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Biomedical subjects

S Sonis

Publications and source records attributed to S Sonis.

At least 19 recordsLinked to original sources
PubMed2006

Palifermin (recombinant keratinocyte growth factor-1): a pleiotropic growth factor with multiple biological activities in preventing chemotherapy- and radiotherapy-induced mucositis.

Oral and intestinal mucositis are among the most significant dose-limiting toxic effects of intensive cancer treatment and are associated with adverse clinical and economic outcomes. Palifermin (Kepivancetrade mark), an N-truncated recombinant human keratinocyte growth factor-1, is the first agent to be approved for prevention of oral mucositis. Keratinocyte growth factor, a potent epithelial mitogen, appears to play a major role in the healing process. Palifermin has multiple biological activities that appear to protect the mucosal epithelium and promote its early regeneration after irradiation- and chemotherapy-induced injury. These include inhibition of epithelial cell apoptosis and DNA damage, up-regulation of detoxifying enzymes and down-regulation of pro-inflammatory cytokines, as well as enhanced migration, proliferation and differentiation of epithelial cells. Palifermin reduces the incidence, severity and duration of oral mucositis in patients with haematological malignancies undergoing myelotoxic conditioning therapy and haematopoietic stem-cell transplantation. Clinical sequelae, including febrile neutropenia and resource use (opioid analgesia and parenteral feeding), are concomitantly reduced. Other potential applications being explored include use in the solid tumour setting, reduction of intestinal mucositis and reduction of GVHD in allogenic transplantation. Thus, the development of palifermin and other potential new agents for preventing chemotherapy- and radiotherapy-induced mucositis represents an important breakthrough in oncological supportive care.

Animals↗
PubMed2006

Gene expression changes in peripheral blood cells provide insight into the biological mechanisms associated with regimen-related toxicities in patients being treated for head and neck cancers.

UNLABELLED: Patients treated with radiotherapy are prone to a constellation of local and systemic toxicities including mucositis, xerostomia, fatigue and anorexia. The biological complexities and similarities underlying the development of toxicities have recently been realized. Mucosal barrier injury is one of the best studied, and gene expression patterns, based on animal tissue samples, have added to its understanding. While investigations gene expression based on tissue samples was valuable, its use precludes more generalizable conclusions relative to common pathogenic mechanisms. Additionally, attempting to define the kinetics of changes in gene expression by sequential sampling is pragmatically unrealistic. Our objectives were: 1. to determine if changes in gene expression could be detected during toxicity development using PBM from patients receiving chemoradiation; 2. to characterize the relationship of expressed genes using graph theory and pathway analysis; and 3. to evaluate potential relationships between the expression of particular genes, canonical pathways, and functional networks in explaining the pathogenesis of regimen-related toxicities. DESIGN: Microarray analysis was performed using PBM-derived cRNA obtained before and 2 weeks after the initiation of chemoradiation in five patients with head and neck cancer who developed documented regimen-related toxicities. We created a database of those genes newly expressed at 2 weeks and evaluated their potential significance relative to toxicity, by canonical pathway analysis, compilation of regional networks around focus genes, and development of a model globalizing the individual functional networks. There was strong concordance between known pathogenic mechanisms of toxicity and the genes, pathways, and networks developed by our data. A role was elicited for unsuspected genes in toxicity development. Our results support the concept that radiation induced toxicities have common underlying mechanisms and demonstrate the utility of PBM as an RNA source for genetic studies. This methodology could be broadly applicable to the study of regimen-related toxicities.

Adult↗
PubMed2006

Oral mucositis.

Mucositis and xerostomia are the most common oral complications of the non-surgical therapy of cancer. Mucositis, a common sequel of radio- (DXR), chemo-(CXR) and radiochemo-therapy in patients with cancer, or patients requiring haemopoietic stem cell transplants (HSCT), has a direct and significant impact on the quality of life and cost of care, and also affects survival--because of the risk of infection. Apart from dose reduction, preventive and treatment options for mucositis are scarce, although multiple agents have been tested. Evidence suggests that cryotherapy, topical benzydamine and amifostine might provide some benefit in specific situations. The recombinant human keratinocyte growth factor Palifermin (Kepivance) was recently approved as a mucositis intervention in patients receiving conditioning regimens before HSCT for the treatment of haematological malignancies. A number of mechanistically based interventions are in various stages of development. Unfortunately, many other approaches have not been rigorously tested. This paper reviews the clinical features, prevalence, diagnosis, complications, pathogenesis, prophylaxis and management of mucositis.

