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ABSTRACT: Carcinoma showing thymic-like elements (CASTLE) is a rare tumour of the thyroid of thymic origin. The histological appearance of this tumour may be similar to that of squamous cell carcinoma of the thyroid, but outcome associated with CASTLE is more favourable.
A systematic literature review was conducted for case reports on CASTLE. A text word search of the Medline database was made with a manual search of the citations from these references. Twenty-two case reports were found.
In five patients with tumour-negative lymph nodes no local or distant recurrence was observed. Seventeen patients had unknown or involved lymph nodes. Two patients were excluded from further study: one had no follow-up and one was treated by irradiation only. Of the remaining 15, six had local, three had distant and two had local and distant recurrence. In patients with involved or unknown lymph node status, local recurrence was noted in one of five patients treated by surgery and irradiation, and in seven of ten patients treated by surgery alone. Irradiation or systemic chemotherapy was given to four patients with recurrent tumours, with variable response.
CASTLE with tumour-negative lymph nodes has a low risk of recurrence and surgery without adjuvant therapy is sufficient. Radiotherapy seems indicated when lymph nodes are tumour positive and can be effective for recurrent tumours. In selected patients surgery for recurrent tumour can improve quality of life and outcome.
British Journal of Surgery 03/2004; 91(2):142-5. · 4.61 Impact Factor
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H Stöger,
H Samonigg,
M Krainer,
M Ploszczynski,
G Nirnberger,
S Maca,
W Hehenwarter,
M Wirth, J Schüller,
N Vavra,
W Scheithauer,
G Kornek,
M Stierer,
C C Zielinski
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ABSTRACT: A randomised phase II/III study was conducted in patients with advanced breast cancer to determine the dose intensity achievable through an acceleration of administration of chemotherapy with epidoxorubicin and cyclophosphamide (EC) alone, as compared with the combination of this regimen with two different schedules of granulocyte-macrophage colony stimulating factor (GM-CSF). 73 patients received EC intravenous (i.v.) (epidoxorubicin 100 mg/m2, cyclophosphamide 600 mg/m2) on day 1 (group A), or the same chemotherapy plus sub-cutaneous (s.c.) GM-CSF (5 micrograms/kg/day) either from days 3 to 12 (group B) or from days -6 to -3 (group C). The primary objective of the study was the investigation of dose intensity delivered in the three treatment arms, whereas the secondary objective was response rate. A significant increase (P = 0.006) in dose intensity of 21% was observed for treatment group B, whereas the increase in dose intensity achieved in group C (7%) was not significant (P = 0.086). Response rates (complete response (CR) + partial response (PR)) of 56% were observed in group A, 65% in group B, and 57% in group C, respectively. This difference in response rates did not reach statistical significance (P = 0.271). We thus conclude that an acceleration of the EC regimen over the standard schedule could be accomplished with postchemotherapeutic GM-CSF support, leading to an increase in dose intensity, whereas pretherapeutic short-term GM-CSF administration did not reach this goal.
European Journal of Cancer 04/1998; 34(4):482-8. · 5.54 Impact Factor
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ABSTRACT: The in vitro binding rate of epirubicin (EPR) to different plasma proteins, control serum, red blood cells and whole blood was investigated without and with the cytoprotective agent amifostine. The binding rate of EPR to plasma proteins fractions and red blood cells dependend on the concentration of the matrix components. EPR was bound more than 90% to human serum alpha-globulin (alpha-HSG), to human serum albumine (HSA) and human serum beta-globuline (beta-HSG) at 80 to 90%, in the case of human serum gamma-globulin (gamma-HSG) the binding rate amounted 75%. The binding rate of EPR to RBCs in whole blood samples reached 38%. Within the observed concentration range of proteins (1-40 micrograms/ml, depending on the protein concentration) AMI caused a reduction of the protein-bound amount of EPR in the range from 2 to 19% of HSA, 4 to 20 in the case of beta-HSG, 2 to 32% in the case of alpha-HSG and 17 to 21% for gamma-HSG. In the whole blood samples the binding of EPR to proteins dropped from 45 to 32% and RBC-partitioning from 38 to 32%. Two compounds with free thiol groups, cystein and glutathione, were compared with AMI in regard to lowering the binding rate of EPR to HSA: the effect was exactly in the same order of magnitude: -17% for AMI, -21.0% for cystein and -20.8% for glutahion (p < 0.002). For a negative control, cystin and phenylalanin were tested, too: both compounds showed no influence on the protein binding of EPR: 63.8% binding rate in the control group, 65.2% in the presence of cystin and 64.6% in the presence of phenylalanin (statistically not significant). The present results indicate, that binding of EPR to serum proteins is reduced in the presence of AMI by interaction of the thiol-group with the protein and that the thiophosphoric ester bond in the test solution must cleave rapidly.
