Salivary BPIFA proteins are altered in patients undergoing hematopoietic cell transplantation.

OBJECTIVE: The aim of this study was to evaluate the expression of BPIFA proteins in the saliva and salivary glands of hematopoietic cell transplant (HCT) patients. MATERIAL AND METHODS: This longitudinal study included patients who had undergone autologous HCT (auto-HCT) and allogeneic HCT (allo-HCT), and unstimulated saliva was collected at three time points, with a fourth collection at oral chronic graft-versus-host disease (cGVHD) onset. BPIFA expression was analysed by Western blotting in saliva and immunostaining in the minor salivary glands of cGVHD patients. RESULTS: Auto-HCT patients showed increased levels of BPIFA1 (p = .021) and BPIFA2 at D+7 (p = .040), whereas allo-HCT group demonstrated decreased expression of BPIFA2 at D+8 (p = .002) and at D+80 (p = .001) and a significant association between BPIFA2 low levels and hyposalivation was observed (p = .02). BPIFA2 was significantly lower in the cGVHD patients when compared to baseline (p = .04). CONCLUSIONS: The results of this study show distinct pattern of expression of BPIF proteins in both auto-HCT and allo-HCT recipients with decreased levels of BPIFA2 during hyposalivation and cGVHD. Further studies are necessary to elucidate these proteins mechanisms and their clinical implications in these groups of patients.

MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy.

BACKGROUND: Mucositis is a significant toxicity of cancer therapy with numerous systemic sequelae. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for the management of mucositis. METHODS: The literature was reviewed systematically to identify interventions for mucositis. Studies were rated according to the presence of major and minor flaws according to previously published criteria. The body of evidence for each intervention and in each treatment setting was assigned a level of evidence based on previously published criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, suggestion, or no guideline possible. RESULTS: The guideline covers evidence from 1197 publications related to oral or gastrointestinal mucositis. Thirteen new guidelines were developed for or against the use of various interventions in specific treatment settings, and 11 previous guidelines were confirmed after aa review of new evidence. Thirteen previously established guidelines were carried over because there was no new evidence for these interventions. CONCLUSIONS: The updated MASCC/ISOO Clinical Practice Guidelines for mucositis provide professional health caregivers with a clinical setting-specific, evidence-based tool to help with the management of mucositis in patients who have cancer.

A systematic review of oral herpetic viral infections in cancer patients: commonly used outcome measures and interventions.

PURPOSE: To review the literature for outcome measures for oral viral infections in cancer patients. A secondary aim was to update the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) clinical practice guidelines for the management of oral viral infections in cancer patients. METHODS: Databases were searched for articles published in the English language, 1981-2013. Studies that met the eligibility criteria were reviewed systematically. The data about the outcome measures were classified according to the aim of the study: prevention, treatment, or non-interventional. The results of interventional studies were compared to the 2010 MASCC/ISOO publication. RESULTS: Multiple clinical and laboratory tests were used to measure oral viral infections, with great variability between studies. Most of the studies were about Herpes Simplex Virus (HSV). The outcome measure that was most commonly used was the presence of HSV infection diagnosed based on a combination of suggestive clinical presentation with a positive laboratory result. HSV culture was the most commonly reported laboratory outcome measure. Acyclovir and valacyclovir were consistently reported to be efficacious in the management of oral herpetic infections. No new data on the quality of life and economic aspects was found. CONCLUSIONS: Considering the variability in outcome measures reported to assess oral herpetic infections the researcher should select carefully the appropriate measures based on the objective of the study. Acyclovir and valacyclovir are effective in the management of oral herpetic infections in patients receiving treatment for cancer. Studies on newer anti-viral drugs may be useful to address the issue of anti-viral resistance.

Tooth alterations in areas of bisphosphonate-induced osteonecrosis.

