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)

The development of pharmacological approaches for preventing the loss of muscle proteins would be extremely valuable for cachectic patients. For example, severe wasting in cancer patients correlates with a reduced efficacy of chemotherapy and radiotherapy. Pentoxifylline (PTX) is a very inexpensive xanthine derivative, which is widely used in humans as a haemorheological agent, and inhibits tumor necrosis factor transcription. We have shown here that a daily administration of PTX prevents muscle atrophy and suppresses increased protein breakdown in Yoshida sarcoma-bearing rats by inhibiting the activation of a nonlysosomal, Ca(2+)-independent proteolytic pathway. PTX blocked the ubiquitin pathway, apparently by suppressing the enhanced expression of ubiquitin, the 14-kDa ubiquitin conjugating enzyme E2, and the C2 20S proteasome subunit in muscle from cancer rats. The 19S complex and 11S regulator associate with the 20S proteasome and regulate its peptidase activities. The mRNA levels for the ATPase subunit MSS1 of the 19S complex increased in cancer cachexia, in contrast with mRNAs of other regulatory subunits. This adaptation was suppressed by PTX, suggesting that the drug inhibited the activation of the 26S proteasome. This is the first demonstration of a pharmacological manipulation of the ubiquitin-proteasome pathway in cachexia with a drug which is well tolerated in humans. Overall, the data suggest that PTX can prevent muscle wasting in situations where tumor necrosis factor production rises, including cancer, sepsis, AIDS and trauma.
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PMID:Manipulation of the ubiquitin-proteasome pathway in cachexia: pentoxifylline suppresses the activation of 20S and 26S proteasomes in muscles from tumor-bearing rats. 1036 54

This report summarizes our experience with the combination of mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) for patients with gynecological sarcomas. We reviewed the records of all patients who had received the MAID regimen for a gynecological sarcoma between 1993 and 2000. The MAID regimen was administered intravenously every 4 weeks in the hospital as follows: (1) mesna 1500 mg/m2/day x 4 days; (2) doxorubicin 15 mg/m2/day x 3 days; (3) ifosfamide 1500 mg/m2/day x 3 days; (4) dacarbazine 250 mg/m2/day x 3 days. The results of treatment with MAID were disappointing. Overall, the response rate was 9% with one complete response and one partial response (both in patients with uterine leiomyosarcoma). We did not observe any responses among the patients with carcinosarcomas of either ovarian or uterine origin. The median progression-free interval and survival were 11 months and 29 months, respectively. This regimen was associated with substantial toxicity (including a death from neutropenic sepsis) as well as high cost and inconvenience due to the requirement for inpatient administration. Although our study contains a limited number of patients with a variety of gynecological sarcomas, our review has led us to discontinue using MAID. It remains to be established if any combination chemotherapy regimen is better than single agent treatment.
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PMID:Mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) chemotherapy for gynecological sarcomas. 1244 53

The systemic side effects of isolated limb perfusion (ILP) with rhTNF alpha and melphalan are characterised by the induction of a systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT), a serum marker of bacterial sepsis, was investigated with respect to its role in SIRS after TNF-ILP. Serum-PCT was analysed in 24 patients (12 male, 12 female), who treated by ILP for regionally metastasized melanoma (n = 8) or locally advanced soft tissue sarcoma (n = 16). Serum samples were analysed pre- and intraoperatively, and at defined intervals after reperfusion of the limb. In addition to PCT, serum IL-6 and IL-8 were analysed in 11 patients. PCT was significantly elevated over baseline after ILP with a maximum between 8 and 36 hours (p < 0.001). Even 96 hours after reperfusion, PCT was still significantly elevated as compared to baseline levels (p = 0.005). There was no correlation to the systemic leakage rate during the perfusion. IL-6 and IL-8 were also significantly increased after ILP (p = 0.001), but the maximum peaks of both cytokines were reached much earlier than for PCT (IL-8 max. at 1 hour and IL-6 max. at 4 hours after reperfusion). Serum procalcitonin is induced as part of the specific SIRS after ILP with rhTNF alpha and melphalan. It may be induced directly by rhTNF alpha or by different cytokines, as serum peaks of IL-6 and IL-8 are reached well before the peak of PCT. Determination of PCT prior to and after ILP with TNF might be useful to assess patients at risk of developing hyperdynamic shock.
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PMID:[Procalcitonin as marker of systemic inflammatory reaction after isolated extremity perfusion]. 1451 84

