WT1 gene expression as a prognostic marker in advanced serous epithelial ovarian carcinoma: an immunohistochemical study

BACKGROUND: WT1 is a tumor suppressor gene responsible for Wilms' tumor. WT1 reactivity is limited to ovarian serous carcinomas. Recent studies have shown that WT1 plays an important role in the progression of disease and indicates a poorer prognosis of human malignancies such as acute myeloid leukemia and breast cancer. The aims of this study were to determine the survival and recurrence-free survival of women with advanced serous epithelial ovarian carcinoma in relation to WT1 gene expression. METHODS: The study accrued women over an 18-year period, from 1987–2004. During the study period, 163 patients were diagnosed with advanced serous epithelial ovarian carcinoma and had undergone complete post-operative chemotherapy, but the final study group comprised 99 patients. The records of these women were reviewed and the paraffin-embedded tissue of these women stained with WT1 immunostaining. Survival analysis was performed using Kaplan-Meier and Cox regression methods. RESULTS: Fifty patients showed WT1 staining and forty-nine did not. Five-year survival of non-staining and staining groups were 39.4% and 10.7% (p < 0.00005); five-year recurrence-free survival of these groups were 29.8% and ≤ 7.5% (p < 0.00005), respectively. For survival the HR of WT1 staining, adjusted for residual tumor and chemotherapy response, was 1.98 (95% CI 1.28–3.79), and for recurrence-free survival the HR was 3.36 (95% CI 1.60–7.03). The HR for recurrence-free survival was not confounded by any other variables. CONCLUSION: This study suggests that expression of WT1 gene may be indicative of an unfavorable prognosis in patients with advanced serous epithelial ovarian carcinoma

The effect of early pregnancy following chemotherapy on disease relapse and foetal outcome in women treated for gestational trophoblastic tumours

Little literature exists on the safety of early pregnancy following chemotherapy. Here we assess the rate of relapse and foetal outcome in women who have completed single and multi-agent chemotherapy for gestational trophoblastic tumours. The records of 1532 patients treated for persistent gestational trophoblastic tumours at Charing Cross Hospital between 1969 and 1998 were reviewed. Patients were defined as receiving single agent or multi-agent treatment. Relapse rates and foetal outcome were reviewed in the 230 patients who became pregnant within 12 months of completing chemotherapy. In the single agent group 153 (22%) of 691 patients conceived early. Three subsequently relapsed. In the multi-agent group, 77 (10%) of 779 patients conceived early, two then relapsed. Relapse rates were 2% (3 out of 153) and 2.5% (2 out of 77) for each group compared to 5% and 5.6% in the comparative non-pregnant groups. Outcomes of 230 early pregnancies: 164 (71%) delivered at full term, 35 (15%) terminations, 26 (11%) spontaneous abortions, three (1.3%) new hydatidiform moles and two (1%) stillbirths. Early pregnancies were more common in the single agent group (P<0.001), but spontaneous miscarriages and terminations were more likely to occur in the multi-agent group (P=0.04 and 0.03, respectively). Of the full-term pregnancies, three (1.8%) babies were born with congenital abnormalities. Patients in either group who conceive within 12 months of completing chemotherapy are not at increased risk of relapse. Though, we still advise avoiding pregnancy within 12 months of completing chemotherapy, those that do conceive can be reassured of a likely favourable outcome

A change in microsatellite instability caused by cisplatin-based chemotherapy of ovarian cancer

To clarify the mechanism of acquired CDDP resistance in ovarian cancer, we compared the microsatellite instability (MSI) by the amplification of 10 microsatellite loci and immunohistochemical detection of hMSH2 and hMLH1 expression between the primary resected tumours and the secondary resected residual tumours after 5 or 6 courses of CDDP-based chemotherapy in the 24 cases of ovarian cancer. Of the 24 primary resected tumours, 9 (37.5%) showed MSI (7 cases of MSI-L, 2 cases of MSI-H), while 15 (72.5%) were microsatellite stable tumours (MSS). The primary tumours also had MSI in the residual tumours after CDDP-based chemotherapy. However, all of the cases with MSS in the primary resected tumours exhibited MSI (2 cases were MSI-L, and 13 cases were MSI-H) in the residual tumours after CDDP-based chemotherapy (P< 0.001). Furthermore, 11 (73.3%) of these cases which changed from MSS to MSI also had a change in the expression of hMLH1 from positive to undetectable (P< 0.001). Our data suggest that tumour MSI changes during CDDP-based chemotherapy, and that the loss of hMLH1 expression is one of the factors that has the greatest effect on this transformation. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Directed evolution of a magnetic resonance imaging contrast agent for noninvasive imaging of dopamine

