Free-electron lasing with compact beam-driven plasma wakefield accelerator.

The possibility to accelerate electron beams to ultra-relativistic velocities over short distances by using plasma-based technology holds the potential for a revolution in the field of particle accelerators1-4. The compact nature of plasma-based accelerators would allow the realization of table-top machines capable of driving a free-electron laser (FEL)5, a formidable tool to investigate matter at the sub-atomic level by generating coherent light pulses with sub-ångström wavelengths and sub-femtosecond durations6,7. So far, however, the high-energy electron beams required to operate FELs had to be obtained through the use of conventional large-size radio-frequency (RF) accelerators, bound to a sizeable footprint as a result of their limited accelerating fields. Here we report the experimental evidence of FEL lasing by a compact (3-cm) particle-beam-driven plasma accelerator. The accelerated beams are completely characterized in the six-dimensional phase space and have high quality, comparable with state-of-the-art accelerators8. This allowed the observation of narrow-band amplified radiation in the infrared range with typical exponential growth of its intensity over six consecutive undulators. This proof-of-principle experiment represents a fundamental milestone in the use of plasma-based accelerators, contributing to the development of next-generation compact facilities for user-oriented applications9.

Guiding of Charged Particle Beams in Curved Plasma-Discharge Capillaries.

We present a new approach that demonstrates the deflection and guiding of relativistic electron beams over curved paths by means of the magnetic field generated in a plasma-discharge capillary. We experimentally prove that the guiding is much less affected by the beam chromatic dispersion with respect to a conventional bending magnet and, with the support of numerical simulations, we show that it can even be made dispersionless by employing larger discharge currents. This proof-of-principle experiment extends the use of plasma-based devices, that revolutionized the field of particle accelerators enabling the generation of GeV beams in few centimeters. Compared to state-of-the-art technology based on conventional bending magnets and quadrupole lenses, these results provide a compact and affordable solution for the development of next-generation tabletop facilities.

Improved overall survival in patients developing endocrine toxicity during treatment with nivolumab for advanced non-small cell lung cancer in a prospective study.

PURPOSE: Immune checkpoint inhibitors (ICPIs) disrupting PD-1/PD-L1 axis have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Some studies identified the development of endocrine toxicity as predictor of better survival in cancer patients treated with ICPIs. The aim of study was to evaluate survival and new onset of immune-related endocrine adverse events (irAEs) in patients treated with nivolumab for advanced NSCLC. METHODS: In a prospective study, 73 patients with previously treated advanced NSCLC received nivolumab in monotherapy. Blood samples were collected at each cycle to monitor thyroid autoimmunity, thyroid, adrenal and somatotroph axes, while thyroid morphology was evaluated by ultrasonography. RESULTS: An impaired thyroid function was recorded in 23.4% of patients (n = 15). Eight patients developed asymptomatic transient thyrotoxicosis (ATT) evolving to hypothyroidism in 50% of cases. In addition, seven patients developed overt hypothyroidism without ATT and with negative autoantibodies. Patients who developed hypothyroidism proved to have better overall survival (OS) as compared with non-developers at both univariate (p = 0.021) and multivariate analyses (p = 0.023). The survival curve of patients with reduced IGF-I at baseline, or displaying its reduction during the follow-up, showed significantly reduced median survival compared to patients with normal/high IGF-I levels (p = 0.031). CONCLUSIONS: Thyroid function abnormalities are the major irAEs in patients treated with nivolumab, and hypothyroidism onset is associated with prolonged survival. Our findings indicate that the development of hypothyroidism is a positive predictive biomarker of nivolumab antitumor efficacy in patients with NSCLC. Low IGF-I levels could represent a negative prognostic factor during nivolumab therapy.

Stable Operation of a Free-Electron Laser Driven by a Plasma Accelerator.

