UMLS:C0178874 - FACTA Search

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Query: UMLS:C0178874 (tumor progression)
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To assess safety, antitumor response, and immunological and virological activity of interferon-alpha 2a and zidovudine combination therapy in patients with AIDS-related Kaposi's sarcoma, we conducted an open-label, Phase II, multicenter study. Sixty-three patients with biopsy-proven Kaposi's sarcoma and no previous interferon-alpha therapy received zidovudine 600 mg/day and interferon-alpha 2a 18 x 10(6) U/day. The median duration of follow-up was 49 weeks. Of 62 evaluable patients, 25 (40%; 95% confidence interval, 0.28-0.52) showed a complete (26%) or partial (15%) antitumor response. Eight of 30 patients (27%) with < 100 CD4 cells/mm3 and 17 of 32 patients (53%) with > or = 100 CD4 cells/mm3 had a response. The median time to response was 36 weeks. Of the 25 patients with a response, four developed tumor progression. The median duration of response was 22.4 weeks. Eight patients (13%) developed another AIDS-defining event and 13 (21%) died. The major toxicities included anemia (16%), neutropenia (27%), elevated serum transaminases (16%), weight loss (16%), malaise (14%), fatigue (14%), fever (10%), and headache (6%). Therapy with intermediate-dose interferon-alpha 2a and zidovudine resulted in tumor regression in patients with AIDS-related Kaposi's sarcoma who had a wide range of CD4 cell counts; this therapy was relatively well tolerated.
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PMID:A phase II study of recombinant human interferon-alpha 2a and zidovudine in patients with AIDS-related Kaposi's sarcoma. AIDS Clinical Trials Group. 860 Dec 24

This trial tested the assumed efficacy and safety of external beam-radiotherapy combined with daily administration of low dose cisplatin (CDDP) (ERCLC therapy) for patients with glioblastoma multiforme (GBM). Thirty adult patients with supratentorial GBM received daily postoperative treatment with low dose intravenous CDDP (4-6 mg/m2) administered 30 minutes before external irradiation. In 10 patients, intraoperative radiotherapy (IORT) following surgery was given prior to ERCLC therapy. Tumor response on MRI, interval to tumor progression, survival, and toxicities were analyzed. None of the patients showed a tumor response to ERCIC therapy. Overall, the median time to tumor progression was 6 months with a 1-year tumor progression-free rate of 26.7% and a 2-year rate of 0%. The median survival time was 15 months with a 1-year survival rate of 69.9% and a 2-year rate of 31.5%. The survival rate of patients with IORT was better than that of those without IORT, however, there was no significant difference. Anorexia associated with nausea occurred in 70% and general fatigue in 10.0%. Leukopenia and thrombocytopenia occurred in 26.7% and 33.3%, respectively. However, none of the patients had to be withdrawn from therapy due to these toxicities. Other toxicities were not observed. This clinical study showed that daily administration of low dose CDDP did not enhance tumor response to irradiation for GBM on MRI. Regarding toxicity, however, ERCLC therapy was well tolerated. Although this trial did not provide sufficient data to determine whether ERCLC therapy was effective for GBM due to the small number of patients, additional clinical trials of this therapy may be warranted because that the survival rate in this study was equal to the better results recently reported for newly diagnosed GBM.
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PMID:Clinical trial of external beam-radiotherapy combined with daily administration of low-dose cisplatin for supratentorial glioblastoma multiforme--a pilot study. 926 43

