The association between donor and recipient statin use and infections after allogeneic hematopoietic cell transplantation.

Recent studies have reported that statin use may be associated with improved outcomes in patients with sepsis or respiratory viral infections. In the setting of allogeneic hematopoietic cell transplantation (HCT), it has been shown that donor and recipient statin use is associated with reduced risks of GVHD. We assessed in retrospective analysis whether donor or recipient statin use impacts infection risk after allogeneic HCT (n=1191). Although recipient statin use was associated with the increased incidence of Gram-negative bacteremia (adjusted hazard ratio (aHR) 2.22, (95% confidence interval (CI) 1.2-4.2), P=0.01) without affecting mortality, donor statin use was associated with an increased incidence of respiratory viral infections in recipients (aHR 2.84 (95% CI 1.3-6.0), P=0.007). The overall incidence of invasive fungal infections and CMV reactivation and CMV disease were not impacted by recipient or donor statin use. In conclusion, this study suggests that recipient or donor statin use may be associated with an increased incidence of some infections without adversely affecting mortality.

Fractal dimension evaluation of cone beam computed tomography in patients with bisphosphonate-associated osteonecrosis.

OBJECTIVES: The aim of this study was to (1) evaluate the fractal dimension (FD) in regions of the mandible on cone beam CT (CBCT) images of patients with bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) and (2) to select the most suitable region of interest (ROI) for further study on detection of bone alterations associated with bisphosphonates. METHODS: CBCT images of patients with BP-ONJ were included with matched controls. Values of FD were compared between groups. Selected ROIs were: ROI-1 - below the mandibular foramen; ROI-2 - above the mandibular foramen; ROI-3 - anterior to the mental foramen; ROI-4 - above the mandibular canal. The area of bone exposure was included as ROI-5. The results were analysed using generalized estimating equations and conditional logistic regression. RESULTS: There were 36 patients (67% female) with a mean age of 60.7 years. The mean FDs were: ROI-1 - 1.678 for controls and 1.673 for patients (P = 0.81); ROI-2 - 1.657 for controls and 1.653 for patients (P = 0.78); ROI-3 - 1.661 for controls and 1.684 for patients (P = 0.17); and ROI-4 - 1.670 for controls and 1.698 for patients (P = 0.03). The value of the FD in the area of exposed bone was the highest (1.729). The odds of being a BP-ONJ patient vs being a control was six times as high for individuals with a higher FD score at ROI-4, although the confidence interval was quite wide owing to the small sample size. CONCLUSION: In this preliminary study, BP-ONJ patients had higher FD values than controls at regions close to the alveolar process. The results suggest that FD is a promising tool for detection of bone alterations associated with BP-ONJ.

Folic acid supplementation during methotrexate immunosuppression is not associated with early toxicity, risk of acute graft-versus-host disease or relapse following hematopoietic transplantation.

Methotrexate (MTX) is used as an immunosuppressive agent for acute graft-versus-host disease (GVHD) prophylaxis following hematopoietic cell transplantation (HCT). Concerns that folate intake may impair MTX effectiveness or selectively rescue leukemic cells have led to variations in clinical practice regarding supplemental folic acid during MTX administration. A retrospective, observational study was undertaken to determine the association between folic acid intake (days 0-18 post transplant) and MTX toxicity and efficacy following HCT. The study population consisted of 311 adult patients who received a myeloablative HCT for chronic myelogenous leukemia, all four scheduled doses of MTX, and did not require leucovorin rescue. Multiple linear regression models were used to assess the relationships between folic acid intake (days 0-18 post-HCT) and oral mucositis index (OMI) scores, time to engraftment and risk of detectable acute GVHD. No statistically significant differences in mean OMI scores, time to engraftment, risk of acute GVHD, days to acute GVHD, risk of relapse or survival were observed when comparing patients taking, on average, <400 (14%), 400 (58%) or >400 microg (28%) folic acid per day. Our results suggest that concurrent folic acid supplementation does not change MTX effectiveness or toxicity in this patient population.