OBJECTIVE: Osteonecrosis of the jaw is a potential side effect when using bisphosphonates. Most studies on the effects of bisphosphonates on teeth have been conducted in vitro or in animal models of tooth development. Therefore, the aim of this study was to describe alterations found in human teeth extracted from areas of bisphosphonate-induced osteonecrosis. MATERIALS AND METHODS: Using a retrospective study design, 16 teeth from 13 patients were extracted from areas of bisphosphonate-induced osteonecrosis during surgical debridement. The specimens were decalcified and embedded in paraffin. A series of 5-µm sections were prepared, stained with hematoxylin and eosin (H&E) and observed under a light microscope. RESULTS: The majority of the patients were female (53.85 %), with a mean age of 60.23 ± 13.18 years. Zoledronate (IV) was the most common bisphosphonate used (92.3 %), over a mean period of 2 years. The commonest alteration observed was hypercementosis (87.5 %), followed by pulpar necrosis (81.25 %), pulp stones attached to the dentine and loose pulp stones in the pulp chamber and root canals in addition to linear calcifications (68.75 %), dentinoid/osteoid material formation (18.75 %), and dental ankylosis (6.25 %). CONCLUSIONS: Patients undergoing bisphosphonate therapy present diverse tooth alterations, which should be closely monitored by clinicians to prevent complications. CLINICAL RELEVANCE: It is paramount that the teeth involved in oral lesions are always examined. Attention should be drawn to the need to establish preventive measures, in terms of dental treatment, for patients prior to starting bisphosphonate therapy.

Randomized double-blind clinical trial comparing clobetasol and dexamethasone for the topical treatment of symptomatic oral chronic graft-versus-host disease.

Patients who undergo allogeneic stem cell transplantation frequently develop an immunologic disease caused by the reactivation of the graft to the host tissues. This disease is called graft-versus-host disease (GVHD) and it is usually a systemic disorder. In a large proportion of cases, oral disorders that are related to a chronic phase of GVHD (cGVHD) occur, and their treatment involves the use of topical immunosuppressive drugs. Several medications have been studied for this purpose, but only a small number of clinical trials have been published. The present study is a randomized, double-blind clinical trial that compares topical clobetasol and dexamethasone for the treatment of symptomatic oral cGVHD. Patients were randomly assigned to treatment with clobetasol propionate .05% or dexamethasone .1 mg/mL for 28 days. In both arms, nystatin 100,000 IU/mL was administered with the corticosteroid. Oral lesions were evaluated by the modified oral mucositis rating scale (mOMRS) and symptoms were registered using a visual analogue scale. Thirty-five patients were recruited, and 32 patients were randomized into the study groups: 18 patients (56.3%) to the dexamethasone group and 14 patients (43.8%) to the clobetasol group. The use of clobetasol resulted in a significant reduction in mOMRS total score (P = .04) and in the score for ulcers (P = .03). In both groups, there was significant symptomatic improvement but the response was significantly greater in the clobetasol group (P = .02). In conclusion, clobetasol was significantly more effective than dexamethasone for the amelioration of symptoms and clinical aspects of oral lesions in cGVHD.

Magnetic resonance imaging evaluation of the disc morphology of temporomandibular joint in patients with severe hemophilia.

OBJECTIVES: This study aimed to assess the morphological differences in the articular disc (AD) between hemophilic patients and healthy individuals of the control group for further association with signs and symptoms. METHODS: Fourteen severe hemophilic patients had their AD evaluated by magnetic resonance imaging (MRI). The morphological findings were compared to those of a control group consisting of 14 healthy individuals. MRI was used to evaluate all the components of the temporomandibular (TMJ), including the AD, resulting in sequential T1-weighted parasagittal images. All the images were acquired with teeth in maximum intercuspation position. RESULTS: Morphological alterations showed significant statistical differences (P-value = 0.0068), whereas no statistical differences were found in the other variables, including TMJ pain, headache, bruxism and mouth opening limitation. In the group of non-hemophilic individuals, only two (14.29%) presented AD with non-biconcave features, whereas in the group of hemophilic patients, nine (64.29%) presented AD with a morphology other than biconcave. CONCLUSIONS: In patients with severe hemophilia, there seems to be a pattern of morphological alterations in the articular disc over time. The standard biconcave morphology of AD tends to change into other ones, particularly biplanar, hemiconvex and folded.

