Side effects of therapy: case 2. Tamoxifen and uterine abnormalities.
Explore the source record for details and available documents.
Antineoplastic Agents, Hormonal↗
Biomedical subjects
E G de Vries
Publications and source records attributed to E G de Vries.
[The effects of tamoxifen on the female genital tract].
Tamoxifen has both agonistic and antagonistic effects on the female genital tract, depending on the ambient oestradiol concentration and the menopausal status of the patient. In postmenopausal women tamoxifen has an oestrogen agonistic effect on the vaginal epithelium, the uterine myometrium and the endometrium. It may induce benign cystic hyperplasia of the endometrial stroma and cause an increase in poly formation. The risk of endometrial cancer increases 2-3-fold after an exposure of up to 5 years. In asymptomatic tamoxifen users, gynaecological surveillance is not recommended. However, if there is postmenopausal bleeding, then transvaginal ultrasonography and histology of the endometrium are indicated. Tamoxifen can aggravate hot flushes and have a negative effect on sexual function. In premenopausal women, tamoxifen may induce ovarian cysts resulting in high serum-oestradiol levels. Oligomenorrhoea and amenorrhoea will occur in half of the patients. Tamoxifen has an antagonistic effect on the endometrium in premenopausal women and is associated with hot flushes and impaired sexual functioning. Teratogenic effects on the foetus have been described. Despite its gynaecological side effects, the benefits of tamoxifen in breast-cancer treatment outweigh the risks. Patients need to be informed about these side effects. Irregular or postmenopausal blood loss must always be reported to the treating physician.
Breast Neoplasms↗
[Prevention of colorectal cancer: acetylsalicyclic acid and cyclo-oxygenase-2 inhibitors are only partially effective].
Acetylsalicylic acid was recently shown to inhibit the development of colorectal adenomas in subjects with a moderately increased risk for colorectal cancer. The mechanisms by which acetylsalicylic acid and other NSAIDs, including COX-2 inhibitors, exert this effect include: inhibition of COX-2, induction of apoptosis and induction of the P21 protein that controls the development of crypt cells. For the majority of the population, a healthy lifestyle and healthy eating habits are the best means of preventing colorectal cancer. In addition, population-wide screening should be encouraged. For people with an increased risk of colorectal cancer, acetylsalicylic acid only has a partial effect and therefore endoscopic surveillance is still indicated. Sulindac or celecoxib may be useful for patients with familial adenomatous polyposis and in particular for inhibiting the development of rectal adenomas after subtotal colectomy with ileorectal anastomosis. However, in these cases endoscopic surveillance is also still necessary.
Adenoma↗
Tamoxifen effects on subjective and psychosexual well-being, in a randomised breast cancer study comparing high-dose and standard-dose chemotherapy.
To evaluate the impact of tamoxifen on subjective and psychosexual well-being in breast cancer patients in relation to type of prior chemotherapy and menopausal status. Longitudinal interview study in breast cancer patients during and after adjuvant tamoxifen use. Menopausal status was defined by last menstrual period and serum oestradiol and FSH levels. Gynaecology outpatient clinic, Tertiary Referral Hospital, January 1995 to September 1999. Breast cancer patients <56 years of age, participating in a randomised trial comparing adjuvant high-dose (n=45) and standard-dose (n=53) chemotherapy, followed by radiotherapy and tamoxifen. Relative incidence and correlation of subjective and psychosexual symptoms during and after tamoxifen. During tamoxifen the most frequent complaints were hot flushes (85%), disturbed sleep (55%), vaginal dryness and/or dyspareunia (47%), decreased sexual desire (44%) and musculo-skeletal symptoms (43%). Disturbed sleep correlated with hot flushes (P<0.0005) and concentration problems (P<0.05). Decreased sexual interest correlated with vaginal dryness (P<0.0005) and/or dyspareunia (P<0.0005). In the high-dose group more patients became postmenopausal (95% vs 33%) and more patients reported symptoms than in the standard-dose group (P<0.05). After discontinuation of tamoxifen, symptoms decreased significantly. However, hot flushes, disturbed sleep and vaginal dryness persisted more often in patients who remained postmenopausal after high-dose chemotherapy (P<0.05). Overall, during tamoxifen patients reported many symptoms. More patients become postmenopausal after high-dose chemotherapy, and they remain often symptomatic after tamoxifen.
