Abstract We present first results obtained with a prototype 4D-tracking demonstrator, using sensors and electronics developed within the TimeSPOT project, and tested on a positive charged pion beam ...at CERN SPS. The setup consists of five small tracking layers in a row, having area of about 3 mm 2 each, three of which equipped with 3D-trench silicon sensors and two with 3D-column diamond sensors. The five layers are then read-out by a KC705 Xilinx board on a PC. We describe the demonstrator structure and operation and illustrate preliminary results on its tracking capabilities.
Patients often ask oncologists how long a cancer has been present before causing symptoms or spreading to other organs. The evolutionary trajectory of cancers can be defined using phylogenetic ...approaches but lack of chronological references makes dating the exact onset of tumours very challenging.
Here, we describe the case of a colorectal cancer (CRC) patient presenting with synchronous lung metastasis and metachronous thyroid, chest wall and urinary tract metastases over the course of 5 years. The chest wall metastasis was caused by needle tract seeding, implying a known time of onset. Using whole genome sequencing data from primary and metastatic sites we inferred the complete chronology of the cancer by exploiting the time of needle tract seeding as an in vivo ‘stopwatch’. This approach allowed us to follow the progression of the disease back in time, dating each ancestral node of the phylogenetic tree in the past history of the tumour. We used a Bayesian phylogenomic approach, which accounts for possible dynamic changes in mutational rate, to reconstruct the phylogenetic tree and effectively ‘carbon date’ the malignant progression.
The primary colon cancer emerged between 5 and 8 years before the clinical diagnosis. The primary tumour metastasized to the lung and the thyroid within a year from its onset. The thyroid lesion presented as a tumour-to-tumour deposit within a benign Hurthle adenoma. Despite rapid metastatic progression from the primary tumour, the patient showed an indolent disease course. Primary cancer and metastases were microsatellite stable and displayed low chromosomal instability. Neo-antigen analysis suggested minimal immunogenicity.
Our data provide the first in vivo experimental evidence documenting the timing of metastatic progression in CRC and suggest that genomic instability might be more important than the metastatic potential of the primary cancer in dictating CRC fate.
3D trench silicon pixel sensors, recently developed by the TimeSPOT collaboration, have shown excellent performance in terms of spatial resolution, timing precision and detection efficiency. The ...combination of these three features make them one of the best candidate for inner tracking detectors operating in high luminosity hadron colliders experiments. This article presents systematic characterisations of these devices made with minimum ionising particles on irradiated sensors with neutrons up to 2.5 ⋅ 10 16 1 MeV n eq cm −2 . The results show that 3D trench pixels have extremely high resistance to radiation. The measured time resolution and the detection efficiency of irradiated sensors match those of non-irradiated ones if a slightly higher bias voltage, few tens of Volts, is applied to the pixels. As of today, 3D trench pixels are the only sensors capable of achieving 10 ps time resolution after being irradiated at extremely high fluences, extending by far the capabilities of future tracking systems of HEP experiments operating under extreme conditions.
Lethal-7 (let-7) is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS. A single-nucleotide polymorphism (rs61764370, T > G base substitution) in the let-7 ...complementary site 6 (LCS-6) of KRAS mRNA has been shown to predict prognosis in early-stage colorectal cancer (CRC) and benefit from anti-epidermal growth factor receptor monoclonal antibodies in metastatic CRC.
We analysed rs61764370 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX plus or minus cetuximab in locally advanced rectal cancer. DNA was isolated from formalin-fixed paraffin-embedded tumour tissue and genotyped using a PCR-based commercially available assay. Kaplan–Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.
A total of 155/164 (94.5%) patients were successfully analysed, of whom 123 (79.4%) and 32 (20.6%) had the LCS-6 TT and LCS-6 TG genotype, respectively. Carriers of the G allele were found to have a statistically significantly higher rate of complete response (CR) after neoadjuvant therapy (28.1% versus 10.6%; P = 0.020) and a trend for better 5-year progression-free survival (PFS) 77.4% versus 64.5%: hazard ratio (HR) 0.56; P = 0.152 and overall survival (OS) rates (80.3% versus 71.9%: HR 0.59; P = 0.234). Both CR and survival outcomes were independent of the use of cetuximab. The negative prognostic effect associated with KRAS mutation appeared to be stronger in patients with the LCS-6 TT genotype (HR PFS 1.70, P = 0.078; HR OS 1.79, P = 0.082) compared with those with the LCS-6 TG genotype (HR PFS 1.33, P = 0.713; HR OS 1.01, P = 0.995).
This analysis suggests that rs61764370 may be a biomarker of response to neoadjuvant treatment and an indicator of favourable outcome in locally advanced rectal cancer possibly by mitigating the poor prognosis of KRAS mutation. In this setting, however, this polymorphism does not appear to predict cetuximab benefit.
For the next generation of vertex detectors, the accurate measurement of the charged particle timing at the pixel level is considered to be the ultimate solution in experiments operating at very high ...instantaneous luminosities. This work shows that the 55 μm × 55 µm wide 150 µm thick 3D trench-type pixels, developed by the TimeSPOT Collaboration, achieve a time resolution close to 10 ps with minimum ionizing particles while maintaining a detection efficiency close to 100% when operated at a tilt angle larger than 10° from normal incidence. This record performance is obtained with software-based constant-fraction algorithms applied to signal waveforms. However, time resolutions as good as 25 ps can be achieved using a simple leading-edge discriminating technique, without any amplitude correction. Similar timing performances can also be achieved when the charged particles cross two nearby pixels if both signal amplitudes are measured. 3D trench-type pixels, as of today, are the fastest charged-particles pixel detectors available and represent a very promising solution for the future upgrade of tracking systems of many HEP experiments operating in extreme conditions.
Sensors fabricated from high resistivity, float zone, silicon material have been the basis of vertex detectors and trackers for the last 30 years. The areas of these devices have increased from a few ...square cm to >200m2 for the existing CMS tracker. High Luminosity Large Hadron Collider (HL-LHC), CMS and ATLAS tracker upgrades will each require more than 200 m2 of silicon and the CMS High Granularity Calorimeter (HGCAL) will require more than 600 m2. The cost and complexity of assembly of these devices is related to the area of each module, which in turn is set by the size of the silicon sensors. In addition to large area, the devices must be radiation hard, which requires the use of sensors thinned to 200 microns or less. The combination of wafer thinning and large wafer diameter is a significant technical challenge, and is the subject of this work. We describe work on development of thin sensors on 200 mm wafers using wafer bonding technology. Results of development runs with float zone, Silicon-on-Insulator and Silicon-Silicon bonded wafer technologies are reported.
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