Targetclone: A multi-sample approach for reconstructing subclonal evolution of tumors

Most tumors are composed of a heterogeneous population of subclones. A more detailed insight into the subclonal evolution of these tumors can be helpful to study progression and treatment response. Problematically, tumor samples are typically very heterogeneous, making deconvolving individual tumor subclones a major challenge. To overcome this limitation, reducing heterogeneity, such as by means of microdissections, coupled with targeted sequencing, is a viable approach. However, computational methods that enable reconstruction of the evolutionary relationships require unbiased read depth measurements, which are commonly challenging to obtain in this setting. We introduce TargetClone, a novel method to reconstruct the subclonal evolution tree of tumors from single-nucleotide polymorphism allele frequency and somatic single-nucleotide variant measurements. Furthermore, our method infers copy numbers, alleles and the fraction of the tumor component in each sample. TargetClone was specifically designed for targeted sequencing data obtained from microdissected samples. We demonstrate that our method obtains low error rates on simulated data. Additionally, we show that our method is able to reconstruct expected trees in a testicular germ cell cancer and ovarian cancer dataset. The TargetClone package including tree visualization is written in Python and is publicly available at https://github.com/UMCUGenetics/targetclone

Molecular heterogeneity and early metastatic clone selection in testicular germ cell cancer development

Background Testicular germ cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an embryonic germ cell. This study determines intratumour heterogeneity to unravel tumour progression from initiation until metastasis. Methods In total, 42 purified samples of four treatment-resistant nonseminomatous (NS) TGCC were investigated, including the precursor germ cell neoplasia in situ (GCNIS) and metastatic specimens, using whole-genome and targeted sequencing. Their evolution was reconstructed. Results Intratumour molecular heterogeneity did

Variation in neurosurgical management of traumatic brain injury

Background: Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe. Methods: A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP). Results: The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions. Conclusion: Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care

Prolonging the duration of post-infusion scalp cooling in the prevention of anthracycline-induced alopecia: a randomised trial in patients with breast cancer treated with adjuvant chemotherapy

Item does not contain fulltex

Beneficial and nature-based sediment use - Experiences from Dutch pilots

The natural sediment cycle is disrupted and impacted by human interventions world-wide, such as dams in rivers, port developments in estuaries, dredging activities for the maintenance of existing ports and waterways, and pollution from industrial activities. Coasts, shores, lakes and rivers suffer from an imbalance in sediment quantity and poor sediment quality. This impacts human industrial activities (e.g. navigation, logistic and tourism), life and safety (e.g. space for living, flood safety, food security and loss of productivity). In addition, shortage of sand cause by excessive sand mining or lack of sand in the environment in many locations of the world brings a special focus on fine and soft sediment, generally considered an unsuitable resource if not a contaminated waste. In line with this world-wide demand, EcoShape - Building with Nature is executing various pilots in the Netherlands and Indonesia to improve knowledge and demonstrate practical nature-based solutions regarding management, use and reuse of (fine and soft) sediments. These pilots are bonded in the EcoShape Living Lab for Mud initiative. These pilots cover the entire range from sediment in suspension to sediment as building material, embedding ecology, operations as well as socio-economic considerations. This presentation will focus on two of these pilots located in the Netherlands: the Mud Motor and de Kleirijperij (also part of the Eems-Dollard 2050 program). The Mud Motor explored potential for beneficial use of dredge sediments to feed salt marshes, through strategic disposal and optimal use of natural processes. The Kleirijperij studies the technical and financial feasibility of turning dredge sediments into clay-soil for dike construction. During the presentations we will focus on technical results as well as governance challenges and triggers critical for the realization of sustainable beneficial sediment use projects. These pilots and this presentation tight also to the 2017 CEDA and the 2018 PIANC working groups on Beneficial Sediment Use.</p