Pharmazie 11/1996; 51(11):897-901. · 1.01 Impact Factor
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ABSTRACT: The concentration-time profile of 5-fluorouracil (5FU) in serum of patients during continuous infusion of 5FU for five days was investigated. The coadministration of each of 5 million units interferon-alpha-2b (IFN) on day 2 and 4 of the infusion causes an accumulation of 5FU in the serum at about 120% on day 3 in compare to the control (day 1 of infusion without IFN). On day 5 of the infusion the mean 5FU serum concentrations are about 170% higher than on day 1 with a level of probability ranging from p < 0.0003 to p < 0.043. Mean AUC-values increase from 5454 ng/ml.h (day 1) to 12069 ng/ml.h (day 3, p < 0.05) and subsequently to 14919 ng/ml.h on day 5 (p < 0.005). IFN causes an decrease of the total body clearance from 2949 ml/h (day 1) to 1959 ml/h on day 3 and to 1258 ml/h on day 5 (p < 0.008), respectively. There might exist a linear correlation between the order of magnitude of the 5FU serum concentrations and its pharmacokinetic parameters on day 1, 3 and 5 and the administration of IFN, because a close correlation ranging from R = 0.972 to R = 0.999 have been found in regression analysis.
Pharmazie 07/1995; 50(6):416-9. · 1.01 Impact Factor
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ABSTRACT: The influence of interferon-alpha-2b (CAS 99210-65-8, IFN) on the pharmacokinetics of epirubicin (CAS 56420-45-2, EPR) was investigated in 10 patients (4 male, 6 female). EPR was injected as an i.v. bolus over 2 min in a dose of 60 mg/m2 IFN was pre-administered 3 times a week in a dose of 5 x 10(6) IU as a s.c. injection. The comparison of the pharmacokinetics after injection of EPR and EPR+IFN did not show remarkable differences. A statistical significant influence in regard to the terminal elimination half-life (gamma-HL) and the total clearance (CLtot) was found, indicating a reduction of gamma-HL from 18.18 +/- 16.7 for EPR to 8.47 +/- 8.67 h for EPR+IFN and a reduction of the total clearance from 72.33 +/- 55.4 ml/min for EPR to 48.41 +/- 12.7 ml/min for EPR+IFN. The area under the concentration-time curve (AUC, according to the 3-compartment model) increases under the influence of IFN from 2004 +/- 1105 ng/ml.h for EPR up to 2582 +/- 1024 ng/ml.h for EPR+IFN. However, this increase is statistically irrelevant due to the high deviation ranges. Besides, the influence of IFN on the interactions of EPR with red blood cells (RBCs) was investigated in 6 patients under the above conditions. The percental concentration of EPR in RBCs is reduced from 35.4% to 34.7% after administration of IFN. Two metabolites, 13-dihydroepirubicin (M I) and 7-deoxydoxorubicinone (M II), were detected both in serum and RBCs, whereas IFN showed no significant interference with the metabolism or with the binding of the metabolites to RBCs.
