Alpa Administrative Manual Section 409a
• 70 Downloads • Summary We reviewed 55 cases of streptococcal bacteremia in adult patients who received cytotoxic chemotherapy for treatment of acute leukemia. Viridans group streptococci were the most frequent species isolated (45 isolates). Hemolytic streptococci (four isolates), pneumococci (three isolates), and enterococci (three isolates) were infrequent.
Clinical features of streptococcal bacteremia included fever, upper and lower respiratory infection, respiratory distress syndrome, soft tissue infection, and septic shock. Forty patients who had only streptococci, but no other organisms isolated from their blood, were compared with 36 cases of gram-negative bacillary bacteremia that occurred during the same study period within the same population at risk. The comparison showed that patients with streptococcal bacteremia had more often received high dose cytosine arabinoside as part of their chemotherapy (17 vs.
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Treatment-related morbidity, and in some cases, mortality, associated with autologous and allogeneic bone marrow transplantation has decreased in the past decade largely due to the use of blood stem cells combined with hematopoietic growth factors. However, these procedures remain morbid, with several series documenting regimen-related injury to the oral mucous membranes, the worst form of toxicity from a patient perspective. The pathophysiology of transplant-related mucositis is related to two major events: direct mucosal basal cell injury leading to atrophy and ulcerations, and local infections that can become systemic, the latter of which are exacerbated by the severe neutropenia accompanying high-dose chemotherapy. Recent investigational agents designed to interfere with these two aspects of mucositis have been developed and are showing promise in early clinical trials. In particular, keratinocyte growth factor (KGF) and interleukin-11 appear active.
They increase basal cell proliferation, prevent apoptosis due to the preparative regimen, and appear to ameliorate the mucositis seen with high-dose chemotherapy regimens. Oral, nonabsorbable anti-infective agents are also being tested in an attempt to prevent both local and systemic infections. Devoid of significant side-effects, KGF is now in large phase 2 trials that, if positive, will be a significant advance in promoting less morbid transplants by reducing pain and the risk of secondary infections and thus may reduce supportive care costs. Bone Marrow Transplantation (2001) 27, Suppl. Oral mucositis is undoubtedly one of the most debilitating toxicities of hematopoietic stem cell transplantation. Until recently, the only successful way to manage this common complication was to provide good oral hygiene and copious amounts of narcotic analgesics.,,,, However, with the recent investigation of several experimental agents that may not only diminish the severity of mucositis but also decrease its frequency, an emphasis on pathophysiology and accurate measurement has taken center stage in the transplant arena. In the next few years several active agents will likely be available to significantly diminish both the frequency and severity of mucositis associated with transplantation.
To assess benefit, however, a clear understanding of the mechanisms by which chemotherapy and radiation cause mucositis and an accurate method to grade its severity is required. This review describes what is known about the incidence and severity of mucositis, as well as its measurement, pathophysiology, and clinical consequences. Additionally, an overview of several investigational agents being tested to control mucositis is presented.
Various studies have demonstrated that significant oral mucositis occurs in about 75% of patients undergoing stem cell transplantation.,,, Regimens including total body irradiation (TBI) plus chemotherapy lead to a higher rate of mucositis than chemotherapy alone. Severity varies widely among chemotherapy agents; high-dose etoposide and melphalan appear to cause the most severe forms of mucositis. A recent in-depth survey of 38 patients who had completed their transplants was undertaken to assess the importance of mucositis to the patient.
Forty-two percent felt that mucositis was their most significant transplant-related toxicity, compared to 13% who cited nausea and vomiting. Our center (BMT Program, Loyola University Medical Center, Maywood, IL, USA) recently performed a retrospective survey of the toxicities of bone marrow transplantation (BMT) in 41 patients who underwent either allogeneic (11) or autologous (30) transplantation. Of the 41 patients, 21 received high-dose chemotherapy alone and 20 received chemotherapy and radiation as their preparative regimen. Twenty-five underwent transplant more than 1 year prior to the survey, and 11 less than 6 months prior to the survey. As shown in, mucositis was felt to be the most debilitating toxicity by 50% of all the patients, by 30% of patients receiving high-dose chemotherapy alone, and by 65% of patients receiving TBI-based regimens.
