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At least 127 records · Page 7Linked to original sources

PubMed2003

Gene expression screening using a cDNA macroarray to clarify the mechanisms of peritoneal dissemination of pancreatic cancer.

PURPOSE: Pancreatic cancer is associated with the poorest prognosis of any digestive cancer due to the high incidence of peritoneal dissemination, which is the cause of death in most cases. To determine the mechanisms of peritoneal dissemination in pancreatic cancer, we established a mouse model of high peritoneal dissemination. METHODS: A novel highly peritoneal-disseminating cell line was established from the human pancreatic cancer cell line; CAPAN-1. The new cell line, CAPAN-1P4a, was established from CAPAN-1 by repeated in vivo selection (four times) of the tumor cell line. To clarify the candidate genes implicated in peritoneal dissemination of pancreatic cancer, global gene expression screening was done using a cDNA macroarray. RESULTS: CAPAN-1P4a cells showed 100% metastasis 3 weeks after injection and high reproducibility in the inoculated mice. Twenty-seven genes were upregulated and 14 genes were downregulated in CAPAN-1P4a cells compared with CAPAN-1 cells. The genes differentially expressed in the two cell lines were included as tumor suppressor/apoptosis genes, regulatory transcription factor, membrane receptors, cell adhesion protein, membrane receptors, and so on. CONCLUSIONS: Our established CAPAN-1P4a model offers a new means of conducting global gene expression analysis of pancreatic cancer cells with peritoneal dissemination and it has the potential to provide new insights into the mechanism of peritoneal dissemination in human pancreatic cancer.

Adenocarcinoma↗

PubMedDate not supplied

Does antibody to mycobacterial antigens, including lipoarabinomannan, limit dissemination in childhood tuberculosis?

Serum immunoglobulin (Ig) G responses to a variety of mycobacterial antigens were measured in children from the UK, in children with tuberculosis from Hyderabad, India and Dhaka, Bangladesh, classified according to whether the disease was disseminated or localized, and in non-tuberculous controls. Anti-lipoarabinomannan (LAM) IgG responses in UK children showed a marked trough between 6 months and 3 years coincident with the reported peak incidence of disseminated tuberculosis. Geometric mean IgG responses to sonicates of slow-growing mycobacteria (rich in LAM) in 36 children with disseminated tuberculosis were markedly lower than in 99 children with localized tuberculous lesions (for Mycobacterium scrofulaceum P < 0.01, for M. tuberculosis P < 0.01, and for M. vaccae P < 0.01). Responses to purified LAM were also lower in the disseminated tuberculosis group (P < 0.05) but there was no difference between the groups in their response to mycobacterial 65 kDa protein. Multiple regression analysis showed that the reduced response to sonicated mycobacterial antigens and to LAM in children with disseminated disease was independent of age, nutritional status, skin test reactivity, duration of previous symptoms, and city of origin. There was no evidence for sequestration of antibody to immune complexes. These findings are compatible with the hypothesis that children with low levels of antibody to sonicated mycobacterial antigen and to LAM, or those who cannot mount an antibody response, are predisposed to dissemination. A role for antibody in preventing disseminated forms of tuberculosis in childhood has implications for the development of improved vaccines and for the optimum timing of vaccination with bacille Calmette-Guérin.

Adolescent↗

PubMed2005

Cancer cell dissemination during curative surgery for colorectal liver metastases.

AIM: The amount of cancer cells disseminated during curative surgery for colorectal liver metastases (CRLM) may be responsible for recurrence. Haematogenous and intrahepatic cancer cell dissemination was evaluated, and its impact on cancer recurrence was assessed. METHOD: Twenty patients with resectable CRLM were included in a prospective study. Twelve patients underwent curative resection for 21 metastases. Ten selected metastases in eight patients were treated with radiofrequency ablation (RFA) followed by resection at the same operative session. Cancer cell dissemination was determined before, during and after surgery using 'real time' quantitative RT-PCR assay, based on detection and quantification of CEA and CK20 mRNA transcripts. RESULTS: Circulating cancer cells were detected in 80% and intrahepatic cancer cells in 37% of the patients, though without impact on cancer recurrence. The amounts of disseminated cancer cells were significantly increased after surgery. This increase was similar in patients treated with and without RFA. RFA caused complete tumour destruction. CONCLUSION: Curative surgery for CRLM significantly increases the amount of disseminated cancer cells. Radiofrequency ablation can completely destroy selected resectable CRLM without excessive cancer cell dissemination. Neither haematogenous nor intrahepatic cancer cell dissemination were related to cancer recurrence in this small patient series.