Anti-Inflammatory Agents↗
PubMed2002

A phase I/II double-blind, placebo-controlled study of recombinant human interleukin-11 for mucositis and acute GVHD prevention in allogeneic stem cell transplantation.

Interleukin-11 (IL-11) decreases cytokine release and increases survival in murine BMT models. In these systems, it reduces gut permeability, partially polarizes T cells to a Th2 phenotype, down-regulates IL-12, prevents mucositis, and accelerates recovery of oral and bowel mucosa. We conducted a randomized double-blind pilot study of rhIL-11 administered with cyclosporine/MTX prophylaxis after cytoxan/TBI conditioning and allogeneic stem cell transplantation for hematologic malignancies. Patients received rhIL-11, 50 microg/kg subcutaneously daily or placebo in a 3:1 ratio. Treatment was administered prior to the start of conditioning and continued up to 21 days. The study was designed to assess safety with stopping rules for cardiac arrhythmias and mortality. Although projected to accrue 20 patients, only 13 patients (10 IL-11, three placebo) were enrolled because the early stopping rule for mortality was triggered. Of 10 evaluable patients who received IL-11, four died by day 40 and one died on day 85. Deaths were attributable to transplant-related toxicity. One of three placebo recipients died of suicide, the other two are alive. Patients receiving IL-11 had severe fluid retention and early mortality, making it impossible to determine whether IL-11 given in this schedule can reduce the rate of GVHD. Grade B-D acute GVHD occurred in two of eight evaluable patients on IL-11 and one of three patients on placebo. The primary adverse events of the study were severe fluid retention resistant to diuresis (average weight gain 9 +/- 4%) and multiorgan failure in five of 10 evaluable patients. The use of IL-11 as GVHD prophylaxis in allogeneic transplantation cannot be recommended as administered in this trial.

Adult↗
PubMed1999

The biological basis for the attenuation of mucositis: the example of interleukin-11.

Oral mucositis is common, painful, dose-limiting toxicity of drug and radiation therapy for cancer. In granulocytopenic patients, the ulcerations which accompany mucositis are frequent portals of entry for indigenous oral bacteria often leading to bacteremias or sepsis. The complexity of mucositis as a biological process has only recently been appreciated. The condition appears to represent a sequential interaction of the oral mucosal cells and tissues, pro-inflammatory cytokines, and local environmental factors in the mouth such as microorganisms and saliva. The recognition that the pathophysiology of mucositis is a multifactorial process has presented opportunities for intervention based on biological attenuation. Interleukin-11, a pleotropic cytokine, has a range of activities which is potentially relevant to mucositis. Consequently, it has been used successfully to modify the development, severity and course of mucositis in an animal model which closely mimics the equivalent human condition.

Animals↗
PubMed1995

Alteration in the frequency, severity and duration of chemotherapy-induced mucositis in hamsters by interleukin-11.

Ninety-five young, male Golden Syrian hamsters were randomly divided into five equally sized groups. One group served as a placebo control while the animals in the others received one of four doses of interleukin-eleven (IL-11) twice daily given by subcutaneous injection beginning on the first day of chemotherapy (day 0) and continuing to day 14. Mucositis was induced with 5-fluorouracil using a standard regimen of 60 mg/kg, intraperitoneally on days 0 and 2 followed by superficial mucosal irritation on day 4. Animals were evaluated daily beginning on day 6. Mucositis was assessed using a standardised technique in which randomly numbered daily mucosal photographs were scored by three blinded independent observers at the conclusion of the experiment. IL-11 favourably affected the frequency, severity and duration of mucositis. This phenomenon appeared to be dose dependent. Hamsters receiving 30 and 100 micrograms per day of IL-11 demonstrated significantly (P < 0.05) lower mucositis scores than did either the control or animals receiving 3 or 10 micrograms per day, although the latter had marginal beneficial effects. Additionally, survival was significantly better for hamsters receiving higher doses of IL-11 (85%) compared to the placebo control (46%). IL-11 administration also favourably affected weight loss. While stimulation of platelet production was noted in animals receiving IL-11, a lack of difference in bone marrow cellularity between test and control animals suggests that the mechanism by which IL-11 modifies mucositis is mediated at the epithelial or connective tissue level rather than through the marrow. The kinetics of IL-11 alteration of mucositis induction supports such a hypothesis. Further investigation is currently underway to establish a definitive mechanism by which IL-11 protects the oral mucosa.

