Frequency-Dependent Squeezed Vacuum Source for the Advanced Virgo Gravitational-Wave Detector.

In this Letter, we present the design and performance of the frequency-dependent squeezed vacuum source that will be used for the broadband quantum noise reduction of the Advanced Virgo Plus gravitational-wave detector in the upcoming observation run. The frequency-dependent squeezed field is generated by a phase rotation of a frequency-independent squeezed state through a 285 m long, high-finesse, near-detuned optical resonator. With about 8.5 dB of generated squeezing, up to 5.6 dB of quantum noise suppression has been measured at high frequency while close to the filter cavity resonance frequency, the intracavity losses limit this value to about 2 dB. Frequency-dependent squeezing is produced with a rotation frequency stability of about 6 Hz rms, which is maintained over the long term. The achieved results fulfill the frequency dependent squeezed vacuum source requirements for Advanced Virgo Plus. With the current squeezing source, considering also the estimated squeezing degradation induced by the interferometer, we expect a reduction of the quantum shot noise and radiation pressure noise of up to 4.5 dB and 2 dB, respectively.

Are there country-specific differences in the use of pegvisomant for acromegaly in clinical practice? An analysis from ACROSTUDY.

OBJECTIVE: A comprehensive picture of pegvisomant use for treating acromegaly in routine clinical practice in different countries is lacking. We aimed, therefore, to document country-specific behaviors in real-life pegvisomant use, and the main safety and effectiveness outcomes in the ACROSTUDY. DESIGN: ACROSTUDY is an open-label, non-interventional, post-marketing safety surveillance study. METHODS: A descriptive analysis was performed using data from the six top-recruiter ACROSTUDY countries, i.e., Germany (n = 548 patients), Italy (n = 466), France (n = 312), USA (n = 207), Spain (n = 200) and the Netherlands (n = 175). These nations accounted for > 85% of the ACROSTUDY cases. RESULTS: The mean pegvisomant dose at treatment start was lowest in the Netherlands (9.4 mg/day), whereas it ranged between 10.9 and 12.6 mg/day in the other countries. At year 5, the mean pegvisomant dose was around 15 mg/day in all countries, except France (18.1 mg/day). At starting pegvisomant, patients treated with monotherapy ranged between 15% in the Netherlands and 72% in Spain. Monotherapy remained lowest over time in the Netherlands. In all countries, the percentage of patients with normal IGF-1 increased steeply from < 20% at baseline to 43-58% at month 6 and 51-67% at year 1. After that, we observed minor changes in the rate of acromegaly control in all countries. The Netherlands peaked in disease control at year 2 (72%). The proportion of patients reporting changes in pituitary tumor size was generally low. Serious treatment-related adverse events were < 5% in all countries. CONCLUSIONS: Our study provided a detailed summary of real-life use of pegvisomant in the six top-recruiter ACROSTUDY nations.

Giant mesenteric fibromatosis associated with non-Hodgkin lymphoma. A case report and literature review.

BACKGROUND: Mesenteric fibromatosis is a benign locally-aggressive mesenchymal neoplasm that lacks the potential for metastasis. It is related to Gardner's Syndrome, previous trauma, abdominal surgery, and prolonged intake of oestrogen. Differentially diagnosing this from similar tumours is crucial in order for establishing the appropriate treatment and only immunohistochemical features can be used for a definitive diagnosis. Although medical therapies play a role in the treatment of mesenteric fibromatosis, surgical resection is the gold-standard procedure. METHODS: Our case study is a 40-year-old male with a concomitant diagnosis of non-Hodgkin lymphoma and mesenteric fibromatosis, not associated with any of the risk factors mentioned above. We performed CT and PET scans and observed a vascularised and well-defined mesenteric centre-abdominal hypermetabolic solid mass in contact with the gastric body, duodenum, body and tail of the pancreas, transverse colon, and spleen. An ultrasound-guided tru-cut biopsy revealed features suggestive of mesenteric fibromatosis. RESULTS: An elective laparotomy was carried out and a giant mass, arising from mesentery, was excised, including a partial gastrectomy and segmental resection of the transverse colon. Distal pancreatectomy, small bowel resection and successive splenectomy were performed due to a large hypertensive component. The postoperative period was uneventful. The histopathology of the surgical pieces was compatible with intra-abdominal desmoid fibromatosis. CONCLUSION: As far as we know from the literature, this is the largest mesenteric fibromatosis tumour ever to be excised. We also noticed that this is the first reported case of the concomitant presence of mesenteric fibromatosis and non-Hodgkin lymphoma that is not related to any of the described risk factors. Further research is needed to establish what type of association this presentation may indicate.