Adult↗
A phase I and pharmacokinetic study of intraperitoneal topotecan.
PURPOSE: To evaluate the feasibility and pharmacology of intraperitoneal (IP) topotecan. PATIENTS AND METHODS: Fifteen patients with recurrent ovarian cancer in a phase I trial were treated with escalating IP topotecan doses (5-30 mg/m(2)) for pharmacokinetic analysis. RESULTS: Dose limiting toxicity (DLT) was acute hypotension, chills and fever at the 30 mg/m(2) dose level. Haematological toxicity and abdominal pain were mild for all dose levels studied. PHARMACOKINETICS: Peak plasma levels of total topotecan were reached at 2.7 +/- 1.1 h after IP instillation. The apparent V(ss) was 69.9 +/- 25.4 L/m(2), plasma clearance 13.4 +/- 2.5 L/h/m(2) and plasma T1/2 3.7 +/- 1.3 h. The plasma AUC was correlated with the dose (R = 0.95, P < 0.01). The plasma AUC ratio of lactone versus total topotecan (lactone + carboxy-forms) increased with the dose from 16% to 55%, (R = 0.84, P < 0.01). Peritoneal total topotecan was cleared from the peritoneal cavity at 0.4 +/- 0.3 L/h.m(2) with a T1/2 = 2.7 +/- 1.7 h. The mean peritoneal/plasma AUC ratio for total topotecan was 54 +/- 34. CONCLUSION: A substantial dose of topotecan can be delivered by the IP route, achieving cytotoxic plasma levels of topotecan, with acceptable toxicity. The recommended dose for further phase II trials is 20 mg/m(2) IP, which enables combination with active doses of other cytotoxic drugs, in view of its limited myelotoxicity when given by this route.
Adult↗
Expression of cyclooxygenase-2 and inducible nitric oxide synthase in human ovarian tumors and tumor-associated macrophages.
This study investigates whether and to what extent cyclooxygenase type-2 (COX-2) and inducible nitric oxide-synthase (iNOS), both known to have an immunosuppressive effect, are expressed in human ovarian tumors. Because COX-2 and iNOS can be expressed by activated macrophages, the presence of tumor-associated macrophages and the expression of COX-2 and iNOS by these tumor-associated macrophages were determined. The results obtained may provide insight into the function of COX-2 and iNOS expression by tumors. The expression of COX-2 and iNOS in tumor cells and macrophages was assessed in 18 malignant, 15 borderline, and 14 benign human ovarian tumors by immunohistochemical staining of frozen tissue sections. The intra- and peritumoral macrophages were stained using an anti-CD68 monoclonal antibody. Most of the malignant tumors (15 of 18), 10 of 15 borderline, and 9 of 14 benign tumors showed COX-2 expression in the epithelial cells, a result which indicates that COX-2 expression is not exclusive to malignancy. In addition, COX-2 staining was more intense in the epithelial cells of benign and borderline tumors than in malignant tumors. Weak iNOS staining was observed in 5 of 18 malignant, 4 of 15 borderline, and 5 of 14 benign tumors. The number of tumor-associated macrophages varied widely between the different tumors. The highest number of tumor-associated macrophages (> or =20/0.125 mm(2)) was observed in malignant tumors, whereas low to moderate intra- and peritumoral macrophage infiltration (5-20/0.125 mm(2)) was observed in the borderline and benign tumors. COX-2-positive tumor-associated macrophages were found in 3 of 18 malignant tumors, 7 of 15 borderline tumors, and 1 of 14 benign tumors. The number of COX-2-positive tumor-associated macrophages ranged from 3 to 30% of the total macrophage population. Some malignant (4 of 18), borderline (5 of 15), and benign (2 of 14) tumors contained iNOS-positive macrophages. Notable was that COX-2- and iNOS-positive macrophages were predominantly located in the tumor stroma, the regions between tumor and stroma, and in the lumina of the tumor when located in the tumor tissue. These data indicate that not only malignant but also borderline and benign ovarian tumors can exhibit increased levels of COX-2 and iNOS expression. In addition, a small proportion of the tumor-associated macrophages found in malignant, borderline, and benign tumors seems to be in an activated state, judged by their iNOS and COX-2 expression. This subpopulation of tumor-associated macrophages was invariably located in the tumor stroma or in the lumina of the tumor, specifically suggesting that macrophages outside the tumor can be tumor cytotoxic.