The breakthrough provided by plasma-based accelerators enabled unprecedented accelerating fields by boosting electron beams to gigaelectronvolt energies within a few centimeters [1-4]. This, in turn, allows the realization of ultracompact light sources based on free-electron lasers (FELs) [5], as demonstrated by two pioneering experiments that reported the observation of self-amplified spontaneous emission (SASE) driven by plasma-accelerated beams [6,7]. However, the lack of stability and reproducibility due to the intrinsic nature of the SASE process (whose amplification starts from the shot noise of the electron beam) may hinder their effective implementation for user purposes. Here, we report a proof-of-principle experiment using plasma-accelerated beams to generate stable and reproducible FEL light seeded by an external laser. FEL radiation is emitted in the infrared range, showing the typical exponential growth of its energy over six consecutive undulators. Compared to SASE, the seeded FEL pulses have energies 2 orders of magnitude larger and stability that is 3 times higher.

Time-resolved study of nonlinear photoemission in radio-frequency photoinjectors.

Photoemission is one of the fundamental processes that describes the generation of charged particles from materials irradiated by photons. The continuous progress in the development of ultrashort lasers allows investigation into the dynamics of the process at the femtosecond timescale. Here we report about experimental measurements using two ultrashort ultraviolet laser pulses to temporally probe the electrons release from a copper cathode in a radio-frequency photoinjector. By changing their relative delay, we studied how the release mechanism is affected by two-photon photoemission when tens of GW/cm2 intensities are employed. We evaluated the limits it poses on the achievable beam brightness and analyzed the resulting emission yield in terms of the electronic temperature by modeling the cathode as a two-temperature system.

PRRT: identikit of the perfect patient.

Peptide receptor radionuclide therapy (PRRT) has been strengthened since the publication of NETTER-1. Nevertheless, the correct positioning in the therapeutic algorithm is debated, and no optimal sequence has yet been standardized. Possible criteria to predict the response to PRRT in neuroendocrine tumors (NET) have been proposed. The aim of this review is to define the perfect identity of the eligible patient who can mostly benefit from this therapy. Possible predictive criteria which have been analysed were: primary tumor site, grading, tumor burden, FDG PET and 68Ga-PET uptake. Primary tumor site and 68Ga-PET uptake do not play a pivotal role in predicting the response, while tumor burden, FDG PET uptake and grading seem to represent predictive/prognostic factors for response to PRRT. The heterogeneity in trial designs, patient populations, type of radionuclides, previous therapies and measurement of outcomes, inevitably limits the strength of our conclusions, therefore care must be taken in applying these results to clinical practice. In conclusion, the perfect patient, selected by 68Ga-PET uptake, will likely have a relatively limited liver tumor burden, a ki67 index <20% and will respond to PRRT irrespective to primary tumor. Nevertheless, we have mostly prognostic than predictive factors to predict the efficacy of PRRT in individual patients, while a promising tool could be the NETest. However, to date, the identikit of the perfect patient for PRRT is a puzzle without some pieces and still we cannot disregard a multidisciplinary discussion of the individual case to select the patients who will mostly benefit from PRRT.

Longitudinal Phase-Space Manipulation with Beam-Driven Plasma Wakefields.

The development of compact accelerator facilities providing high-brightness beams is one of the most challenging tasks in the field of next-generation compact and cost affordable particle accelerators, to be used in many fields for industrial, medical, and research applications. The ability to shape the beam longitudinal phase space, in particular, plays a key role in achieving high-peak brightness. Here we present a new approach that allows us to tune the longitudinal phase space of a high-brightness beam by means of plasma wakefields. The electron beam passing through the plasma drives large wakefields that are used to manipulate the time-energy correlation of particles along the beam itself. We experimentally demonstrate that such a solution is highly tunable by simply adjusting the density of the plasma and can be used to imprint or remove any correlation onto the beam. This is a fundamental requirement when dealing with largely time-energy correlated beams coming from future plasma accelerators.

Acceleration and focusing of relativistic electron beams in a compact plasma device.

