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Backoround There is much debate on the necessity of regionalization of ovarian cancer care. We investigated the association between hospital type and survival of patients with ovarian cancer in The Netherlands. Methods A retrospective, population-based cohort study was performed on all Dutch patients diagnosed with ovarian cancer from January 1, 1996, through December 31, 2003. We used data from the Netherlands Cancer Registry that were linked to mortality data from the Statistics Netherlands database to obtain the date and cause of death. Five-year relative survival ratios, defined as the ratio of the observed survival in the patient population to the expected survival of women in the general population with the same age, were determined for the total population and for groups stratified by tumor stage and/or hospital type. The association between hospital type and disease-specific survival was analyzed by use of multivariable Cox regression analyses. Results We analyzed data from 8621 women with epithelial ovarian cancer, of whom 3482 (40%) were treated in general hospitals, 3510 (41%) were treated in semispecialized hospitals, and 1557 (18%) were treated in specialized hospitals. Five-year relative overall survival ratios of patients treated in general, semispecialized, and specialized hospitals were 38.0% (95% confidence interval [CI] = 36.0% to 39.9%), 39.4% (95% CI = 37.5% to 41.4%), and 40.3% (95% CI = 37.4% to 43.1%), respectively; median survival of patients aged 50-75 years was 36 months (interquartile range [IQR] = 13 to >54 months), 37 months (IQR = 14 to >54 months), and 38 months (IQR = 15 to >55 months), respectively. Age and cancer stage were associated with the relationship between hospital type and ovarian cancer-specific survival but histologic tumor type, grade, year of diagnosis, and socioeconomic status were not. Among patients with early-stage ovarian cancer, treatment in semispecialized and specialized hospitals was associated with lower risks of ovarian cancer-specific mortality than treatment in general hospitals. Among patients with stage I-IIA disease who were aged 50-75 years, risk of ovarian cancer-specific mortality was 30% and 42% lower after treatment in semispecialized and specialized hospitals, respectively, than in general hospitals (for semispecialized hospitals, hazard ratio [HR] = 0.70, 95% CI = 0.53 to 0.93; for specialized hospitals, HR = 0.58, 95% CI = 0.38 to 0.87). Among patients with advanced ovarian cancer, hospital type was not associated with survival. Conclusion Hospital type was statistically significantly associated with survival among Dutch ovarian cancer patients with early-stage ovarian cancer: Patients who were treated in specialized and semispecialized hospitals survived longer than patients treated in general hospitals.

Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer.

The management of melanoma during pregnancy is challenging as maternal benefits and fetal risks need to be balanced. Here, we present an overview of the incidence, the demographic and clinical characteristics and the treatment modalities used. After analysis of obstetric, fetal and maternal outcome, recommendations for clinical practice are provided. From the ‘International Network on Cancer, Infertility and Pregnancy’ database, pregnant patients with melanoma were identified and analysed. Sixty pregnancies were eligible for analysis. Fifty percent of the patients presented with advanced melanoma during pregnancy (14 stage III and 16 stage IV), and 27% were diagnosed with recurrent melanoma. Surgery was the main therapeutic strategy during pregnancy. Only four patients with advanced melanoma were treated during pregnancy with systemic therapy (n=1) or radiotherapy (n=3). Premature delivery was observed in 18% of the ongoing pregnancies, all which were induced and 78% of which involved patients with advanced melanoma. Thirty-nine percent of the patients died within 5 years; all had been diagnosed with stage III or IV disease during pregnancy. Melanoma can present in a more advanced stage during pregnancy. New systemic therapies may be beneficial for patients with metastatic melanoma but may not be pregnancy compatible. In these patients, preterm induction of labour need to be discussed, despite the short-term and long-term negative effects on the child.

Background: In preclinical models recruitment of bone-marrow derived (endothelial) progenitor cells (BD(E)PCs) contributes to tumor growth and metastasis formation. Here we investigated whether these (E)PCs and mobilizing cytokines are released after partial hepatectomy or radiofrequency ablation (RFA) for liver tumors. In addition, we tested whether G-CSF could play a role in EPC mobilization in mice and in human volunteers.Methods: Before, during and after liver surgery plasma and mononuclear cells were collected from 12 patients undergoing partial hepatectomy or RFA. To explore the role of G-CSF C57Bl/6 mice and 20 human volunteers received G-CSF (0.3 or 3 μg). In all individuals, (E)PC numbers were determined by flow cytometry at predefined timepoints shortly after therapy. Plasma levels of G-CSF, VEGF and SDF-1α were measured by ELISA>Results: Patients undergoing partial hepatectomy or RFA showed a instantaneous release of EPCs following laparotomy and mobilization of the liver. Elevated EPC levels were maintained during the entire procedure, but dropped to near-baseline levels 4 hours after completion of the procedure. Plasma G-CSF levels showed a 5-10-fold increase after the procedure and low-dose G-CSF administration to mice or healthy volunteers was sufficient to induce an immediate release of EPCs. Surgery also caused an increase in the plasma levels of VEGF, but not SDF1.Conclusion: Compliant with previous published data concerning VDA and chemotherapy treatment,liver surgery induces an instantaneous release of EPCs, conceivably in response to elevated G-CSF levels. This suggests the value of exploring therapeutic avenues to prevent this process.

Ischemia/reperfusion (I/R) is often inevitable during hepatic surgery and may stimulate the outgrowth of colorectal micrometastases. Postischemic microcirculatory disturbances contribute to I/R damage and may induce prolonged tissue hypoxia and consequent stabilization of hypoxia-inducible factor (HIF)-1α. The aim of this study was to evaluate the contribution of postischemic microcirculatory disturbances, hypoxia, and HIF-1α to I/R-accelerated tumor growth. Partial hepatic I/R attributable to temporary clamping of the left liver lobe induced microcirculatory failure for up to 5 days. This was accompanied by profound and prolonged perinecrotic tissue hypoxia, stabilization of HIF-1α, and massive perinecrotic outgrowth of pre-established micrometastases. Restoration of the microcirculation by treatment with Atrasentan and l-arginine minimized hypoxia and HIF-1α stabilization and reduced the accelerated outgrowth of micrometastases by 50%. Destabilization of HIF-1α by the HSP90 inhibitor 17-DMAG caused an increase in tissue necrosis but reduced I/R-stimulated tumor growth by more than 70%. In conclusion, prevention of postischemic microcirculatory disturbances and perinecrotic hypoxia reduces the accelerated outgrowth of colorectal liver metastases after I/R. This may, at least in part, be attributed to the prevention of HIF-1α stabilization. Prevention of tissue hypoxia or inhibition of HIF-1α may represent attractive approaches to limiting recurrent tumor growth after hepatic surgery.