Chemotherapeutic efficacy is hampered by occurrence of drug resistance. Several mechanisms cause this phenomenon. A final common factor is the reduced capacity of resistant cells to go into apoptosis following treatment with DNA-damaging agents. It is therefore interesting to search for ways to facilitate this apoptotic process following use of chemotherapeutic drugs. The death receptor ligands tumor necrosis factor (TNF), FasL and TNF-related apoptosis-inducing ligand (TRAIL) might be interesting candidates as they are able to induce apoptosis by binding to their cell membrane receptors. Recombinant forms of these ligands potentiate chemotherapeutic drug effects in preclinical models. For the clinical application of TNF, FasL and TRAIL, it is of primary importance that their safety be guaranteed. RhTNF is the only ligand currently used in humans. However, systemic rhTNF has shown low antitumor activity and higher doses induce severe sepsis-like toxicity. Perfusion setting aimed at limb preservation with rhTNF plus melphalan is currently used in sarcoma patients. A number of options have been tested in the preclinical setting that might allow circumvention of TNF toxicity in the clinic. Systemic rhFasL administration in humans is not yet feasible because of observed severe liver toxicity in mice due to Fas-mediated apoptosis of hepatocytes. Measures to circumvent liver toxicity have not yet been exploited. Another option for using FasL in the clinic may be to identify an alternative route of administration. In the animal model, FasL appeared to be less toxic for the liver compared with anti-Fas antibodies when administered intraperitoneally. There are relatively nontoxic modulators of the Fas death pathway, such as interferon and nonsteroidal antiinflammatory drugs (NSAIDs), which might prove interesting in combination with chemotherapy. Finally, it may be possible to produce a modified FasL with a reduced toxicity profile. TRAIL, produced as soluble, zinc-stabilized rhTRAIL seems to be without preclinical toxicity. Agonistic DR4 and DR5 antibodies against their TRAIL death receptor are being studied as another potential clinical option to induce apoptosis. Due to the synergistic effect observed in the preclinical setting between death receptor ligands and other modulators of the death receptor pathways and chemotherapy, it may well be that this approach is especially of value in the clinic when combined with chemotherapy. Ideally, choices for specific (modified) death receptor ligands for the treatment of patients can be rationally made based on tumor characteristics.
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PMID:Modulation of death receptor pathways in oncology. 1498 48

The aim of this study was to evaluate the systemic and haemodynamic postoperative effects of ILP with medium-low dose of TNF alpha in patients diagnosed with primary or recurrent limb melanoma or sarcoma, and to compare the resulting toxicity with Systemic Inflammatory Response Syndrome (SIRS). A prospective study on 17 consecutive patients with primary or recurrent limb tumor (melanoma or sarcoma) subjected to ILP with escalating doses of TNF alpha (0.5-2.0mg) was carried out. Seventeen patients with primary or recurrent limb melanoma or sarcoma were subjected to ILP with escalating doses of TNF alpha. ILP was carried out with the standard techniques, blood being warmed at 42 degrees C for an hour. Serial serum TNF alpha determinations were performed before, during and after limb perfusion in nine patients. Systemic and pulmonary haemodynamics, by a radial and pulmonary artery catheter inserted before the induction of anesthesia, were monitored at 5 different times: before the induction of anesthesia (T0), and 6, 12, 24 and 48 hours after treatment (T1-4). Complete isolation of the limb was not always achieved, therefore leakage of TNF alpha occurred frequently during the perfusion in all patients with maximum systemic TNF alpha concentrations ranging from 431 to 111000 pg/ml. After perfusion only two patients showed detectable TNF alpha levels in peripheral blood which returned to baseline values within nine hours. These two patients had serious systemic toxicity: shock and respiratory failure secondary to pulmonary edema. Acute pulmonary edema was also observed in another patient. All three cases required supportive therapy provided by means of mechanical ventilation. In the remaining 14 patients a sepsis-like syndrome was observed. The most significant haemodynamic changes were due to the CO, which rose by 35%, and the SVR, which remained consistently low throughout. A reduction in Hb was observed in all patients (with an average decrease of 4 g/dl), while DO2 and VO2 levels rose, though not to statistically significant levels. Hypoxia occurred in all 14 patients. In three of the remaining 14 cases bilateral pulmonary leaks were noted, however the use of mechanical ventilation was not required. No perioperative death occurred and the aforementioned side effects were all reversible resulting in a patient's mean postoperative ICU permanence of 4 days (range 3 to 7 days). In conclusion, ILP with TNF alpha induces cardiovascular, respiratory and hematological toxicity with haemodynamic parameters being similar to those noted in SIRS probably due to leakage of TNF alpha in the systemic circulation during the perfusion. Nevertheless, this systemic toxicity was short-lived resulting in an acute reaction following a single application.
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PMID:Systemic and haemodynamic toxicity after isolated limb perfusion (ILP) with TNF-alpha. 1535 6