Utilizing a 1–10 severity scale (), patients who listed mucositis as their most toxic side-effect rated it on average as a 9. No patient listed it at less than 7. Additionally, 84% reported their mucositis as more severe than expected and 65% reported either no symptom control or 50% improvement at best with palliative symptom control. In contrast, those citing nausea and vomiting as the worst toxicity reported their symptoms controlled on average greater than 50% of the time. Most importantly, of those reporting mucositis as the worst toxicity, 65% still had residual oral symptoms at the time of the survey, including symptomatic xerostomia in nearly 50% and a higher rate of cavities compared to pretransplant in 21%. The conclusions from these surveys indicate that mucositis, while transient in the post-BMT period (lasting on average 7–10 days), is considered by patients to be their worst and most severe toxicity.
Despite our best efforts at good hygiene and narcotic use – at our center, mucositis is treated with oral rinses and topical anesthetics, as well as systemic narcotics – our patients are still experiencing significant mucositis-associated morbidity. More importantly, as will be discussed, several recent reports demonstrate that severe mucositis is not only associated with a decrease in quality of life, but may be associated with increased mortality, extended hospitalization, and increased costs.
The second phase of mucosal injury begins at the point of mucosal ulceration, at which time aerobic and anaerobic bacteria develop in and exacerbate lesions. Neutropenia complicates these local infections. From 25% to 75% of bacteremias seen post-transplant may have disrupted oral mucus membranes as the portal of infection.,,,, This phase is likely complicated by the use of broad-spectrum antibiotics, which can lead to local and eventually systemic gram-negative, viral, and fungal infections.
With routine use of acyclovir for herpes simplex viral (HSV) infections and topical or systemic anticandidal therapies, HSV and Candidal infections are now uncommon. Uncontrolled local infections (often due to poor hygiene predisposing to pseudomembrane formation) and deep ulcerations are factors that can delay wound healing and also lead to increased pain. However, they are largely prevented by good oral hygiene including salt solutions and nonalcohol mouthwashes.,,, Basal cell regeneration normally begins 9–14 days after injury, and thus mucositis begins to resolve at about the time of neutrophil reconstitution following transplant. Epithelial cell regeneration is also associated with the return of a normal oral bacterial flora. However, chronic injury including persistent xerostomia and increased dental cavities is not uncommon despite repair of the acute injury. With the development of potentially effective therapies to prevent or decrease the severity of mucositis, it is critical to have an accurate description of the anatomic changes of mucositis, as well as methods to measure its severity.,, While the World Health Organization (WHO) toxicity grading scale () is widely used, it has long been felt to be too subjective to accurately represent the anatomic and pathophysiologic changes that occur during mucositis.
Indeed, the symptoms that this scale measures may not be due to mucositis at all, but to local infection, hemorrhage, or the presence of an underlying malignancy. The WHO scale can be assigned without even examining the patient, and thus can potentially reflect ideologies other than clinical mucositis. However, it may be the most accurate measure of the clinical consequences of mucositis (ie pain and the requirement of parenteral medication and nutrition). The lack of specificity in the WHO scale has led to scales that ‘measure’ mucositis objectively such as the modified Oral Mucositis Assessment Scale (OMAS; ) and the Western Consortium for Cancer Nursing Research (WCCNR) scale (),, as well as scales that use a combination of both anatomic and subjective measures such as the Oral Assessment Guide (OAG; ). The advantages and disadvantages of more complicated scales are obvious. The OMAS scale is the most technically challenging as it measures lesion size and erythema at nine different sites in the oral cavity. Obviously, this scale is very difficult to use in patients with severe pain who are unable to open their mouths for a sufficient oral examination, a very common phenomenon in the BMT setting.
The OMAS and WCCNR scales are strictly observational tools; the revised WCCNR is the less cumbersome of the two, particularly for patients with severe mucositis. Download Free Roxanne Shantae Go On Girl Zip Line here. The OAG combines both subjective and objective measures and might suffice as a single scale to measure mucositis. In addition to pain and decreased quality of life, recent studies have begun to more accurately measure the specific medical complications and consequences of mucositis.
