The pathogenesis of mucositis: updated perspectives and emerging targets.

Mucositis research and treatment are a rapidly evolving field providing constant new avenues of research and potential therapies. The MASCC/ISOO Mucositis Study Group regularly assesses available literature relating to pathogenesis, mechanisms, and novel therapeutic approaches and distils this to summary perspectives and recommendations. Reviewers assessed 164 articles published between January 2011 and June 2016 to identify progress made since the last review and highlight new targets for further investigation. Findings were organized into sections including established and emerging mediators of toxicity, potential insights from technological advances in mucositis research, and perspective. Research momentum is accelerating for mucositis pathogenesis, and with this has come utilization of new models and interventions that target specific mechanisms of injury. Technological advances have the potential to revolutionize the field of mucositis research, although focused effort is needed to move rationally targeted interventions to the clinical setting.

Oral chronic GVHD outcomes and resource utilization: a subanalysis from the chronic GVHD consortium.

OBJECTIVES: This study evaluated the extent to which oral chronic graft-versus-host disease (cGVHD) consensus assessments are predictive of management across institutions with and without oral medicine (OM) centers, and whether ancillary care guidelines are followed within clinical practice. METHODS: Longitudinal oral cGVHD data were abstracted from the cGVHD Consortium, and additional mouth-specific management data were analyzed across five transplant centers. RESULTS: Seventy-nine patients with 656 visits were observed for a median of 7.1 months with one visit per follow-up month. Ancillary therapies for oral cGVHD were prescribed for 67% of patients for a median of 0.46 months (per follow-up month) at OM centers and 0.78 months at non-OM centers. Patients treated with ancillary therapy were more likely to have an National Institutes of Health (NIH) mouth score of ≥1 (P < 0.001, odds ratio: 5.1) and mouth pain (P = 0.01, odds ratio: 2.6). The odds ratios of receiving ancillary therapy from OM experts were higher than transplant physicians (53%; P = 0.03). CONCLUSIONS: Oral cGVHD consensus assessments corresponding with ancillary therapy use were mouth pain and NIH mouth score, with higher odds ratios of receiving therapy from OM experts. Ancillary care guidelines for oral cGVHD are reflected in academic clinical practice with respect to utilization of recommended prescriptions.

Post-allogeneic Hematopoietic Stem Cell Transplantation (HSCT) changes in inorganic salivary components.

Recent studies have considered the qualitative and quantitative assessment of salivary flow, as well the biochemical components of saliva, as possible biomarkers that might contribute to the pathogenesis of chronic graft-versus-host disease (cGHVD) in hematopoietic stem cell transplantation (HSCT) patients. The aim of this study was to evaluate prospectively the inorganic salivary status at different periods of allogeneic HSCT. Saliva collection and oral examination were performed prior to the HSCT, ​between days 8 and 10, days 80 and 100, and at the cGVHD onset. Concentrations of calcium (Ca), phosphate (Pi), chloride (Cl), magnesium (Mg), potassium (K), and sodium (Na) were performed using colorimetric reactions and atomic absorption. Fifty-five consecutive patients undergoing first allogeneic HSCT were included in this study. Between days 8 and 10, the salivary flow rate was significantly higher (p = 0.05), Pi concentration was decreased (p = 0.007), and Na and Cl were increased (p = 0.001 and p = 0.001, respectively), compared with the baseline. Salivary flow rate during the same period showed a negative correlation with Pi concentration (p = 0.02) and a positive correlation with Na and Cl concentrations (p = 0.003 and p = 0.001, respectively). The salivary flow rate was decreased between days 80 and 100 (p = 0.02) and Na, Cl, and K concentrations were increased (p = 0.03, p = 0.02, and p = 0.003, respectively). Salivary flow rate showed a negative correlation with Na and Cl (p = 0.01 and p = 0.013, respectively). At cGVHD onset, the salivary flow rate showed no statistical difference compared with the other studied periods. A trend was observed in the higher Na concentration compared with the baseline (p = 0.06) and Pi concentration presented a significant decrease (p = 0.004). Ca and Mg concentrations showed no changes during all evaluation periods. The present study showed changes in inorganic salivary components in post-HSCT periods, mainly during the early period post-HSCT and at the cGVHD onset. We speculate that Na, Cl, and Pi in saliva could be used as a potential biomarker in further studies.

