adjacent to the target volume of head and neck radiotherapy treatment, leading to reduced acute and chronic side effects. This study describes a digital workflow to produce an oral positioning radiotherapy stent and analyze its efficacy by measuring dosimetric variations with and without this stent. An oral positioning radiotherapy stent was created according to a digital workflow that included intraoral scanning, digital design, and 3D printing for a patient with squamous cell carcinoma of the tongue. The patient underwent computed tomography to evaluate radiotherapy treatment by intensity-modulated radiation therapy with and without the use of the 3D-printed oral stent. The use of a 3D-printed oral positioning radiotherapy stent is a feasible and reproducible technique that reduced the planning target volume and radiation doses delivered to the hard palate, right parotid gland, and left parotid gland by 42%, 21%, and 8.5%, respectively.

Leukemic cells are rarely present in the oral cavity, and there are very few reports regarding such cases. However, we identified some reports of leukemic cells infiltrating tissues in the oral cavity, including gingival involvement. Recurrent painful oral ulcerations and prominent generalized periodontal destruction are the most common oral features of neutrophil disorders, and they may even be the initial symptoms of the disease. The ulcers may affect any part of the oral mucosa, including the tongue and palate. The objective of this report is to describe and discuss a case of myeloid sarcoma in the oral cavity of a 48-year-old male patient.

Objective The aim of this sub-analysis was to highlight the MASCC/ISOO clinical practice guidelines for the management of oral mucositis (OM) in pediatric patients and to present unique considerations in this patient population. Methods This sub-analysis of the pediatric patient population is based on the systematic review conducted by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISSO) published in 2019/2020. Studies were scored and assigned a level of evidence based on previously published criteria. Data regarding adverse effects and compliance was collected from the original publications. Results A total of 45 papers were included and assessed in this sub-analysis, including 21 randomized controlled trials (RCTs). Chewing gum was demonstrated to be not effective in preventing OM in pediatric cancer patients in 2 RCTs. The efficacy of all other interventions could not be determined based on the available literature. Conclusion There is limited or conflicting evidence about interventions for the management of OM in pediatric cancer patients, except for chewing gum which was ineffective for prevention. Therefore, currently, data from adult studies may need to be extrapolated for the management of pediatric patients. Honey and photobiomodulation therapy in this patient population had encouraging potential. Implementation of a basic oral care protocol is advised amid lack of high level of evidence studies.