Brazilian dental consensus on dental management in hematopoietic stem cell transplantation - Part I - pre-HSCT.

The oral involvement in the Hematopoietic Stem Cell Transplantation is well described in the literature. The goal of the dental treatment and management of the oral lesions related to the HSCT is to reduce the harm caused by preexisting oral infection or even the worsening of oral acute/chronic GVHD and late effects. The aim of this guideline was to discuss the dental management of patients subjected to HSCT, considering three phases of the HSCT: pre-HSCT, acute phase, and late phase. The literature published from 2010 to 2020 was reviewed in order to identify dental interventions in this patient population. The selected papers were divided into three groups: pre-HSCT, acute and late, and were reviewed by the SBTMO Dental Committee's members. When necessary, an expertise opinion was considered for better translating the guideline recommendations to our population dental characteristics. This manuscript focused on the pre-HSCT dental management. The objective of the pre-HSCT dental management is to identify possible dental situations that can worsening during the acute phase after the HSCT. Each guideline recommendations were made considering the Dentistry Specialties. The clinical consensus on dental management prior to HSCT provides professional health caregivers with clinical setting-specific information to help with the management of dental problems in patients to be subjected to HSCT.

Oral involvement of chronic graft-versus-host disease in hematopoietic stem cell transplant recipients.

Oral manifestations are common in patients who are diagnosed with chronic graft-versus-host-disease (cGVHD). These manifestations can present as oral mucosal lesions, salivary gland dysfunction, or reduction of the mouth opening due to cutaneous sclerosis. Although several studies have reported the prevalence of oral involvement in cGVHD, few have reported details of different types and severity of oral lesions of cGVHD, according to the NIH. Furthermore, the authors are aware of only one published study concerning oral manifestations of cGVHD in Brazil. The purpose of this study was to evaluate the prevalence and severity of oral involvement of cGVHD. Oral evaluation of hematopoietic stem cell transplant (HSCT) recipients was conducted on 22 patients (12 men and 10 women) from December 2007 to May 2009. The following categories were assessed: Age, gender, underlying disease, time postHSCT, history of GVHD, therapy for GVHD, oral lesions, xerostomia, resting salivary flow rate, and mouth opening. Oral lesions were classified according to NIH criteria, and the results were submitted to a descriptive analysis. According to the NIH, patients presented diagnostic (40.9%), distinctive (31.9%), and common (9.1%) features of oral cGVHD. Oral involvement of cGVHD was identified in 81.8% of patients, 68.2% as mucosal lesions and 59.1% as salivary gland dysfunction. Reduced mouth opening was observed in 12 patients (80%), with one case associated with cutaneous sclerosis. Oral involvement was frequent in these patients; for many, it was the first clinical manifestation of cGVHD.

Perforin and granzyme B involvement in oral lesions of lichen planus and chronic GVHD.

BACKGROUND: Oral lesions of lichen planus and chronic graft-vs.-host disease (cGVHD) have similar clinical and histological features, but distinct etiology. Apoptosis induced by cytotoxic T lymphocyte has been proposed as a mechanism of keratinocytes death. Cytotoxicity can be mediated by granules containing granzyme B and perforin. Since common features can reflect similarities in immunological mechanisms, we studied the role of those molecules in both diseases. METHODS: We analyzed 29 cases of oral lichen planus and 27 of oral cGVHD. The sections were studied on H&E, perforin and granzyme B staining. RESULTS: The total means (epithelium plus connective tissue number) of the granzyme B- and perforin-positive cells were significantly higher in cGVHD than in oral lichen planus lesions (P<0.05). Also, it was found that the higher the number of perforin+ cells, the higher the number of granzyme-B+ cells in the epithelium and in the connective tissue for both groups (P < 0.05). In oral lichen planus, the number of single apoptotic bodies had a positive correlation with connective tissue granzyme immunostaining and a negative correlation with perforin (P<0.01). On the contrary, in oral cGVHD, the number of apoptotic body clusters presented a positive correlation with connective tissue perforin (P<0.01). CONCLUSIONS: Our findings indicate that apoptosis in oral lichen planus seems to be correlated with granzyme B release, while in oral cGVHD, perforin seems to be more important. Although these diseases present clinical and histological similarities, subtle differences seem to exist in their pathogenetic mechanisms.