The development of molecular probes that allow in vivo imaging of neural signaling processes with high temporal and spatial resolution remains challenging. Here we applied directed evolution techniques to create magnetic resonance imaging (MRI) contrast agents sensitive to the neurotransmitter dopamine. The sensors were derived from the heme domain of the bacterial cytochrome P450-BM3 (BM3h). Ligand binding to a site near BM3h's paramagnetic heme iron led to a drop in MRI signal enhancement and a shift in optical absorbance. Using an absorbance-based screen, we evolved the specificity of BM3h away from its natural ligand and toward dopamine, producing sensors with dissociation constants for dopamine of 3.3–8.9 μM. These molecules were used to image depolarization-triggered neurotransmitter release from PC12 cells and in the brains of live animals. Our results demonstrate the feasibility of molecular-level functional MRI using neural activity–dependent sensors, and our protein engineering approach can be generalized to create probes for other targets.Charles A. Dana Foundation. Brain and Immuno-ImagingRaymond and Beverley Sackler FoundationNational Institutes of Health (U.S.) (grant R01-DA28299)National Institutes of Health (U.S.) (grant DP2-OD2441)National Institutes of Health (U.S.) (grant R01-GM068664)Jacobs Institute for Molecular Engineering for Medicine. Jacobs Institute for Molecular Engineering for MedicineNational Institutes of Health (U.S.) (grant R01-DE013023

Activity of chemotherapy in mucinous ovarian cancer with a recurrence free interval of more than 6 months: results from the SOCRATES retrospective study

<p>Abstract</p> <p>Background</p> <p>Mucinous ovarian carcinoma have a poorer prognosis compared with other histological subtypes. The aim of this study was to evaluate, retrospectively, the activity of chemotherapy in patients with platinum sensitive recurrent mucinous ovarian cancer.</p> <p>Methods</p> <p>The SOCRATES study retrospectively assessed the pattern of care of a cohort of patients with recurrent platinum-sensitive ovarian cancer observed in the years 2000–2002 in 37 Italian centres. Data were collected between April and September 2005. Patients with recurrent ovarian cancer with > 6 months of platinum free interval were considered eligible.</p> <p>Results</p> <p>Twenty patients with mucinous histotype and 388 patients with other histotypes were analyzed. At baseline, mucinous tumours differed from the others for an higher number of patients with lower tumor grading (p = 0.0056) and less advanced FIGO stage (p = 0.025). At time of recurrence, a statistically significant difference was found in performance status (worse in mucinous, p = 0.024). About 20% of patients underwent secondary cytoreduction in both groups, but a lower number of patients were optimally debulked in the mucinous group (p = 0.03). Patients with mucinous cancer received more frequently single agent platinum than platinum based-combination therapy or other non-platinum schedules as second line therapy (p = 0.026), with a response rate lower than in non-mucinous group (36.4% vs 62.6%, respectively, p = 0.04). Median time to progression and overall survival were worse for mucinous ovarian cancer. Finally, mucinous cancer received a lower number of chemotherapy lines (p = 0.0023).</p> <p>Conclusion</p> <p>This analysis shows that platinum sensitive mucinous ovarian cancer has a poor response to chemotherapy. Studies dedicated to this histological subgroup are needed.</p

Combination therapy with irinotecan and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer

To evaluate the response rate and toxicity of the combination of irinotecan (CPT-11) and cisplatin in a neoadjuvant setting, a phase II study was conducted regarding the regimen of this combination in patients with locally advanced cervical cancer. Eligibility included patients with previously untreated stage Ib2, IIb, or IIIb squamous cell carcinoma with good performance status. CPT-11 (60 mg m−2) was administered intravenously on days 1, 8 and 15, followed by cisplatin (60 mg m−2) given intravenously on day 1. Treatment was repeated every 4 weeks for a total of two or three cycles. Among 23 eligible patients (median age: 59 years), three showed complete response (13%), 15 showed partial response (65%), for an overall response rate of 78% (95% confidence interval 58–90%). Stable disease was observed in four cases (17%) and progressive disease in one (4%). The median time to failure and median survival time have not yet been reached. Of the 52 treatment cycles administered, diarrhoea and grade 3 or 4 neutropenia were observed in 10% and 75% respectively. There were no therapy-related deaths. The combination of CPT-11 with cisplatin is a promising regimen for neoadjuvant chemotherapy in locally advanced cervical cancer. The toxicities of this regimen are well tolerated. © 1999 Cancer Research Campaig