The impact of morphological and immunohistological changes in minor salivary glands on the health of the oral cavity in HSCT patients.

The objective of this study was to test the relationship between histological changes in minor salivary glands (MSG) and chronic GVHD (cGVHD) severity and OS of hematopoietic SCT (HSCT) patients, and to discriminate the participation of events preceding HSCT that damage MSG, from those linked to cGVHD. The MSG of 57 HSCT patients who were divided into two groups-oral cGVHD (36 cases) and non-cGVHD (21 cases)-were compared with the MSG of a control group of 19 non-HSCT individuals. cGVHD changes were assessed according to National Institutes of Health (NIH) consensus and the systems of Horn et al. Acinar areas and mononuclear cell subsets were set through morphometry. Horn's 'periductal lymphocytic infiltrate' correlated with an extensive form of cGVHD and NIH 'periductal lymphocytes with exocytosis into duct' correlated with global survival. Measurements of the acinar area differed between the three groups, being the lowest in cGVHD patients, but also reduced in non-cGVHD patients. Significant differences among CD45, CD45RO, CD4 and CD8 immunomarked cells/mm(2) were found by comparing the two groups of HSCT patients. In brief, periductal lymphocytic infiltrate and exocytosis implies inflammatory activity and, consequently, might reflect the cGVHD status and influence survival. Acini loss in non-cGVHD patients may be due to pre-transplant events, but massive lymphocyte infiltrate is part of the cGVHD process.

Pigmented lichenoid drug eruption secondary to chloroquine therapy: an unusual presentation in lower lip.

Antimalarial drugs, like chloroquine, may produce hyperpigmentation of the oral mucosa, affecting most commonly the palate. Its pathogenesis is not clear; an increased production of melanin is currently believed to be the cause of this oral manifestation. The purpose of this study was to report a case of atypical oral mucosal hyperpigmentation secondary to antimalarial therapy. A 66-year-old, dark skinned woman was evaluated for oral pigmentation. The patient had a history of chloroquine therapy, and presented a diffuse blue-gray pigmentation in the hard palate and, mainly, in the lower lip. Diagnostic hypothesis were of physiologic pigmentation, drug-induced pigmentation, pigmentation associated with systemic diseases, smoker's melanosis and post-inflammatory pigmentation. Incisional biopsy was conducted and histopathological examination revealed lichenoid dermatitis and pigment incontinence. Fontana-Masson staining was positive for melanin, but Perl's iron staining was negative. The histopathological diagnosis was consistent with melanin incontinence related to drug-induced lichenoid reaction secondary to chloroquine therapy. Adequate correlation of clinical and microscopic aspects was essential for the definitive diagnosis, especially in atypical cases. This diagnosis is of great relevance for the patient, since the oral manifestation might be an early sign of ocular complications due to antimalarial therapy. Therefore, the identification of these oral manifestations indicates regular evaluations by an ophtalmologist, preventing greater complications of antimalarial therapy for the patient.

Oral epithelial dysplasia and squamous cell carcinoma following allogeneic hematopoietic stem cell transplantation: clinical presentation and treatment outcomes.