Clinical and histomorphometric evaluation of extraction sockets treated with an autologous bone marrow graft.

PURPOSE: The aim of this study was to evaluate the potential of an autologous bone marrow graft in preserving the alveolar ridges following tooth extraction. MATERIALS: Thirteen patients requiring extractions of 30 upper anterior teeth were enrolled in this study. They were randomized into two groups: seven patients with 15 teeth to be extracted in the test group and six patients with 15 teeth to be extracted in the control group. Hematologists collected 5 ml of bone marrow from the iliac crest of the patients in the test group immediately before the extractions. Following tooth extraction and elevation of a buccal full-thickness flap, titanium screws were positioned throughout the buccal to the lingual plate and were used as reference points for measurement purposes. The sockets were grafted with an autologous bone marrow in the test sites and nothing was grafted in the control sites. After 6 months, the sites were re-opened and bone loss measurements for thickness and height were taken. Additionally, before implant placement, bone cores were harvested and prepared for histologic and histomorphometric evaluation. RESULTS: The test group showed better results (P<0.05) in preserving alveolar ridges for thickness, with 1.14+/-0.87 mm (median 1) of bone loss, compared with the control group, which had 2.46+/-0.4 mm (median 2.5) of bone loss. The height of bone loss on the buccal plate was also greater in the control group than in the test group (P<0.05), 1.17+/-0.26 mm (median 1) and 0.62+0.51 (median 0.5), respectively. In five locations in the control group, expansion or bone grafting complementary procedures were required to install implants while these procedures were not required for any of the locations in the test group. The histomorphometric analysis showed similar amounts of mineralized bone in both the control and the test groups, 42.87+/-11.33% (median 43.75%) and 45.47+/-7.21% (median 45%), respectively. CONCLUSION: These findings suggest that the autologous bone marrow graft can contribute to alveolar bone repair after tooth extraction.

Skin and oral lesions associated to imatinib mesylate therapy.

INTRODUCTION: Imatinib mesylate is a tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML) throughout all the phases of the disease. In most cases, this drug is well tolerated; however, some cases experience side effects. RESULTS AND DISCUSSION: Skin rashes and oral lesions are uncommon and appear to be dose-dependent. The authors report two cases of CML Ph+ in chronic phase patients who presented skin and oral lesions probably induced by imatinib therapy.

Clinical Metabolomics Identifies Blood Serum Branched Chain Amino Acids as Potential Predictive Biomarkers for Chronic Graft vs. Host Disease.

The allogeneic hematopoietic stem cell transplantation procedure-the only curative therapy for many types of hematological cancers-is increasing, and graft vs. host disease (GVHD) is the main cause of morbidity and mortality after transplantation. Currently, GVHD diagnosis is clinically performed. Whereas, biomarker panels have been developed for acute GVHD (aGVHD), there is a lack of information about the chronic form (cGVHD). Using nuclear magnetic resonance (NMR) and gas chromatography coupled to time-of-flight (GC-TOF) mass spectrometry, this study prospectively evaluated the serum metabolome of 18 Brazilian patients who had undergone allogeneic hematopoietic stem cell transplantation (HSCT). We identified and quantified 63 metabolites and performed the metabolomic profile on day -10, day 0, day +10 and day +100, in reference to day of transplantation. Patients did not present aGVHD or cGVHD clinical symptoms at sampling times. From 18 patients analyzed, 6 developed cGVHD. The branched-chain amino acids (BCAAs) leucine and isoleucine were reduced and the sulfur-containing metabolite (cystine) was increased at day +10 and day +100. The area under receiver operating characteristics (ROC) curves was higher than 0.79. BCAA findings were validated by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in 49 North American patients at day +100; however, cystine findings were not statistically significant in this patient set. Our results highlight the importance of multi-temporal and multivariate biomarker panels for predicting and understanding cGVHD.