Arzneimittel-Forschung 03/1995; 45(2):212-5. · 0.72 Impact Factor
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ABSTRACT: Resistance to cytotoxic chemotherapy is a major problem in the management of patients with metastatic breast cancer. Various data suggest P-glycoprotein-associated multidrug resistance (MDR) to be a relevant resistance mechanism in this tumor. The purpose of this study was to evaluate feasibility and activity of combining oral dexverapamil, a second-generation chemosensitizer currently in clinical development for MDR reversal, with epirubicin in patients with epirubicin-refractory high-risk metastatic breast cancer. Patients first received epirubicin alone at 120 mg/m2. In cases of clinical refractoriness, epirubicin was continued at the same dose and schedule but supplemented with oral dexverapamil. Dexverapamil was given at 300 mg every 6 h for a total of 13 doses and commenced 2 days prior to epirubicin administration. At the time of this interim analysis, 41 patients had received epirubicin alone and 20 proceeded to treatment with epirubicin plus dexverapamil. Of the 20 patients, 14 were considered evaluable for toxicity and activity. Addition of dexverapamil resulted in a significant decrease in mean heart rate and blood pressure as well as prolongation of PQ time as compared to epirubicin alone. However, these cardiovascular effects of dexverapamil were usually mild, and subjective tolerance of treatment was good. In 7/14 patients, dose escalation of dexverapamil was feasible. Dexverapamil had no effect on epirubicin toxicities and did not require reduction of the epirubicin dose. In 2/14 patients, the addition of dexverapamil to epirubicin was able to convert progressive disease and no changes respectively, into partial responses. In 3 patients with progressive disease, addition of dexverapamil temporarily prevented further tumor progression. Analyses of dexverapamil and nor-dexverapamil plasma levels, of in vitro reversal activity of patient sera containing dexverapamil, and of epirubicin pharmacokinetics without and with dexverapamil are currently in progress. Addition of oral dexverapamil to epirubicin 120 mg/m2 proved to be feasible in a multiinstitutional setting. Patient accrual is continuing to determine whether dexverapamil is capable of overcoming epirubicin refractoriness in a significant number of patients with metastatic breast cancer.
Journal of Cancer Research and Clinical Oncology 02/1995; 121 Suppl 3:R3-6. · 2.56 Impact Factor
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ABSTRACT: The pharmacokinetics of the antimetabolite 5-fluorouracil (5FU, CAS 51-21-8) were investigated under the influence of the biomodulating agents folinic acid (FA), FA combined with dipyridamole (DPM), DPM, interferon-alpha-2b (IFN), and IFN combined with DPM. IFN as well as IFN/DPM cause an enormous increase of the 5FU plasma concentrations resulting in a statistically significant change of the pharmacokinetics. The mean initial plasma concentrations of 5FU are increased at about 143% under the influence of IFN and at 162% under the influence of IFN/DPM. Accordingly, the mean area under the concentration-time curve is elevated at 114% for IFN and at 184% for IFN/DPM. The volume of distribution (IFN - 39%, IFN/DPM - 38%) as well as the total body clearance (IFN - 30%, IFN/IFN - 44%) are lowered distinctly. In contrary, the coadministration of either FA or DPM or FA/DPM to 5FU does not lead to a significant change in the pharmacokinetic profile of 5FU, but also causes higher plasma concentrations. The present results indicate that the coadministration of biomodulators can lead to distinct changes of the 5FU kinetics, but must not be useful in each case.