Background: The intestinal microbiota (IM) has been shown to play a vital role in regulating host immunity. In allogeneic hematologic stem cell transplantation (allo- HSCT), IM disruption also seems to affect the incidence of graft versus host disease (GVHD), overall survival (OS), and underlying disease relapse. The oral microbiota (OM) directly influences human health. Changes in the OM in patients undergoing allo- HSCT are known to be associated with respiratory signs and symptoms and oral mucositis; however, no correlation between OM and allo-HSCT outcomes have been reported to date. Objectives: The study aims to evaluate whether the OM modulated the host systemic immune response and outcomes in patients who underwent allo-HSCT. Patients and Methods: We collected samples from the oral mucosa of patients who underwent allo-HSCT between January 2016 and April 2018. Samples were collected at three time points: before the conditioning regimen, at aplasia, and at engraftment. DNA extraction: Bacterial cells were recovered from oral mucosa swabs through vortexing in TE buffer supplemented with 6 μL PureLink RNAse A. DNA was extracted using a QIAamp DNA Blood Mini Kit and stored at -80°C. 16S rRNA amplicon sequencing: 16S rRNA amplicon sequencing, 12.5ng DNA and prevalidated primers were used to amplify 16S rRNA hypervariable regions V3-V4. Amplicons were sequenced as described elsewhere on an Illumina MiSeq platform. Results: We analyzed 30 patients. The most common diagnosis was acute leukemia (60%), most patients received reduced-intensity conditioning (60%). Donors were haploidentical in 33%, matched sibling in 30%, matched unrelated in 30%, and mismatched unrelated in 7%. Peripheral blood was the most common stem cell source (67%). We stratified patients into low or high diversity at each collection time. A swimmer plot was used to illustrate these correlations at preconditioning (Fig. 1). High OM diversity at preconditioning was associated with a lower risk of relapse at 3 years when compared with low diversity (33% versus 68%, respectively, P = 0.04; Fig. 2). The presence of dominance by any genus at preconditioning was also associated with an increased risk of relapse at 3 years when compared with the absence of dominance (63% versus 36%, respectively, P = 0.03; Fig. 3). The presence of dominance by any genus at preconditioning was also associated with inferior PFS (19% versus 55%, respectively, P = 0.01; Fig. 4) and OS (38% versus 81%, respectively, P = 0.02; Fig. 5). After adjusting analyses for the DRI, there was a trend toward a higher risk of relapse/progression in those with low OM diversity (HR = 0.30, 95% CI: 0.08-1.09, P = 0.07), and bacterial dominance of any genus remained significantly associated with the risk of relapse (HR = 4.19, 95% CI: 1.25-14.1, P = 0.02) and worse PFS (HR = 4.14, 95% CI: 1.15-14.89, P = 0.03); there was a tendency for bacterial dominance of any genus to also be related to worse OS (HR = 4.12, 95% CI: 0.89-19.13, P = 0.07). To further evaluate the association between preconditioning OM and transplant outcomes, we analyzed whether non-core genera were associated with a higher risk of relapse. Of the 18 genera that matched the selection criteria tested in univariate analysis for relapse (Fig. 6), only Solobacterium was significantly associated with lower relapse risk (9% versus 56%, respectively, P = 0.04; Fig. 7), and this association remained significant after adjusting for DRI (HR = 0.20, 95% CI: 0.06-0.67, P = 0.01). Conclusion: High OM diversity and presence of dominance by any genus (more importantly Solobacterium)at preconditioning was associated with a lower risk of relapse. Prospective trials and validation cohorts are needed to confirm these findings and to test whether early interventions to correct OM dysbiosis or more aggressive strategies to prevent relapse in OM dysbiotic patients, such as early immunosuppression withdrawal, maintenance therapy, or prophylactic donor lymphocyte infusions, could improve allo-HSCT outcomes. Disclosures No relevant conflicts of interest to declare.

Oncologic patients undergoing chemotherapy and during the immunosuppressive phase are more susceptible to the reactivation of viral infections from the family Herpesviridae. Oral ulcerations related to cytomegalovirus (CMV) are uncommon and rarely described in patients with solid tumors. A 65-year-old male patient under oncologic treatment because of a high-grade astrocytoma was admitted to our service complaining of pain on the right lateral border of the tongue with 5 weeks of evolution, without clinical improvement with topical corticosteroid use. Physical examination revealed an oval ulcerated lesion approximately 0.5 cm in diameter with necrotic center. An excisional biopsy was performed, and results showed areas of superficial ulceration, a chorion with lymphoplasmacytic inflammatory infiltrate, and presence of occasional endothelial and stromal cells with massive cytoplasm and nuclear inclusions with cytopathic effect by cytomegalovirus, confirmed by immunohistochemistry. The lesion completed healed after 15 days, and no further treatment was necessary.

To assess the current knowledge regarding medication-related osteonecrosis of the jaw (MRONJ); the adverse effects of anti-resorptive (AR) and anti-angiogenic (AA) drugs; strategies for MRONJ prevention and treatment; and perception of the dentist’s role in assisting patients who use these drugs among physicians, dentists, and nurses. Using questionnaires, the current knowledge of MRONJ was assessed among dentists, physicians, and nurses, who were divided into group I, which included specialties that directly assist cancer patients, and group II, which included other specialties. The questionnaires assessed the characteristics of the health professionals, training time, and specialties; their knowledge of AR and AA drugs; and their knowledge of MRONJ. A total of 1370 health professionals participated in the study, including 1032 dentists, 239 physicians, and 99 nurses. Among dentists and physicians, the training time (p = 0.036 and p

Diffuse large b-cell non-Hodgkin lymphoma is an aggressive neoplasm, uncommon in the oral cavity and characterized by morphologic, immunophenotypic, and molecular heterogeneity. In this case report, a 67-year-old, obese, white, male patient reported a recent loss of 10 kg of weight in the last 5 months and instability of the maxillary denture. On intraoral examination, it was observed a nodule with inaccurate limits, discreetly purplish coloration in the right hard palate. An incisional biopsy of the lesion on the palate was performed and morphologic findings and immunohistochemical panel with immunoreactivity for ACL, CD20, and ki67 (> 90%); BCL2, CD3, and MUM1 led us to the diagnosis of diffuse large b-cell lymphoma. The patient was submitted to chemotherapy with 6 cycles of R-CHOP with systemic control of the disease and is under medical follow-up.