Aged↗

PubMed2004

Could neonatal disseminated herpes simplex virus infections be treated earlier?

INTRODUCTION: Neonatal disseminated herpes simplex virus (HSV) infection can cause rapidly progressive multiple organ failure with an 85% mortality if untreated. Early recognition and treatment may improve outcome [N Engl J Med 324(1991)450]. OBJECTIVES: (i) To determine the number and presentation of neonates with disseminated HSV admitted to an intensive care unit. (ii) To determine paediatric Specialist Registrar (SpR) awareness of the diagnosis and management of a typical potential case of neonatal disseminated HSV. METHODS: (i) A 10-year review of case notes of neonates admitted to the intensive care unit (ICU) at Great Ormond Street Hospital. (ii) A telephone questionnaire of 'on-call' Paediatric SpR's in the London area. RESULTS: Eight cases of confirmed disseminated HSV infection were identified. All died. Each case followed a similar clinical course with presentation between days 5-9 of life (median day 7). A short prodrome preceded the rapid development of disseminated intravascular coagulopathy (DIC), hepatitis and multiple organ failure. Only three cases received antiviral treatment in the first 24 h after hospital admission. None of the 30 registrars who were interviewed initially considered disseminated HSV in the differential diagnosis of a 7-day-old baby presenting with non-specific signs of sepsis. Only 4/30 referring unit protocols included disseminated HSV in the differential diagnosis of neonatal sepsis. CONCLUSIONS: HSV infection should be considered in the differential diagnosis of the acutely unwell neonate. This condition is rare but well documented in the literature. Effective antiviral therapies exist but are often not started early in the clinical course. Awareness of this condition needs to be increased.

Diagnosis, Differential↗

PubMed2004

PTEN gene mutation and high MIB-1 labeling index may contribute to dissemination in patients with glioblastoma.

Dissemination of glioblastomas is often observed, but the underlying mechanism is not well clarified especially from the genetic viewpoints. The present study examined whether PTEN gene mutations and MIB-1 labeling index (LI) correlate with the dissemination in 39 consecutive patients with glioblastomas. Dissemination was defined as leptomenigeal enhancement by magnetic resonance imaging performed in all patients every 2-3 months. We examined PTEN mutations in 26 patients using cDNA-based direct sequencing and MIB-1 LI in 38 patients. Median survival time of the 39 patients was 16.2 months. Dissemination was found in 17 of 39 patients (43.6%). PTEN mutation was significantly associated with dissemination (P=0.0140), and higher MIB-1 LI (> or =35%) resulted in earlier dissemination (P=0.0156). Kaplan-Meier survival plots showed a significantly poorer survival for patients with PTEN mutation (P=0.0012). The results indicate that the evaluation of PTEN mutation and MIB-1 LI are useful to predict dissemination and prognosis of glioblastomas.

Adult↗

PubMed2005

The effects of different knowledge-dissemination interventions on the mastitis knowledge of Tanzanian smallholder dairy farmers.