Mammalian cell entry genes in Streptomyces may provide clues to the evolution of bacterial virulence

Understanding the evolution of virulence is key to appreciating the role specific loci play in pathogenicity. Streptomyces species are generally non-pathogenic soil saprophytes, yet within their genome we can find homologues of virulence loci. One example of this is the mammalian cell entry (mce) locus, which has been characterised in Mycobacterium tuberculosis. To investigate the role in Streptomyces we deleted the mce locus and studied its impact on cell survival, morphology and interaction with other soil organisms. Disruption of the mce cluster resulted in virulence towards amoebae (Acanthamoeba polyphaga) and reduced colonization of plant (Arabidopsis) models, indicating these genes may play an important role in Streptomyces survival in the environment. Our data suggest that loss of mce in Streptomyces spp. may have profound effects on survival in a competitive soil environment, and provides insight in to the evolution and selection of these genes as virulence factors in related pathogenic organisms

Phase I–II study of irinotecan (CPT-11) plus nedaplatin (254-S) with recombinant human granulocyte colony-stimulating factor support in patients with advanced or recurrent cervical cancer

Combination chemotherapy with irinotecan (CPT-11) and platinum compounds is effective for treating cervical cancer. Nedaplatin (254-S) is a new cisplatin analogue that achieves a high response rate (53%) in patients with primary cervical cancer. We performed a phase I–II study of combination chemotherapy with CPT-11 plus 254-S for advanced or recurrent cervical cancer. The inclusion criteria were stage IV disease or recurrence. CPT-11 and 254-S were administered intravenously on day 1, while rhG-CSF (50 μg) was given on days 3–12. This regimen was repeated after 4 weeks. Dose escalation was carried out in tandem (CPT-11/254-S: 50/70, 50/80, and 60/80 mg m−2). A total of 27 patients (stage IV=seven, recurrence=20) were enrolled. The phase I study enrolled eight patients. At dose levels 1 and 2, no dose-limiting toxicities were observed. At dose level 3, the first two patients developed DLTs. The maximum tolerated dose of CPT-11 and 254-S was 60 and 80 mg m−2, respectively, and the recommended doses were 50 and 80 mg m−2. Grade 3/4 haematologic toxicity occurred in 67% in phase II study, but there were no grade 3 nonhaematologic toxicities except fot nausea or lethargy. In all 27 patients, there were two complete responses (7%) and 14 Partial responses (52%), for an overall response rate of 59% (95% confidence interval: 39–78%). Among the 12 responders with recurrent disease, the median time to progression and median survival were 161 days (range: 61–711 days) and 415 days (range: 74–801 days). This new regimen is promising for cervical cancer

Cytogenetic alterations in ovarian clear cell carcinoma detected by comparative genomic hybridisation

Ovarian clear cell carcinoma (OCCC) accounts for a small but significant proportion of all ovarian cancers and is a distinct clinical and pathological entity. It tends to be associated with poorer response rates to chemotherapy and with a worse prognosis. Little is known about possible underlying genetic changes. DNA extracted from paraffin-embedded samples of 18 pure OCCC cases was analysed for genetic imbalances using comparative genomic hybridisation (CGH). All of the 18 cases showed genomic alterations. The mean number of alterations detected by CGH was 6 (range 1–15) indicating a moderate level of genetic instability. Chromosome deletions were more common than amplifications. The most prominent change involved chromosome 9 deletions in 10 cases (55%). This correlates with changes seen in other epithelial ovarian cancers. This deletion was confirmed using microsatellite markers to assess loss of heterozygosity (LOH) at four separate loci on chromosome 9. The most distinct region of loss detected was around the IFNA marker at 9p21 with 41% (11 out of 27cases) LOH. Other frequent deletions involved 1p (five out of 18; 28%); 11q (four out of 18; 22%) and 16 (five out of 18; 28%). Amplification was most common at chromosome 3 (six out of 18; 33%); 13q (four out of 18; 22%) and 15 (three out of 18; 17%). No high-level amplifications were identified. These features may serve as useful prognostic indicators in the management of OCCC