Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Between October 1985 and January 1989, 33 patients with stage I (31) or clinically occult stage II (2) endometrial cancer at a high risk for recurrence were entered in a prospective study evaluating adjuvant cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy. Eligibility criteria included grade 2 tumors with middle- or outer-third myometrial invasion (16), grade 3 tumors with any degree of myometrial invasion (17), presence of extrauterine disease with no gross residual (17), or a high-risk histologic subtype including papillary serous (4), adenosquamous (5), or clear cell (1) tumors. Patients received PAC (50/50/500 mg/m2) at 4-week intervals for six cycles. Thirty patients (90%) completed therapy. Toxicity included severe neutropenia in 14 patients, neutropenic sepsis in 2 patients, and doxorubicin-related cardiomyopathy in 1 patient. There were no treatment deaths. Current median follow-up is 25 months. Nine patients (27%) have developed a recurrence, 7 of whom died, after a median interval of 14 months. Eight of the 9 with recurrence initially had extrauterine disease (P = 0.02). The resulting 2-year actuarial progression-free and overall survival rates were 79 and 83%, respectively. The median progression-free interval was 29 months for patients with extrauterine disease and 45+ months for those with no extrauterine disease (P = 0.02). These results suggest that a phase 3 randomized trial comparing adjuvant PAC with radiation therapy is warranted.
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PMID:Adjuvant chemotherapy with cisplatin, doxorubicin, and cyclophosphamide (PAC) for early-stage high-risk endometrial cancer: a preliminary analysis. 222 40

Long-term intermittent venous access was established in 26 children by means of a central venous catheter (CVC) with a subcutaneous injection port (Port-A-Cath) (PAC). As of December, 1985, PACs had been in place for 20-750 days (cumulative 10,890 days) with 647 entries into the system. The PACs were used for blood sampling and administration of chemotherapy, antibiotics, fluids, total parenteral nutrition (TPN), and blood products. One patient with sever neutropenia (absolute neutrophil granulocyte count [ANC] less than 0.1 x 10(9)/L) at the time of the PAC implant developed an infection around the port after 2 days, with subsequent septicemia (Bacillus cereus) necessitating removal of the PAC. Otherwise, no definite PAC-related infections occurred, including 258 days of neutropenia (ANC less than 0.5 x 10(9)/L). Two PACs were found occluded with greyish deposits of fat and organic material after long-term (45 and 61 days) continuous TPN and were removed. Malposition of catheter, extravasation, thrombosis, and other potential technical or psychological complications were not observed. The children continued normal activities, and the easy venous access decreased emotional stress during treatment. Local doctors were trained to use the PACs, with which they administered maintenance chemotherapy. We conclude that the use of PACs in children is safe, even in the first year of life, and has many advantages when compared with other CVCs currently in use. Strict indications, meticulous implantation technique, and adequate handling are, however, mandatory.
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PMID:Central venous catheter with subcutaneous injection port (Port-A-Cath): clinical experience with children. 315 37

Forty-three consecutive patients with metastatic breast cancer and clearly measurable disease were treated with sequential multiagent chemotherapy. Therapy consisted of the administration in fixed sequence of cisplatin, doxorubicin, and cyclophosphamide (PAC) (four cycles), vinblastine, doxorubicin, and dexamethasone (VAD) (six cycles), and VP-16, methotrexate, and 5-fluorouracil (VMF) (six cycles). At the conclusion of 16 cycles of chemotherapy, all treatment was stopped. Patients were assessed for toxicity and disease response after each treatment. Duration of response and survival rate were determined for 41 evaluable patients. The overall response rate was 80% with 24% complete responses, 15% to PAC alone. Median duration of response (8 months) and median survival (17 months) were not superior to other reported multiagent chemotherapeutic programs. Toxicity included neutropenic fever, sepsis, renal failure, and electrolyte imbalance. Administration of sequential multiagent chemotherapy with a cisplatin-containing combination did not improve response rate, complete responses (CR), duration of response, or survival in this group of previously untreated breast cancer patients.
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PMID:Sequential multiagent chemotherapy incorporating cisplatin, doxorubicin, and cyclophosphamide in the treatment of metastatic breast cancer. 317 23

