Background

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy without an available effective systemic chemotherapy. Insulin growth factor 2 (IGF-2) overexpression leading to the activation of the IGF-1 receptor (IGF-1R)/mammalian target of rapamycin (mTOR) pathway is well described in ACC. Cixutumumab, a fully human IgG1 monoclonal antibody directed at IGF-1R was combined with temsirolimus on the basis of preclinical data.

Methods

Patients received cixutumumab, 3-6 mg kg(-1) intravenously (IV) weekly, and temsirolimus, 25-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks.

Results

Twenty-six patients were enrolled (13 (50%) men); median age, 47 years; median number of prior therapies, 4. Five patients previously received an IGF-1R inhibitor and one, temsirolimus. The most frequent toxicities, at least possibly drug related, were grade 1-2 thrombocytopenia (38%), mucositis (58%), hypercholesterolaemia (31%), hypertriglyceridemia (35%), and hyperglycaemia (31%). In all, 11 of 26 patients (42%) achieved stable disease (SD) >6 months (duration range=6-21 months) with 3 of the 11 having received a prior IGF-1R inhibitor.

Conclusion

Cixutumumab combined with temsirolimus was well tolerated and >40% of patients achieved prolonged SD.

Background

This retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval.

Methods

Eighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival.

Results

Retreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156).

Conclusion

Our data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed.

A scintillating bolometer based on a large cubic Li2100MoO4 crystal (45 mm side) and a Ge wafer (scintillation detector) has been operated in the CROSS cryogenic facility at the Canfranc underground laboratory in Spain. The dual-readout detector is a prototype of the technology that will be used in the next-generation 0ν2β experiment CUPID . The measurements were performed at 18 and 12 mK temperature in a pulse tube dilution refrigerator. This setup utilizes the same technology as the CUORE cryostat that will host CUPID and so represents an accurate estimation of the expected performance. The Li2100MoO4 bolometer shows a high energy resolution of 6 keV FWHM at the 2615 keV γ line. The detection of scintillation light for each event triggered by the Li2100MoO4 bolometer allowed for a full separation (∼8σ) between γ(β) and α events above 2 MeV . The Li2100MoO4 crystal also shows a high internal radiopurity with 228Th and 226Ra activities of less than 3 and 8 μBq/kg, respectively. Taking also into account the advantage of a more compact and massive detector array, which can be made of cubic-shaped crystals (compared to the cylindrical ones), this test demonstrates the great potential of cubic Li2100MoO4 scintillating bolometers for high-sensitivity searches for the 100Mo 0ν2β decay in CROSS and CUPID projects.

The CUPID Collaboration is designing a tonne-scale, background-free detector to search for double beta decay with sufficient sensitivity to fully explore the parameter space corresponding to the inverted neutrino mass hierarchy scenario. One of the CUPID demonstrators, CUPID-Mo, has proved the potential of enriched Li2100MoO4 crystals as suitable detectors for neutrinoless double beta decay search. In this work, we characterised cubic crystals that, compared to the cylindrical crystals used by CUPID-Mo, are more appealing for the construction of tightly packed arrays. We measured an average energy resolution of (6.7 ± 0.6) keV FWHM in the region of interest, approaching the CUPID target of 5 keV FWHM. We assessed the identification of α particles with and without a reflecting foil that enhances the scintillation light collection efficiency, proving that the baseline design of CUPID already ensures a complete suppression of this α-induced background contribution. We also used the collected data to validate a Monte Carlo simulation modelling the light collection efficiency, which will enable further optimisations of the detector.

Precise characterization of detector time resolution is of crucial importance for next-generation cryogenic-bolometer experiments searching for neutrinoless double-beta decay, such as CUPID, in order to reject background due to pile-up of two-neutrino double-beta decay events. In this paper, we describe a technique developed to study the pile-up rejection capability of cryogenic bolometers. Our approach, which consists of producing controlled pile-up events with a programmable waveform generator, has the benefit that we can reliably and reproducibly control the time separation and relative energy of the individual components of the generated pile-up events. The resulting data allow us to optimize and benchmark analysis strategies to discriminate between individual and pile-up pulses. We describe a test of this technique performed with a small array of detectors at the Laboratori Nazionali del Gran Sasso, in Italy; we obtain a 90% rejection efficiency against pulser-generated pile-up events with rise time of ~15ms down to time separation between the individual events of about 2ms.

