Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer.

PURPOSE: To determine the side effects and feasibility of cisplatin and carboplatin each in combination with paclitaxel as front-line therapy in advanced epithelial ovarian cancer. PATIENTS AND METHODS: Patients were randomly allocated to receive paclitaxel 175 mg/m(2) intravenously as a 3-hour infusion followed by either cisplatin 75 mg/m(2) or carboplatin (area under the plasma concentration-time curve of 5), both on day 1. The schedule was repeated every 3 weeks for at least six cycles. Women allocated to paclitaxel-cisplatin were admitted to the hospital, whereas the carboplatin regimen was administered to outpatients. RESULTS: A total of 208 eligible patients were randomized. Both regimens could be delivered in an optimal dose and without significant delay. Paclitaxel-carboplatin produced significantly less nausea and vomiting (P: <.01) and less peripheral neurotoxicity (P: =.04) but more granulocytopenia and thrombocytopenia (P: <.01). The overall response rate in 132 patients with measurable disease was 64% (84 of 132 patients), and in patients with elevated CA 125 levels at start, it was 74% (132 of 178 patients). With a median follow-up time of 37 months, the median progression-free survival time of all patients was 16 months and the median overall survival time was 31 months. The small number of patients entered onto the study caused wide confidence intervals (CIs) around the hazards ratio for progression-free survival of paclitaxel-carboplatin compared with paclitaxel-cisplatin (hazards ratio, 1.07; 95% CI, 0.78 to 1.48) and did not allow conclusions about efficacy. CONCLUSION: Paclitaxel-carboplatin is a feasible regimen for outpatients with ovarian cancer and has a better toxicity profile than paclitaxel-cisplatin.     

Hydroxychloroquine potentiates Fas-mediated apoptosis of rheumatoid synoviocytes

Inadequate apoptosis may contribute to the synovial hyperplasia associated with rheumatoid arthritis (RA). The Fas-associated death domain protein (FADD)-like interleukin (IL)-1beta-converting enzyme (FLICE)-inhibitory protein (FLIP), which is an apoptotic inhibitor, has been implicated in the resistance to Fas-mediated apoptosis of synoviocytes. This study investigated whether hydroxychloroquine (HCQ), an anti-rheumatic drug, induces the apoptosis of rheumatoid synoviocytes, and modulates the expression of FLIP. Fibroblast-like synoviocytes (FLS) were prepared from the synovial tissues of RA patients, and were cultured with various concentrations of HCQ in the presence or absence of the IgM anti-Fas monoclonal antibodies (mAb) (CH11). Treatment with HCQ, ranging from 1 to 100 microM, induced the apoptosis of FLS in a dose- and time-dependent manner. The increase in synoviocytes apoptosis by HCQ was associated with caspase-3 activation. A combined treatment of HCQ and anti-Fas mAb increased FLS apoptosis and caspase-3 activity synergistically, compared with either anti-Fas mAb or HCQ alone. The Fas expression level in the FLS was not increased by the HCQ treatment, while the FLIP mRNA and protein levels were decreased rapidly by the HCQ treatment. Moreover, time kinetics analysis revealed that the decreased expression of FLIP by HCQ preceded the apoptotic event that was triggered by HCQ plus anti-Fas mAb. Taken together, HCQ increases the apoptosis of rheumatoid synoviocytes by activating caspase-3, and also sensitizes rheumatoid synoviocytes to Fas-mediated apoptosis. Our data suggest that HCQ may exert its anti-rheumatic effect in rheumatoid joints through these mechanisms.     

Requisite role for complement C5 and the C5a receptor in granulomatous response to mycobacterial glycolipid trehalose 6,6'-dimycolate

