Cholangiocarcinoma (CCA) encompasses diverse epithelial tumors historically associated with poor outcomes due to an aggressive disease course, late diagnosis, and limited benefit of standard ...chemotherapy for advanced disease. Comprehensive molecular profiling has revealed a diverse landscape of genomic alterations as oncogenic drivers in CCA. TP53 mutations, CDKN2A/B loss, and KRAS mutations are the most common genetic alterations in CCA. However, intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA) differ substantially in the frequency of many alterations. This includes actionable alterations, such as isocitrate dehydrogenase 1 (IDH1) mutations and a large variety of FGFR2 rearrangements, which are found in up to 29% and ∼10% of patients with iCCA, respectively, but are rare in eCCA. FGFR2 rearrangements are currently the only genetic alteration in CCA for which a targeted therapy, the fibroblast growth factor receptor 1-3 inhibitor pemigatinib, has been approved. However, favorable phase III results for IDH1-targeted therapy with ivosidenib in iCCA have been published, and numerous other alterations are actionable by targeted therapies approved in other indications. Recent advances in next-generation sequencing (NGS) have led to the development of assays that allow comprehensive genomic profiling of large gene panels within 2-3 weeks, including in vitro diagnostic tests approved in the United States. These assays vary regarding acceptable source material (tumor tissue or peripheral whole blood), genetic source for library construction (DNA or RNA), target selection technology, gene panel size, and type of detectable genomic alterations. While some large commercial laboratories offer rapid and comprehensive genomic profiling services based on proprietary assay platforms, clinical centers may use commercial genomic profiling kits designed for clinical research to develop their own customized laboratory-developed tests. Large-scale genomic profiling based on NGS allows for a detailed and precise molecular diagnosis of CCA and provides an important opportunity for improved targeted treatment plans tailored to the individual patient's genetic signature.
•CCA is a relatively rare, aggressive, heterogeneous malignancy associated with poor outcomes.•Comprehensive molecular profiling has revealed a diverse landscape of oncogenic genomic alterations in CCA.•Advances in NGS have allowed large gene panels to be assayed with high sensitivity and specificity and at reduced cost.•Large-scale genomic profiling has found actionable genomic alterations targeted by therapies approved in other indications.•Large-scale genomic profiling may allow precise molecular diagnostics to guide treatment decisions in CCA.
We present the first limits on inelastic electron-scattering dark matter and dark photon absorption using a prototype SuperCDMS detector having a charge resolution of 0.1 electron-hole pairs (CDMS ...HVeV, a 0.93 g CDMS high-voltage device). These electron-recoil limits significantly improve experimental constraints on dark matter particles with masses as low as 1 MeV/c^{2}. We demonstrate a sensitivity to dark photons competitive with other leading approaches but using substantially less exposure (0.49 g d). These results demonstrate the scientific potential of phonon-mediated semiconductor detectors that are sensitive to single electronic excitations.
We report results from a reanalysis of data from the Cryogenic Dark Matter Search (CDMS II) experiment at the Soudan Underground Laboratory. Data taken between October 2006 and September 2008 using ...eight germanium detectors are reanalyzed with a lowered, 2 keV recoil-energy threshold, to give increased sensitivity to interactions from weakly interacting massive particles (WIMPs) with masses below ∼10 GeV/c(2). This analysis provides stronger constraints than previous CDMS II results for WIMP masses below 9 GeV/c(2) and excludes parameter space associated with possible low-mass WIMP signals from the DAMA/LIBRA and CoGeNT experiments.
The CDMS low ionization threshold experiment (CDMSlite) uses cryogenic germanium detectors operated at a relatively high bias voltage to amplify the phonon signal in the search for weakly interacting ...massive particles (WIMPs). Results are presented from the second CDMSlite run with an exposure of 70 kg day, which reached an energy threshold for electron recoils as low as 56 eV. A fiducialization cut reduces backgrounds below those previously reported by CDMSlite. New parameter space for the WIMP-nucleon spin-independent cross section is excluded for WIMP masses between 1.6 and 5.5 GeV/c^{2}.
We present limits on spin-independent dark matter-nucleon interactions using a 10.6 g Si athermal phonon detector with a baseline energy resolution of σE = 3.86 ± 0.04 ( stat ) +0.19 −0.00 ( syst ) ...eV . This exclusion analysis sets the most stringent dark matter-nucleon scattering cross-section limits achieved by a cryogenic detector for dark matter particle masses from 93 to 140 MeV / c2 , with a raw exposure of 9.9 g d acquired at an above-ground facility. This work illustrates the scientific potential of detectors with athermal phonon sensors with eV-scale energy resolution for future dark matter searches.
