Topical Corticosteroids a Viable Solution for Oral Graft versus Host Disease? A Systematic Insight on Randomized Clinical Trials

Background and Objectives: This research attempts to provide a clear view of the literature on randomized clinical trials (RCTs) concerning the efficacy of topical dexamethasone, clobetasol and budesonide in oral graft versus host disease (GVHD). Materials and Methods: An electronic search of the PubMed, Web of Science and Scopus databases was carried out for eligible RCTs. Studies were included if they had adult patients with oral GVHD treatment with topical corticosteroids, and if the RCT study was published in English. The Cochrane Risk of Bias tool was used to assess the quality of these studies. Overall, three RCTs were included (an Open, Randomized, Multicenter Trial; a Randomized Double-Blind Clinical Trial; and an Open-Label Phase II Randomized Trial). Results: The trials involved 76 patients, of which 44 patients received topical dexamethasone, 14 patients received topical clobetasol and 18 patients received topical budesonide. Topical agents were most frequently used when oral tissues were the sole site of involvement. It appears that the best overall response is present for budesonide with no difference between the four arms, followed by clobetasol, and then by dexamethasone. The limitation of the current study is mainly represented by the fact that overall response was derived in two of the studies from other parameters. Moreover, both budesonide and clobetasol were used in only one study each, while two assessed dexamethasone. Conclusions: Based on the clinical trials, all three agents seem to be effective in treating oral GVHD and had a satisfactory safety profile. There is still a need for assessing high quality RCTs to assess the efficacy of these therapies on a larger cohort.

The Salivary Microbiome and Oral Cancer Risk: A Pilot Study in Fanconi Anemia

Fanconi anemia (FA) is a rare genetic disease characterized by chromosomal instability and impaired DNA damage repair. FA patients develop oral squamous cell carcinoma (OSCC) earlier and more frequently than the general population, especially after hematopoietic stem cell transplantation (HSCT). Although evidence of an etiological role of the local microbiome and carcinogenesis has been mounting, no information exists regarding the oral microbiome of FA patients. The aim of this study was to explore the salivary microbiome of 61 FA patients regarding their oral health status and OSCC risk factors. After answering a questionnaire and receiving clinical examination, saliva samples were collected and analyzed using 16S rRNA sequencing of the V3-V4 hypervariable region. The microbial profiles associated with medical and clinical parameters were analyzed using general linear models. Patients were young (mean age, 22 y) and most had received HSCT ( n = 53). The most abundant phyla were Firmicutes [mean relative abundance (SD), 42.1% (10.1%)] and Bacteroidetes [(25.4% (11.4%)]. A history of graft-versus-host disease (GVHD) ( n = 27) was associated with higher proportions of Firmicutes (43.8% × 38.5%, P = 0.05). High levels of gingival bleeding were associated with the genera Prevotella (22.25% × 20%), Streptococcus (19.83% × 17.61%), Porphyromonas (3.63% × 1.42%, P = 0.03), Treponema (1.02% × 0.28%, P = 0.009), Parvimonas (0.28% × 0.07%, P = 0.02) and Dialister (0.27% × 0.10%, P = 0.04). Finally, participants transplanted over 11 y ago showed the highest levels of Streptococcus (18.4%), Haemophilus (12.7%) and Neisseria (6.8%). In conclusion, FA patients that showed poor oral hygiene harbored higher proportions of the genera of bacteria compatible with gingival disease. Specific microbial differences were associated with a history of oral GVHD and a history of oral mucositis.

