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Introduction: Endometrial cancer patients with high grade tumours, deep myometrial invasion or advanced stage disease have a poor prognosis. Randomised studies have demonstrated the prevention of loco-regional relapses with radiotherapy (RT) with no effect on overall survival (OS). The possible additive effect of chemotherapy (CT) remains unclear. Two randomised clinical trials (NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III) were undertaken to clarify if sequential combination of chemotherapy and radiotherapy improves progression-free survival (PFS) in high-risk endometrial cancer. The two studies were pooled. Methods: Patients (n = 540; 534 evaluable) with operated endometrial cancer International Federation of Obstetrics and Gynaecology (FIGO) stage I-III with no residual tumour andprognostic factors implying high-risk were randomly allocated to adjuvant radiotherapy with or without sequential chemotherapy. Results: In the NSGO/EORTC study, the combined modality treatment was associated with 36% reduction in the risk for relapse or death (hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.41-0.99; P = 0.04); two-sided tests were used. The result from the Gynaecologic Oncology group at the Mario Negri Institute (MaNGO)-study pointed in the same direction (HR 0.61), but was not significant. In the combined analysis, the estimate of risk for relapse or death was similar but with narrower confidence limits (HR 0.63, CI 0.44 0.89; P = 0.009). Neither study showed significant differences in the overall survival. In the combined analysis, overall survival approached statistical significance (HR 0.69, CI 0.46-1.03; P = 0.07) and cancer-specific survival (CSS) was significant (HR 0.55, CI 0.35-0.88; P = 0.01). Conclusion: Addition of adjuvant chemotherapy to radiation improves progression-free survival in operated endometrial cancer patients with no residual tumour and a high-risk profile. A remaining question for future studies is if addition of radiotherapy to chemot

Structure-activity relationships of three related series of 4-phenylthiazol-5-ylacetic acids, derived from two hits emanating from a focused library obtained by in silico screening, have been explored as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. Several compounds with double digit nanomolar binding affinity and full antagonistic efficacy for human CRTH2 receptor were obtained in all subclasses. The most potent compound was [2-(4-chloro-benzyl)-4-(4-phenoxy-phenyl)-thiazol-5-yl]acetic acid having an binding affinity of 3.7nM and functional antagonistic effect of 66nM in a BRET and 12nM in a cAMP assay with no functional activity for the other PGD2 DP receptor (27muM in cAMP).

Patients and methods: Patients previously treated with less than two or two previous chemotherapy lines were randomized to receive trabectedin 1.5 mg/m(2) 24 h (arm A, n = 54) or 1.3 mg/m(2) 3 h (arm B, n = 53). Objective response rate (ORR) per RECIST was the primary efficacy end point. Toxic effects were graded according to the National Cancer Institute-Common Toxicity Criteria v. 2.0. Results: ORR was 38.9% [95% confidence interval (CI) 25.9% to 53.1%; arm A] and 35.8% (95% CI 23.1% to 50.2%; arm B) (intention-to-treat primary analysis). Median time to progression was 6.2 months (95% CI 5.3-8.6 months; arm A) and 6.8 months (95% CI 4.6-7.4 months; arm B). Frequent severe adverse events were nausea/vomiting (24%, arm A; 15%, arm B) and fatigue (15%, arm A; 10%, arm B). Common severe laboratory abnormalities were transient, noncumulative neutropenia (55%, arm A; 37%, arm B) and transaminase increases (alanine aminotransferase, 55%, arm A; 59%, arm B). Conclusions: Both every-3-weeks trabectedin regimes, 1.5 mg/m(2) 24 h and 1.3 mg/m(2) 3 h, were active and reasonably well tolerated in AOC platinum-sensitive patients. Trabectedin every-3-weeks has promising activity and deserves to be further evaluated in relapsed AOC.