Animals↗
PubMed1993

Assessment of the need for treatment of postendodontic asymptomatic periapical radiolucencies in bone marrow transplant recipients.

Oral screening and treatment of existing oral disease before bone marrow transplantation have been reported to decrease the incidence of infectious complications during bone marrow transplantation. Information about the adverse sequelae of specific preexisting oral diseases during bone marrow transplantation is lacking. The presence of postendodontic periapical radiolucencies may suggest recurrent or latent infection. The purpose of this study was to compare the effect of endodontic treatment with nontreatment of asymptomatic postendodontic periapical radiolucencies on the frequency of infectious oral complications during bone marrow transplantation. The records of 276 patients undergoing bone marrow transplantation examined between July 1988 and June 1991 were reviewed retrospectively. Twenty-three postendodontic periapical radiolucencies were identified in 8 women and 15 men. The mean age of patients was 41 years (range, 25 to 58 years). Fourteen of the lesions were untreated, and nine were treated before bone marrow transplantation. When outcomes of transplant complications were compared, neither increased systemic infection as measured by neutropenic days febrile nor local oral infectious complications were significantly different. These results suggest that nontreatment of asymptomatic postendodontic periapical radiolucencies does not increase the incidence of infectious complications during bone marrow transplantation.

Adult↗
PubMed1991

Prevention and management of oral mucositis induced by antineoplastic therapy.

Oral complications almost always occur as a consequence of treatment for head and neck cancer. In addition, approximately 40% of patients with nonhead and neck malignancies develop oral problems following exposure to chemotherapeutic agents and x-ray therapy. Patient-related risk factors for these problems include the type of malignancy, patient age, and the level of oral health before and during therapy. The authors discuss direct and indirect stomatotoxicity and present an overview of various methods of ameliorating and/or preventing oral mucositis.

Antineoplastic Agents↗
PubMed1988

Impact of improved dental services on the frequency of oral complications of cancer therapy for patients with non-head-and-neck malignancies.

An earlier study by our group reported a frequency of about 40% for oral problems associated with cancer therapy for patients with non-head-and-neck malignancies. Since then, we have instituted a variety of preventive and treatment protocols aimed at the aggressive management of the mouth in patients being treated for malignant disease. In the present study we evaluated the frequency and nature of oral problems associated with cancer treatment in 495 patients treated for non-head-and-neck malignancies between 1978 and 1986. Our analysis indicates that the frequency of oral problems in the study population was 10.5%, compared to 38.7% in 1978. The specific nature and distribution of oral problems by diagnosis, by patient's age, and by type were remarkably consistent. Our results suggest that early and aggressive dental intervention in standardized protocols reduces the frequency of oral problems associated with cancer therapy.

Adolescent↗
PubMed1987

Increased efficiency of immunotherapy using irradiated tumor cells.

The efficacy of irradiated tumor cells combined with chemotherapy or non-specific immunostimulation with complete Freund's adjuvant was tested in a model of minimal residual tumor-bearing syngeneic mice. Male C57BL/6J mice were innoculated in the right rear leg with live tumor cells from a methylcholanthrene induced fibrosarcoma. The tumor was resected when it reached 0.7 cm in diameter and animals were treated with doses of irradiated tumor cells (XTC) from the primary tumor ranging in number from 1 X 10(3) to 9 X 10(3). Best survival was noted using 5 X 10(3) XTC combined with irradiated tumor cells of liver or pulmonary metastases origin, complete Freund's adjuvant or cytoxan. The combination of irradiated tumor cells of metastatic origin did not enhance the therapeutic effect of XTC alone. Freund's adjuvant was not of benefit in enhancing the efficacy of XTC. However, improved survival was noted when chemotherapy in the form of cytoxan was used to supplement XTC. Our data suggests that XTC is more efficacious as a mode of immunotherapy than are live tumor cells. The dose of XTC used is critical in determining its effect. Chemotherapy appears to enhance the benefit of XTC.

Animals↗
PubMed1983

Polymorphonuclear leukocyte regulation of lymphocyte proliferation and differentiation.