Late complications of allogeneic hematopoietic stem cell transplantation (HSCT) include a risk of secondary malignancies. Optimization for early diagnosis and treatment of oral premalignant or malignant lesions requires an assessment of potential predisposing risk factors. The medical records of patients who developed oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC) following allogeneic-HSCT were reviewed. Data on HSCT course, chronic graft-versus-host disease (cGVHD), and clinical outcome were recorded; landmark survival was calculated. Twenty-six patients with OED (n=8) and OSCC (n=18) were identified with a median follow-up of 26.5 and 21.5 months, respectively. Premalignant and malignant oral lesions were diagnosed at a median time of 2.5 and 8 years after HSCT, respectively. Chronic GVHD was present in 96% of patients and of these, 96% had oral involvement. Multifocal oral cancer was found in 28% of cases, and localized recurrence was observed in 44% of cases. These results suggest that oral cGVHD may be considered a potential risk factor for the development of OSCC following allogeneic-HSCT. The observation that oral cancers were frequently multifocal and recurred locally suggests that these cancers may be more aggressive. Vigilant follow-up and coordination of care are critical.

Taste disorders and oral evaluation in patients undergoing allogeneic hematopoietic SCT.

The aim of this study was to evaluate taste perception, salivary flow rate and oral pathologies in three different groups of patients undergoing hematopoietic SCT (HSCT) classified according to time post transplant. Group I (n=20) up to 150 days after HSCT, group II (n=20) between 151 and 1095 days and group III (n=21) more than 1095 days. Taste acuity was measured by four basic tastes of four solutions, in three concentrations (M): NaCl, sucrose, citric acid and caffeine. Patients classified flavors as sweet, sour, salty, bitter and without flavor. The intensity was considered high, medium and low. Unstimulated saliva was collected and salivary flow rates (ml/min) were determined. Of 61 patients, 31 had chronic GVHD. For the sweet solution, the high and low concentrations represented a challenge for those patients. No patients were sensitive to the low concentration of caffeine solution (P=0.05). Saliva flow rate was diminished in 10 of 61 (16%) patients and hyposalivation was more intense in groups II/III (P=0.007). There was no correlation between taste dysfunction and oral chronic GVHD. The results indicated taste alterations only for the sweet and salty tastes even in patients up to 3 years after HSCT and may not correlate with oral chronic GVHD and with hyposalivation.

Detection of human herpesvirus 6 in patients with oral chronic graft-vs-host disease following allogeneic progenitor cell transplantation.

INTRODUCTION: Chronic graft-vs-host disease (cGVHD) is a major cause of morbidity in long-term survivors of allogeneic hematopoietic progenitor cell transplantation. Herpesviruses are involved in the occurrence and progression of various oral diseases. AIM: The aim of this study was to investigate the role of human herpesvirus 6 (HHV6) in patients with oral manifestations of cGVHD. MATERIALS AND METHODS: Peripheral blood and oral fluids (whole saliva, gingival crevicular fluid and parotid gland saliva) from 19 cGVHD patients, and 28 blood donors were examined for HHV6. Oral tissue samples were collected from 12 cGVHD patients and 12 healthy individuals. Nested polymerase chain reaction was employed to identify the HHV6. RESULTS AND CONCLUSION: The virus was detected in whole saliva in 13 cGVHD patients (68%) and in 19 blood donors (67%). HHV6 was not identified in any of the gingival crevicular fluid and parotid gland saliva samples in cGVHD patients. In the control group 14.3% of both, four gingival crevicular fluid and four parotid gland saliva samples were positive. Two oral tissue samples of cGVHD patients were positive for HHV6. These results indicate that patients with oral manifestations of cGVHD and healthy individuals present high and similar incidence of HHV6 in blood and oral fluids. These data do not support the importance of HHV6 in oral lesions of cGVHD.

Risk factors and characteristics of ocular complications, and efficacy of autologous serum tears after haematopoietic progenitor cell transplantation.