BACKGROUND: Mast cell-derived prostaglandin D2 (PGD2), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a high affinity receptor for prostaglandin D2, mediates trafficking of TH2-cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology. METHODS: Affinity for and antagonistic potency of TM30089 on many mouse receptors including thromboxane A2 receptor mTP, CRTH2 receptor, and selected anaphylatoxin and chemokines receptors were determined in recombinant expression systems in vitro. In vivo effects of TM30089 and ramatroban on tissue eosinophilia and mucus cell histopathology were examined in a mouse asthma model. RESULTS: TM30089, displayed high selectivity for and antagonistic potency on mouse CRTH2 but lacked affinity to TP and many other receptors including the related anaphylatoxin C3a and C5a receptors, selected chemokine receptors and the cyclooxygenase isoforms 1 and 2 which are all recognized players in allergic diseases. Furthermore, TM30089 and ramatroban, the latter used as a reference herein, similarly inhibited asthma pathology in vivo by reducing peribronchial eosinophilia and mucus cell hyperplasia. CONCLUSION: This is the first report to demonstrate anti-allergic efficacy in vivo of a highly selective small molecule CRTH2 antagonist. Our data suggest that CRTH2 antagonism alone is effective in mouse allergic airway inflammation even to the extent that this mechanism can explain the efficacy of ramatroban Udgivelsesdato: february

A management program for FIGO stage I-II nonserous, nonclear-cell adenocarcinomas was evaluated. Histopathology and DNA ploidy were used to estimate postoperatively the risk of progression or death of disease and to tailor treatment. The patient material was a population-based consecutive cohort of all women with endometrial cancer in the Southern Swedish Health Care Region diagnosed between June 1993 and June 1996 (n=553). Of these, 335 were eligible for the management program. Patients estimated to be at low risk were treated by surgery only, while high-risk patients also received vaginal brachytherapy. A large low-risk group consisting of 84% (n=283) of the patients with an estimated disease-specific 5-year survival of 96% (95% CI=93-98%) was identified. The high-risk group (n=52, 16%) showed a worse outcome with an 80% 5-year disease-specific survival (95% CI=65-89%). The difference in survival between the groups was highly significant (P<0.0001). Half of the progressions were distant in the high-risk group. Although there is a clear indication for adjuvant therapy for this group, locoregional radiotherapy could be expected to fail in cases with distant progression. Thus, effective systemic treatments need to be developed. Low-risk patients, constituting the majority (84%) of the patients, can be safely treated by surgery only.

Synthesis, in vitro biological evaluation and structure-activity relationships of 4-acylamino-and 4-ureidobenzamides as novel hMCH1R-antagonists are disclosed. The nature of the amine side chains could be varied considerably in contrast to the central benzamide scaffold and aromatic substituents.

Dose-dense weekly administration of paclitaxel has the potential advantage of allowing a larger percentage of cancer cells to enter the vulnerable phase of their cell cycle when cytotoxic paclitaxel concentrations are present. The lower doses and shorter infusion times used with weekly dosing should also minimize bone marrow suppression and other toxicities associated with standard paclitaxel 3-weekly administration. Clinical studies have confirmed that paclitaxel can be safely delivered on a weekly schedule as a 1-h infusion to patients with advanced ovarian cancer. Weekly administration of paclitaxel also appears to be better tolerated than 3-weekly administration. Single-agent weekly paclitaxel is associated with response rates of 20-65%. Combination therapy with weekly paclitaxel has mainly involved carboplatin and response rates with such regimens range from 60-88%. Triple-drug combination therapy has produced response rates of 42-67.5%. Such therapy has included weekly paclitaxel in combination with carboplatin/cisplatin plus topotecan, and carboplatin plus doxorubicin. In an attempt to avoid problems with high corticosteroid doses, dexamethasone doses of 10 and 8 mg have been used successfully in premedication regimens for weekly paclitaxel in ovarian cancer. ⌐ 2002 Elsevier Science Ireland Ltd. All rights reserved.