Soft tissue sarcomas in the first year of life are rare, and the most common sarcomas in infancy are embryonal rhabdomyosarcoma, Ewing sarcoma/primitive neuroectodermal tumor, congenital infantile fibrosarcoma, and primitive sarcomas such as undifferentiated sarcoma. In this study, we report 6 cases of a primitive myxoid mesenchymal tumor of infancy (PMMTI), which previously may have been included under the diagnostic categories of congenital-infantile fibrosarcoma or infantile fibromatosis. PMMTI occurred in 6 infants, 3 of whom had a congenital presentation of a soft tissue mass. All patients were otherwise healthy. The tumors occurred on the trunk, extremities, and head and neck. Grossly, the tumors were nonencapsulated and had a multinodular appearance with focal infiltrative growth, a white fleshy cut surface, and a tumor diameter ranging from 2 to 15 cm. Histologically, a diffuse growth of primitive spindle, polygonal, and round cells occurred in a myxoid background. The tumor cells were arranged in a vaguely nodular pattern with peripheral collagenized stroma, higher cellularity at the periphery, and a delicate vascular network in the background. Immunohistochemically, the tumors displayed diffuse reactivity for vimentin and no reactivity for smooth muscle actin, muscle specific actin, desmin, S-100 protein, or myogenin. Electron microscopy documented a poorly differentiated fibroblastic proliferation. Four cases tested negative for the ETV6-NTRK3 gene fusion by RT-PCR. One tumor had a complex karyotypic abnormality with rearrangements involving chromosomes Y, 9, and 3. Three patients had recurrences or metastasis treated with a combination of surgery and chemotherapy. One patient is alive with persistent locally aggressive disease, 2 are alive with no evidence of recurrence, 1 had a recurrence treated surgically without further follow-up information, 1 patient died with persistent tumor and sepsis 6 weeks after diagnosis, and 1 patient was lost to follow-up. The morphologic appearance combined with the ultrastructural features and absence of the typical gene rearrangement of congenital-infantile fibrosarcoma are unique, and we propose that PMMTI represents a new category of pediatric fibroblastic-myofibroblastic tumor.
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PMID:Primitive myxoid mesenchymal tumor of infancy: a clinicopathologic report of 6 cases. 1653 60

Pulmonary carcinosarcoma, consisting of both carcinoma and sarcoma with a heterologous element, is a rare subtype, comprising approximately 0.3% of primary lung neoplasia. A 57-year-old man was admitted because of severe dyspnea. A tumor wholly occupying the right thorax was biopsied and diagnosed as pleomorphic sarcoma. The tumor did not respond to chemotherapy, and the patient died of respiratory failure and sepsis. At autopsy, pleomorphic sarcoma was histologically dominant and contained a liposarcoma element confirmed by histocytological and electron microscopic analysis. Adenocarcinoma component with papillary and tubular patterns was confined to the medial lesion of the right lower lobe (3x8 cm), which was found in the chest X-ray 3 years before admission, and had continuously merged with the sarcomatous lesion through the histological transition of both components. Aggressive and rapid growth of the sarcoma derived from the earlier adenocarcinoma became prevalent and contributed to the severe clinical outcome. This is the first documented case of primary lung carcinosarcoma with a liposarcoma element.
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PMID:Lung carcinosarcoma with liposarcoma element: autopsy case. 1687 39