Expected and paradoxical effects of obesity on cancer treatment response.

Obesity, whose prevalence is pandemic and continuing to increase, is a major preventable and modifiable risk factor for diabetes and cardiovascular diseases, as well as for cancer. Furthermore, epidemiological studies have shown that obesity is a negative independent prognostic factor for several oncological outcomes, including overall and cancer-specific survival, for several site-specific cancers as well as for all cancers combined. Yet, a recently growing body of evidence suggests that sometimes overweight and obesity may associate with better outcomes, and that immunotherapy may show improved response among obese patients compared with patients with a normal weight. The so-called 'obesity paradox' has been reported in several advanced cancer as well as in other diseases, albeit the mechanisms behind this unexpected relationship are still not clear. Aim of this review is to explore the expected as well as the paradoxical relationship between obesity and cancer prognosis, with a particular emphasis on the effects of cancer therapies in obese people.

Globus pallidus internus activity during simultaneous bilateral microelectrode recordings in status dystonicus.

Limited data are available regarding the electrophysiology of status dystonicus (SD). We report simultaneous microelectrode recordings (MERs) from the globus pallidus internus (GPi) of a patient with SD who was treated with bilateral deep brain stimulation (DBS). Mean neuronal discharge rate was of 30.1 ± 10.9 Hz and 38.5 Hz ± 11.1 Hz for the right and left GPi, respectively. On the right side, neuronal electrical activity was completely abolished at the target point, whereas the mean burst index values showed a predominance of bursting and irregular activity along trajectories on both sides. Our data are in line with previous findings of pallidal irregular hypoactivity as a potential electrophysiological marker of dystonia and thus SD, but further electrophysiological studies are needed to confirm our results.

The DNA damage response pathway as a land of therapeutic opportunities for colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) represents a major cause of cancer deaths worldwide. Although significant progress has been made by molecular and immune therapeutic approaches, prognosis of advanced stage disease is still dismal. Alterations in the DNA damage response (DDR) pathways are emerging as novel targets for treatment across different cancer types. However, even though preclinical studies have shown the potential exploitation of DDR alterations in CRC, systematic and comprehensive testing is lagging and clinical development is based on analogies with other solid tumors according to a tissue-agnostic paradigm. Recently, functional evidence from patient-derived xenografts and organoids have suggested that maintenance with PARP inhibitors might represent a therapeutic opportunity in CRC patients previously responsive to platinum-based treatment. DESIGN AND RESULTS: In this review, we highlight the most promising preclinical data and systematically summarize published clinical trials in which DDR inhibitors have been used for CRC and provide evidence that disappointing results have been mainly due to a lack of clinical and molecular selection. CONCLUSIONS: Future preclinical and translational research will help in better understanding the role of DDR alterations in CRC and pave the way to novel strategies that might have a transformative impact on treatment by identifying new therapeutic options including tailored use of standard chemotherapy.

Deer keds on wild ungulates in northern Italy, with a taxonomic key for the identification of Lipoptena spp. of Europe.

Deer keds (Lipoptena spp.) are blood-sucking ectoparasites of domestic and wild animals, and also accidentally of humans. In Europe, five Lipoptena spp. have been recorded, although the lack of specific taxonomic keys has often led to mistaken identification or to missing data. The present study aimed to develop an identification key of the European species and also to identify Lipoptena spp. found on wild ungulates in northern Italy. In total, 390 hippoboscids were collected from Rupicapra rupicapra, Capreolus capreolus, Cervus elaphus and Ovis aries musimon in an Alpine area of Italy. After morphological identification, 140 specimens were subjected to phylogenetic analysis based on mitochondrial (CO1) and nuclear (CAD) gene sequences. Despite the expected presence of slight morphological variations, all specimens examined were identified both microscopically and molecularly as Lipoptena cervi (100% identity for both CO1 and CAD genes). The massive increase in wild ungulate populations can favour the possibility of detecting other species of Lipoptena. The identification keys proposed in the present study may help with monitoring the presence of Lipoptena species, particularly in European countries where this ectoparasite is neglected and for which various data (from diffusion to control methods) are still missing.