The polymorphonuclear neutrophil (PMN) regulates in vivo and in vitro immune responses. We report that the immunoenhancing properties of PMN culture supernatants from PMN recruited by the bacterium Actinomyces viscosus (AV) show its exclusive effects on the T cell lymphocyte population. A study of the effect of PMN supernatants on normal Balb/c splenocytes to T and B cell mitogens showed enhancing effects on T cell mitogens, but no effect on B cell mitogen responses when compared to a control. Adherent cells (macrophages) were not required for the enhancing effect, indicating that the supernatant worked directly on the T cell. Proliferation of El-4, a Lyt-1.2 positive lymphoma helper cell, was directly affected by these supernatants. Functionally, T cell-dependent plaque-forming cell responses to sheep red blood cells (SRBC) were enhanced. The polyclonal, T cell-independent plaque-forming cell response was unaffected when generated with LPS as assayed with Protein-A-SRBC. These results indicate that PMN supernatants from cells recruited by AV act on a helper T cell population to enhance both proliferation and differentiation in lymphocyte populations. These interactions provide insight into local inflammatory responses of PMN-lymphocyte infiltration with altered cell-mediated immunity.

Actinomyces↗
PubMed1980

Oral pathoses as diagnostic indicators in leukemia.

A retrospective chart review of 500 leukemia patients was carried out to analyze the role of oral pathoses in the presentation of leukemia and to determine those factors which affect the frequency of oral involvement during the initial clinical phases of the disease. The data indicate that oral pathoses were frequent signs or symptoms in patients with undiagnosed acute leukemia but were less prevalent in patients with undiagnosed chronic leukemia. Neither age nor sex appeared to be a significant factor affecting oral involvement. Oral signs of thrombocytopenia were the most prevalent complaint of patients seeking diagnosis for their leukemia because of an oral problem, and they were also most frequently responsible for oral problems found at initial physical examination. Head and neck lymphadenopathy was also a frequent presenting sign or symptom. Dentists were responsible for initiating the diagnosis of leukemia in a significant number of patients with acute nonlymphoblastic leukemia.

Adolescent↗
PubMed1978

Circulating immune complexes in patients following clinically curative resection of colorectal cancer.

Sixty-nine patients have been followed prospectively after curative resection of Dukes-Kirklin B-2 or C colorectal cancer. Serial plasma samples were studied in selected patients to determine changes in circulating immune complex concentrations (CIC) following primary tumor resection, and to compare serial plasma CIC and carcinoembryonic antigen (CEA) levels. CIC was determined in an average of seven serial samples per patient by inhibition of antibody-dependent cell-mediated cytotoxicity (ADCC). CEA assays were performed by the Hanson Z-gel method. Two distinct patterns of serial CIC have emerged. In seven patients with no known tumor recurrences, serial CEA levels and CIC oscillated regularly and were inversely related. In seven of eight patients whose tumors recurred, both CEA and CIC rose together. In three patients with elevated plasma CEA levels due to inflammatory bowel disease, serial Ag-Ab complex concentrations did not vary, nor did separated Ag or Ab fractions inhibit ADCC. These data suggest that, in patients following curative resection of colorectal cancer, serial changes in circulating immune complexes may discriminate between transient CEA elevations which occur despite no known tumor recurrence and tumor recurrence which is beyond the capacity of adequate host antitumor defense.

Adenocarcinoma↗
PubMed1977

Assessment of drug sensitivity of human leukaemic myeloblasts. I. Labelling human myeloblasts with 125IUdR for survival studies in mice.

The compound (125)IUdR can be incorporated in a stable form into the DNA of cells. The isotope is released if labelled cells or their progeny die. Consequently the rate of (125)I excretion from mice can be used to follow the fate of labelled cells in vivo. Using these principles we show:(1) Sufficient label can be incorporated in vitro into both fresh and cryopreserved human leukaemic myeloblasts, in non-toxic concentrations, to allow their survival in mice to be estimated by whole-body counting;(2) The release of isotope from labelled cells is sufficiently slow to offer reasonable expectation that this technique can be used for assessing the sensitivity of myeloblasts to cytotoxic agents in vivo (an application described in the second paper in this series, Sonis, Falcão and MacLennon, 1977);(3) The rate of (125)Iexcretion from mice injected with myeloblasts from different donors varies. This probably reflects different rates of spontaneous death of injected myeloblasts;(4) Active rejection of myeloblasts starts within 48 h of their injection into mice;(5) Indirect evidence that phagocytic cells may be active agents in myeloblast destruction in mice;(6) Various methods of immunologically depriving mice were assessed to see if they would result in a useful increase in survival of injected human myeloblasts. We conclude that there is little advantage and some limitations in using mice thus deprived;(7) One of the agents used for immunological deprivation-silica powder-markedly decreased the rate of (125)I loss from mice injected with labelled killed myeloblasts. This experience emphasizes the importance of including the killed-cell control in this assay.

Animals↗