Rapoport et al sought to identify predictors of mucositis following stem cell transplantation. They utilized the OAG as their measure of mucositis severity and made the peak score for mucositis (MUCPEAK) of the OAG one of their study endpoints. They found that a diagnosis of leukemia, the use of TBI in the preparative regimen, and allogeneic BMT were all significantly associated with mucositis. Severe mucositis (ie MUCPEAK score of ⩾18) was correlated with an increased incidence of bacteremia and mortality. In their study, 60% of those with a score ⩾18 developed bacteremia compared with 30% of those with lower MUCPEAK scores ( P = 0.001). In addition, patients with scores ⩾18 had a mortality rate of 24% compared to a 4% mortality rate for those with lower scores ( P = 0.001).
A multivariate analysis of the independent risk factors could not be performed in this study because many of the variables associated with mucositis overlapped (eg acute leukemia and the use of TBI). Thus firm correlation of mucositis and mortality cannot be assumed.
Nevertheless, for the group with the highest mortality, those undergoing allogeneic transplantation, the correlation of mucositis and mortality was significant. In addition, as total parenteral nutrition (TPN) use correlated with the presence of bacteremia ( P = 0.0001) and mortality ( P = 0.003), it is certainly likely that high MUCPEAK scores were associated with overall transplant costs.
The results of a recent study showed similar clinical correlates to severity of mucositis, and strongly suggested a high economic price caused by severe mucositis in the BMT population. Using the OMAS scale, Horowitz et al studied 84 patients from eight centers. This diverse group included both autologous (46%) and allogeneic (54%) transplant patients, and utilized the mean OMAS score for each patient calculated over a 28-day period starting on the day the preparative regimen began.
This mean score was analyzed for significant correlations with the incidence of infection, number of febrile days, days of TPN, 100-day morbidity, and total hospital charges. They found a significant correlation between the mean OMAS scores and both total days of TPN and total charges.
Logistic regression analysis demonstrated that each increase in the OMAS score of 1.0 was associated with a significant increase in infections ( P = 0.05). Linear regression analysis showed that a 1.0 increase in mean OMAS score was associated with a significant increase in febrile days ( P = 0.02), days of TPN ( P >0.01), increased days of parenteral narcotic use ( P >0.01), and $28554 of additional transplant charges.
Mortality did not correlate with OMAS scores in this study. These and additional data from Ruescher et al validate the hypothesis that serious infection can result from severe mucositis. In that report, streptococcal infections in patients with severe ulcerative mucositis were three times higher than in patients with mild symptoms. As septic shock can develop from streptococcal bacteremia, it is not surprising that in one of these studies, mortality was higher in patients with the most severe forms of mucositis. A direct cause and effect cannot be proven, as those with the most severe mucositis were treated with the highest doses of TBI, suggesting that other nonhematopoietic toxicities may have contributed to the increased mortality.
Nevertheless, because of the association, efforts at decreasing severe mucositis appear appropriate as these studies do suggest a link between mucositis, sepsis, and its ultimate complication, death. Overall, it appears that the various mucositis scales employed in these studies not only accurately measure the objective and subjective features associated with mucositis, but the clinical consequences associated with mucositis as well. Quality of life, particularly as it relates to pain, appears to be accurately measured by the OAG scale, as was found in the analysis of a novel therapy for mucositis, keratinocyte growth factor (KGF, described later).
Oral hygiene, rinses and nutritional supplements Poor dental care pre-BMT is associated with a higher frequency of local and possibly systemic infection during BMT. Therefore, it is important that dental care be optimized before the patient is subjected to the transplant procedure. In general, teeth brushing is usually not recommended during periods of mucositis in the BMT setting due to the fear of significant oral bleeding and/or the promotion of bacteremia from ulcerative lesions. Most centers treat patients with oral nonalcohol rinses (eg salt solutions) and topical anesthetics (eg dyclonine or xylocaine). A randomized study in the BMT setting comparing rinses alone to aggressive oral care including tooth brushing was recently reported. Sepsis was not higher in the aggressive oral care group, nor were days of fever. Furthermore, differences between the groups in the number of patients with moderate to severe mucositis was unremarkable (70/75 in the rinses-only group and 64/75 in the intensive therapy group), confirming a lack of a benefit of aggressive oral hygiene.