Oral graft-versus-host disease.

Hematopoietic cell transplantation is used to treat malignancies, hematologic and immune deficiency states, marrow failure syndromes, and autoimmune diseases. Graft-versus-host disease (GVHD) is a clinical syndrome seen following allogeneic transplantation where donorderived immunocompetent T cells and inflammatory responses attack host tissues. GVHD can cause significant morbidity and even result in mortality. The oral cavity is a frequently involved site with clinical changes resembling autoimmune collagen vascular diseases. Recognition, diagnosis, and monitoring of oral GVHD can help with diagnosis and grading of GVHD and judging responses to therapy. Topical and local management of symptomatic oral GVHD can reduce oral symptoms that can interfere with oral function and quality of life, and can reduce the need for more intensive immunosuppressive systemic therapies.

Brazilian dental consensus on dental management in hematopoietic stem cell transplantation− Part I− pre-HSCT

ABSTRACT The oral involvement in the Hematopoietic Stem Cell Transplantation is well described in the literature. The goal of the dental treatment and management of the oral lesions related to the HSCT is to reduce the harm caused by preexisting oral infection or even the worsening of oral acute/chronic GVHD and late effects. The aim of this guideline was to discuss the dental management of patients subjected to HSCT, considering three phases of the HSCT: pre-HSCT, acute phase, and late phase. The literature published from 2010 to 2020 was reviewed in order to identify dental interventions in this patient population. The selected papers were divided into three groups: pre-HSCT, acute and late, and were reviewed by the SBTMO Dental Committee's members. When necessary, an expertise opinion was considered for better translating the guideline recommendations to our population dental characteristics. This manuscript focused on the pre-HSCT dental management. The objective of the pre-HSCT dental management is to identify possible dental situations that On behalf of the Dental Committee of the Brazilian Society of Gene Therapy and Bone Marrow Transplantation (SBTMO) can worsening during the acute phase after the HSCT. Each guideline recommendations were made considering the Dentistry Specialties. The clinical consensus on dental management prior to HSCT provides professional health caregivers with clinical setting-specific information to help with the management of dental problems in patients to be subjected to HSCT.

Oral involvement in chronic graft versus host disease: a prospective study of 19 Brazilian patients.

Chronic graft versus host disease (cGVHD) is the most common late complication of allogeneic bone marrow transplantation. The oral cavity is the most common site of cGVHD involvement. This study sought to investigate the incidence of oral cGVHD, as well as the disease's impact on a patient's quality of life and the kind of lesions that resulted. Nineteen patients with cGVHD received a medical and dental evaluation; 18 (94.7%) had oral lesions. Nine patients (47.3%) demonstrated xerostomia and 6 (35.2%) demonstrated dysphagia. Six patients (35.2%) had a lichenoid clinical form of cGVHD in the oral cavity, 6 (35.2%) had an atrophic-ulcerative clinical form, 3 (17.6%) had a hyperceratotic clinical form, and 2 (10.5%) had mixed forms. The results demonstrated predominance of lichenoid and ulcerative-atrophic forms with similar incidence of these lesions. No factor that could contribute to the severity of cGVHD oral lesions was found.

Primary oral and perioral amyloidosis associated with multiple myeloma.

Three years after being diagnosed with multiple myeloma, a patient sought treatment for swelling on the floor of the mouth, associated with hardening of the soft tissues on the right perioral region, loss of facial expression, and difficulty opening his mouth. The patient reported improvement following an incisional biopsy for microscopic diagnosis. Eighteen months later, the patient showed no clinical alterations.

Foreign Body in Jugal Mucosa.