Adenocarcinoma↗
[Tamoxifen; wider indications, more frequent controls?].
Explore the source record for details and available documents.
Antineoplastic Agents, Hormonal↗
Relevance of high and low penetrance.
Explore the source record for details and available documents.
Genetic Predisposition to Disease↗
Telomere length in breast cancer patients before and after chemotherapy with or without stem cell transplantation.
High-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT) may accelerate telomere length loss in haematopoietic stem cells. As data including pre-and post-treatment samples are lacking, we studied leukocyte telomere length and telomerase activity before and after treatment in breast cancer patients randomized to receive 5 adjuvant courses FEC (5-FU, epirubicin and cyclophosphamide) (n = 17), or 4 x FEC followed by high-dose cyclophosphamide, thiotepa, carboplatin and autologous PBSCT (n = 16). Haemoglobin, MCV, leukocyte-and platelet numbers were assessed prior to (t(0)), 5 months after (t(1)) and 9 months after chemotherapy (t(2)); these parameters were decreased at t(1)and t(2)compared to t(0)(high-dose: all parameters; standard-dose: leukocytes and platelets), and all parameters were lower after high-dose than standard-dose treatment at t(1). Paired individual leukocyte samples of t(0)and t(1)showed telomere length change (determined by telomere restricted fragment (TRF) assay) ranging from +0.8 to -2.2 kb, with a decreased TRF length in 9 patients of both groups. Telomerase activity (determined by TRAP assay) was below detection limit in leukocyte samples of t(0)and t(1). Thus, standard-and high-dose chemotherapy negatively affect haematological reconstitution in this setting. In individual patients, telomere length can be remarkably changed following haematological proliferative stress after treatment.
Antineoplastic Combined Chemotherapy Protocols↗
Prospective evaluation of early cardiac damage induced by epirubicin-containing adjuvant chemotherapy and locoregional radiotherapy in breast cancer patients.
PURPOSE: To evaluate prospectively the cardiotoxic effects of epirubicin-containing adjuvant chemotherapy in breast cancer patients. PATIENTS AND METHODS: Patients (median age, 46 years; range, 28 to 55 years) were treated with five cycles of fluorouracil, epirubicin (90 mg/m2), and cyclophosphamide (FEC) (group I, n = 21) or with four cycles of FEC followed by high-dose chemotherapy consisting of cyclophosphamide, thiotepa, and carboplatin (group II, n = 19). Locoregional radiotherapy was applied subsequently. Cardiac evaluation was performed before chemotherapy (T0), 1 month after chemotherapy, 1 month after radiotherapy (T2), and 1 year after start of chemotherapy (T3). Left ventricular ejection fraction (LVEF) was determined by radionuclide ventriculography and diastolic function by echocardiography. Autonomic function was assessed by 24-hour ECG registration for heart rate variability (HRV) analysis. Time-corrected QT (QTc) was assessed and N-terminal atrial natriuretic peptide (NT-ANP) and brain natriuretic peptide (BNP) were measured as biochemical markers of cardiac dysfunction. RESULTS: No patient developed overt congestive heart failure (CHF) and the mean LVEF declined from 0.61 at T0 to 0.54 at T3 (P =.001), resulting in an LVEF below 0.50 (range, 0.42 to 0.49) in 17% of the patients, whereas 28% had a decline of more than 0.10. Plasma NT-ANP levels increased gradually from 237 pmol/L at T0 to 347 pmol/L at T3 (P <.01), whereas plasma BNP levels increased from 2.9 pmol/L to 5.1 pmol/L (P =.04). Mean QTc increased from 406 msec at T0 to 423 msec at T3 (P <.01). No persistent alterations were found in diastolic function and HRV. CONCLUSION: Relatively low doses of epirubicin in adjuvant chemotherapy for breast cancer results in mild subclinical myocardial damage demonstrated by a decline in LVEF, an increase in natriuretic peptide levels, and an increase in QTc, which may indicate a long-term risk of CHF.
Adult↗
MLH1 and MSH2 protein expression as a pre-screening marker in hereditary and non-hereditary endometrial hyperplasia and cancer.