The development of pulmonary granulomatous lesions during mycobacterial infection is a complex phenomenon, in part caused by responses elicited towards the surface glycolipid trehalose 6,6'-dimycolate (TDM; cord factor). The molecular mechanisms underlying granuloma formation following challenge with TDM are not yet completely understood. The present study defines pathologic differences in acute response to Mycobacterium tuberculosis TDM in C57BL/6 mice and mice lacking the C5a receptor (C5aR-/-). Mice were intravenously injected with TDM prepared in water-in-oil-in-water emulsion and examined for histologic response and changes in proinflammatory cytokines and chemokines in lung tissue. Control C5a receptor-sufficient mice demonstrated a granulomatous response that peaked between days 4 and 7. Increased production of macrophage inflammatory protein-1 alpha (MIP-1alpha), interleukin-1beta (IL-1beta) and CXC chemokine KC (CXCL1) correlated with development of granulomas, along with modest change in tumor necrosis factor-alpha (TNF-alpha). In contrast, the C5aR-/- mice revealed markedly exacerbated inflammatory response. The receptor-deficient mice also demonstrated a lack of coherent granulomatous response, with severe oedema present and instances of lymphocytic cuffing around pulmonary vessels. Lung weight index was increased in the C5aR-/- mice, correlating with increased MIP-1alpha, KC, IL-1beta and TNF-alpha over that identified in the congenic C5aR-sufficient controls. Correlate experiments performed in C5-deficient (B10.D2-H2d H2-T18c Hco/oSnJ) mice revealed similar results, leading to the conclusion that C5 plays a significant role in mediation of chemotactic and activation events that are the basis for maturation of granulomatous responses to TDM.     

Endocytic collagen degradation: a novel mechanism involved in protection against liver fibrosis

Fibrosis of the liver and its end-stage, cirrhosis, represent major health problems worldwide. In these fibrotic conditions, activated fibroblasts and hepatic stellate cells display a net deposition of collagen. This collagen deposition is a major factor leading to liver dysfunction, thus making it crucially important to understand both the collagen synthesis and turnover mechanisms in this condition. Here we show that the endocytic collagen receptor, uPARAP/Endo180, is a major determinant in governing the balance between collagen deposition and degradation. Cirrhotic human livers displayed a marked up-regulation of uPARAP/Endo180 in activated fibroblasts and hepatic stellate cells located close to the collagen deposits. In a hepatic stellate cell line, uPARAP/Endo180 was shown to be active in, and required for, the uptake and intracellular degradation of collagen. To evaluate the functional importance of this collagen receptor in vivo, liver fibrosis was induced in uPARAP/Endo180-deficient mice and littermate wild-type mice by chronic CCl(4) administration. A strong up-regulation of uPARAP/Endo180 was observed in wild-type mice, and a quantitative comparison of collagen deposits in the two groups of mice clearly revealed a fibrosis protective role of uPARAP/Endo180. This effect appeared to directly reflect the activity of the collagen receptor, since no compensatory events were noted when comparing the mRNA expression profiles of the two groups of mice in an array system focused on matrix-degrading components. This function of uPARAP/Endo180 defines a novel role of intracellular collagen turnover in fibrosis protection.     

Prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX chemotherapy

Background:

There have been controversies in prognostic impact of mucinous histology on colorectal cancer, and its implication in patients treated with adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is unclear.

Methods:

Stage II and III colorectal cancer patients who underwent curative resection followed by adjuvant FOLFOX were included. Patients were grouped according to the mucinous content: >50%, mucinous adenocarcinoma (MAC); <50%, adenocarcinoma with intermediated mucinous component (AIM); and without any mucinous component, non-MAC (NMA). Clinicopathological features and disease-free survival (DFS) were compared.

Results:

Among a total of 521 patients, 27 patients (5.2%) had MAC, 41 patients (7.9%) had AIM, and 453 patients (86.9%) had NMA. Mucinous adenocarcinoma and AIM had higher frequency of proximal location and microsatellite instability, but lower frequency of angiolymphatic invasion. Disease-free survival was significantly worse in the MAC compared with NMA (3-year DFS 57% and 86%, respectively; P<0.001) and AIM (3-year DFS 87%, P=0.01 vs MAC). Multivariate analysis revealed MAC as an independent negative prognostic factor of DFS (adjusted hazard ratio 7.96, 95% confidence interval 3.76–16.8).

Conclusion:

Adenocarcinoma with intermediated mucinous component and MAC have distinct clinicopathological features compared with NMA. Mucinous adenocarcinoma has an adverse prognostic impact on stage II or III colorectal cancer treated with adjuvant FOLFOX.     