The objective of the study was to evaluate the frequency and clinical characteristics of ocular complications and their risk factors, as well as autologous serum tears (AST) for the treatment of dry eye in these patients. Data from the files of 124 patients who had undergone allogeneic haematopoietic progenitor cell transplantation (HPCT) were evaluated. In addition, 33 HPCT patients were examined and their data were compared with controls. Analysis of tears and AST was performed. Dry eye manifestation occurred in 32% of patients and was positively correlated with age over 27 years (P = 0.05), peripheral blood progenitor cell transplant (P = 0.002), chronic graft-versus-host disease (P = 0.0027), and chronic or acute myeloid leukaemia (P = 0.001). Dry mouth and Schirmer test < 5 mm were predictive factors for dry eye in HPCT patients (P = 0.002 and odds ratio 3.9 and P = 0.007, odds ratio = 5.9, respectively). Microbiological analysis revealed that six of 11 AST samples were contaminated after 30 days of use. The present study supports the role of potential risk factors for ocular complications and key elements to detect alterations in the tear film from HPCT patients. In addition, AST contamination must be considered after longer periods of use.

Major salivary gland damage in allogeneic hematopoietic progenitor cell transplantation assessed by scintigraphic methods.

Salivary gland dysfunction is a common sequela of hematopoietic progenitor cell transplantation (HPCT). The investigation of major salivary gland dysfunction with sodium pertechnetate scintigraphy is a non-invasive method that provides images of the parotid and submandibular glands. In this prospective trial, 20 HPCT patients were submitted to scintigraphic study with 99mTc-pertechenate and 67Ga in order to evaluate the major salivary glands early involvement following HPCT. Major salivary glands were evaluated prior to HCPT as well as at Days +30, +60 and +100 post transplant. Major salivary glands uptake and clearance of 99mTc-pertechenate results did not demonstrate any functional differences between pre- versus post transplant periods. Results of the 67Ga scan revealed inflammatory infiltration following HPCT, primarily in submandibular glands, suggest a persistent involvement of major salivary glands up to Day +100 after HPCT.

Oral avascular bone necrosis associated with chemotherapy and biphosphonate therapy.

BACKGROUND: Oral avascular bone necrosis is an important adverse effect of chemotherapy and biphosphate therapy. OBJECTIVE: To report our experience in oral avascular bone necrosis in cancer patients assigned to undergo chemotherapy. PATIENTS AND METHODS: Fourteen patients presenting oral avascular bone necrosis were selected from the clinical files of five Stomatological Clinics in Brazil. Clinical data as well as treatment and prognosis information were obtained from all 14 patients. RESULTS: Twelve patients (86%) were submitted to biphosphonate therapy. The most important symptom was pain, present in all cases, and the mandible was the most common involved site. Most patients (79%) had their conditions managed by antibiotic therapy and surgical debridation; however complete response was achieved in only three cases (21%). CONCLUSION: Avascular bone necrosis is a serious oral side-effect of cancer chemotherapy, particularly in patients using biphosphonates, and antibiotic therapy and surgical debridation were not able to promote complete response in most cases.

Late effects of chronic graft-vs.-host disease in minor salivary glands.

BACKGROUND: The established pathologic criteria for minor salivary gland (MSG) involvement in chronic graft-vs.-host disease (cGVHD) could play a role in monitoring response to therapy. METHODS: We evaluated MSG sequential biopsies during cGVHD therapy in 14 allogeneic bone marrow transplantation (BMT) patients. Nine patients that did not develop GVHD after BMT entered the control group. Biopsies were examined using hematoxylin-eosin, Periodic acid-Schiff (PAS) and leukocyte common antigen staining. RESULTS: A significant loss of PAS+ acinar volume was observed at the diagnosis of cGVHD as much as at the end of treatment when compared with the control group. In the second evaluation, the inflammatory infiltrate was still greater than control group. CONCLUSIONS: The results suggest that persistent xerostomia after cGVHD treatment is because of maintenance of lymphocytic infiltrate and consequent absence of MSG secretory unit recovery. This data may be useful to provide improved insight into the histopathology of this organ involvement.

Chronic GVHD in minor salivary glands and oral mucosa: histopathological and immunohistochemical evaluation of 25 patients.