Benzydamine HCl for prophylaxis of radiation-induced oral mucositis: results from a multicenter, randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Benzydamine was evaluated in patients with head and neck carcinoma for treatment of radiation-induced oral mucositis, a frequent complication of radiation therapy (RT) for which there is no predictable therapy or preventive treatment currently available. METHODS: The safety and efficacy of 0.15% benzydamine oral rinse in preventing or decreasing erythema, ulceration, and pain associated with oral mucositis during RT were evaluated in a randomized, placebo-controlled trial conducted in patients with head and neck carcinoma. Subjects were to rinse with 15 mL for 2 minutes, 4-8 times daily before and during RT, and for 2 weeks after completion of RT; study evaluations were conducted before RT and routinely thereafter up to 3 weeks after RT. RESULTS: During conventional RT, regimens up to cumulative doses of 5000 centigrays (cGy) benzydamine (n = 69) significantly (P = 0.006) reduced erythema and ulceration by approximately 30% compared with the placebo (n = 76); greater than 33% of benzydamine subjects remained ulcer free compared with 18% of placebo subjects (P = 0.037), and benzydamine significantly delayed the use of systemic analgesics compared with placebo (P < 0.05). Benzydamine was not effective in subjects (n = 20) receiving accelerated RT doses (> or = 220 cGy/day). The incidence of adverse events between treatment groups was comparable without significant differences. Early discontinuation because of adverse events occurred in 6% of benzydamine subjects and 5% of placebo subjects, and there was 1 death (related to the primary diagnosis) in a placebo subject. CONCLUSIONS: Benzydamine oral rinse was effective, safe, and well tolerated for prophylactic treatment of radiation-induced oral mucositis.

Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism.

This study investigated whether a polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T) modifies responses to methotrexate (MTX) in patients undergoing bone marrow transplantation. About 10% to 12% of the population carry the MTHFR TT genotype (enzyme activity, 30% of wild type [CC]). Patients (n = 220) with chronic myelogenous leukemia underwent marrow allografts and were given a short course of MTX. MTX toxicity measures included the oral mucositis index (OMI), speed of engraftment (platelet and granulocyte counts), and bilirubin. Patients with lower MTHFR activity (TT genotype) had 36% higher mean OMI during days 1 to 18 (+5.7, P =.046) and 20% higher OMI between days 6 and 12 (+3.8, P =.27). Platelet counts recovered more slowly among patients with the TT genotype compared to wild type (24% slower recovery to 10 000 platelets/microL, P =.23; 34% slower to 20 000/microL, P =.08). Patients with decreased MTHFR activity appear at risk of higher MTX toxicity. Because of the high prevalence of the TT genotype, these results may have implications for MTX dosage.

Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation.

PURPOSE: To explore the relationship between oral mucositis and selected clinical and economic outcomes in blood and marrow transplant patients. PATIENTS AND METHODS: Subjects consisted of 92 transplant patients from eight centers who participated in a multinational pilot study of a new oral mucositis scoring system (Oral Mucositis Assessment Scale [OMAS]). In the pilot study, patients were evaluated for erythema and ulceration/pseudomembrane formation beginning on the first day of conditioning and continuing for 28 days. We examined the relationship between patients' peak OMAS scores and days with fever (body temperature > 38.0 degrees C), the occurrence of significant infection, days of total parenteral nutrition (TPN), and days of injectable narcotic therapy (all over 28 days), days in hospital (over 60 days), total hospital charges for the index admission, and vital status at 100 days. RESULTS: Patients' peak OMAS scores spanned the full range of possible values (0 to 5) and were significantly (P <.05) correlated with all of the outcomes of interest except days with fever (P =.21). In analyses controlling for type of graft (autologous v allogeneic) and study center, a 1-point increase in peak OMAS score was associated with (1) 1.0 additional day with fever (P <.01), (2) a 2.1-fold increase in risk of significant infection (P <.01), (3) 2.7 additional days of TPN (P <.0001), (4) 2.6 additional days of injectable narcotic therapy (P <.0001), (5) 2.6 additional days in hospital (P <.01), (6) $25,405 in additional hospital charges (P <.0001), and (7) a 3.9-fold increase in 100-day mortality risk (P <.01). Mean hospital charges were $42,749 higher among patients with evidence of ulceration compared with those without (P =.06). CONCLUSION: Oral mucositis is associated with significantly worse clinical and economic outcomes in blood and marrow transplantation.