Postoperative radiotherapy in stage II and III renal adenocarcinoma. A randomized trial by the Copenhagen Renal Cancer Study Group

Since 1979, 11 urological and surgical departments and 2 oncological departments in the greater Copenhagen area have been investigating the role of postoperative radiotherapy (XRT) in patients with renal adenocarcinoma Stage II and III staging modified from Holland. After nephrectomy, patients were randomized to receive XRT (50 Gy in 20 F to the kidney bed, regional ipsi- and contralateral lymph nodes) or no further treatment. Patients in both arms were followed until relapse, death, or 5 years after operation. Seventy-two were randomized by January 1984. An update of the treatment results showed the following: 7/72 were excluded from further analysis because of major protocol violations, 34/65 were in Stage II and 31/65 in Stage III. There were 43 men and 22 women, median age 61 years, range 34-75; 33/65 were randomized in observation, 32/65 to XRT. Relapse was found in 28/65 or 43% during the follow-up period without any difference between the two groups. According to protocol criteria 27/32 randomized to XRT accomplished treatment. Significant complications from stomach, duodenum, or liver occurred in 12/27 or 44%, median 5 mo. range 1-44 mo. after XRT. In 5/27 or 19% the postirradiatory complications contributed to the death of the patients. The median survival in the XRT-group was 26 mo. The survival at 26 mo., in the observation group, was 62%. This difference is not statistically significant. We conclude that postoperative XRT, as given in the present study in patients nephrectomized for Stages II and III renal adenocarcinoma, is without any beneficial effect on relapse rate and survival. Moreover, XRT is associated with an unacceptable complication rate and the protocol has been closed for further patient accrual since January 1984.     

39A composite role of vitronectin and urokinase in the modulation of cell morphology upon expression of the urokinase receptor

The urokinase receptor, uPAR, is a GPI-anchored membrane protein engaged in pericellular proteolysis and cellular adhesion, migration and modulation of cell morphology. A direct matrix adhesion is mediated through the binding of uPAR to vitronectin and this event is followed by downstream effects including changes in the cytoskeletal organization. However, it remains unclear if the adhesion through uPAR-vitronectin is the only event capable of initiating these morphological rearrangements, or if lateral interactions between uPAR and other membrane proteins can induce the same response. In this paper, we show that both of these triggering mechanisms can be operative and that uPAR dependent modulation of cell morphology can indeed occur independently of vitronectin binding. Expression of wildtype uPAR on HEK-293 cells led to pronounced vitronectin adhesion and cytoskeletal rearrangements whereas a mutant uPAR, uPAR_W32A with defective vitronectin binding, failed to induce both phenomena. However, upon saturation of uPAR_W32A with the protease ligand, pro-uPA or its receptor-binding domain, the ability to induce cytoskeletal rearrangements was restored even though this did not rescue the vitronectin binding and adhesion capability. On the other hand, using other uPAR variants, we could show that uPAR-vitronectin adhesion is indeed capable and sufficient to induce the same morphological rearrangements. This was shown with cells expressing a different single-site mutant, uPAR_Y57A, in the presence of a synthetic uPAR-binding peptide, as well as with wildtype uPAR which underwent cytoskeletal rearrangements even when cultivated in uPA deficient serum.     

Reliability of X-rays and bone scans for the assessment of changes in skeletal metastases from breast cancer

AIMS: To examine the level of agreement among observers regarding changes between serial images of bone metastases. METHODS: Thirty-five pairs of bone X-rays and 30 pairs of bone scans were selected from the files of patients with breast cancer involving the skeleton. All images in a pair were of the same site and had been taken at least 12 weeks apart. Thirteen radiologists and 14 nuclear medicine physicians examined the X-ray and bone scan pairs, respectively. Each assessed whether the changes between sequential films represented improvement, stability or worsening. Inter-observer agreement was analysed using the kappa statistic (kappa). RESULTS: There was only fair overall agreement among radiologists regarding changes between X-rays (kappa = 0.23), but there was substantial agreement among nuclear medicine physicians for bone scan assessments (kappa = 0.62). Neither the experience of the observers nor the time between images had a significant effect on agreement. For X-rays, agreement was poorer if the response category was 'improvement' and if the type of bone lesion was mixed lytic/sclerotic. CONCLUSIONS: Evaluation of serial X-rays is unreliable for determining the response of bone metastases. Scintigraphic evaluation has a higher internal validity for the determination of response, but it should not be used in isolation from other clinical data.