Development and external validation of a multivariable [68^{68}Ga]Ga-PSMA-11 PET-based prediction model for lymph node involvement in men with intermediate or high-risk prostate cancer

PURPOSE To develop and evaluate a lymph node invasion (LNI) prediction model for men staged with [$^{68}$Ga]Ga-PSMA-11 PET. METHODS A consecutive sample of intermediate to high-risk prostate cancer (PCa) patients undergoing [$^{68}$Ga]Ga-PSMA-11 PET, extended pelvic lymph node dissection (ePLND), and radical prostatectomy (RP) at two tertiary referral centers were retrospectively identified. The training cohort comprised 173 patients (treated between 2013 and 2017), the validation cohort 90 patients (treated between 2016 and 2019). Three models for LNI prediction were developed and evaluated using cross-validation. Optimal risk-threshold was determined during model development. The best performing model was evaluated and compared to available conventional and multiparametric magnetic resonance imaging (mpMRI)-based prediction models using area under the receiver operating characteristic curves (AUC), calibration plots, and decision curve analysis (DCA). RESULTS A combined model including prostate-specific antigen, biopsy Gleason grade group, [$^{68}$Ga]Ga Ga-PSMA-11 positive volume of the primary tumor, and the assessment of the [$^{68}$Ga]Ga-PSMA-11 report N-status yielded an AUC of 0.923 (95% CI 0.863-0.984) in the external validation. Using a cutoff of  ≥ 17%, 44 (50%) ePLNDs would be spared and LNI missed in one patient (4.8%). Compared to conventional and MRI-based models, the proposed model showed similar calibration, higher AUC (0.923 (95% CI 0.863-0.984) vs. 0.700 (95% CI 0.548-0.852)-0.824 (95% CI 0.710-0.938)) and higher net benefit at DCA. CONCLUSIONS Our results indicate that information from [$^{68}$Ga]Ga-PSMA-11 may improve LNI prediction in intermediate to high-risk PCa patients undergoing primary staging especially when combined with clinical parameters. For better LNI prediction, future research should investigate the combination of information from both PSMA PET and mpMRI for LNI prediction in PCa patients before RP

Determining the impactor of the Ordovician Lockne crater : oxygen and neon isotopes in chromite versus sedimentary PGE signatures

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Earth and Planetary Science Letters 306 (2011): 149-155, doi:10.1016/j.epsl.2011.04.028.Abundant chromite grains with L-chondritic composition in the resurge deposits of the Lockne impact crater (458 Myr old; dia. ~10 km) in Sweden have been inferred to represent relict fragments of an impactor from the break-up of the L-chondrite parent body at 470 Ma. This view has been challenged based on Ir/Cr and platinum group element (PGE) patterns of the same resurge deposits, and a reinterpretation of the origin of the chromite grains. An impactor of the non-magmatic iron meteorite type was proposed instead. Here we show that single-grain oxygen and noble-gas isotope analyses of the chromite grains from the resurge deposits further support an origin from an L-chondritic asteroid. We also present PGE analyses and Ir/Cr ratios for fossil L-chondritic meteorites found in mid-Ordovician marine limestone in Sweden. The L-chondritic origin has been confirmed by several independent methods, including major element and oxygen isotopic analyses of chromite. Although the meteorites show the same order-of-magnitude PGE and Cr concentrations as recent L chondrites, the elements have been redistributed to the extent that it is problematic to establish the original meteorite type from these proxies. Different PGE data processing approaches can lead to highly variable results, as also shown here for the Lockne resurge deposits. We conclude that the Lockne crater was formed by an L-chondritic impactor, and that considerable care must be taken when inferring projectile type from PGEs in sedimentary ejecta deposits.The WiscSIMS Lab is partially funded by NSF-EAR (0319230, 0516725, 0744079). The Robert A. Pritzker Center for Meteoritics and Polar Studies is supported by the Tawani Foundation

Categorical versus continuous circulating tumor cell enumeration as early surrogate marker for therapy response and prognosis during docetaxel therapy in metastatic prostate cancer patients