Arzneimittel-Forschung 04/1993; 43(3):387-90. · 0.72 Impact Factor
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Archiv der Pharmazie 07/1992; 325(6):373-4. · 1.71 Impact Factor
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Pharmazie 06/1992; 47(5):387. · 1.01 Impact Factor
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ABSTRACT: Interferon alfa has been demonstrated to enhance the effect of fluorouracil (5-FU) on human colon cancer cell lines as well as in clinical studies. By several authors interest in focussed on the question whether the interaction between these two agents is reflected by changes of 5-FU kinetics. In the present study the pharmacokinetic behavior of 5-FU was investigated in combination with interferon alfa (IFN-alpha-2b) and further after adding the second well-established biomodulating agent folinic acid (FA). Ten patients with advanced gastrointestinal cancer received 5-FU as a weekly bolus injection of 750 mg/m2, IFN-alpha-2b 5 million units three times per week subcutaneously and FA as a short time infusion at 200 mg/m2. 5-FU plasma levels were determined by high performance liquid chromatography as a baseline measurement on day 1 before starting IFN-alpha-2b. Analysis was repeated at the second or third cycle of 5-FU administration 1 hour after the last IFN-alpha-2b injection, and finally after also adding FA immediately infused before 5-FU injection. Biomodulation of 5-FU by IFN-alpha-2b alone resulted in a significant alteration of 5-FU kinetic parameters as demonstrated by an increase of area under the curve by 80%, and of blood concentration (co) by 65%, and a decrease of total clearance at 50%. These data may partly explain the observed enhancement of antiproliferative and toxic effects of this combination. On the other hand, when FA was added to this schedule, no significant changes of 5-FU kinetics could be documented. Therefore the theoretical benefit of such a double modulation cannot be supported by our findings. Further preclinical and clinical investigations are required to define the role of a triple combination of 5-FU with IFN-alpha-2b and FA.
Seminars in Oncology 05/1992; 19(2 Suppl 3):93-7. · 3.50 Impact Factor
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ABSTRACT: The pharmacokinetics of interferon alfa-2b (IFN-alpha-2b) were determined following intraperitoneal (IP) infusion of escalating doses, ie, 5, 10, and 15 million units (MU) and intrahepatal-intraarterial (IA) (IA, bolus v 24 hours continuous infusion of 3 and 5 MU) administration in patients with metastatic cancer. Pharmacokinetic parameters show that bioavailability of IFN-alpha-2b after IP administration is 30 times higher for the peritoneal fluid (PF) than for peripheral blood (PB) explaining also the low incidence of side effects. The high affinity of IFN-alpha-2b to the peritoneal cavity is furthermore substantiated by the total compartment clearance, which is only about 1 1/minute for the PF in comparison to about 30 1/minute as determined for PB. IFN-alpha-2b is eliminated from the PF with a half life (t1/2) of elimination 10 to 32 hours and from the blood with t1/2 of 5 to 13 hours. After IA bolus, IFN is distributed from the blood with a t1/2 below, 2 hours, with dose-dependent serum peak concentrations (c = 47 IU for 3 MU and 145 IU for 5 MU). Twenty-four-hour infusion leads to a steady state within 4 to 6 hours and maximum concentration of 8.5 or 12.5 IU/mL, respectively. During infusion IFN alpha-2b is slowly eliminated with a t1/2 of 16 hours. The lower area under the curve levels after bolus injection may suggest a better tissue uptake of IFN-alpha-2b by the liver. Further studies on pharmacokinetics are warranted to establish exact dose recommendations for an optimal schedule using this route and mode of IFN-alpha-2b administration in mono- and combination therapies.
Seminars in Oncology 05/1992; 19(2 Suppl 3):98-104. · 3.50 Impact Factor
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ABSTRACT: The in vivo binding of the antineoplastic agent 5-fluorouracil (1) to erythrocytes in the whole blood of patients was investigated. The vascular availability of 1 is influenced by erythrocytes at 38.6 +/- 7.2% (calculated as AUC0-60-values), the coefficient of partition is 0.65 +/- 0.18. In comparison with serum, the volume of distribution and the total clearance are elevated by the erythrocytes, the half-lives of the compartment distribution and of the terminal elimination are not influenced.