Introduction Foreign body in the oral cavity may be asymptomatic for long time and only sometimes it can lead to a typical granulomatous foreign body reaction. Some patients may complain of oral pain and present signs of inflammation with purulent discharge. A granuloma is a distinct, compact microscopic structure composed of epithelioid-shaped macrophages typically surrounded by a rim of lymphocytes and filled with fibroblasts and collagen. Nowadays, the increase of cosmetic invasive procedures such as injection of prosthetic materials in lips and cheeks may lead to unusual forms of inflammatory granulomas. Objectives Describe an unusual presentation of a foreign body reaction in the buccal mucosa due to previous injection of cosmetic agent. Resumed Report A 74-year-old woman was referred to the Department of Otorhinolaryngology, Head and Neck Surgery to investigate the presence of multiple painless, bilateral nodules in the buccal mucosa, with progressive growth observed during the previous 2 months. The histologic results showed a foreign body inflammatory reaction. Conclusion Oral granulomatosis lesions represent a challenging diagnosis for clinicians and a biopsy may be necessary. Patients may feel ashamed to report previous aesthetic procedures, and the clinicians must have a proactive approach.

cGVHD-Related Caries and Its Shared Features with Other 'Dry-Mouth'-Related Caries.

Several systemic diseases and their medical treatment may predispose the development of aggressive dental caries. Head and neck radiotherapy, chemotherapy, Sjögren's syndrome and long-standing treatment with drugs that induce hyposalivation are some of these conditions. The aim of this article is to describe the clinical features of five patients who developed chronic graft-versus-host-disease (cGVHD) as a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and, in spite of close dental follow-up, subsequently developed rampant caries. In these cases, the restorations showed early failure and the caries still progressed until generalized teeth destruction. The majority of the teeth therefore had to be extracted due to advanced dental caries and rapid clinical progression. Herein the term "cGVHD-related caries" is proposed to describe this under-recognized complication of cancer treatment that may evolve in allo-HSCT recipients that develop cGVHD. This condition is poorly recognized in the literature and may represent the final result of the clustering of oral complications in cGVHD patients, including mucositis, oral pain, hyposalivation, taste loss and oral infections, leading to rampant caries due to impaired oral hygiene and increased intake of highly cariogenic food. Consequently, the knowledge of this oral complication should improve the medical and dental management of cGVHD oral manifestations and improve the quality of life of patients with this post allo-HSCT complication.

Human herpesvirus 6 in oral fluids from healthy individuals.

BACKGROUND: Human herpesvirus 6 (HHV6) is the etiologic agent of exanthem subitum. The virus is latent in salivary glands and saliva is the main form of viral transmission. The objective of this study was to assess HHV6 incidence in the fluids from healthy individuals using a standardised technique for collecting and extracting viral DNA from gingival crevicular fluid, whole saliva and parotid gland saliva. DESIGN: Samples of oral fluids and peripheral blood were collected from 28 blood donors and HHV6 was detected using PCR assay. Parotid gland saliva and gingival crevicular fluid were collected by endodontic paper cones in order to not contaminate these fluids with whole saliva. RESULTS: Of the 28 donors, 20 (71.4%) presented positive results in at least one of the three oral fluids researched. Whole saliva was positive in 19 (67.8%) volunteers, while only four (14.2%) samples of gingival crevicular fluid and four of parotid gland saliva proved to be positive. CONCLUSIONS: The results suggest that HHV6 is present in the saliva of a large proportion of the healthy adult population. The use of endodontic paper cones for oral fluid collection and viral extraction was efficient, simple, cheap and painless. In spite of, the small number of cases studied it was possible to demonstrate that neither gingival crevicular fluid nor parotid gland saliva were the principal source of HHV6 in whole saliva.

Oral metastasis of a hepatocellular carcinoma.

Hepatocellular carcinoma is a relatively common tumor that etiologically is closely linked to previous hepatitis B infection. Oral metastatic hepatocellular carcinoma is very rare, with only 61 cases reported in the literature. We describe a case of hepatocellular carcinoma metastatic to the anterior mandibular gingivae of a 60-year-old man. The patient also exhibited tumor metastases to the lungs, left knee, little finger of the left hand, scalp, and the skin of the neck. He died 6 months after the diagnosis of the oral metastasis because of systemic tumor dissemination.