Beneficial and nature-based sediment use - Experiences from Dutch pilots

The natural sediment cycle is disrupted and impacted by human interventions world-wide, such as dams in rivers, port developments in estuaries, dredging activities for the maintenance of existing ports and waterways, and pollution from industrial activities. Coasts, shores, lakes and rivers suffer from an imbalance in sediment quantity and poor sediment quality. This impacts human industrial activities (e.g. navigation, logistic and tourism), life and safety (e.g. space for living, flood safety, food security and loss of productivity). In addition, shortage of sand cause by excessive sand mining or lack of sand in the environment in many locations of the world brings a special focus on fine and soft sediment, generally considered an unsuitable resource if not a contaminated waste. In line with this world-wide demand, EcoShape - Building with Nature is executing various pilots in the Netherlands and Indonesia to improve knowledge and demonstrate practical nature-based solutions regarding management, use and reuse of (fine and soft) sediments. These pilots are bonded in the EcoShape Living Lab for Mud initiative. These pilots cover the entire range from sediment in suspension to sediment as building material, embedding ecology, operations as well as socio-economic considerations. This presentation will focus on two of these pilots located in the Netherlands: the Mud Motor and de Kleirijperij (also part of the Eems-Dollard 2050 program). The Mud Motor explored potential for beneficial use of dredge sediments to feed salt marshes, through strategic disposal and optimal use of natural processes. The Kleirijperij studies the technical and financial feasibility of turning dredge sediments into clay-soil for dike construction. During the presentations we will focus on technical results as well as governance challenges and triggers critical for the realization of sustainable beneficial sediment use projects. These pilots and this presentation tight also to the 2017 CEDA and the 2018 PIANC working groups on Beneficial Sediment Use.</p

Comparison of Two Prostate Cancer Risk Calculators that Include the Prostate Health Index

Background: Risk prediction models for prostate cancer (PCa) have become important tools in reducing unnecessary prostate biopsies. The Prostate Health Index (PHI) may increase the predictive accuracy of such models. Objectives: To compare two PCa risk calculators (RCs) that include PHI. Design, setting, and participants: We evaluated the predictive performance of a previously developed PHI-based nomogram and updated versions of the European Randomized Study of Screening for Prostate Cancer (ERSPC) RCs based on digital rectal examination (DRE): RC3 (no prior biopsy) and RC4 (prior biopsy). For the ERSPC updates, the original RCs were recalibrated and PHI was added as a predictor. The PHI-updated ERSPC RCs were compared with the Lughezzani nomogram in 1185 men from four European sites. Outcomes were biopsy-detectable PC and potentially advanced or aggressive PCa, defined as clinical stage >T2b and/or a Gleason score ≥7 (clinically relevant PCa). Results and limitations: The PHI-updated ERSPC models had a combined area under the curve for the receiver operating characteristic (AUC) of 0.72 for all PCa and 0.68 for clinically relevant PCa. For the Lughezzani PHI-based nomogram, AUCs were 0.75 for all PCa and 0.69 for clinically relevant PCa. For men without a prior biopsy, PHI-updated RC3 resulted in AUCs of 0.73 for PCa and 0.66 for clinically relevant PCa. Decision curves confirmed these patterns, although the number of clinically relevant cancers was low. Conclusion: Differences between RCs that include PHI are small. Addition of PHI to an RC leads to further reductions in the rate of unnecessary biopsies when compared to a strategy based on prostate-specific antigen measurement. Patient summary: Risk prediction models for prostate cancer have become important tools in reducing unnecessary prostate biopsies. We compared two risk prediction models for prostate cancer that include the Prostate Health Index. We found that these models are equivalent to each other, and both perform better than the prostate-specific antigen test alone in predicting cancer. Prostate-specific antigen screening reduces prostate cancer mortality but leads to many unnecessary prostate biopsies and overdiagnosis. Inclusion of the Prostate Health Index results in an equivalent increase in predictive ability for both the Lughezzani and the updated European Randomized Study of Screening for Prostate Cancer models