Archiv der Pharmazie 03/1992; 325(2):73-5. · 1.71 Impact Factor
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ABSTRACT: The binding of 5-fluorouracil (1) to erythrocytes and to serum proteins under in vitro conditions was investigated. The binding rate of 1 to erythrocytes is dose-independent and amounts from 16.8 to 31.7% (concentration range 1 to 20 micrograms/ml). The mean coefficient of partition for erythrocytes is 0.25 (+/- 0.03), no binding to ghosts was observed. 1 is bound at about 4% to proteins, whereby 0.7% are bound to alpha-globulin, 0.8% to beta-globulin, 1.6% to gamma-globulin, and 0.8% to albumine. The mean partition coefficient for proteins is 0.04 (+/- 0.006).
Archiv der Pharmazie 03/1992; 325(2):69-71. · 1.71 Impact Factor
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ABSTRACT: The blood-plasma levels in 28 patients, suffering from colorectal cancer with liver metastases, which were treated by a cyclic chemotherapy with fluorouracil (1) after p.o. and intraarterial (i.a.) administration of 1 or its prodrug ftorafur (2), respectively, were compared with those obtained after i.v. administration and the pharmacokinetics were calculated. In the case of 1 as well as of 2 the i.a. administration has been found to be optimal for distribution into the tumor tissue of liver metastases due to lowered blood-plasma concentrations. The absolute bioavailability, was 78% for p.o. and 57% for the i.a. administration of 1 respectively, and 98% for p.o. and 61% for the i.a. administration of 1 (given as 2), Accordingly, p.o. administration of both substances leads to therapeutical sufficiently high plasma levels with a steady state of css = 2.9 micrograms/ml/tss = 14 min for 1 and css = 3.5 micrograms/ml/tss = 20 min for 2.
Pharmazie 09/1991; 46(8):587-8. · 1.01 Impact Factor
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ABSTRACT: The plasma levels of fluorouracil (5-fluorouracil, 5FU; CAS 51-21-8) after intravenous administration have been monitored without, under influence of interferon-alpha-2b (IFN) and under influence of IFN combined with folic acid (FA). IFN causes a highly significant change of the pharmacokinetic parameters of 5FU (p less than 0.001) compared to 5FU administration without IFN. The bioavailability of 5FU (compared as the AUC0-60 values) is elevated to 80%. In contrary, the combination of IFN with FA leads to a non-significant change of the 5FU pharmacokinetics, although the bioavailability is increased to 18%. The higher plasma levels of 5FU under the influence of IFN might be causes by a changed renal clearance, which is indicated by the reduction of the total plasma clearance at about 53%. The combination IFN/FA did not show a similar effect. Yet, in both cases an improvement of the tumor response and of the clinical picture could be observed.
Arzneimittel-Forschung 09/1991; 41(8):860-3. · 0.72 Impact Factor
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ABSTRACT: The concentration-profile of the antineoplastic agent carboplatinum in serum and intraperitoneal-fluid (IPF) of six female patients was studied. Pharmacokinetical analysis showed a rapid distribution-phase between both compartments within the first 4h after administration (t1/2 serum = 4.4 h, t1/2 IPF = 3.3 h). Elimination half-life of carboplatinum of 20.3 h from the blood-vessel-system was significantly higher than from the intraperitoneal-compartment (t1/2 = 10.6 h). The relative bioavailability (calculated as AUC-values) was at least 6 times higher for the IPF than for serum within the first 48 h. 98% of measured amount were eliminated from both compartments within this time. The desired high IPF-levels support this route of administration.