Topical Tacrolimus and Periodontal Therapy in the Management of a Case of Oral Chronic GVHD Characterized by Specific Gingival Localization

Background. Chronic graft versus host disease (cGVHD) is a complication following bone marrow transplantation. The oral lesions are difficult to control with a systemic pharmacological therapy.Case Description. A 63-year-old female patient, who underwent an allogeniec transplantation for acute myeloid leukemia, developed a chronic oral and cutaneous GVHD. The patient was treated with topical tacrolimus 0.1%, twice daily for two months, and underwent a protocol of oral hygiene characterized by 3 appointments of scaling, root planning, and daily oral hygiene instructions. The patient showed marked resolution of gingival lesions and a significant improvement of related pain and gingival inflammatory indexes.Clinical Implications. This case report suggests that treatment with topical tacrolimus and professional oral hygiene may be helpful in the management of chronic oral GVHD with severe gingival involvement.

Frequent Genomic Alterations in Epithelium Measured by Microsatellite Instability Following Allogeneic Hematopoietic Cell Transplantation in Humans.

While typically found in cancers, frameshift mutations in microsatellites have also been detected in chronically inflamed tissues. Allogeneic hematopoietic cell transplantation (HCT) may potentially produce chronic tissue stress through graft-versus-host reactions. Therefore, we examined non-neoplastic epithelial tissues (colon, buccal) obtained 1 to 5061 days after human allogeneic HCT for the presence of genomic alterations at three tetranucleotide (SEE33, THO-1, D14S120) and three mononucleotide (ZP3, BAT26, SRY) microsatellite loci. All except two colon biopsies examined had histological signs of GvHD. No signs of mucositis or oral GvHD were present at the time of buccal sampling. Novel bands indicative of microsatellite instability (MSI) were detected in laser-capture microdissected (LCM) colonic crypts in 12 out of 16 patients (75%) and in buccal smears in 10 out of 24 (42%) allografted patients. In contrast to the allografted patients, no MSI was found in the LCM crypts obtained from 4 patients after intensive chemotherapy or from 7 control subjects with no history of either colon malignancy or chemotherapy, and in the buccal smears obtained from 8 patients after autologous HCT or from 9 healthy controls. MSI was found only at tetranucleotide markers but not at mononucleotides. There was no statistical correlation between the presence of MSI in colon and the underlying disease, the previous history of multiple (>=3) intensive chemotherapies before transplantation, the type of preparative regimen for HCT, the overall GVHD grade any time before sampling or the GvHD stage in colon at sampling. The MSI found in colon, which was often affected by graft-versus-host disease, was not due to loss of expression or nitrosylation of DNA repair proteins (MLH1, MSH2, MSH3, APE-1, XPA). There was no significant association between MSI in the buccal mucosa and patient age, gender, disease, type of conditioning, history of oral GvHD or overall GvHD occured at any point before buccal sampling. Interestingly, we found a significant association between the time of buccal sampling after transplantation and the presence of MSI (p=0.008). MSI was also found in three post-transplant squamous cell cancers examined. The frameshift alterations found in post-transplant tumors often differed from those in the associated non-malignant tissues. Our data show that genomic alterations in epithelium regularly occur after allogeneic HCT. This previously unacknowledged genomic instability after allogeneic HCT may be implicated in the evolution of post-transplant diseases, including secondary cancer.

Graft-vs.-Host Disease

Bone marrow transplantation (BMT) is the treatment of choice for many leukemias, lymphomas, bone marrow failure syndromes, and immundeficiency disorders, and is the primary and salvage therapy for many solid malignancies. With the establishment of national and international marrow banks, unrelated allogeneic BMT is being performed with increasing frequency. Graft-vs.-host disease (GVHD) remains a major complication of allogeneic BMT, occurring in 25% to 70% of patients despite GVHD prophylaxis, with the skin, gastro-intestinal tract, and liver as primary target organs. Oral findings are seen in both acute and chronic GVHD. In acute GVHD, the oral lesions are often painful, erythematous, ulcerative, and desquamative. In chronic GVHD, they are lichenoid with associated erythema and ulcerations; additionally, they may be associated with a sicca syndrome characterized by xerostomia and progressive salivary gland atrophy. General principles of BMT are discussed, as are systemic and local therapeutic options for oral GVHD.