We developed three different knowledge-dissemination methods for educating Tanzanian smallholder farmers about mastitis in their dairy cattle. The effectiveness of these methods (and their combinations) was evaluated and quantified using a randomised controlled trial and multilevel statistical modelling. To our knowledge, this is the first study that has used such techniques to evaluate the effectiveness of different knowledge-dissemination interventions for adult learning in developing countries. Five different combinations of knowledge-dissemination method were compared: 'diagrammatic handout' ('HO'), 'village meeting' ('VM'), 'village meeting and video' ('VM+V'), 'village meeting and diagrammatic handout' ('VM+HO') and 'village meeting, video and diagrammatic handout' ('VM+V+HO'). Smallholder dairy farmers were exposed to only one of these interventions, and the effectiveness of each was compared to a control ('C') group, who received no intervention. The mastitis knowledge of each farmer (n=256) was evaluated by questionnaire both pre- and post-dissemination. Generalised linear mixed models were used to evaluate the effectiveness of the different interventions. The outcome variable considered was the probability of volunteering correct responses to mastitis questions post-dissemination, with 'village' and 'farmer' considered as random effects in the model. Results showed that all five interventions, 'HO' (odds ratio (OR)=3.50, 95% confidence intervals (CI)=3.10, 3.96), 'VM+V+HO' (OR=3.34, 95% CI=2.94, 3.78), 'VM+HO' (OR=3.28, 95% CI=2.90, 3.71), 'VM+V' (OR=3.22, 95% CI=2.84, 3.64) and 'VM' (OR=2.61, 95% CI=2.31, 2.95), were significantly (p<0.0001) more effective at disseminating mastitis knowledge than no intervention. In addition, the 'VM' method was less effective at disseminating mastitis knowledge than other interventions. Combinations of methods showed no advantage over the diagrammatic handout alone. Other explanatory variables with significant positive associations on mastitis knowledge included education to secondary school level or higher, and having previously learned about mastitis by reading pamphlets or attendance at an animal-health course.

Animals↗

PubMed1988

Progressive disseminated histoplasmosis in patients with acquired immunodeficiency syndrome.

PURPOSE: Progressive disseminated histoplasmosis is now diagnosed frequently in patients with the acquired immunodeficiency syndrome (AIDS) living in the central United States. Previous review articles of AIDS have failed to mention this infection. Herein, we describe 48 AIDS patients with progressive disseminated histoplasmosis in an effort to better understand the clinical presentation and diagnosis of the condition in this setting and to assess the efficacy of antifungal chemotherapy. PATIENTS AND METHODS: In the Houston metropolitan area, there were 66 cases of progressive disseminated histoplasmosis among 1,300 confirmed cases of AIDS from January 1983 to July 1987. Of AIDS patients in East Texas with histoplasmosis, 16 patients were available for follow-up by one of us, and the histories of 32 were obtained by examination of hospital charts and physician records. RESULTS: Fever, weight loss, and splenomegaly were the most common presenting signs and symptoms, occurring in 81, 52, and 31 percent, respectively. One-third of the patients had hematologic abnormalities. Infiltrates on chest roentgenograms were observed in 52 percent. Progressive disseminated histoplasmosis was the initial manifestation of AIDS in almost three-fourths of our patients. Biopsy and culture of the bone marrow established the diagnosis of progressive disseminated histoplasmosis in 69 percent. Clinical or autopsy proof of relapse occurred in three patients despite an initial course of more than 2 g of amphotericin B chemotherapy followed by ketoconazole suppression. CONCLUSION: Progressive disseminated histoplasmosis is often the first sign of immunodeficiency in patients with AIDS, and the diagnosis of this condition is most often established by bone marrow biopsy and culture. Because of the permanence of the immunodeficient state in these patients, progressive disseminated histoplasmosis is resistant to treatment.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Relevance of disseminated tumour cells in blood and bone marrow of patients with solid epithelial tumours in perspective.

Currently-used systems to predict prognosis in patients with solid epithelial tumours after surgical resection of the tumour do not give any guarantees for the individual patient. In this respect the clinical relevance of the presence of disseminated tumour cells in blood and bone marrow has been frequently studied. Because of growing awareness that information on merely the presence of disseminated tumour cells is not sufficient for prognostic and therapeutic purposes, attention for characterization of disseminated tumour cells has increased. Numerous reviews have already been published on the detection and clinical relevance of disseminated tumour cells. Therefore, this paper will mainly focus on the biological significance of these cells and discusses the (in)efficiency of the metastatic process, the genotypic and phenotypic characteristics of disseminated tumour cells, and their structure of appearance. Despite the fact that information gained on the several individual aspects is substantial, it did not render any solid solutions for individual patient management yet. Hence, a combined approach of several aspects of disseminated tumour cells together with characteristics and behaviour of the primary tumour is needed to substantially improve our knowledge on the role of disseminated tumour cells in the complex process of tumour metastasis.