Biliary tract cancer is an uncommon cancer with a poor outcome. We assembled data from the National Cancer Research Institute (UK) ABC-02 study and 10 international studies to determine prognostic ...outcome characteristics for patients with advanced disease.
Multivariable analyses of the final dataset from the ABC-02 study were carried out. All variables were simultaneously included in a Cox proportional hazards model, and backward elimination was used to produce the final model (using a significance level of 10%), in which the selected variables were associated independently with outcome. This score was validated externally by receiver operating curve (ROC) analysis using the independent international dataset.
A total of 410 patients were included from the ABC-02 study and 753 from the international dataset. An overall survival (OS) and progression-free survival (PFS) Cox model was derived from the ABC-02 study. White blood cells, haemoglobin, disease status, bilirubin, neutrophils, gender, and performance status were considered prognostic for survival (all with P < 0.10). Patients with metastatic disease {hazard ratio (HR) 1.56 95% confidence interval (CI) 1.20–2.02} and Eastern Cooperative Oncology Group performance status (ECOG PS) 2 had worse survival HR 2.24 (95% CI 1.53–3.28). In a dataset restricted to patients who received cisplatin and gemcitabine with ECOG PS 0 and 1, only haemoglobin, disease status, bilirubin, and neutrophils were associated with PFS and OS. ROC analysis suggested the models generated from the ABC-02 study had a limited prognostic value 6-month PFS: area under the curve (AUC) 62% (95% CI 57–68); 1-year OS: AUC 64% (95% CI 58–69).
These data propose a set of prognostic criteria for outcome in advanced biliary tract cancer derived from the ABC-02 study that are validated in an international dataset. Although these findings establish the benchmark for the prognostic evaluation of patients with ABC and confirm the value of longheld clinical observations, the ability of the model to correctly predict prognosis is limited and needs to be improved through identification of additional clinical and molecular markers.
We report the result of a blinded search for weakly interacting massive particles (WIMPs) using the majority of the SuperCDMS Soudan data set. With an exposure of 1690 kg d, a single candidate event ...is observed, consistent with expected backgrounds. This analysis (combined with previous Ge results) sets an upper limit on the spin-independent WIMP-nucleon cross section of 1.4×10^{-44} (1.0×10^{-44}) cm^{2} at 46 GeV/c^{2}. These results set the strongest limits for WIMP-germanium-nucleus interactions for masses >12 GeV/c^{2}.
We report a first search for weakly interacting massive particles (WIMPs) using the background rejection capabilities of SuperCDMS. An exposure of 577 kg days was analyzed for WIMPs with mass <30 ...GeV/c(2), with the signal region blinded. Eleven events were observed after unblinding. We set an upper limit on the spin-independent WIMP-nucleon cross section of 1.2×10(-42) cm(2) at 8 GeV/c(2). This result is in tension with WIMP interpretations of recent experiments and probes new parameter space for WIMP-nucleon scattering for WIMP masses <6 GeV/c(2).
We report results of a search for weakly interacting massive particles (WIMPS) with the silicon detectors of the CDMS II experiment. This blind analysis of 140.2 kg day of data taken between July ...2007 and September 2008 revealed three WIMP-candidate events with a surface-event background estimate of 0.41(-0.08)(+0.20)(stat)(-0.24)(+0.28)(syst). Other known backgrounds from neutrons and 206Pb are limited to <0.13 and <0.08 events at the 90% confidence level, respectively. The exposure of this analysis is equivalent to 23.4 kg day for a recoil energy range of 7-100 keV for a WIMP of mass 10 GeV/c2. The probability that the known backgrounds would produce three or more events in the signal region is 5.4%. A profile likelihood ratio test of the three events that includes the measured recoil energies gives a 0.19% probability for the known-background-only hypothesis when tested against the alternative WIMP+background hypothesis. The highest likelihood occurs for a WIMP mass of 8.6 GeV/c2 and WIMP-nucleon cross section of 1.9×10(-41) cm2.
SuperCDMS is an experiment designed to directly detect weakly interacting massive particles (WIMPs), a favored candidate for dark matter ubiquitous in the Universe. In this Letter, we present ...WIMP-search results using a calorimetric technique we call CDMSlite, which relies on voltage-assisted Luke-Neganov amplification of the ionization energy deposited by particle interactions. The data were collected with a single 0.6 kg germanium detector running for ten live days at the Soudan Underground Laboratory. A low energy threshold of 170 eVee (electron equivalent) was obtained, which allows us to constrain new WIMP-nucleon spin-independent parameter space for WIMP masses below 6 GeV/c2.
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