The predictive value of MLH1 or MSH2 protein expression for the presence of truncating germline mutations was examined in benign and (pre)malignant endometrial samples from 3 patient groups: (I) 10 endometrial cancer patients from hereditary non-polyposis colorectal cancer (HNPCC) families with (n = 6) or without (n = 4) a known germline mutation; (II) 15 women from HNPCC families with (n = 7) or without (n = 8) a known germline mutation, who underwent endometrial sampling for non-malignant reasons; (III) 38 endometrial cancer patients <50 years of age, without HNPCC family history. Immunostaining for MLH1 and MSH2 was performed on paraffin-embedded sections. In group III, tumor DNA was examined for microsatellite instability (MSI) and MLH1, MSH2 and MSH6 mutation analysis was carried out. In 6/6 MLH1/MSH2 mutation carriers with endometrial cancer (group I), concordance was found between protein loss in the tumor and the corresponding mutation. In 3 MLH1 mutation carriers, MLH1 protein loss was also observed in concurrent endometrial hyperplasia. In group II, no protein loss was detected in normal endometrial tissue samples; in 3/4 patients with endometrial hyperplasia, MLH1/MSH2 protein loss was observed. In group III, protein loss was detected in 12/38 patients (9 MLH1, 3 MSH2), while in 3/11 patients with concurrent endometrial hyperplasia protein loss was also observed in the hyperplasia. MSI analysis in group III revealed 26 MSI-low and 12 MSI-high tumors. Mutation analysis in 28/38 patients showed only 1 missense MSH6 and no MLH1 or MSH2 germline mutations. In group III, loss of MLH1/MSH2 protein expression was not related to the presence of MSI or MLH1/MSH2 germline mutations. In conclusion, MLH1 or MSH2 protein loss in HNPCC-related endometrial neoplasia is strongly related to corresponding germline mutations. This relation was not clearly present in young sporadic endometrial cancer patients. Immunohistochemical pre-screening of the MLH1 and MSH2 proteins in endometrial hyperplasia or cancer can thus be helpful in HNPCC families. Frequent loss of MLH1 or MSH2 protein in endometrial hyperplasia indicates that this loss is an early event in endometrial carcinogenesis.
Adaptor Proteins, Signal Transducing↗
Telomerase in relation to clinicopathologic prognostic factors and survival in cervical cancer.
We investigated, in cervical cancer, the relation between telomerase activity, telomerase RNA (hTR) and mRNA of the catalytic subunit of telomerase, hTERT, with "classic" clinicopathological factors as well as survival. Frozen specimens were obtained from 107 consecutive patients with cervical cancer, treated with surgery or radiotherapy with or without chemotherapy. Telomerase activity was determined with fluorescence-based TRAP and hTR and hTERT with semi-quantitative RT-PCR. Eight normal cervical specimens served as controls. Analysis of prognostic factors and survival was limited to early-stage patients, treated primarily with radical hysterectomy. Telomerase activity was not detected in normal cervices and was present in 85 of 107 (79%) cervical cancers (p < 0.001). hTR was detected in all normal cervices and cervical cancers, while hTERT mRNA was detected in 1 of 8 (13%) normal cervices and in 83 of 104 (80%) cervical cancers (p < 0.001). In contrast to semi-quantitative hTR expression levels, semi-quantitative hTERT mRNA levels were related to telomerase activity levels (p < 0.01). In all patients, telomerase activity levels were related to differentiation grade (p < 0.05) but not to stage and histotype. In early-stage patients, telomerase activity, hTR and hTERT were not related to tumor volume, vascular invasion or presence of metastatic lymph nodes. Tumor volume, vascular invasion and presence of metastatic lymph nodes were related to (progression-free) survival, while telomerase activity and its subunits were not. Frequent up-regulation of telomerase activity and hTERT mRNA is especially observed in cervical cancers, while hTR is also detected in normal cervices. Telomerase is not applicable as a prognostic factor in early-stage cervical cancer patients.
Cervix Uteri↗
Ultrastructural morphology and localisation of cisplatin-induced platinum-DNA adducts in a cisplatin-sensitive and -resistant human small cell lung cancer cell line using electron microscopy.