Animals↗

PubMed2005

Common polymorphisms in critical genes of innate immunity do not contribute to the risk for chronic disseminated candidiasis in adult leukemia patients.

Chronic disseminated candidiasis is a serious fungal infection in immunocompromised patients, particularly those undergoing therapy for acute leukemia. Coordination between innate and adaptive immune system is critical to resistance or susceptibility to Candida infection. In order to investigate possible genetic contribution to chronic disseminated candidiasis of key molecules in the innate immune pathway, we performed a case control study using the candidate gene approach. Forty subjects with chronic disseminated candidiasis and 50 controls without chronic disseminated candidiasis but an underlying diagnosis of leukemia were enrolled in the Helsinki University Central Hospital during the period 1980-1998. Candidate genes were selected for analysis based upon the following criteria: a common polymorphism (>5% frequency) and existence a priori of clinical and biological data suggesting a role for the variant in the pathogenesis of chronic disseminated candidiasis. Six genes were selected from critical microbicidal and innate immune pathways, including three low-affinity Fcgamma receptors (FCGR2A, FCGR3A and FCGR3B), chitotriosidase (CHIT1), p22-phox NADPH oxidase (CYBA), and mannose binding lectin (MBL2). There was no statistically significant association of susceptibility to chronic disseminated candidiasis with the polymorphisms in this study. Common variants in the six studied genes most likely do not contribute to the risk for chronic disseminated candidiasis in patients with acute leukemia.

Acute Disease↗

PubMed1997

Markedly elevated serum lactate dehydrogenase levels are a clue to the diagnosis of disseminated histoplasmosis in patients with AIDS.

Disseminated histoplasmosis is a common late manifestation of AIDS, but the diagnosis may be unsuspected in some patients because the clinical presentation of histoplasmosis may mimic other opportunistic infections. High serum lactate dehydrogenase (LDH) levels have been associated with disseminated histoplasmosis. We therefore evaluated whether markedly increased LDH levels were useful for making a diagnosis of disseminated histoplasmosis by comparing admission LDH levels for 15 patients with culture-proven disseminated histoplasmosis with those for 30 patients with advanced AIDS who were admitted to the hospital for evaluation of pulmonary infiltrates and fever. The mean admission LDH level in patients with disseminated histoplasmosis was 1,356 IU/L (range, 145-5,410 IU) whereas it was 332 (range, 77-832 IU) in the patients with other pulmonary processes. Admission LDH levels were >600 IU in 11 (73%) of the 15 patients with disseminated histoplasmosis vs. 3 (10%) of controls (P < .001). We conclude that markedly elevated admission LDH levels may be a clinical clue to the diagnosis of disseminated histoplasmosis in patients with AIDS.

AIDS-Related Opportunistic Infections↗

PubMed1992

Systemic dissemination by a newly recognized intestinal microsporidia species in AIDS.

OBJECTIVE: Primarily to determine whether an intestinal microsporidian recently identified in AIDS patients disseminates from the bowel to infect other organs. DESIGN: Disseminated microsporidiosis has been reported in immunocompromised humans, but never due to Enterocytozoon bieneusi, the most common species in AIDS patients and one that evidently infects only enterocytes. In animals, dissemination follows ingestion of Encephalitozoon cuniculi spores, apparently via macrophages, and pathology occurs in, for example, kidneys and brain. A second, un-named Encephalitozoon-like intestinal microsporidia has been identified in five AIDS patients with chronic diarrhea; because it infects lamina propria macrophages, it was logical to investigate its dissemination. METHODS: Light and transmission electron microscopy were used to study urine sediment from four out of five patients with biopsy-documented small intestinal infection due to the second intestinal microsporidian. The gall bladder from one patient and autopsy specimens from an E. bieneusi-infected patient were similarly studied. RESULTS: Systemic dissemination was documented by detecting abundant spores, both free and within renal tubular and transitional cells, in the urine of two patients. Many of the lamina propria macrophages in these two patients' intestinal biopsies contained microsporidia, while those of the two negative patients either contained only Mycobacterium avium complex or only occasional parasites. The gall bladder was co-infected with this microspordian and with cytomegalovirus. At autopsy, the patient with documented enteritis due to E. bieneusi 2 years before death had disseminated microsporidiosis, not of E. bieneusi, but apparently of the second intestinal species. The microsporidian had caused severe tubulointerstitial nephritis. Parasites were also observed in non-parenchymal cells of the liver and bronchial epithelium. CONCLUSION: A newly described Encephalitozoon-like intestinal microsporidian, which causes chronic diarrhea in AIDS patients, can disseminate and cause renal pathology.