A new xenograft model of multiple myeloma (MM), where growth is strongly regulated by interleukin-6 (IL-6), was established in severe combined immunodeficiency (SCID) mice. In this model, endogenous IL-6 from SCID mice was ineffective at eliciting growth of the established human MM cell line KPMM2; these cells achieved autonomous growth through their autocrine secretion of IL-6. The etiopathology in this disease model is consistent with that of human MM. When greater than 3 x 10(6) KPMM2 cells were injected intravenously (IV), tumors developed in all mice and were predominantly localized in their bone marrow. Tumors were also apparent in the lymph nodes, but absent from other organs. Immunostaining of cell surface antigen (CD38) showed that more than 40% of bone marrow cells in femur were of myeloma origin in the advanced stage of tumor progression (day 37). Histologic analysis of these mice show that bone marrow was largely occupied by plasmablastic cells and bones had developed osteolytic lesions at multiple sites. Concurrently, there was a decrease in bone density throughout the body and a significant increase in ionized plasma calcium. M-protein was detected in the serum within 10 days after transplantation, which correlated with the tumor progression. Between 30 and 40 days after the transplantation, mice presented with a rapid and severe loss of body weight, hind leg paralysis, and fatigue. Subsequently, the mice died within a week. A single IV injection of 0.2 mg humanized anti-IL-6 receptor antibody (hPM1) into mice on the day after tumor transplantation substantially suppressed the elevation of serum M-protein and development of the tumor-associated abnormalities and significantly increased in the life span of tumor-bearing mice. Our data show the usefulness of this model to analyze the pathologic role of IL-6 in MM and the efficacy of targeting the IL-6 receptor in IL-6-dependent KPMM2 cells.
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PMID:New xenograft model of multiple myeloma and efficacy of a humanized antibody against human interleukin-6 receptor. 931 Apr 95

We evaluated the pharmacokinetics of 5-fluorouracil (5-FU) combined with recombinant human interferon (IFN)-alpha 2a in 10 previously untreated patients with advanced colorectal carcinoma. 5-FU was administered as a continuous i.v. infusion, 750 mg/m2/day for 5 days during week 1. One s.c. injection of IFN-alpha 2a, 9 x 10(6) IU, was administered during week 2. Beginning with week 3, a continuous i.v. infusion of 5-FU 750 mg/m2/day for 5 days was administered in combination with IFN-alpha 2a, 9 x 10(6) IU s.c. three times per week. The combination of 5-FU and IFN-alpha 2a was continued every other week until either 3 months after complete remission or tumor progression. No grade 4 toxicity was observed. Granulocytopenia (two patients), leukopenia (one patient), thrombocytopenia (one patient), stomatitis (two patients), fatigue (one patient) and hand-foot syndrome (one patient) were the major (grade 3) toxic reactions encountered. Overall, one complete and six partial responses were noted. The results of the paired t-test showed no statistically significant differences between the means of the two treatments, 5-FU and 5-FU plus IFN-alpha 2a, with respect to the steady-state plasma concentration, area under the concentration-time curve, total body clearance, or steady-state volume of distribution of 5-FU, or the serum concentration of IFN. We conclude that 5-FU and IFN-alpha 2a do not interact pharmacokinetically at the doses and schedules in the regimen studied.
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PMID:Pharmacokinetics of recombinant human interferon-alpha 2a combined with 5-fluorouracil in patients with advanced colorectal carcinoma. 982 27