BACKGROUND: Graft-vs.-host disease (GVHD) is the major cause of morbidity and mortality in patients undergoing allogeneic Bone Marrow Transplantation (BMT). The aim of our study was to identify the most relevant histological features for diagnosis of chronic Graft-vs.-Host Disease (cGVHD) in oral mucosa and minor salivary glands of 25 patients, as well as to evaluate the immunophenotype of the inflammatory cells. METHODS: Sixteen patients that were submitted to allogeneic BMT but did not present cGVHD were selected as a control group. The sections were studied on H & E and CD68, CD45, CD4, CD8, CD20 staining. RESULTS: The most frequent histologic findings in oral mucosa at the day of diagnosis of cGVHD were: hydropic degeneration of the basal layer of the epithelium, apoptotic bodies, lymphocytic infiltration, and focal or total cleavage between the epithelial and connective tissue. In the labial salivary glands (LSG), lymphocytic infiltration, acinar loss and fibrosis were the main alterations. Cytotoxic CD8-T cells and macrophages were predominant both in the epithelium and connective tissue, as well as in minor salivary glands. CONCLUSIONS: Histological features were useful in the diagnosis of oral cGVHD. It is suggested that CD8-T cells and macrophages play important role in the pathogenesis of the disease.

Mouth metastasis of peripheral primitive neuroectodermal tumor.

We describe a case of oral metastasis of peripheral primitive neuroectodermal tumor (pPNET) in a 68-year-old man, who presented the primary lesion in the chest. Oral metastasis of pPNETs is very rare and we have not found any similar case reported in the English literature. Clinical examination showed an extensive and ulcerated fleshy mass measuring 3.0 x 3.5 cm in the right lower gingivae. Microscopic examination showed sheets of proliferating small, hyperchromatic, round cells. Tumor cells were reactive to neuron-specific enolase (NSE), vimentin and MIC-2 gene by immunohistochemistry, consistent with PNET. The patient died 3 weeks later because of respiratory insufficiency.

Primary aspergillosis affecting the tongue of a leukemic patient.

We describe a case of primary aspergillosis involving the tongue of a patient with acute myeloid leukemia. Intraoral aspergillosis is very rare and we found only 23 cases reported in the English literature. Clinically it was a 2-cm, ulcerated, grayish lesion on the dorsum of the tongue. Microscopically there was invasion of the epithelium, connective tissue and muscle of the tongue by fungal hyphae branching at 45 degrees angle. The large hyphae were easily seen by H & E stain, and were strongly positive for periodic acid-Schiff and Grocott methenamine. The patient was successfully treated with intravenous amphotericin B. Based on clinical, microscopic and culture data, the diagnosis of primary aspergillosis of the tongue was established. Invasive oral aspergillosis is a potentially lethal disease and it should be considered in immunosuppressed patients.

Ultrastructure of hepatocyte abnormalities in perimetastatic areas.

The ultrastructural pathology of non-invaded hepatocytes located in close proximity to metastases from diverse gastrointestinal carcinomas was studied. Observed abnormalities included swelling of rough and smooth endoplasmic reticulum, proliferation of lysosomes, and mitochondrial alterations as presence of granules and paracrystalline inclusions, marked pleomorphism, and lack of cristae. These results show that, contrary to the classical conception, the non-invaded cells surrounding primary tumours or their metastases could be abnormal.

A randomised, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of haematological malignancies.