Ultrastructural morphology (transmission electron microscopy) and localisation of cisplatin-induced platinum (Pt)-DNA adducts (immunoelectron microscopy) were analysed in the human small cell lung cancer cell line GLC(4) and its 40-fold in vitro acquired cisplatin-resistant subline GLC(4)-CDDP, which is characterised by, among other things, a decreased DNA platination. Immunolabelling of Pt-DNA adducts was performed with the polyclonal antibody GPt, known to detect the main Pt-containing intrastrand and interstrand DNA adducts. Morphological analysis of GLC(4) and GLC(4)-CDDP at the ultrastructural level showed cells with a high nucleus/cytoplasm ratio with the majority of nuclei containing one or more nucleoli. GLC(4)-CDDP showed, in contrast to GLC(4), an extensive Golgi apparatus and an increased number of mitochondria. DNA platination was detectable in both GLC(4) and GLC(4)-CDDP. Immunoelectron microscopy showed Pt-DNA adducts primarily in the nucleus, preferentially at loci with high-density chromatin (e.g. heterochromatin, pars granulosa around nucleoli, condensed DNA in proliferating and apoptotic cells), and in mitochondria. The level of detectable Pt-DNA adducts was cell cycle status-dependent. In both cell lines, Pt-DNA adduct levels increased from non-dividing interphase cells to dividing cells and were highest in cells undergoing apoptosis. Overall localisation of Pt-DNA adducts was comparable in GLC(4) and GLC(4)-CDDP cells.
Antibodies↗
Apoptosis induction by sennoside laxatives in man; escape from a protective mechanism during chronic sennoside use?
Chronic sennoside use induces melanosis coli (MC) and possibly increases colorectal cancer risk. Sennosides alter colonic crypt length, proliferative activity, and bcl-2 expression 18 h after administration. To investigate possible mechanisms for carcinogenesis, the effects of acute sennoside use and the presence of MC on colorectal epithelium were studied. Colorectal biopsies from 15 subjects receiving sennosides 6 h before sigmoidoscopy (Sen), 15 controls (NSen), and 27 with MC [11 moderate (MMC) and 16 severe (SMC)]. were analysed for degree of apoptosis (H&E staining), immunohistochemical p53, p21/WAF and bcl-2 expression, and proliferative activity (labelling index, LI). Apoptosis (p=0.0004), intensity of p53 staining (p=0.01), and p21/WAF expression (p=0.008) were increased in Sen and SMC compared with NSen and MMC. p53 expression was increased in Sen (p=0.004). No difference in bcl-2 expression or LI was observed. Crypts were shorter in Sen (p=0.05) and longer in SMC (p=0.04) than in NSen. It is concluded that sennosides acutely induce apoptosis of colonic epithelial cells, presumably by a p53, p21/WAF-mediated pathway, resulting in shorter crypts. In severe melanosis coli, apoptosis seems to be delayed, causing longer crypts without a rise in proliferative activity or bcl-2 expression. This escape from a presumably protective mechanism may enhance the risk of carcinogenesis during chronic sennoside use.
Adolescent↗
Pharmacokinetics of MEN-10755, a novel anthracycline disaccharide analogue, in two phase I studies in adults with advanced solid tumours.
The doxorubicin analogue MEN-10755 has been identified as a compound with promising antitumour activity based on structure-activity studies of a new series of anthracycline disaccharides. The high antitumour activity of MEN-10755 in human tumour xenografts, including doxorubicin-resistant xenografts, and its unique pharmacological and biological properties made this novel disaccharide analogue an interesting candidate for clinical evaluation. Two pharmacokinetic phase I studies with different dosing schedules were performed in adults with solid refractory malignancies. The pharmacokinetics of MEN-10755 were studied after a 15-min i.v. infusion given once every 3 weeks or once every week for 3 weeks followed by 1 week rest. Plasma and urine levels of MEN-10755 were measured by HPLC with fluorescent detection. It was possible to combine the pharmacokinetic results of the two studies because there was no accumulation of MEN-10755 before the next infusion of MEN-10755 in the weekly study with 1 week rest. The administered dose levels on day 1 in this study were all in the lower range from the 3-weekly study. The postinfusion plasma kinetics of MEN-10755 were best described by a triexponential model. The plasma peak levels (Cmax) of MEN-10755 showed a linear relationship with the administered dose. Peak plasma MEN-10755 levels ranged between 474 and 21,587 microg/l. The mean elimination half-life (T(1/2gamma)) was 20.7+/-9.0 h. The AUC(0-infinity) was proportional to the administered dose. The mean plasma clearance of MEN-10755 was 6.0+/-2.2 l/h per m2 with a mean volume of distribution (Vss) of 95.6+/-43.4 l/m2. The mean renal excretion of unchanged drug within 24 h was 4.3+/-1.8%. Compared to epirubicin and doxorubicin, the pharmacokinetics of MEN-10755 were characterized by an approximately twofold shorter terminal half-life, a much lower total plasma clearance and a much smaller volume of distribution.