Oral complications of pediatric hematopoietic cell transplantation: diagnosis and management.

Oral complications are a significant cause of morbidity and potential mortality for children undergoing hematopoietic cell transplant (HCT). Oral complications can occur at all stages of HCT and can interfere significantly with transplant recovery. Mucosal disease caused by conditioning regimen toxicity and infection are frequent clinical problems. Untreated dental caries and periodontal disease may result in severe infections of the mouth and/or life-threatening systemic spread of the microbial pathogens. In the course of chronic graft-versus-host disease (GVHD), which can complicate HCT, lichenoid and ulcerative lesions of the mucosa are observed. Furthermore, total-body irradiation utilized in the conditioning regimens can cause early xerostomia and consequent dental decay and also result in significant dental and skeletal developmental anomalies. The dental health care team should have a key role in the support of HCT patients. The team's primary responsibilities are those related to the prevention of severe infections originating in the mouth, which includes providing instruction on oral prophylaxis and hygiene as well as direct intervention. Prevention and/or diagnosis and management of oral complications of HCT by the dental team can improve the success of a transplant by reducing morbidity, improving the quality of life, and reducing the cost of care. The authors present specific protocols for the diagnosis and prevention and for the management of oral complications in pediatric HCT.

Pilot trial of cytoprotection with amifostine given with high-dose chemotherapy and autologous peripheral blood stem cell transplantation.

In an attempt to limit toxicities associated with dose-intensive therapy used for transplant regimens, we performed a pilot study using amifostine with high-dose busulfan (12 mg/kg), melphalan (100 mg/m2), and thiotepa (500 mg/m2) in 21 patients with a variety of malignancies. After 3 days of oral busulfan, amifostine was given at 910 mg/m2 IV for 10 minutes, preceding the infusion of each of 2 doses of melphalan and thiotepa given for 4 days. Antiemetic premedication for amifostine was given to all patients. The median patient age was 50 years (range: 32-65 years). Twenty-one patients received 82 separate amifostine infusions. One patient discontinued amifostine after the second dose because of severe nausea and emesis, and two infusions were temporarily held secondary to hypotension. Of these 82 cycles, there was a total of 37 episodes of nausea/vomiting, 28 episodes of sneezing, 11 episodes of flushing, and 1 episode of oral paresthesia. Systolic blood pressure and mean arterial pressure decreased by a mean of 8.4 mm Hg and 5.0 mm Hg, respectively. In general, the infusion was well tolerated. Patients were observed until discharge home (N = 15), until initiation of an additional tandem transplant procedure (N = 4), or until death (N = 2). All twenty-one patients experienced nonhematologic toxicities grade II or greater. Grade II toxicities included mucositis (N = 21), gastrointestinal (N = 3), skin (N = 1), and liver (N = 1), and grade III toxicities included liver (N = 1). Mucositis was also scored according to a detailed toxicity assessment. Mucositis did not appear to be improved with amifostine when compared with a control group of patients not receiving amifostine. Renal dysfunction after transplantation was decreased in the amifostine group, whereas there was no significant effect on posttransplant hepatic dysfunction. Although these data demonstrate the feasibility of delivering parenteral amifostine in conjunction with dose-intensive chemotherapy and autologous peripheral blood stem cell transplantation, there was no evidence of a significant reduction in nonmarrow toxicities.

Symptom profile of nasopharyngeal cancer patients during radiation therapy.