This study aimed to characterize the oral shedding of virus of the Herpesviridae family at 3 different sites in the oral cavity (oral mucosa, supragingival, and subgingival) of adult patients who underwent allogeneic hematopoietic stem cell transplantation to investigate its potential relationship with oral mucositis (OM). We characterized viral excretion and OM development in 31 consecutive adult patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT). The samples were collected in all locations at 5 time points during follow-up (C1-C5), adding 2 more collections in patients who developed ulcerative OM—beginning and resolution of the lesion (M1-M2). Polymerase chain reaction (PCR) and enzymatic digestion were used to identify different virus of the Herpesviridae family. Herpes simplex virus (HSV)-1, Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus (HHV)-6 A, HHV-6 B, and HHV-7 were detected in 4.97%, 16.02%, 4.41%, 2.20%, 3.31%, and 68% of samples in the oral mucosa; in 4.41%, 16.57%, 5.52%, 2.20%, 5.52%, and 63.53% of samples in the supragingival tissue, and in 4.41%, 18.23%, 2.76%, 1.65%, 2.75%, and 35.91% samples in the subgingival tissue, respectively. The presence of HHV-7 at C2 was significantly increased in patients who developed OM compared with those who did not. The patients who develop OM presented 3.32 times more likely HHV-7 shedding in the oral cavity, suggesting that this disorder might be related to HHV-7 presence.

Soft tissue changes in the oral cavity associated with leukemia such as oral bleeding, mucosal petechiae, mucosal ulceration, and infection are commonly described. Leukemic cells may infiltrate the oral cavity as leukemic infiltration to the gingival tissue but rarely involve other areas. The objective of this report is to describe a case of leukemic infiltration (myeloid sarcoma) in the oral cavity. A 48-year-old male patient was admitted to our service complaining of malaise, fever, and gingival bleeding. At clinical examination, beyond the gingival bleeding involvement, a rare clinical presentation characterized by the development of a persistent ulceration on the lateral border of the tongue was observed, which biopsy results showed the presence of infiltration of immature cells with scarce cytoplasm and hyperchromatic nucleus. Blood test revealed 119.000/mm3 leukocytes, whereas the myelogram demonstrated 87% of blasts carrying a myeloid differentiation confirmed by flow cytometry positivity confirming the diagnosis of acute myeloid leukemia.

Oncohematologic patients after hematopoietic stem cell transplantation (HSCT) are at risk of developing opportunistic oral infections and malignant neoplasms. The objective of this report is to describe 3 diagnostic challenges of oral lesions that affected the same posttransplant patient: an atypical herpes simplex virus lesion in ventral tongue, a gingival actinomycosis infection, and later a leukemic infiltration on the soft palate. A 57-year-old female patient first complained of a progressive and painful sublingual nodule for 3 days at D+35 of HSCT by extranodal natural killer/T-cell lymphoma, and final diagnoses were atypical herpes simplex virus 1 and 2 infection. Two months later, ulcerated lesions in the vestibular and palatal gingival margin of the left upper molars were noted, with final diagnosis of Actinomyces sp infection. Fifteen days later, an erythematous lesion with necrotic center was observed in the soft palate, and the diagnosis was palatal infiltration by extranodal natural killer/T-cell lymphoma.

Late recurrence of Burkitt lymphoma (BL) is rare, especially in the oral region. A 58-year-old woman, treated 9 years ago for a BL in the tonsil, described a 2-week history of sensitive alteration and pain in the chin region. Physical examination revealed a complete paresthesia involving the bilateral chin and lower lip. No other alterations were found at cone beam computed tomography and at clinical examination. Through magnetic resonance exam, it was possible to identify an alteration in the mandibular body extending to the entire right side. An intraosseous biopsy was performed and the immunohistochemical profile revealed positivity to BCL-6, CD-10, CD-20, C-MYC, and PAX-5 demonstrating the presence of a mature B cell lineage, consistent with the diagnosis of BL. The in situ hybridization was negative for Epstein-Barr virus. The rescue chemotherapy treatment was initiated and the patient is under follow-up care.