Glutamine, an essential amino acid, appeared to improve mucosal integrity in preclinical models., Glutamine-rich diets and rinses have been tested as mucositis therapy based on these favorable results. In a small, randomized, blinded study, oral glutamine 2 g/m 2 twice daily during and after conventional-dose chemotherapy led to a reduction in oral pain. Several randomized, double-blind studies have been undertaken in the BMT setting.
Schloerb et al studied 66 BMT patients randomized to either oral glutamine or a glycine control at a dose of 10 g three times daily. When TPN became necessary, those randomized to glutamine received i.v. Glutamine in their TPN. Those randomized to control did not. No significant difference was found in hospital stay, TPN days, neutrophil recovery, incidence of positive blood cultures, sepsis, diarrhea, and most importantly, mucositis. In a second study, MacBurney et al evaluated in a double-blind prospective trial glutamine-supplemented TPN in the transplant setting.
In contrast to the first trial, they found an improvement in nitrogen balance, shorter hospital stays, a decrease in positive blood cultures, and lower rates of clinical infection in the glutamine-supplemented patients. In addition, hospital charges were found to be nearly $22000 less per patient in the glutamine-supplemented group, suggesting that i.v. Glutamine when given in TPN routinely post transplant can improve outcomes.
In the largest study to date, Anderson et al evaluated in a randomized, double-blind, placebo-controlled trial oral glutamine 1 g/m 2 four times per day in 193 BMT patients. In the autologous transplant patients ( n = 87), glutamine was associated with significantly less oral pain by both patient reporting and narcotic use ( P = 0.005). There was no improvement in these parameters in allogeneic transplant patients.
No significant differences were observed in either group for TPN use, rate of relapse, progression of malignancy, parenteral antibiotic use, graft-versus-host disease (GVHD), or days of hospitalization. The authors suggested that benefit was not seen in the allogeneic transplant patients because they were treated with methotrexate for GVHD prophylaxis. Taken together, these clinical trial data indicate a potential role for parenteral glutamine supplementation in mucositis management. Hematopoietic growth factors Myeloid growth factors: Myeloid growth factors, given after standard-dose chemotherapy, appear to partially ameliorate mucositis. The rationale for their use is their known proliferative effects on nonhematopoietic tissues. In the initial clinical trial that explored granulocyte colony-stimulating factor (G-CSF) for the prevention of neutropenic fevers and infection, Crawford et al noted a drop in the overall incidence of mucositis in the G-CSF group from 63% to 46% ( P = 0.02).
A second study by Gabrilove et al demonstrated a decrease in mucositis from 44% to 11% for G-CSF patients receiving an M-VAC regimen (methotrexate, vinblastine, adriamycin, cisplatinum) over the first two cycles of chemotherapy. Similar results have also been seen for patients treated with conventional chemotherapy and granulocyte–macrophage colony-stimulating factor (GM-CSF). In the transplant setting, the benefits of myeloid growth factors have been less impressive. While Nemunaitis et al noted a reduction in mucositis in patients undergoing a human leukocyte antigen (HLA)-matched sibling allograft with post-transplant GM-CSF treatment, no difference was seen in the incidence and severity of mucositis in patients receiving an HLA-matched sibling transplant with high-dose busulfan and cyclophosphamide in the study by Atkinson et al. Topically administered G-CSF and GM-CSF is also under investigation.,, The rationale for topical use is based on data in animal models that suggest enhanced wound contraction and healing. To date, studies indicate a marginal benefit, if any, when evaluated in a randomized fashion. Interleukin 11 (IL-11): IL-11, a member of the IL-6 cytokine family, ameliorates thrombocytopenia following myelosuppressive chemotherapy.
Other actions, demonstrated in vitro, suggest its potential value in the modulation of mucositis., IL-11 increases proliferation of the mucosal basal cell layer and partially suppresses apoptosis, thus protecting basal cells from the toxic effects of radiation and chemotherapy. Enhanced survival was seen when it was administered pre-radiotherapy in a murine model., In a preclinical model of GVHD, IL-11 prevented the disease and led to enhanced survival, presumably by protecting the basal cell layer of the gastrointestinal tract from the toxic effects of the preparative regimen and by decreasing endogenous production of TNF-α, endotoxin, and IL-2 in the gastrointestinal tract., To date, only one trial has been reported exploring IL-11 in the human BMT setting to reduce mucositis. This randomized, placebo-controlled, dose-finding study explored doses of IL-11 from 3 μg/kg/day to 50 μg/kg/day along with high-dose chemotherapy using BuMelTT (busulfan, melphalan, thiotepa). IL-11 was given daily after busulfan was completed (ie before melphalan and thiotepa) and was continued for a total of 15 days. At doses of 3, 10, and 25 μg/kg, there was no difference in the rate of grade 3 or 4 mucositis (WHO scale) compared to the placebo group.
