Clinical utility of trabectedin for the treatment of ovarian cancer: current evidence

Among the pharmaceutical options available for treatment of ovarian cancer, attention has been increasingly focused on trabectedin (ET-743), a drug which displays a unique mechanism of action and has been shown to be active in several human malignancies. Currently, single agent trabectedin is approved for treatment of patients with advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, and in association with pegylated liposomal doxorubicin for treatment of patients with relapsed partially platinum-sensitive ovarian cancer. This review aims at summarizing the available evidence about the clinical role of trabectedin in the management of patients with epithelial ovarian cancer. Novel perspectives coming from a better understanding of trabectedin mechanisms of action and definition of patients subgroups likely susceptible to benefit of trabectedin treatment are also presented

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Gli ultrasuoni in ginecologia.

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Agreement of two-dimensional and three-dimensional transvaginal ultrasound with magnetic resonance imaging with regard to parametrial infiltration in cervical cancer.

Objectives: To compare two-dimensional (2D) and three-dimensional (3D) transvaginal ultrasound with magnetic resonance imaging (MRI) as gold standard in the assessment of parametrial infiltration of cervical cancer, and to determine if all parts of the cervix are equally assessable with ultrasound. Methods: Patients with histologically confirmed macroscopically evident cervical cancer were staged using FIGO criteria and underwent MRI, 2D- and 3D-ultrasound before treatment. When assessing parametrial infiltration with 3D-ultrasound and MRI, the cervix was (virtually) divided into three cylinders of equal size (cranial, middle, caudal) and each cylinder into six sectors in a clockwise manner following a consensus between radiologists and ultrasound examiners. The presence and the extent of parametrial invasion were recorded for each sector. The results for 2D-ultrasound, 3Dultrasound and MRI were compared, results being reported as percentage agreement and Kappa value. Results: 29 consecutive patients were included. The percentage agreement between 2D-ultrasound and MRI in assessing parametrial infiltration (yes or no) was 76% (kappa 0.459), that between 3Dultrasound and MRI 79% (kappa 0.508). 2D-ultrasound showed the following agreement with MRI: 90% for the ventral parametria (kappa 0.720), 72% for the right lateral parametrium (kappa 0.494), 69% for the left lateral parametrium (kappa 0.412), 58.5% for the dorsal parametria (kappa 0.017). 3D-ultrasound showed the following agreement with MRI: 62.5% for the ventral parametria (kappa 0.176), 81% for the right lateral parametrium (kappa 0.595), 70% for the left lateral parametrium (kappa 0.326), 52% for the dorsal parametria (kappa 0.132). The best agreement between 3Dultrasound and MRI was obtained for the middle cervical cylinder (agreement 76%, kappa 0.438) and the poorest agreement for the caudal cylinder (agreement 34.5%, kappa 0.125). Conclusion: 2D- and 3D-ultrasound showed similar moderate agreement with MRI. 2D- and 3Dultrasound are cheaper and more easily available than MRI and should be considered in the preoperative work-up of cervical cancer

Phase II study of NGR-hTNF in combination with doxorubicin in relapsed ovarian cancer patients

BACKGROUND: The NGR-hTNF (asparagine-glycine-arginine-human tumour necrosis factor) is able to promote antitumour immune responses and to improve the intratumoural doxorubicin uptake by selectively damaging tumour blood vessels. METHODS: Patients progressing after ≥ 1 platinum/taxane-based regimen received NGR-hTNF 0.8 μg m(-2) and doxorubicin 60 mg m(-2) every 3 weeks. Primary endpoint was a Response Evaluation Criteria in Solid Tumors-defined response rate with a target of more than 6 out of 37 responding patients. RESULTS: A total of 37 patients with platinum-free interval lower than 6 months (PFI<6; n=25), or between 6 and 12 months (PFI=6-12; n=12) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6 per ml (interquartile range, 1.2-2.1). In all, 18 patients (49%) received more than 6 cycles. Febrile neutropaenia was registered in one patient (3%). Among 35 assessable patients, 8 (23%; 95% CI 12-39%) had partial response (2 with PFI<6; 6 with PFI=6-12) and 15 (43%) had stable disease (10 with PFI<6; 5 with PFI=6-12). Median progression-free survival (PFS) was 5.0 months for all patients, 3.8 months for patients with PFI<6, and 7.8 months for patients with PFI=6-12. Median overall survival (OS) was 17.0 months. Patients with baseline PBLC higher than the first quartile had improved PFS (P=0.01) and OS (P=0.001). CONCLUSION: Tolerability and activity of this combination warrant further randomised testing in patients with PFI<6. The role of PBLC as a blood-based biomarker deserves further investigation

Imaging techniques for the evaluation of cervical cancer

Improvements in the treatment of cervical carcinoma have made it possible to offer optimal and personalised treatment. Cervical cancer staging is based on clinical examination and histological findings. Many diagnostic methods are used in clinical practice. Magnetic resonance imaging is considered the optimal method for staging cervical carcinoma because of its high accuracy in assessing local extension of disease and distant metastases. Ultrasound has gained increased attention in recent years; it is faster, cheaper, and more widely available than other imaging techniques, and is highly accurate in detecting tumour presence and evaluating local extension of disease. Magnetic resonance imaging and ultrasound are often used together with computed tomography or positron emission tomography combined with computed tomography to assess the whole body, a more accurate detection of pathological lymph nodes and metabolic information of the disease

Which imaging technique should we use in the follow up of gynaecological cancer?

Follow-up routines after gynaecological cancer vary. The optimal approach is unknown, and no randomised-controlled trials comparing surveillance protocols have been published. In this chapter, we summarise the diagnostic performance of ultrasound, computed tomography, and magnetic resonance imaging in the follow up of women treated for ovarian or uterine cancers. Computed tomography is today the standard imaging method for the follow up of women treated for endometrial, cervical, or ovarian cancer. Six-monthly or annual follow-up examinations have not been shown to positively affect survival. Instead, a combination of transvaginal and transabdominal ultrasound examination with clinical examination might be a more cost-effective strategy for early detection of recurrence. Positron-emission tomography might play a role in women with clinical or serological suspicion of recurrence but without evidence of disease at conventional diagnostic imaging. To create guidelines, more studies, preferably randomised-controlled trials, on follow-up strategies are needed