PURPOSE: This prospective, longitudinal study was aimed to describe the prevalence, severity, and pattern of symptoms over the course of radiation therapy in persons with nasopharyngeal carcinoma and to explore symptom severity by treatment modality. DESCRIPTION OF STUDY: Thirty-seven patients completed this study, and 46% received chemotherapy before radiation therapy. A self-reported radiation symptom checklist and an objective mucositis assessment tool were used weekly to document oropharyngeal, skin, nose or ear, or more general side effects, and mucositis. RESULTS: Oropharyngeal problems were the most severe complaints during radiation therapy. All patients experienced dry mouth, taste change, difficulty in swallowing, difficulty in opening their mouths, hoarseness, sore throat, and observable mucositis. Most reported moderate-to-severe dry mouth, difficulty in swallowing, and sore throat from weeks 3 through 7. Skin problems were not prominent until week 4. Patients also lost an average of 3.9 kg during the therapy. Sequential chemotherapy and radiation therapy was associated with more severe oropharyngeal problems than radiation therapy alone, but no significant differences in other problems were found. CLINICAL IMPLICATIONS: Despite recognition of the oropharyngeal side effects associated with irradiation, effective management protocols for such symptoms have not been implemented in the studied institution. The frequency and intensity of the symptoms reported indicate an urgent need for increased vigilance about radiation-related side effects and pain management. As well, patient education about expected side effects may help mitigate the anxiety that patients experience when these symptoms occur.

Oral mucositis in myelosuppressive cancer therapy.

Because the etiology of mucositis is multifactorial , approaches to prevention and management have also been multifactorial. Effective prevention and management of mucositis will reduce the pain and suffering experienced during cancer treatment. Oropharyngeal pain in cancer patients frequently requires systemic analgesics, adjunctive medications, physical therapy, and psychologic therapy in addition to oral care and topical treatments. Good oral hygiene reduces the severity of oral mucositis and does not increase the risk of bacteremia. Current approaches to management include frequent oral rinsing with saline or bicarbonate rinses, maintaining excellent oral hygiene, and using topical anesthetics and analgesics. Cryotherapy is a potential adjunctive approach in some cases. There are a number of approaches that appear to represent viable candidates for further study. Biologic response modifiers offer the potential for prevention and for acceleration of healing. Various cytokines will enter clinical trials in the near future; these offer the potential for reduction of epithelial cell sensitivity to the toxic effects of cancer therapy or for stimulation of repair of the damaged tissue. Other approaches include the use of medications to reduce exposure of the oral mucosa to chemotherapeutic drugs that are secreted in saliva. Antimicrobial approaches have met with conflicting results, little effect being seen with chlorhexidine and systemic antimicrobials in the prevention of mucositis in radiation patients. In patients with BMT and patients with leukemia, chlorhexidine may not be effective in preventing mucositis, although there may be reduction in oral colonization by Candida. Initial studies of topical antimicrobials that affect the gram-negative oral flora have shown reductions in ulcerative mucositis during radiation therapy but have not been assessed in leukemia/BMT. Among other approaches that require further study are low-energy lasers and anti-inflammatory medications. These approaches to management have undergone initial study, but additional investigation is needed to determine their effectiveness with respect to the prevention of mucositis and symptom management and to determine appropriate doses and frequencies of intervention. Current studies and our increasing understanding of the pathogenesis of oral mucositis will lead to new approaches to management and improved quality of life for these patients.

Low-energy He/Ne laser in the prevention of radiation-induced mucositis. A multicenter phase III randomized study in patients with head and neck cancer.