Acquired Immunodeficiency Syndrome↗

PubMed2001

A new peritoneal dissemination model established from the human pancreatic cancer cell line.

We established a new cell line, HPC-3P4a, with high peritoneal disseminated potential in nude mice. HPC-3P4a was derived from a human pancreatic carcinoma cell line (HPC-3) that had low capacity for peritoneal dissemination. HPC-3P4a developed peritoneal dissemination in 10 of 11 (90.9%) cases, whereas parental HPC-3 developed peritoneal dissemination in one of six (16.7%) cases. The metastatic foci in the peritoneum showed essentially the same histologic appearance of parental involvement. The tumorigenicity, motility, and adhesive activity of HPC-3P4a to the extracellular matrix were stronger than were those of the HPC-3. In FACS analysis, HPC-3P4a significantly increased the expression of alpha6 and alpha(v)beta5 integrins, while it decreased alpha2 integrin, hCD44H, and hCD44v 10, as compared with HPC-3. The VEGF production of HPC-3P4a was significantly lower than that of HPC-3. Analysis of gene macroarrays showed a variety of cytokines, interleukin, and other immunomodulatory, and their receptors were up-regulated and down-regulated on an mRNA level in HPC-3P4a cells, compared with HPC-3 cells. Intrasplenic injection of HPC-3P4a produced no liver metastasis. We named our original highly liver metastatic cell line HPC-3H4 (previously reported). This HPC-3H4 cell was established by repeated intrasplenic injection from parental cell HPC-3; thus, it developed high liver metastasis. Moreover, HPC-3H4 developed peritoneal dissemination by intra-abdominal injection. In contrast, HPC-3P4a did not develop liver metastasis by intrasplenic injection. These findings are very interesting and might suggest that the process of hematogenous metastasis differed from that of peritoneal dissemination. Thus, this cell line may be useful for investigating the mechanism of peritoneal dissemination in human pancreatic cancer.

Adenocarcinoma↗

PubMed2007

Disseminated tuberculosis: a 10-year experience in a medical center.

Disseminated tuberculosis remains a diagnostic challenge because the presentations are nonspecific. In the current retrospective study we describe the clinical characteristics and outcome of disseminated tuberculosis. From January 1995 to December 2004, patients with culture-confirmed tuberculosis who fulfilled the criteria for disseminated tuberculosis were selected and their medical records reviewed. Their clinical isolates were genotyped. Of the 3058 patients with culture-confirmed tuberculosis, 164 (5.4%) had disseminated disease; 14.0% of patients had acquired immunodeficiency syndrome. The most common radiographic finding was miliary lung lesions (47.0%); 31.1% of patients died at the end of the study. Poor prognostic factors included hypoalbuminemia, hyperbilirubinemia, renal insufficiency, and delayed antituberculosis treatment. Clinical findings suggestive of disseminated tuberculosis were miliary lung lesions, serum ferritin >1000 microg/L, infiltrative liver disease, and adjusted calcium >2.6 mmol/L. Simultaneously performing mycobacterial culture and histopathologic examination of bone marrow biopsy was more sensitive and faster than just performing mycobacterial blood culture in diagnosing disseminated tuberculosis. Of the 64 preserved Mycobacterium tuberculosis isolates, 47 (73.4%) were clustered and 27 (42.2%) were Beijing family. Since prognosis was worse in patients with delayed treatment, a high index of suspicion is required, especially in those with clinical findings suggestive of disseminated tuberculosis.