Resistance may be classified as active (or competitive) (due to excess amount of a factor) vs passive (or non-competitive) (due to a deficiency of a factor). Passive resistance may be important in human solid tumors. In passive resistance, the dose-response curve may be shallow, or may flatten at a relatively low dose. We hypothesized that, if passive resistance were important, it might be advantageous to use low doses of multiple concurrent chemotherapy agents with differing mechanisms of action, rather than using high doses of 2 or 3 drugs. We combined single day cisplatin 60 mg/m2, cyclophosphamide 250 mg/m2, epirubicin 40 mg/m2, paclitaxel 60 mg/m2, and vinblastine 2.5 mg/m2, with 5 days of 5-fluorouracil 200 mg/m2, folinic acid 20 mg/m2 and dexamethasone 4 mg orally q.i.d. every 3 weeks. In later cohorts, doses were escalated, and tamoxifen and verapamil were added. Twenty-three patients were entered. ECOG performance status was 1 in 15 patients and 2 in 8. Number of prior chemotherapy regimens was 0 in 4 patients, 1 in 4, 2 in 8, 3 in 4, 4 in 2, and 7 in 1. Sixteen patients had prior radiotherapy, and 3 had no prior therapy. Myelosuppression and febrile neutropenia were frequent, and 4 heavily pretreated patients died of pneumonia contracted while neutropenic. Diarrhea, nausea and vomiting, and fatigue were also prominent. Among 9 patients with non-small cell lung cancer, one had a partial remission, 4 had stable disease (including 3 with minor objective responses). Two additional non-small cell lung cancer patients also had objective tumor regression, but were coded as failures, since one had tumor progression in <6 weeks and the other died of respiratory failure (thought to be due to severe mucous plugging) one week after his first course of treatment. Among 14 patients with other tumor types, there was one partial response (esophageal carcinoma), 6 patients with stable disease for >6 weeks (including minor responses in one patient each with adenocarcinomas of kidney and breast), and 7 failures (including one patient with adenocarcinoma unknown primary who had minor tumor regression lasting 4 weeks). Despite the unacceptably high toxic death rate, median survival time was 24 weeks (range, 1 week to >104 weeks). This regimen is toxic, but survival duration is longer than would be expected in this heavily pre-treated population. Doses recommended for further study are those used in the first treatment cohort (as described above). Since myelosuppression is the major toxic effect, hemopoietic growth factors might prove helpful with this regimen.
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PMID:Concurrent use of multiple low dose chemotherapy agents with differing mechanisms of action as a strategy vs passive resistance: A pilot study. 1049 50

A Phase I dose escalation and pharmacokinetic study of the alkylating cytotoxic agent treosulfan was conducted to evaluate the maximum tolerated dose and the dose-limiting toxicities in patients with advanced malignancies rescued by autologous peripheral blood stem cell transplantation. Twenty-two patients (15 ovarian and 7 other carcinomas/lymphomas) with a median age of 48 years were treated with 28 high-dose courses. Treosulfan was infused over 2 h at escalating doses from 20 to 56 g/m2, and pharmacokinetic parameters were analyzed. At 56 g/m2, three of six patients experienced dose-limiting toxicities: diarrhea grade III/IV in three patients; mucositis/stomatitis grade III in one patient; toxic epidermal necrolysis in one patient; and grade III acidosis in one patient. Other low-grade side effects, including erythema, pain, fatigue, and nausea/vomiting, were recorded. Two patients died within 4 weeks after treatment because of rapid tumor progression and fungal infection, respectively. Plasma half-life, distribution volume, and renal elimination of treosulfan were independent of dose, whereas the increase in area under the curve was linear up to 56 g/m2 treosulfan. The maximum tolerated dose of high-dose treosulfan is 47 g/m2. A split-dose or continuous infusion regimen is recommended for future high-dose trials. In consideration of antineoplastic activity and limited organ toxicity, inclusion of high-dose treosulfan in combination protocols with autologous peripheral blood stem cell transplantation seems worthwhile.
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PMID:Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies. 1110 34

The authors report a patient with a rare intrasellar meningioma mimicking pituitary adenoma. A 60-year-old man was admitted to our hospital for evaluation of general fatigue. He had no neurological deficit including visual function. Endocrinological tests revealed panhypopituitarism. The craniogram showed slight enlargement of the sella turcica with thinning of the dorsum sellae. CT scan and MR imaging demonstrated a homogeneously enhanced intrasellar mass with slight suprasellar extension. Partial removal of the mass was performed via the transsphenoidal approach because it was extremely firm and hemorrhagic. Histological diagnosis was transitional meningioma. The patient has been well for two years after surgery without tumor progression on MR imaging. It is mandatory to distinguish intrasellar meningioma from pituitary adenoma preoperatively because of marked difference in their treatment strategies. Despite recent advances in neurodiagnostic imaging, it may still be difficult to differentiate pituitary adenoma from intrasellar meningioma. When we re-evaluated the MR imaging, we recognized that the tumor had demonstrated specific findings, ruling out pituitary adenoma, namely bright and homogeneous enhancement, dense enhancement in the early phase on the dynamic MR study, and flow void signal within the mass. The authors emphasize that careful evaluations of MR imaging will allow the correct preoperative diagnosis in patients with intrasellar meningioma mimicking pituitary macroadenoma.
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PMID:[A case of intrasellar meningioma mimicking pituitary adenoma]. 1145 2