325 implantable catheters (PAC) were successfully used for treatment of 310 patients with neoplastic diseases in 21 French medical centers. 263 were placed in central venous sites; 43 in the hepatic artery and 11 in intra-portal sites. There was no failure at insertion time nor was there any death attributable to the method. While average duration of catheterization was 182 days, 72 catheters remain patent after one year of use or longer. Occlusion risk was found to be 3.6%: 1.5% for IV sites and 13.9% for intra-arterial sites (due to smaller inner diameter). 2.4% of the implantations showed cutaneous necrosis and in 2.7% sepsis occurred. Sepsis was much more likely to occur after percutaneous insertions. These results support the use of this device for long term chemotherapy.
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PMID:Totally implantable catheters for cancer chemotherapy: French experience on 325 cases. 370 35

Three hundred and twenty five implantable catheters (PAC) were used in the treatment of 319 patients with neoplastic disease in 21 French centers. Two hundred and sixty three were inserted in central venous position, 43 in hepatic artery and 11 were intraportal. There were no failures at the time of insertion nor any deaths imputable to the method. Whilst the mean duration of use was 182 days, 72 catheters remain patent after one year of use or more. The risk of obstruction is 3,6% : 1,5% for I.V. sites and 13,9% in intra-arterial because internal caliber are smaller. There were 2,4%, of cases of skin leakage or necrosis and sepsis rate was 2,7%, more frequent er after percutaneous insertion. These result justify the use of this device in long term chemotherapy.
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PMID:[Completely implantable catheters for anticancer chemotherapy. A French experience of 325 cases]. 399 95

Resistance to activated protein C (APCR) has emerged as the most important hereditary cause of venous thromboembolism. Using an aPTT-based method together with DNA technique we investigated 120 healthy neonates and infants < 12 months of age and 24 infants with septicaemia for the presence of this mutation. In addition, data of 11 neonates with vascular occlusion, heterozygous (+/-) for the Arg 506 Gln mutation were included. Results of an aPTT-based method (clotting time using the APC/CaCl2 solution obtained in an undiluted, 1:5 and 1:11 dilution with factor V deficient plasma divided by clotting time with CaCl2 in the same plasma dilution) are shown: Whereas 7 (5.5%) out of 120 healthy neonates were (+/-) carriers for the factor V Arg 506 Gln mutation, concordance with the aPTT-based method (cut-off defined as ratio < 2) was found only when using the 1:11 plasma dilution. Six (four) out of 24 infants with sepsis, not carrying the factor V mutation, would have been classified as APC resistant when using the 1:1 (1:5) plasma dilution. Four (two) out of 18 patients, (+/-) for the Arg 506 Gln mutation showed APC ratios > 2 in the 1:1(1:5) plasma dilution.
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PMID:APC resistance in neonates and infants: adjustment of the APTT-based method. 886 17

Bacteroides fragilis, a Gram-negative colonic bacterium, induces the formation of abscesses associated with intra-abdominal sepsis in humans. The singular ability of this organism to modulate abscess formation in experimental rodent models resides in the structurally distinct and ionically charged capsular polysaccharides A (PS A) and B (PS B). The regulation of abscess formation in animals is dependent on T lymphocytes. However, the manner in which PS A interacts with T cells remains unknown. We therefore tested the T cell stimulatory capacity of purified PS A on mouse and rat lymphocytes in cellular proliferation assays and found that the PS A molecule possesses mitogenic characteristics distinguishable from those of the polyclonal B cell activator LPS, the T cell mitogen Con A, and staphylococcal enterotoxin A superantigen. Further, PS A stimulated proliferation of normal mouse and rat lymphocytes differentially. Mouse B cells responded to PS A in a fashion that did not require exogenous APC function, while rat T lymphocyte responses to PS A required APC function derived from autologous or xenogenic feeder cells. Cellular depletion experiments showed that the CD4+ subset of rat spleen cells was the primary responder cell type to PS A in vitro. The differential stimulatory effects of PS A on mouse and rat lymphocytes may reflect its ability to stimulate different lymphocyte subsets in vivo through the activities of receptor/counter-receptor pairs present on responder lymphocytes and cognate APC.
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PMID:Mitogenic activity of purified capsular polysaccharide A from Bacteroides fragilis: differential stimulatory effect on mouse and rat lymphocytes in vitro. 997 99