Adult↗

PubMed1999

Preventive effect of matrix metalloproteinase inhibitor, R-94138, in combination with mitomycin C or cisplatin on peritoneal dissemination of human gastric cancer cell line TMK-1 in nude mice.

R-94138, a matrix metalloproteinase inhibitor, was examined for the ability to prevent peritoneal dissemination of a human gastric cancer xenograft, TMK-1. When the supernatant of a co-culture of TMK-1 cells and human normal fibroblast cells was subjected to gelatin zymography, it was clear that the protein expression of MMP-2 had been inhibited by R-94138. When TMK-1 was injected intraperitoneally (i.p.) into nude mice at 5 x 10(5) cells/body, the resulting peritoneal dissemination mimicked clinical carcinomatous peritonitis. When the maximum tolerated dose of mitomycin C (MMC) or cisplatin (DDP) was given 12 h after the tumor inoculation, peritoneal dissemination was completely inhibited, while the effect of R-94138 was limited when it was given i.p. at a dose of 20 mg/kg in a schedule of q.d. x 5 starting 12 h after tumor injection. MMC and DDP also suppressed peritoneal dissemination when they were administered 1 week after the tumor inoculation at a single dose of 2 and 3 mg/kg i.p., respectively. R-94138 inhibited peritoneal dissemination when it was administered i.p. at a dose of 30 mg/kg in a schedule of q.d. x 5 starting from 1 week after tumor injection. The combination of MMC and R-94138 increased the preventive effect on peritoneal dissemination. R-94138 seems to be a promising candidate to prevent peritoneal dissemination of gastric cancer.

Acetamides↗

PubMed1995

Differential correlation between interleukin patterns in disseminated and chronic human paracoccidioidomycosis.

In an attempt to understand better the immunoregulatory disorders in paracoccidioidomycosis (PCM), the possible correlation between interleukin pattern, lymphoproliferation, C-reactive protein (CRP) and specific antibody levels was investigated in the polarized clinical forms of this disease. We studied 16 PCM patients, eight with the disseminated disease (four under treatment and four non-treated) and eight with the chronic disease. The patients with disseminated disease exhibited high antibody titres specific to Paracoccidioides brasiliensis antigen compared with patients with the chronic form of disease. Tumour necrosis factor (TNF), IL-1, IL-6 and CRP in the serum of non-treated disseminated PCM patients were increased, which correlated positively with the low mitogenic response of peripheral blood mononuclear cells (PBMC) to phytohaemagglutinin (PHA) (P < 0.01) and with the high antibody titres (P < 0.001) of these patients. Moreover, we found in the disseminated PCM patients positive correlations between IL-1 and IL-6 (P = 0.0007); IL-1 and TNF (P = 0.0045); IL-1 and IL-6 with the high antibody titres (P = 0.0834 and P = 0.0631, respectively); IL-1, IL-6 and TNF with CRP levels. By contrast, no correlations were found with those interleukins in the treated disseminated and chronic patients or in controls. It was interesting to find an inverse correlation between IL-4 and antibody production in non-treated disseminated PCM (r = -0.4770); moreover, a significant correlation (P = 0.0820) was found in chronic PCM patients with respect to the low level of either IL-4 and antibody titres against fungus antigen. Chronic PCM patients also had IL-2 levels inversely correlated with antibody production (r = -0.6313; P = 0.0628). Inverse correlations were also observed between IL-2 and IL-6 levels in non-treated disseminated patients (P = 0.0501) and between IL-2 and IL-4 in chronic patients (P = 0.0131). The inflammatory cytokines might have a pivotal role in the genesis and in control of some aspects of the disease, such as granulomatous reaction, hypergammaglobulinaemia and depression of T cell-mediated immunity in PCM.

Adult↗

PubMed1999

The dissemination of a smoking cessation program to 23 antenatal clinics: the predictors of initial program adoption by managers.