Thirty-nine patients with advanced non-small cell lung cancer, refractory or resistant to platinum or taxanes derivatives were treated on an out-patient basis with vinorelbine 25 mg/m2 intravenous (I.V.) on days 1 and 8 followed by gemcitabine 800 mg/m2 l.V. on days 1 and 8. Chemotherapy was repeated every 3 weeks. The patients were evaluated for response every two cycles of treatment. All 39 patients were assessable for toxicity and 35 were assessable for response. On an intent to treat analysis, only 1 (2.6%) patient achieved a partial response (PR) (95% CI 0.09% to 17.6%); fourteen patients (35.9%, 95% CI 29.45% to 67.4%) had stable disease (SD) and 24 (61.5%) had progressive disease (PD). The median time to tumor progression (TTP) was 4.7 months (range 0.13 to 18.9 months), the median survival time was 7.3 months (range 0.6 to 18.9 months) and the 1-year survival rate was 35%. Clinical benefit response including improvement of PS, dyspnea and anorexia, pain and cough reduction and cessation of hemoptysis and fever was observed in 10% to 50% of patients. Grade 3/4 neutropenia occurred only in 2 (5.2%) patients. Five patients experienced febrile neutropenia, which was successfully treated with G-CSF and broad-spectrum antibiotics. No patient experienced grade 3/4 anaemia or thrombocytopenia. One patient experienced grade 4 fatigue and stopped the treatment. Nausea / vomiting, fatigue, neurotoxicity, diarrhea and fever were mild in the majority of patients and did not result in any clinically significant problem. There were no treatment-related deaths. In conclusion, the combination of gemcitabine and vinorelbine showed low objective response rate in patients previously treated with CDDP/taxanes-containing regimens. This regimen was relatively well-tolerated and was associated with prolonged 1-year survival and improvement in cancer related symptoms. To validate these findings a randomized trial of gemcitabine and vinorelbine versus taxotere or best supportive care is required.
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PMID:An out-patient second-line chemotherapy with gemcitabine and vinorelbine in patients with non-small cell lung cancer previously treated with cisplatin-based chemotherapy. A phase II study of the Hellenic co-operative Oncology Group. 1171 2