However, at the 50 μg/kg dose, only one of three patients developed severe mucositis, and one did not develop mucositis at all. The authors reported a decreased incidence of bacteremia/sepsis in the two highest dose levels (1/7, 14%) as compared to the other groups (12/22, 55%). In addition, the number of days of severe mucositis was reduced in the two highest dose groups.
The limitations of these promising data are the small number of patients treated in the 50 μg/kg/day group, a dose associated with an increased incidence of edema and cardiac arrhythmias as indicated in myelosuppression studies of IL-11. However, toxicity concerns might be appropriately addressed by altering the IL-11 regimen according to a presumed optimal schedule developed in animal models of mucositis (ie initiation of IL-11 3 days prior to the preparative regimen).
Given these promising data, further trials of IL-11 in the prevention of both oral and gastrointestinal mucosal toxicity and their consequences are warranted. Antimicrobial agents It has long been recognized that neutropenic patients not only develop bacteremia from mucositis, but that local infections can contribute to the misery of this transplant complication as well. Controlled trials have been performed with a number of agents including hydrogen peroxide and chlorhexidine.,, In general, these agents have not led to a significant improvement in mucositis. In fact, hydrogen peroxide may actually have a detrimental effect by developing resistant bacteria and interfering with wound healing by modifying oral pH. All of these agents lead to incomplete antimicrobial killing.
While it seems unlikely that any anti-infective agent will prevent or delay damage to the basal cell layer caused by radiotherapy and chemotherapy, a potent anti-infective agent may help alleviate pain, shorten the period of mucositis, decrease the incidence of bacteria/sepsis, and thus contribute to a lessening of morbidity and mortality in this population. One such agent has recently entered clinical trials. IB-367, a naturally occurring antimicrobial agent derived from porcine neutrophil peptides, is active against all microbiological organisms found in the oral cavity of patients. After demonstrating benefit in animal models of chemotherapy-induced mucositis, a randomized phase II trial in the transplant setting was undertaken in 177 patients.
The OMAS scale was used to measure mucositis severity. Patients were randomized up to 1 week pretransplant to receive either IB-367 or placebo. The agent was administered in a 3-ml rinse to be used every 3 h while awake. Patients were instructed to rinse and hold the agent in their mouth for several minutes before expectoration. While there were dropouts due to the inability to take the agent throughout the entire transplant period, the median time on study drug was 17 days, and the major reason for discontinuation was hospital discharge. Overall, the agent reduced OMAS scores by 28% ( P = 0.06).
However, in patients taking the agent for ⩾4 days prior to stem cell infusion, mucositis was reduced by 42% ( P = 0.05). A trend toward a decrease in days of severe mucositis and number of febrile days was also seen. There were no differences in hospital stay between the two groups. There were also no differences between the groups regarding narcotic use or the ability to eat solid food, perhaps because of the fact that the preparative regimens caused damage to the posterior oropharynx and upper esophagus, as well as the agent's likely limited distribution in the oral cavity. Nevertheless, this type of agent may be valuable as a component to the overall strategy to decrease the effects of mucositis, primarily infections. A phase III study of IB-367 in the BMT setting is underway. KGF is a 28 kDa heparin-binding member of the fibroblast growth factor family.