Mutations in the TP53 tumor suppressor gene have been shown to significantly correlate with poor prognosis in endometrial cancer. In the present study we have evaluated a luminometric immunoassay (LIA) for quantitative estimation of TP53 protein expression in 65 cytosol preparations from endometrial cancer, previously analyzed for mutations in TP53 exons 4-10. LIA showed high (= 0.6 ng/mg protein) expression of TP53 protein in all eight tumors with missense mutation, but high protein levels were also detected in 15 tumors with normal TP53 sequence. All four tumors with nonsense or frameshift mutations had low or no TP53 protein expression. LIA was further evaluated in a retrospective study of 201 cytosol samples from endometrial cancer. TP53 overexpression (>= 0.6 ng/mg protein) was observed in 22% of the tumors and correlated with nonendometrioid histology types (P = 0.005), poorly differentiated tumors (P = 0.001), higher FIGO grade (P = 0.001), DNA nondiploidy (P = 0.002), and high S-phase fraction (P = 0.03). After a median follow-up time of 6.8 years (range 0.7-9.9 years), 22 (13%) progressions were observed in the 175 patients with early stage (I-II) disease. TP53 overexpression (P = 0.04), FIGO grade 3 vs. 1 + 2 (P = 0.01), higher age (P = 0.02), and DNA nondiploidy (P < 0.001) showed significant correlation to shorter progression-free survival in these patients. We conclude that TP53 protein analysis by LIA provides an incomplete correlation to mutation status and cannot substitute for mutation analysis in assessment of prognosis in endometrial carcinoma. In comparison to TP53 overexpression and higher FIGO grades, DNA nonploidy status seems to be a better prognostic indicator to define a subset of early stage endometrial cancer patients who may benefit by adjuvant chemotherapy/radiotherapy.

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001, 40: 155-65). This overview on chemotherapy for epithelial ovarian cancer is based on a total of 176 scientific reports. Five meta-analyses including 17 291 patients, 33 prospective randomised studies including 12 340 patients, 36 prospective studies including 3593 patients and one retrospective study including 421 patients. The studies include approximately 33 642 patients. The conclusions reached can be summarized into the following points: ò Radically operated patients with low-risk early ovarian cancer (stage IA or IB non-clear-cell well-differentiated carcinomas or borderline tumours) have a very good prognosis and there is no indication for adjuvant therapy. ò Radically operated patients with high-risk early ovarian cancer (clear cell carcinomas or FIGO stage IA or IB moderately or poorly differentiated carcinomas or stage IC) have a substantial risk for micrometastatic disease. However, the role of adjuvant chemotherapy is unclear and such therapy should, thus, only be used within clinical trials. ò The median overall survival for patients with advanced (FIGO stages II-IV) ovarian cancer randomised to paclitaxel/platinum-containing chemotherapy in three large studies ranged between 36-39 months. Compared with historical data, this represents a six to seven times longer median survival time than after surgery only. The probability for long-term survival for patients treated with a paclitaxel/platinum combination is too early to define. ò In two prospective randomised trials in advanced ovarian cancer, paclitaxel in combination with cisplatin has provided a survival benefit over cyclophosphamide/cisplatin. Based on these trials, paclitaxel/cisplatin is considered to be the standard treatment. ò This choice of

The total population-based material of 426 ovarian malignancies in the Southeast Health Care Region of Sweden during 1984-1987 was surveyed. It seems that with a program of cytoreductive surgery followed by a cisplatinum chemotherapy combination in the metastasizing cases the overall survival figures have improved. A relative overall 5-year survival of 43% was recorded. Age and stage were independent prognostic factors for survival, while histology (epithelial vs, non-epithelial tumors) did not add prognostic information. 384 patients with ovarian carcinomas were analyzcd separately. An overall relative survival of 40% was recorded. Tite overall corrected 5-yearsurvival for patients prescribed protocol treatment was 49 % compared to 33 % for those treated otlJCrwise. The corrected 5-year survival for patients with FIGO stage Ill -IV tumorswas 35 % if optimal primary cy~oreductive surgery wasperfonned.Patientswith residual tumors greater than 1cm had 13% corrected5-yearsurvival. Patients that underwent intestinal surgery as a part of initial surgical debulking had a very poor survival, even compared with 1l1e group of patients with greater than 3 cm residual tumors left after initial surgery ( 4 vs. 13 %). The secondary laparotomy gave prognostic information only in stages I and ll. Eighteen of 68 patients (26 %) who had macroscopic turn or left at the secondary surgery cmdd be rendered tumor free at the secondary laparotomy. This group had about the same survival as those who were foi.Uld to be in complete response at the secondary laparotomy. It was not possible to ~iatc that this was caused by the ~urgeryper se. Geometrical measurements oftumor nuclei on the diagnostic tissue sections generated powerful prognostic factors for survival after secondary laparotomy in 65 patients with advanced ovarian cancer. The existence of very large nuclei seemed to cl1aracterize patients with a bad prognosis. The half-life of the turn or marker CA 125 in serum during induction ch, Papers, included in the Ph.D. thesis, are not registered and included in the posts from 1999 and backwards.