Human protein C is a natural anticoagulant factor, and a recombinant activated form of the molecule (rhAPC) is completing clinical evaluation for treatment of severe sepsis. Because of the pathophysiologic role of endothelial dysfunction in severe inflammatory disease and sepsis, we explored the possibility that rhAPC might directly modulate endothelial function, independent of its anticoagulant activity. Using broad transcriptional profiling, we show that rhAPC directly modulates patterns of endothelial cell gene expression clustering into anti-inflammatory and cell survival pathways. rhAPC directly suppressed expression of p50 and p52 NFkappaB subunits, resulting in a functional decrease in NFkappaB binding at target sites. Further, rhAPC blocked expression of downstream NFkappaB regulated genes following tumor necrosis factor alpha induction, including dose-dependent suppression of cell adhesion expression and functional binding of intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin. Further, rhAPC modulated several genes in the endothelial apoptosis pathway, including the Bcl-2 homologue protein and inhibitor of apoptosis protein. These pathway changes resulted in the ability of rhAPC to inhibit the induction of apoptosis by the potent inducer, staurosporine. This new mechanistic understanding of endothelial regulation and the modulation of tumor necrosis factor-induced endothelial dysfunction creates a novel link between coagulation, inflammation, and cell death and provides insight into the molecular basis for the efficacy of APC in systemic inflammation and sepsis.
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PMID:Gene expression profile of antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis. 1127 52

Sepsis-induced abnormalities of coagulation may contribute to mortality during severe bacterial infection. The aim of this study was to examine changes in coagulation parameters and to assess the role of protein C supplementation during murine S. aureus sepsis. Gram-positive sepsis was characterized by a hypercoagulable state with predominant activation of the external coagulation pathway, registered as an early increase of tissue factor activity and concomitant reduction in protein C. The internal coagulation pathway was unaffected. No correlation between the changes of coagulation parameters and the intensity of inflammation, determined as serum IL-6 levels, was found. Supplementation with neither protein C or APC favoured survival in S. aureus sepsis. Reduction in thrombin generation in response to protein C supplementation was associated with significantly increased survival.
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PMID:Thrombin generation and mortality during Staphylococcus aureus sepsis. 1131 18

It is becoming increasingly clear that coagulation augments inflammation and that anticoagulants, particularly natural anticoagulants, can limit the coagulation induced increases in the inflammatory response. The latter control mechanisms appear to involve not only the inhibition of the coagulation proteases, but interactions with the cells that either generate anti-inflammatory substances, such as prostacyclin, or limit cell activation. Recent studies have demonstrated a variety of mechanisms by which coagulation, particularly the generation of thrombin, factor Xa and the tissue factor-factor VIIa complex, can augment acute inflammatory responses. Many of these responses are due to the activation of one or more of the protease activated receptors. Activation of these receptors on endothelium can lead to the expression of adhesion molecules and platelet activating factor, thereby facilitating leukocyte activation. Therefore, anticoagulants that inhibit any of these factors would be expected to dampen the inflammatory response. The three major natural anticoagulant mechanisms seem to exert a further inhibition of these processes by impacting cellular responses. Antithrombin has been shown in vitro to increase prostacyclin responses and activated protein C has been shown to inhibit a variety of cellular responses including endotoxin induced calcium fluxes in monocytes and the nuclear translocation of NFKB, a key step in the generation of the inflammatory response. In some, but not all, in vivo models, these natural anticoagulants have been able to inhibit endotoxin/E. coli-mediated leukocyte activation and to diminish cytokine elaboration (TNF, IL-6 and IL-8). Phase III clinical studies for treatment of patients with severe sepsis have been completed for APC, which was successful (1), and for antithrombin, which was not (2). A phase III trial with tissue factor pathway inhibitor is in progress. In this review, the mechanisms by which the different natural anticoagulants are thought to function will be reviewed.
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PMID:Role of coagulation inhibitors in inflammation. 1148 41


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