Use of the low-energy helium-neon laser (LEL) appears to be a simple atraumatic technique for the prevention and treatment of mucositis of various origins. Preliminary findings, and significant results obtained for chemotherapy-induced mucositis in a previous phase III study, prompted a randomized multicenter double-blind trial to evaluate LEL in the prevention of acute radiation-induced stomatitis. Irradiation by LEL corresponds to local application of a high-photon-density monochromatic light source. Activation of epithelial healing for LEL-treated surfaces, the most commonly recognized effect, has been confirmed by numerous in vitro studies. The mechanism of action at a molecular and enzymatic level is presently being studied. From September 1994 to March 1998, 30 patients were randomized. Technical specification: 60 mW (25 mW at Reims, 1 patient), He-Ne, wavelength 632.8 nm. The trial was open to patients with carcinoma of the oropharynx, hypopharynx and oral cavity, treated by radiotherapy alone (65 Gy at a rate of 2 Gy/fraction, 5 fractions per week) without prior surgery or concomitant chemotherapy. The malignant tumor had to be located outside the tested laser application areas (9 points): posterior third of the internal surfaces of the cheeks, soft palate and anterior tonsillar pillars. Patients were randomized to LEL or placebo light treatment, starting on the first day of radiotherapy and before each session. The treatment time (t) for each application point was given by the equation : t(s)= energy (J/cm2) x surface (cm2)/Power (W). Objective assessment of the degree of mucositis was recorded weekly by a physician blinded to the type of treatment, using the WHO scale for grading of mucositis and a segmented visual analogue scale for pain evaluation. Protocol feasibility and compliance were excellent. Grade 3 mucositis occured with a frequency of 35.2% without LEL and of 7.6% with LEL (P<0.01). The frequency of "severe pain" (grade 3) was 23.8% without LEL, falling to 1.9% with LEL (P<0.05). Pain relief was significantly reduced throughout the treatment period (weeks 2-7). LEL therapy is capable of reducing the severity and duration of oral mucositis associated with radiation therapy. In addition, there is a tremendous potential for using LEL in combined treatment protocols utilizing concomitant chemotherapy and radiotherapy.

Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Study Group.

BACKGROUND: An impediment to mucositis research has been the lack of an accepted, validated scoring system. The objective of this study was to design, test, and validate a new scoring system for mucositis that can be used easily, is reproducible, and provides an accurate system for research applications. METHODS: A panel of experts, convened to design an objective, simple, and reproducible assessment tool to evaluate mucositis with specific application to multicenter clinical trials, developed a scale that measured objective and subjective indicators of mucositis. Nine centers participated in the study's validation. Paired investigators at each center evaluated patients receiving chemotherapy or head and neck radiation. Objective measures of mucositis evaluated ulceration/pseudomembrane formation and erythema. Subjective outcomes of mouth pain, ability to swallow, and function were measured. Analgesia use for mouth sensitivity was recorded. RESULTS: One hundred eight chemotherapy and 56 radiation therapy patients were evaluated. Seventy-eight percent of chemotherapy patients and 64% of radiation therapy patients had clinically significant mucositis. Cumulative daily mucositis scores demonstrated a high correlation among observers. Using area under the curve analysis, it was found that for chemotherapy patients, the highest correlations (correlation coefficient > 0.92) occurred for the scores that selected the three highest daily values over the course of mucositis assessment. High interobserver correlations were noted for patients receiving radiation therapy. Objective mucositis scores demonstrated strong correlation with symptoms. CONCLUSIONS: The scoring system evaluated was easily used, showed high interobserver reproducibility, was responsive over time, and measured those elements deemed to be associated with mucositis. The use of concomitant symptomatic measurements appeared to be unnecessary.

Graft-vs.-host disease.

Bone marrow transplantation (BMT) is the treatment of choice for many leukemias, lymphomas, bone marrow failure syndromes, and immunodeficiency 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.

Helium-neon laser effects on conditioning-induced oral mucositis in bone marrow transplantation patients.