The CUPID Collaboration is designing a tonne-scale, background-free detector to search for double beta decay with sufficient sensitivity to fully explore the parameter space corresponding to the inverted neutrino mass hierarchy scenario. One of the CUPID demonstrators, CUPID-Mo, has proved the potential of enriched Li$_{2}$$^{100}$MoO$_4$ crystals as suitable detectors for neutrinoless double beta decay search. In this work, we characterised cubic crystals that, compared to the cylindrical crystals used by CUPID-Mo, are more appealing for the construction of tightly packed arrays. We measured an average energy resolution of (6.7$\pm$0.6) keV FWHM in the region of interest, approaching the CUPID target of 5 keV FWHM. We assessed the identification of $\alpha$ particles with and without a reflecting foil that enhances the scintillation light collection efficiency, proving that the baseline design of CUPID already ensures a complete suppression of this $\alpha$-induced background contribution. We also used the collected data to validate a Monte Carlo simulation modelling the light collection efficiency, which will enable further optimisations of the detector.

CUPID is the next generation experiment which will use scintillating cryogenic calorimeters to search for the neutrinoless double β decay. This unobserved process would shed light on the nature of the neutrino, which up to our knowledge could be a Majorana or a Dirac particle, and would give us an important hint to explain the lack of antimatter in the universe. This ambitious search needs a detector with unique characteristics such as an extremely low background level and an excellent energy resolution. CUPID is now in advanced R&D state to optimize the detector design in order to completely exploit the potentialities of scintillating cryogenic calorimeters. In the following I will describe the test performed at the LNGS (Laboratori Nazionali del Gran Sasso) of a single module of the future CUPID detector. In this contribution we present the performance obtained with a novel assembly concept, proving that it matches the requirements for CUPID.

CUORE Upgrade with Particle IDentification (CUPID) is a foreseen ton-scale array of Li2MoO4 (LMO) cryogenic calorimeters with double readout of heat and light signals. Its scientific goal is to fully explore the inverted hierarchy of neutrino masses in the search for neutrinoless double beta decay of 100Mo. Pile-up of standard double beta decay of the candidate isotope is a relevant background. We generate pile-up heat events via injection of Joule heater pulses with a programmable waveform generator in a small array of LMO crystals operated underground in the Laboratori Nazionali del Gran Sasso, Italy. This allows to label pile-up pulses and control both time difference and underlying amplitudes of individual heat pulses in the data. We present the performance of supervised learning classifiers on data and the attained pile-up rejection efficiency.

Precise characterization of detector time resolution is of crucial importance for next-generation cryogenic-bolometer experiments searching for neutrinoless double-beta decay, such as CUPID, in order to reject background due to pileup of two-neutrino double-beta decay events. In this paper, we describe a technique developed to study the pileup rejection capability of cryogenic bolometers. Our approach, which consists of producing controlled pileup events with a programmable wave-form generator, has the benefit that we can reliably and reproducibly control the time separation and relative energy of the individual components of the generated pileup events. The resulting data allow us to optimize and benchmark analysis strategies to discriminate between individual and pileup pulses. We describe a test of this technique performed with a small array of detectors at the Laboratori Nazionali del Gran Sasso, in Italy; we obtain a 90% rejection efficiency against pulser-generated pileup events with rise time of ∼15ms down to time separation between the individual events of about 2ms.

A scintillating bolometer based on a large cubic Li$_{2}$$^{100}$MoO$_4$ crystal (45 mm side) and a Ge wafer (scintillation detector) has been operated in the CROSS cryogenic facility at the Canfranc underground laboratory in Spain. The dual-readout detector is a prototype of the technology that will be used in the next-generation $0 u2\beta$ experiment CUPID. The measurements were performed at 18 and 12 mK temperature in a pulse tube dilution refrigerator. This setup utilizes the same technology as the CUORE cryostat that will host CUPID and so represents an accurate estimation of the expected performance. The Li$_{2}$$^{100}$MoO$_4$ bolometer shows a high energy resolution of 6 keV FWHM at the 2615 keV $\gamma$ line. The detection of scintillation light for each event triggered by the Li$_{2}$$^{100}$MoO$_4$ bolometer allowed for a full separation ($\sim$8$\sigma$) between $\gamma$($\beta$) and $\alpha$ events above 2 MeV. The Li$_{2}$$^{100}$MoO$_4$ crystal also shows a high internal radiopurity with $^{228}$Th and $^{226}$Ra activities of less than 3 and 8 $\mu$Bq/kg, respectively. Taking also into account the advantage of a more compact and massive detector array, which can be made of cubic-shaped crystals (compared to the cylindrical ones), this test demonstrates the great potential of cubic Li$_{2}$$^{100}$MoO$_4$ scintillating bolometers for high-sensitivity searches for the $^{100}$Mo $0 u2\beta$ decay in CROSS and CUPID projects.