Background: Circulating tumor cell (CTCs) counts might serve as early surrogate marker for treatment efficacy in metastatic castration-resistant prostate cancer (mCRPC) patients. We prospectively assessed categorical and continuous CTC-counts for their utility in early prediction of radiographic response, progression-free (PFS) and overall survival (OS) in mCRPC patients treated with docetaxel. Methods: CTC-counts were assessed in 122 serial samples, as continuous or categorical (= 5 CTCs) variables, at baseline (q0) and after 1 (q1),4 (q4) and 10 (q10) cycles of docetaxel (3-weekly, 75 mg/m2) in 33 mCRPC patients. Treatment response (TR) was defined as non-progressive (non-PD) and progressive disease (PD),by morphologic RECIST or clinical criteria at q4 and q10. Binary logistic and Cox proportional hazards regression analyses were used as statistical methods. Results: Categorical CTC-count status predicted PD at q4 already after one cycle (q1) and after 4 cycles (q4) of chemotherapy with an odds ratio (OR) of 14.9 (p = 0.02) and 18.0 (p = 0.01). Continuous CTC-values predicted PD only at q4 (OR 1.04, p = 0.048). Regarding PFS, categorical CTC-counts at q1 were independent prognostic markers with a hazard ratio (HR) of 3.85 (95 % CI 1.1-13.8, p = 0.04) whereas early continuous CTC-values at q1 failed significance (HR 1.02, 95 % CI 0.99-1.05, p = 0.14). For OS early categorical and continuous CTC-counts were independent prognostic markers at q1 with a HR of 3.0 (95 % CI 1.6-15.7, p = 0.007) and 1.02 (95 % CI 1.0-1.040, p = 0.04). Conclusions: Categorical CTC-count status is an early independent predictor for TR, PFS and OS only 3 weeks following treatment initiation with docetaxel whereas continuous CTC-counts were an inconsistent surrogate marker in mCRPC patients. For clinical practice, categorical CTC-counts may provide complementary information towards individualized treatment strategies with early prediction of treatment efficacy and optimized sequential treatment

Cosmic History and a Candidate Parent Asteroid for the Quasicrystal-bearing Meteorite Khatyrka

The unique CV-type meteorite Khatyrka is the only natural sample in which "quasicrystals" and associated crystalline Cu,Al-alloys, including khatyrkite and cupalite, have been found. They are suspected to have formed in the early Solar System. To better understand the origin of these exotic phases, and the relationship of Khatyrka to other CV chondrites, we have measured He and Ne in six individual, ~40-{\mu}m-sized olivine grains from Khatyrka. We find a cosmic-ray exposure age of about 2-4 Ma (if the meteoroid was <3 m in diameter, more if it was larger). The U,Th-He ages of the olivine grains suggest that Khatyrka experienced a relatively recent (<600 Ma) shock event, which created pressure and temperature conditions sufficient to form both the quasicrystals and the high-pressure phases found in the meteorite. We propose that the parent body of Khatyrka is the large K-type asteroid 89 Julia, based on its peculiar, but matching reflectance spectrum, evidence for an impact/shock event within the last few 100 Ma (which formed the Julia family), and its location close to strong orbital resonances, so that the Khatyrka meteoroid could plausibly have reached Earth within its rather short cosmic-ray exposure age.Comment: Submitted to Earth and Planetary Science Letter

Bendamustine: Safety and Efficacy in the Management of Indolent Non-Hodgkins Lymphoma

Bendamustine (Treanda, Ribomustin) was recently approved by the US Food and Drug Administration (FDA) for treatment of patients with rituximab refractory indolent lymphoma and is expected to turn into a frontline therapy option for indolent lymphoma. This compound with amphoteric properties was designed in the former Germany Democratic Republic in 1960s and re-discovered in 1990s with multiple successive well-designed studies. Bendamustine possesses a unique mechanism of action with potential antimetabolite properties, and only partial cross-resistance with other alkylators. Used in combination with rituximab in vitro, bendamustine shows synergistic effects against various leukemia and lymphoma cell lines. In clinical studies, bendamustine plus rituximab is highly effective in patients with relapsed-refractory indolent lymphoma, inducing remissions in 90% or more and a median progression-free survival of 23–24 months. The optimal dosing and schedule of bendamustine administration is largely undecided and varies among studies. Results of ongoing trials and dose-finding studies will help to further help ascertain the optimal place of bendamustine in the management of indolent NHL

Chaperonin CCT Checkpoint Function in Basal Transcription Factor TFIID Assembly

International audienc

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file