BACKGROUND: Oral mucositis is a common complication of bone marrow transplantation (BMT) conditioning therapy. Sequelae consist of increased risk for infection, moderate to severe pain, compromised oral function, and bleeding. This study investigated helium-neon laser treatment for prevention of conditioning-induced oral mucositis in BMT patients. Patterns and severity of mucositis for specific conditioning drug regimens also were analyzed. METHODS: Twenty patients received laser radiation to their oral mucosa, either left or right of midline. The contralateral side was sham-treated and served as a control. Mucositis severity was scored independently by two modified versions of the Oral Mucositis Index Scale (OMI-A and OMI-B) and the Eastern Cooperative Oncology Group (ECOG) Oral Toxicity Scale; pain severity was scored by subjects on a visual analogue scale (VAS). Cumulative scores were analyzed for differences between the laser-treated and sham-treated sides. RESULTS: Oral mucositis and pain scores were significantly lower for the treated versus the untreated side by OMI-A and B (P < 0.005) and VAS (P = 0.027) criteria, respectively. Ulcerative lesions occurred in all patients bilaterally; severity increased until Day +6, and lesions resolved by Day +21. Mucositis was more severe for patients conditioned with busulfan/carboplatin/thiotepa than for patients conditioned with busulfan/cyclophosphamide/etoposide. CONCLUSIONS: Helium-neon laser treatment was well-tolerated and reduced the severity of conditioning-induced oral mucositis in BMT patients.

Identifying and treating HIV-related oral conditions: a clinical grand rounds approach.

The authors describe an innovative method for teaching dental professionals to differentially diagnose and treat HIV-related oral lesions. The method included a half day of didactic presentations and a half day of clinical grand rounds. The clinical grand rounds featured clinical stations where small groups of practitioners observed HIV oral manifestations and interacted with patients. Their observations were discussed with two dentists expert in diagnosing and managing oral complications of HIV. Videotapes of the patients' oral lesions augmented the discussions.

A toxicity study of trimetrexate used in combination with cyclosporine as acute graft-versus-host disease prophylaxis in HLA-mismatched, related donor bone marrow transplants.

This study evaluated the acute toxicity of trimetrexate (TMTX) used in combination with cyclosporine (CsA) for prevention of acute graft-versus-host disease (GVHD) in patients undergoing allogeneic marrow transplantation from HLA-mismatched, related donors. TMTX has a mechanism of action similar to that of methotrexate (MTX); however, unlike MTX, TMTX is not primarily dependent on renal excretion. Patients were conditioned for transplant with cyclophosphamide, anti-thymocyte globulin, and total body irradiation. TMTX, 10 mg/m2 i.v., was administered on days 1, 3, 6, 11, 18, 25, 32, and 39 after transplant. CsA, 1.5 mg/kg i.v., was administered every 12 hr beginning on day-1. Eleven patients with hematologic malignancies or aplastic anemia (median age = 34 yr) received TMTX. Toxicity assessed included nausea, vomiting, fever, rash, time to myeloid and platelet engraftment, mucositis, and hepatic and renal dysfunction. Toxicity of TMTX was not different from that observed with MTX in a similar patient population. One patient died on day 16 before engraftment. The other 10 patients all engrafted and all developed acute GVHD at a median time of 11 days after transplant. The major manifestation of acute GVHD was in the skin, and all but one patient responded to primary therapy with corticosteroids. Seven patients have survived a median of 447 days after transplant. No significant toxicity from TMTX was observed. Further trials are warranted to define the role of TMTX in marrow transplantation.

Cytomegalovirus infection of the tongue following marrow transplantation.

Tongue ulcerations in seven patients who had undergone allogeneic BMT for hematologic or lymphoid malignancies were examined for the presence of CMV. The clinical presentation of these tongue lesions was nonspecific and showed ulcerations similar to those associated with severe preparative conditioning regimen-related mucositis, HSV infection and oral acute GVHD. Tissue biopsies were studied by routine histology, immunocytochemistry for CMV and HSV antigens, in situ hybridization for CMV nucleic acid and standard as well as centrifugation viral cultures. Five of the 7 patients had lesions which were positive for CMV. While CMV oral lesions are known to occur in patients with the acquired immune deficiency syndrome (AIDS), these findings will improve our ability to recognize and diagnose tongue lesions in BMT patients and indicate that CMV should be considered in the differential diagnosis for similar ulcerations in other immunocompromised patients.