Archiv der Pharmazie 04/1991; 324(3):183-4. · 1.71 Impact Factor
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ABSTRACT: Based on in vitro studies that have demonstrated synergy between 5-fluorouracil (5-FU), leucovorin (LV), and cisplatin (CDDP) against human colon cancer cell lines, a clinical trial was initiated to determine the effects of this combination in patients with advanced unresectable colorectal carcinoma. Fifty-nine patients were enrolled in the study and 12 of them had received prior conventional 5-FU chemotherapy. Treatment consisted of 4 weekly courses of high-dose LV (200 mg/m2) administered by intravenous (IV) bolus, followed by 5-FU (550 mg/m2) and CDDP (20 mg/m2) each administered as a 2-hour infusion on 4 consecutive days. After a median of 5.5 treatment cycles, objective tumor response was seen in 20 of 59 patients (34%) (this included 3 complete remissions). The response rate in the 47 previously untreated patients was 38% (95% confidence limits, 26% to 53%). Stable disease occurred in 16 (27%) patients, whereas the tumor progressed in 23 (39%) patients. The median survival time was 11.5 months, with 15% of the patients alive at 2 years. The regimen was well tolerated and the primary side effects were mild and reversible gastrointestinal symptoms and myelosuppression. There was no episode of life-threatening toxicity. Eastern Cooperative Oncology Group (ECOG) Grade III adverse reactions that required 25% dose reductions occurred in only 14% of the patients. The results of this trial suggest that 5-FU, LV, and CDDP is an active, safe, and well-tolerated combination regimen in patients with advanced colorectal cancer.
Cancer 04/1991; 67(5):1294-8. · 4.77 Impact Factor
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ABSTRACT: The influence of the vasopressin-pro-drug glycylpressine (GP) and of a chemoembolisation with Spherex starch-particles (SP) on the availability of mitomycin (CAS 50-07-7, mitomycin C, MMC) was investigated in 30 patients with liver metastases, MMC administration was performed after blocking of the common hepatic artery by different concentrations of SP and after different time-intervals of GP. The comparison of plasma-levels after bolus injection without GP and after administration of MMC after 2, 5 and 15 min of vasoconstriction and after chemoembolisation with 450 mg or 900 mg SP, respectively, showed a remarkable reduction in the systemic circulation of MMC in the blood vessel system at about 40% (GP) and 45% (SP). A statistically significant influence on the pharmacokinetics of MMC with regard to CO, Vd, T 1/2zp, AUC and Cl(tot) was found, but not in t1/2el, t1/2biol and Vl. Both methods cause a distinctly accelerated diffusion of MMC into the tissue of the tumor region by change of the hemodynamics, leading to lowered side-effects. Thus the clinical picture was improved by MMC.
Arzneimittel-Forschung 04/1991; 41(3):260-3. · 0.72 Impact Factor
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Archiv der Pharmazie 02/1991; 324(1):53. · 1.71 Impact Factor
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ABSTRACT: The present trial was designed to evaluate whether interferon (IFN) combined with standard induction chemotherapy and/or interferon remission maintenance treatment improve treatment results in patients with multiple myeloma. Up to now 89 patients have received IFN plus vincristine/melphalan/cyclophosphamide/prednisolone (VMCP) as induction therapy, and 86 conventional VMCP. The proportion of patients with progressive disease was significantly lower (P less than 0.005) under IFN + VMCP as compared to the VMCP treatment group. Survival times were significantly longer (P less than 0.02) after IFN + VMCP induction therapy than after VMCP alone. In the second phase of this investigation, 33 progression-free myeloma patients were assigned to receive IFN as maintenance therapy, and 41 patients served as untreated controls. Patients maintained with IFN showed a tendency towards increased progression-free survival. Haematological side effects were observed significantly more often in patients receiving IFN, with more severe haematological toxicity in patients on the combined IFN + VMCP regimen and an increased number of patients with mild haematological toxicity in the group maintained with IFN. Other side effects, such as fever and fatigue, remained within tolerable limits. In conclusion, the preliminary results of this current clinical trial indicate significant advantages of combined IFN + VMCP induction treatment in terms of reduced disease progression and prolonged survival and possible benefits of IFN maintenance therapy in patients with multiple myeloma.
European Journal of Cancer 02/1991; 27 Suppl 4:S40-5. · 5.54 Impact Factor