We present the results of a prospective, randomised study comparing PBPC and BM focusing on engraftment, acute and chronic GVHD and survival. Forty patients with haematological malignancies received HLA-identical sibling BM (group A) or PBPC (group B). Evaluable patients were 19 (A) and 18 (B). Median age was 35 (17-56) in A and 29.5 (9-51) in B. Conditioning was mainly Bu-Cy2; GVHD prophylaxis was CSA-MTX. PBPC were harvested after 5 days of G-CSF 10 microg/kg/day. Median days for an ANC >0.5 x 10(9)/l was 18 (13-30) in A and 16 (11-25) in B (P = 0.10). Platelets >20 x 10(9)/l occurred at +17 (10-40) in A and +12 (9-36) in B (P = 0.01). The probability of > or =2 grade a-GVHD was 19% (A) and 27% (B) (P = 0.53). The probability of all grade c-GVHD was 70% with BM. In spite of the small number of patients in group B (PBPC), our data suggest the great majority of them will have c-GVHD (P = 0.08); extensive disease was present in 50 and 100%, respectively (P = 0.05). The estimates of overall survival for A and B at 1000 days are 51 and 47%, respectively (P = 0.67); DFS at 1000 days are 52 and 58%, respectively (P = 0.50). PBPC resulted in faster platelet engraftment. The incidence of acute and chronic GVHD was similar in both groups, but the severity of c-GVHD was higher with PBPC. No differences in survival and DFS have been observed to date.

Dimensions of experiential learning at group relations conferences.

Four hundred and seventy-seven professionals attended thirteen group relations conferences. Conferences varied across three dimensions: context, including sponsorship and history: design, involving duration, intensity (residential setting) and complexity; and linkages, the social and authority ties between members and staff. Three month follow-up questionnaires were collected from sixty percent of participants. Significantly more self-assessed learning was reported by those who attended the residential than the non-residential conferences. The results, from a large diversified sample, suggest that a combination of training in a residential setting, strong institutional sponsorship and pre-existing authority and social linkages between members and staff resulted in the most reported learning. Group relations conferences provide unique learning opportunities for mental health professionals, (Correa et al. 1981) and have been increasingly used in the United States and Europe during the last twenty years. Despite this, there is little research evaluating the outcomes of such training in terms of member learning or the differential effectiveness of the alternative forms of conferences currently available. Conferences vary along three major dimensions: a) context, including the institutional sponsorship as well as the history of previous conferences held at the same site, b) design, including the duration, intensity and number of events which make up the conference, and c) linkages, the social and authority relations among members and staff. A review of the first decade of group relations work in the United States concluded that the characteristics of a conference, including the setting have an important impact on member learning, (Klein 1978).(ABSTRACT TRUNCATED AT 250 WORDS)

[Vascular conductance and critical closing pressure in the isolated canine lung in situ. Its natural history]. / La conductancia vascular y la presión crítica de cierre en el lóbulo canino aislado in situ. Su historia natural.

The vascular pressure-flow relationship (P-QL) in West's zone II condition were studied in isolated, in situ, canine, left lower lobe (ISLL) in order to characterize the total resistance in the pulmonary vascular bed (Rp), the normal values for pulmonary vascular conductance (Cv) and for critical closing pressure (PLc). After the basal parameters were obtained, measurements of Cv and PLc were done every 30' in order to know the natural history (NH) of this canine ISLL preparation. The P-QL relationship of the pulmonary vasculature of the ISLL preparation, perfused under classical zone II conditions, can be characterized by a rectilinear segment at high flow, a curvilinear segment at low flow and a pulmonary arterial pressure that exceeds alveolar (PA) pressure at zero flow. This demonstrates the existence of critical closing pressure (PLc) in the pulmonary vascular bed. The mean control Cv and PLc were 38.5 +/- 14 (ml. min)/mmHg and 7.9 +/- 2.2 mmHg respectively; those parameters did not change through the observation of the experiment. PLc was found to be independent of bronchial flow and it was not related to PA when the values for this pressure were less than 5 cm H20. On the contrary, higher levels of PA pressure were significantly related to PLc (r = 0.94, p less than 0.05). We conclude that in this model of ISLL in West's zone II condition it is possible to study the two components of Rp, one given by vessels that determine changes in flow resistance and for the other vessels disclosing critical closure. The values of these components remained stable over 180' of observation.