It binds to its receptor on a variety of epithelial tissues including skin keratinocytes and stratified squamous epithelium, gastrointestinal and oral epithelial cells, hepatocytes, and type II pneumocytes.,,,,, It was initially described in 1989 by Rubin et al, who discovered it in the conditioning media of a human embryonic lung fibroblast cell line. It was found at that time to be capable of stimulating DNA synthesis in a variety of tissues, most notably resting epidermal keratinocytes by greater than 500-fold over baseline. In both animal and human models, KGF causes epithelial thickening of the nonkeratinocyte layers of the oral mucosa, with similar activity in the digestive tract, localized primarily to the stomach and upper small bowel.,,,, KGF administered to mice and nonhuman primates has been shown to protect a variety of tissues exposed to damage (including radiation and chemotherapy damage) and produce oral mucosal proliferation without other significant systemic side-effects. Given to normal volunteers, KGF stimulated the proliferation of oral epithelial cells and increased the percentage of actively dividing cells as measured by an increase in mitotic figures and Ki 67 positivity. These effects were seen in both murine and human models after only 2 to 3 days of administration of recombinant human KGF.,, KGF stimulates not only proliferation and migration of epithelial basal cells, but also their differentiation. Effects appear to be maximal on the oral mucous membranes and the upper digestive tract, primarily stomach and proximal small bowel. KGF also has proliferative effects on the epithelial lining cells of the bladder, where it was shown to ameliorate cyclophosphamide-induced ulcerative hemorrhagic cystitis.
In murine models where mice were treated with 5-fluorouracil, methotrexate and TBI, or TBI alone, KGF increased survival by 55% or greater. In the chemotherapy/radiation combination model, it significantly prevented weight loss during therapy and accelerated weight gain during recovery. KGF has also been shown to increase crypt cell survival in the small bowel by 3.5-fold in this model. KGF may also have a beneficial effect on GVHD and its complications.
When administered in a murine model of GVHD from day −3 to day +7 following allogeneic transplant, KGF significantly reduced GVHD mortality and severity in the gastrointestinal tract by decreasing lipopolysaccharide as well as TNF-α levels. However, there was no adverse effect on antitumor cytotoxic T cell responses. Thus, in this model of P815 leukemia, GVHD was reduced and leukemia-free survival was enhanced significantly compared to controls (42% vs 4% for leukemia-free survival, P. Dosing began at 5 μg/kg/day and increased to a high of 80 μg/kg/day. Oral reactions, generally mild to moderate in severity and presumably due to the biologic effects of the drug, were seen during the initial 3 days of treatment. These included flushing, rash, edema, tingling, white tongue, and thick feeling of the tongue.
The incidence of these reactions was 28% in patients at KGF doses above 20 μg/kg compared to 2% in the placebo group. Onset of the reactions was 36 h after the first dose of KGF, and symptoms resolved in 7 to 10 days. The maximally tolerated, and optimal, dose was 60 μg/kg; as several patients at the 80 μg/kg dose developed what were felt to be moderate skin and oral reactions to KGF (eg xerostomia and minor oral soreness that occurred early, but were similar in nature to mucositis-type symptoms). As expected, the BEAM regimen was only moderately mucotoxic. WHO grade 3–4 mucositis was seen in 22% of the placebo group and 18% of the KGF group. In contrast, at the optimal KGF dose level (60 μg/kg), no grade 4 mucositis was seen, and less than 10% of patients had grade 3 toxicity. The severity of mucositis as measured by the WHO criteria was identical to that for scores using the OAG.
This suggests that complicated assessment scales may be unnecessary in evaluating the response to KGF, an assessment that does not require verification in additional studies. Interestingly, the patients’ own estimates of quality of life paralleled the severity of their mucositis as measured by either the WHO or the OAG scoring system. Based on these results, a randomized phase II trial is underway exploring KGF in the transplant setting using a preparative regimen commonly used to treat patients with lymphoma and leukemia.
In addition to the severe pain and decreased quality of life that many patients with mucositis endure, it is now clear that the complication is associated with an increase in systemic infections, hospital days, and costs. Mucositis is also a major cause of morbidity in patients undergoing radiation therapy for head and neck cancers, and those receiving certain chemotherapeutic agents for a variety of human malignancies. Agents that decrease the incidence, severity, and/or duration of mucositis may therefore not only provide patient comfort, but also decrease the complications associated with mucositis. As indicated by the phase I trial exploring the effect of KGF on mucositis, it is apparent that simple measures to assess mucositis such as pain and the ability to swallow solids or liquids are not only easier to use than more elaborate observational scales, but also appear to be equally predictive of the most severe forms of mucositis. However, in assessing the efficacy of new agents, it would appear appropriate to use not only a subjective scale, but also a more objective scale in which lesions in the oral cavity are at least visually assessed. Ultimately, it appears likely that the misery of mucositis may soon be significantly improved by one or more of these agents used either singly or in combination.