Medical thoracoscopy is not widely available in Australia. A medical thoracoscopy service has been set up in a regional hospital using no specialized equipment and at minimal cost. Of the first 100 procedures carried out, 89 were for investigation of pleural effusion, 6 for pneumothorax and 6 for empyema. Of the 89 pleural effusions, 73 were diagnosed as malignant (43 carcinoma, 24 mesothelioma, 3 lymphoma, 2 melanoma and 1 sarcoma). The sensitivity for a malignant diagnosis was 94.5%, with 100% specificity. Four patients had unsuspected tuberculous effusions. Pleurodesis was carried out with instillation of dry sterile talc in 67 cases. In 92.5% of these, no further drainage procedure was needed. There was one fatality caused by pre-existing sepsis in a debilitated patient with disseminated carcinoma. Medical thoracoscopy is a simple, safe and cost-effective technique for diagnosing and treating pleural effusions and provides a useful service in the setting of a regional hospital.
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PMID:Medical thoracoscopy in an Australian regional hospital. 1738 68

Purpose Because we had observed in the synovial sarcoma subgroup of a broad phase III advanced soft tissue sarcoma study a significantly greater objective regression rate from ifosfamide+doxorubicin (88%) than from doxorubicin alone (20%) (P = 0.02), the Eastern Cooperative Oncology Group (ECOG) decided to further assess this two drug combination in a subsequent Phase II study.Patients Between 1994 and 1999, twelve adult patients with advanced synovial sarcomas were enrolled to receive, as their initial chemotherapy, ifosfamide 7.5 gm/m(2) plus doxorubicin 60 mg/m(2), given intravenously over two consecutive days every 3 weeks.Methods Each day for 2 days doxorubicin 30 mg/m(2) was infused over 5 min through a running i.v., followed by ifosfamide 3750 mg/m(2) over 4 h. Continuous i.v. fluid was infused at 300 mL/h for 3 h on day 1, before chemotherapy was begun; then the infusion was continued at 100 mL/h for a total of 3 days. Mesna 750 mg/m(2) was given 15 min before ifosfamide and at 4 and 8 h after ifosfamide on days 1 and 2 of each treatment cycle. Filgrastim (G-CSF) 5 mug/kg was given subcutaneously each day for 14 days beginning on day 3 of each treatment cycle to limit the severity of neutropenia.Results Five of our 12 patients (42%) experienced partial regression of their advanced synovial sarcomas; however, this first stage result was borderline for proceeding to the second planned stage of accrual and our case accrual was quite poor. Thus, the study was closed after stage one accrual. Our patients received a median of four cycles of chemotherapy (range: 1 to 6). All patients experienced at least grade 3 neutropenia (grade 4 in nine of them), and one patient died of treatment-related sepsis following the initial cycle of chemotherapy. Median survival was 11 months.
Sarcoma 2003
PMID:Phase II Study of Ifosfamide+Doxorubicin in Patients With Advanced Synovial Sarcomas (E1793): A Trial of the Eastern Cooperative Oncology Group. 1852 63

In childhood, the conus medullaris syndrome owing to leukemia is rare. Here, a 12-year-old boy with acute myeloblastic leukemia, maxillary mass, and conus medullaris syndrome is reported. A biopsy from the maxillary mass revealed "granulocytic sarcoma." Lumbosacral magnetic resonance imaging revealed clumped and thickened cauda equina nerve roots, epidural and periradicular diffuse soft tissue, which was enhanced with gadolinium. Cerebrospinal fluid revealed elevated protein but no cells. Chemotherapy and local radiotherapy for both the face and the spine, yielded bone marrow remission and abatement in neurologic and radiologic findings, but he developed bone marrow relapse and died because of sepsis.
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PMID:A patient with acute myeloblastic leukemia who presented with conus medullaris syndrome and review of the literature. 1964 94


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