OBJECTIVE: To investigate whether the method of dissemination, antenatal clinic practice norms for smoking intervention and subjective evaluation of the attributes of a new smoking cessation program are associated with a nurse unit manager's initial decision to adopt the new program. METHOD: Twenty-three hospital clinics were randomly allocated to two groups which received the program either by simple or intensive dissemination methods. Simple dissemination involved a mailout of the 'Fresh Start' program and intensive dissemination involved a mailout which was enhanced by personal contact with midwifery facilitators who provided support and training for the program. It was hypothesised that intensive dissemination would improve program adoption compared to simple dissemination. It was also hypothesised that managers' perceptions of the program and clinic smoking intervention practice norms would predict program adoption. A hierarchical regression analysis was used to examine the association between these variables and the adoption of program components. RESULTS: The results indicated that the method of dissemination and the managers' perceptions of the program are significant predictors of program adoption. CONCLUSIONS: Although clinic practice norm for smoking cessation education is not a significant predictor of program adoption, it appears to mediate managers' perceptions of the program.

Female↗

PubMed1990

SCH-39304 in prevention and treatment of disseminated candidiasis in persistently granulocytopenic rabbits.

To investigate the potential use of SCH-39304 for the prevention and treatment of disseminated candidiasis in granulocytopenic patients, we studied its in vivo antifungal activity as preventive, early, and late treatments in three models (acute, subacute, and chronic) of disseminated candidiasis in persistently granulocytopenic rabbits. SCH-39304 was an effective as amphotericin B alone and fluconazole alone for the prevention of disseminated candidiasis. SCH-39304 alone and fluconazole alone were as effective as amphotericin B plus flucytosine for early treatment of subacute disseminated candidiasis. When treatment was delayed for 5 days to establish chronic disseminated candidiasis, SCH-39304 was less effective than amphotericin B plus flucytosine. In comparison with different treatment regimens, SCH-39304 was more effective in early and preventive treatment. Thus, SCH-39304 was comparable to treatment control regimens in prevention and early treatment of subacute disseminated candidiasis. SCH-39304 also was most effective in granulocytopenic rabbits with disseminated candidiasis when used for prevention or early treatment.

Agranulocytosis↗

PubMed2004

Potent and specific antitumor efficacy of CMC-544, a CD22-targeted immunoconjugate of calicheamicin, against systemically disseminated B-cell lymphoma.

PURPOSE: CMC-544 is a CD22-targeted immunoconjugate of calicheamicin and exerts a potent cytotoxic effect against CD22+ B-cell lymphoma. This study evaluated antitumor efficacy of CMC-544 against systemically disseminated B-cell lymphoma. EXPERIMENTAL DESIGN: Scid mice received i.v. injections of CD22+ Ramos B-cell lymphoma cells for their systemic dissemination. CMC-544, G5/44, CD33-targeted CMA-676 (control conjugate) or rituximab were given i.p. 3, 9, 15, or 21 days after B-cell lymphoma dissemination. Diseased mice were monitored daily for hind-limb paralysis and death. Histopathological examination of CMC-544-treated and vehicle-treated diseased mice was also performed. RESULTS: Mice with disseminated B-cell lymphoma developed hind-limb paralysis within 35 days. When given up to 15 days after B-cell lymphoma dissemination, CMC-544 extended survival of the diseased mice to >100 days, and these mice were considered cured. CMC-544 was efficacious when given during both the early initiation phase and the late established phase of the disease. A single dose of CMC-544 was effective in delaying the occurrence of hind-limb paralysis. In contrast, neither CMA-676 nor unconjugated G5/44 was effective. Rituximab was effective when given early in the disease process but not when the disease was established. Histopathological analysis revealed B-cell lymphoma infiltration in brain, spinal cord, bone marrow, and kidney in vehicle-treated but not in CMC-544-treated diseased mice. Consistent with its efficacy against the disseminated B-cell lymphoma, CMC-544 also caused regression of established Ramos B-cell lymphoma xenografts in scid mice. CONCLUSIONS: CMC-544 confers strong therapeutic activity against systemic disseminated B-cell lymphoma and protects mice from hind-limb paralysis and death. These results support clinical evaluation of CMC-544 in the treatment of CD22+ lymphoid malignancies.

Animals↗