This will be a welcome and long overdue relief to all patients undergoing stem cell transplantation. Sonis S, Clark J. Prevention and management of oral mucositis induced by antineoplastic therapy Oncology 1991 5: 11–18 • • • 2. Woo SB, Sonis ST, Monopoli MM et al. A longitudinal study of oral ulcerative mucositis in bone marrow transplant recipients Cancer 1993 72: 1612–1617 • • • • • 3. McGuire DB, Altomonte V, Peterson DE et al.
Patterns of mucositis and pain in patients receiving preparative chemotherapy and bone marrow transplantation Oncol Nurs Forum 1993 20: 1493–1502 • • • • 4. Pico JL, Avila-Garavito A, Naccachie P. Mucositis: its occurrence, consequences, and treatment in the oncology setting The Oncologist 1998 3: 446–451 • • • 5. Bearman SI, Appelbaum FR, Buckner CD et al.
Regimen-related toxicity in patients undergoing bone marrow transplantation J Clin Oncol 1988 6: 1562–1568 • • • • • 6. Bellm LA, Epstein JB, Rose-Ped A et al. Patient reports of complications of bone marrow transplantation Supp Care Cancer 2000 8: 33–39 • 7. Research advances in oral mucositis Curr Opin Oncol 1999 11: 261–266 • • • • 8. Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity Oral Oncol 1998 34: 39–43 • • • • • 9. Prevention and treatment of oral mucositis following cancer chemotherapy Semin Oncol 1998 25: 538–551 • • • 10. Classen DC, Burke JP, Ford CD et al.
Streptococcus mitis sepsis in bone marrow transplant patients receiving oral antimicrobial prophylaxis Am J Med 1990 89: 441–446 • • • • 11. Gamis AS, Howells WB, De Swarte-Wallace J et al.
Alpha hemolytic streptococcal infection during intensive treatment for acute myeloid leukemia: a report from the Children's Cancer Group Study CCG-2891 J Clin Oncol 2000 18: 1845–1855 • • • • 12. Richard P, Amador Del Valle G, Moreau P et al. Viridans streptococcal bacteraemia in patients with neutropenia Lancet 1995 345: 1607–1609 • • • 13. Heimdahal A, Mattson T, Dahlof G et al. The oral cavity as a port for early infection in patients treated with bone marrow transplantation Oral Surg Oral Med Oral Pathol 1989 68: 711–716 • • • • • 14. Steiner M, Villablanca J, Kersey J et al. Alpha streptococcal shock in bone marrow transplantation patients Blood 1988 72: 409a (Abstr.) • 15.
Xerostomia: diagnosis and management Oncology 1996 10: 7–11 • • • 16. Parulekar W, Mackenzie R, Bjarnason G et al.
Adobe Premiere Pro Cs4 Trial Download Free. Scoring oral mucositis Oral Oncol 1998 34: 63–71 • • • • • 17. Oral complications of cancer therapies. Mucosal alterations NCI Monogr 1990 9: 169–172 • • • 18. Measurement of oral tissue damage and mucositis pain.
In: Chapman OR, Foley KH (eds) Current and Emerging Issues in Cancer Pain: Research and Practice Row Press: New York 1993 247–265 • 19. World Health Organization. Handbook for Reporting Results of Cancer Treatment Geneva: World Health Organization 1979 pp 15–22 • 20. Sonis ST, Eilers JP, Epstein JB et al. Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Study Group Cancer 1999 85: 2103–2113 • • • • • 21.
Western Consortium for Cancer Nursing Research. Development of a staging system for chemotherapy-induced stomatitis Cancer Nurs 1991 14: 6–12 • • • 22. Western Consortium for Cancer Nursing Research. Assessing stomatitis: Refinement of the Western Consortium for Cancer Nursing Research (WCCNR) stomatitis staging system Can Oncol Nurs J 1998 8: 160–165 • • • 23. Eilers J, Berger AM, Petersen MC.
Development, testing, and application of the oral assessment guide Oncol Nurs Forum 1988 15: 325–330 • • • • 24.