Adult↗
Serum response of hepatocyte growth factor, insulin-like growth factor-I, interleukin-6, and acute phase proteins in patients with colorectal liver metastases treated with partial hepatectomy or cryosurgery.
BACKGROUND/AIMS: The aim of the study was to compare the serum response of regeneration factors and acute phase proteins in patients treated with partial hepatectomy or cryosurgery. METHODS: The responses of serum hepatocyte growth factor (HGF), insulin-like growth factor-I (IGF-I) (free and total), interleukin-6 (IL-6) and the acute phase proteins, C-reactive protein (CRP) and serum amyloid A (SAA) were examined in patients with colorectal liver metastases treated with partial hepatectomy (n = 14) or cryosurgery (n = 10). RESULTS: In both groups, IL-6 peak levels at the end of the operation were followed by peak levels at day 1 for HGF and CRP. SAA peak levels occurred on day 1 (hepatectomy group) and on day 4 (cryo group). The total HGF, IGF-I, and IL-6 responses were comparable in both groups. CRP and SAA responses were higher in the patients treated with cryosurgery than in patients after hepatectomy. Free IGF-I trough levels were lower in partial hepatectomy patients than in cryosurgery patients. CONCLUSIONS: In patients with colorectal liver metastases the responses of the regenerating factors HGF, IGF-I, and IL-6 are comparable to those in patients treated with partial hepatectomy. Upregulation of acute phase protein production is higher in patients after cryosurgery than in patients after partial hepatectomy.
Acute-Phase Proteins↗
Increased cancer risk after liver transplantation: a population-based study.
BACKGROUND/AIMS: Development of de novo malignancies emerges as a serious long term complication after liver transplantation. METHODS: We reviewed the medical records of 174 adult one-year survivors for de novo malignancies. The observed cancer rates were compared with the expected cancer rates in the Dutch population. RESULTS: Twenty-one of the 174 patients developed 23 malignancies (12%). Skin and lip cancer accounted for 12 of the 23 malignancies (52%). Only one patient had a B-cell lymphoma. The cumulative risk for de novo malignancy was 6, 20, and 55% at 5, 10, and 15 years after transplantation, respectively. The overall relative risk (RR) as compared with the general population was 4.3 (95% confidence interval 2.4-7.1). Significantly increased RRs were observed for non-melanoma skin cancer (RR 70.0), non-skin solid cancer (RR 2.7), renal cell cancer (RR 30.0), and colon cancer (RR 12.5). Multivariate analysis showed that an age > 40 years and pretransplant use of immunosuppression were significant risk factors. CONCLUSIONS: An increased risk of cancer exists after liver transplantation, for both for skin/lip cancer, and other solid tumors. Older age and the use of immunosuppression are risk factors.
Adult↗
Differentiated thyroid carcinoma in the elderly.
The overall prognosis of patients with differentiated thyroid cancer is excellent, but the prognosis is rapidly worsening, when the disease is diagnosed in elderly patients. Old patients more often present with poor prognostic features, such as large tumors, follicular or Hürthle cell subtypes, extrathyroidal growth and distant metastases. Therefore, an optimal therapeutic approach is recommended. Current therapy includes a total thyroidectomy, if necessary combined with a lymph node dissection and followed by high dose radioiodine ablation. Radioiodine therapy in elderly patients meets specific problems, concerning thyroid hormone withdrawal, side effects of 131I and nursing problems. Additional treatment of residual, recurrent or metastatic disease must be tailored, according to the stage of the disease, and should not be denied on the basis of chronological age. Lifelong treatment with suppressive thyroid hormone therapy does not lead to important long-term side effects at old age.
Aged↗