Plasma wakefield acceleration represented a breakthrough in the field of particle accelerators by pushing beams to gigaelectronvolt energies within centimeter distances. The large electric fields excited by a driver pulse in the plasma can efficiently accelerate a trailing witness bunch paving the way toward the realization of laboratory-scale applications like free-electron lasers. However, while the accelerator size is tremendously reduced, upstream and downstream of it the beams are still handled with conventional magnetic optics with sizable footprints and rather long focal lengths. Here we show the operation of a compact device that integrates two active-plasma lenses with short focal lengths to assist the plasma accelerator stage. We demonstrate the focusing and energy gain of a witness bunch whose phase space is completely characterized in terms of energy and emittance. These results represent an important step toward the accelerator miniaturization and the development of next-generation table-top machines.

Possible protective role of metformin therapy on colonic polyps in acromegaly: an exploratory cross-sectional study.

CONTEXT: Colonic polyps occur in 30-40% of acromegalic patients, increasing the risk of colon carcinoma. Although debated, there is emerging evidence that metformin may play a protective role in diabetic and non-diabetic patients with colonic polyps and its use in chemoprevention is currently explored. OBJECTIVE: Evaluate the prevalence of colonic polyps in acromegalic patients treated or not with metformin and explore its possible protective role. DESIGN: Exploratory cross-sectional study in two tertiary Italian referral centres. MET: hods: Out of 153 acromegalic patients, we selected 58 patients (36-82 years; f: 33) who had at least one colonoscopy performed within the first 2 years of diagnosis. Presence of colonic polyps/cancer and related risk factors, current metformin and acetylsalicylic acid intake, disease duration, therapies for acromegaly, hormonal and metabolic parameters were assessed. RESULTS: An overall prevalence of 36% polyps was found. Based on the presence of polyps, we identified two groups, comparable for age, BMI, disease duration, glucose, insulin, HOMA-IR, HbA1c, GH and IGF-I levels. Of the patients with polyps (including three adenocarcinomas) only 24% were treated with metformin vs 57% of patients without polyps. Multivariate analysis confirmed a significant negative association between colonic polyps and metformin intake (OR: 0.22, 95% CI: 0.06-0.77, P = 0.01), whereas no significant association was found between polyps and age (P = 0.10), overweight/obesity (P = 0.54), smoking (P = 0.15), acetylsalicylic acid intake (P = 0.99), disease duration (P = 0.96), somatostatin analogues treatment (P = 0.70). CONCLUSIONS: These findings, though deriving from an exploratory study, could suggest a protective role of metformin on the development of colonic polyps in acromegaly, and need to be confirmed in an extended study population.

Second primary neoplasms in patients with lung and gastroenteropancreatic neuroendocrine neoplasms: Data from a retrospective multi-centric study.

BACKGROUND: Patients with sporadic neuroendocrine neoplasms may exhibit a higher risk of a second primary tumor than the general population. AIM: This study aimed to analyze the occurrence of second primary malignancies. METHODS: A retrospective cohort of 2757 patients with sporadic lung and gastro-entero-pancreatic neuroendocrine neoplasms, managed at eight Italian tertiary referral Centers, was included. RESULTS: Between 2000 and 2019, a second primary malignancy was observed in 271 (9.8%) neuroendocrine neoplasms patients with 32 developing a third tumor. There were 135 (49.8%) females and the median age was 64 years. The most frequent locations of the second tumors were breast (18.8%), prostate (12.5%), colon (9.6%), blood tumors (8.5%), and lung (7.7%). The second primary tumor was synchronous in 19.2% of cases, metachronous in 43.2%, and previous in 37.6%. As concerned the neuroendocrine neoplasms, the 5- and 10-year survival rates were 87.8% and 74.4%, respectively. PFS for patients with a second primary malignancy was shorter than for patients without a second primary malignancy. Death was mainly related to neuroendocrine neoplasms. CONCLUSION: In NEN patients the prevalence of second primary malignancies was not negligible, suggesting a possible neoplastic susceptibility. Overall survival was not affected by the occurrence of a second primary malignancy.

A case of severe vestibular root angulation.

In this article, we describe the appearance and management of an impacted permanent tooth with severe vestibular root angulation. In addition, the possible origin of this type of root malformation as well as some of their epidemiologic aspects are discussed.