Dipyridamole, an inhibitor of nucleoside transport, increases the activity of 5-fluorouracil in a dose-dependent manner. The purpose of the present study was to determine whether dipyridamole with 5-fluorouracil and leucovorin gave an improved therapeutic outcome. Sixty patients entered in the present pilot study had previously received 5-fluorouracil (450 mg/m2) and leucovorin (100 mg/m2), every week, and relapsed during this treatment, which ended at least 6 weeks prior to study entry. Dipyridamole was administered at three different dosing schedules (DS) and methods of administration in three groups of patients. DS I: dipyridamole, 30 mg/m2 in normal saline solution, in 90 min iv infusion, followed by leucovorin, 100 mg/m2 iv push, followed by 5-fluorouracil, 450 mg/m2 in normal saline solution, in 60 min iv infusion, dipyridamole tablets (75 mg) every 12 hrs, continuously during the time of chemotherapy. DS II: dipyridamole, 50 mg/m2 in normal saline solution, in 90 min iv infusion, and the rest was the same as DS I. DS III: without oral dipyridamole, patients received dipyridamole (50 mg/m2) iv in the same manner as in DS I and II. Treatment was continued until tumor progression or unacceptable toxicity. All patients (n = 60) entered in the present study were assessable for response and toxicity. No complete response was observed. No patient at DS I responded, whereas 2 patients at DS II and 3 at DS III had a partial response (P <0.1). Stable disease was found with DS I (n = 1), DS II (n = 8) and DS III (n = 9) (P <0.01). More patients progressed at DS I (n = 19) than at DS II (n = 10) and DS III (n = 8) (P <0.0007). The median duration of response was 11 weeks (range, 8-16). Time to progression was 17 weeks for DS I, 15 weeks (range, 10-19) for DS II, and 14 weeks (range, 11-21) for DS III (P = 0.43). Median survival did not differ significantly between DS I (29 weeks; range, 14-48), DS II(31.5 weeks; range, 17-63) and DS III (36 weeks; range, 16-58) (P = 0.2). Neutropenia was most severe with DS I (grade 2, P<0.01) and DS II (grade 1, P<0.05) and nausea/vomiting with DS I (grade 0, P < 0.0005, grade 1, P <0.0002, grade 2, P <0.02) and DS III (grade 3, P<0.0009). Diarrhea was most severe in DS II (grade 3, P <0.005). Mucositis was increased in DS II (grade 0, P <0.008), anorexia in DS II (grade 0, P <0.032) and fatigue in DS I (grade 0, P <0.003). More patients in DS I than with the other two DS experienced headache (P <0.044). According to the response achieved at DS III (15% partial response and 45% stable disease) and the toxicity which was well tolerated mainly in this DS (except for nausea and vomiting grade 3, P <0.009), it can be stated that DS III is the appropriate dose and the simplest schedule of administration (administration of dipyridamole during therapy only). In conclusion, it appears that dipyridamole might still have a role in enhancing the clinical activity of drugs involved in the inhibition of the thymidylate synthetase biochemical pathway and its activity in combination with these agents (5-fluorouracil + leucovorin) as frontline treatment should therefore be explored in future phase II studies.
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PMID:Leucovorin + 5-fluorouracil plus dipyridamole in leucovorin + 5-fluorouracil-pretreated patients with advanced colorectal cancer: a pilot study of three different dipyridamole regimens. 1176 78

Many conditions that would not be considered normal in a younger population are routinely accepted in older people as a part of so-called "normal" aging. Among these conditions are many chronic and debilitating conditions such as chronic pain, insomnia, weakness, fatigue, and anemia. This article reviews current evidence regarding the relationships among age, fatigue, weakness, anemia, and erythropoiesis. Anemia in the elderly is important because it can lead to weakness, fatigue, limitations in activity, and may increase cardiovascular risk. Recent studies of the effect of erythropoietin in an aging population support the hypothesis that anemia is associated with pathologic factors and not with normal aging. While older individuals admitted to hospitals are more likely to be anemic, these same individuals have a bone marrow mass and numbers of cultured progenitor cells that are similar to that of the younger population; therefore, the predicted response to erythropoietin, and thus the function of the bone marrow and cellular progenitors, is maintained. Thus, we can conclude that anemia is a correctable pathologic finding in elderly people. A number of studies have shown a strong relationship between fatigue and anemia, but few studies investigate to what degree age is a factor in weakness and fatigue. In a study of 375 anemic cancer patients with a median age of 61 years, age as a covariate in multiple linear regression analysis failed to reach significance for most measures of function and quality of life (QOL), including measures of energy, activities, mental health, general cancer-related QOL, and overall QOL. Additional analysis suggests that other factors, including cancer progression, hemoglobin change, and baseline hemoglobin levels, are much more important in determining change in functional and quality-of-life scores. In another set of 2,000 cancer patients and 1,000 controls, cancer patients experienced significantly more fatigue compared with controls. There was no correlation between cancer patient age and fatigue, while in controls the cohort aged 65 or more reported more fatigue than did younger subjects. Finally, measurement of QOL in the general population demonstrated, for both the Short-Form 36 and Functional Assessment of Cancer Therapy - Anemia questionnaires, that age alone is not significantly correlated with QOL. We suggest that chronic conditions such as fatigue and anemia are no more "normal" in an aging population than in a general population, and that all patients with chronic conditions be adequately treated and counseled for their condition.
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PMID:Age, anemia, and fatigue. 1208 55

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