Quasi-thresholdless Photon Upconversion in Metal-Organic Framework Nanocrystals.

Photon upconversion based on sensitized triplet-triplet annihilation ( sTTA) is considered as a promising strategy for the development of light-managing materials aimed to enhance the performance of solar devices by recovering unused low-energy photons. Here, we demonstrate that, thanks to the fast diffusion of excitons, the creation of triplet pairs in metal-organic framework nanocrystals ( nMOFs) with size smaller than the exciton diffusion length implies a 100% TTA yield regardless of the illumination condition. This makes each nMOF a thresholdless, single-unit annihilator. We develop a kinetic model for describing the upconversion dynamics in a nanocrystals ensemble, which allows us to define the threshold excitation intensity  Ithbox required to reach the maximum conversion yield. For materials based on thresholdless annihilators, Ithbox is determined by the statistical distribution of the excitation energy among nanocrystals. The model is validated by fabricating a nanocomposite material based on nMOFs, which shows efficient upconversion under a few percent of solar irradiance, matching the requirements of real life solar technologies. The statistical analysis reproduces the experimental findings, and represents a general tool for predicting the optimal compromise between dimensions and concentration of nMOFs with a given crystalline structure that minimizes the irradiance at which the system starts to fully operate.

Lateral ankle ligament anatomic reconstruction for chronic ankle instability: Allograft or autograft? A systematic review.

BACKGROUND: To investigate if there is any evidence in favour of autograft or allograft use for anatomic reconstruction of lateral ankle ligaments in patients with symptomatic chronic ankle instability. METHODS: A literature search was performed in PubMed MEDLINE, Cochrane Library, EMBASE and Google Scholar databases, over the years 1994-2017, to identify the studies presenting clinical results of anatomic lateral ankle ligaments reconstruction using various combinations of the keywords "lateral ankle ligaments reconstruction", "anatomic reconstruction", "chronic ankle instability", "allograft", "autograft". The surgical procedure was considered anatomic if consistent with the description of lateral ankle ligaments made by Burks and Morgan in 1994. RESULTS: Among the 89 papers matching the search terms, only 12 could be included in which 357 anatomic lateral ankle ligaments reconstructions were performed. One was a comparative case series (level of evidence III - LOE III) while other papers were retrospective case series (LOE IV), the mean Modified Coleman Methodology Score (MCMS) was fair: 56.7 (SD±5.2). Due to the low level of evidence of the available literature only a qualitative analysis was performed. The limited evidence from the studies analysed suggests that there is no difference in graft survivorship, graft-dependent variables, patient's satisfaction, clinical outcome measures and radiographic results between allograft and autograft. CONCLUSIONS: Given the low number of studies, their poor methodology score and their low level of evidence it is not possible to determine if allograft is better or safer than autograft. LEVEL OF EVIDENCE: Level IV, review paper of level III and level IV studies.

Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer.

The tropomyosin receptor kinase (TRK) family of receptor tyrosine kinases are encoded by NTRK genes and have a role in the development and normal functioning of the nervous system. Since the discovery of an oncogenic NTRK gene fusion in colorectal cancer in 1986, over 80 different fusion partner genes have been identified in a wide array of adult and paediatric tumours, providing actionable targets for targeted therapy. This review describes the normal function and physiology of TRK receptors and the biology behind NTRK gene fusions and how they act as oncogenic drivers in cancer. Finally, an overview of the incidence and prevalence of NTRK gene fusions in various types of cancers is discussed.

Quantum Spin Ice Dynamics in the Dipole-Octupole Pyrochlore Magnet Ce_{2}Zr_{2}O_{7}.

Neutron scattering measurements on the pyrochlore magnet Ce_{2}Zr_{2}O_{7} reveal an unusual crystal field splitting of its lowest J=5/2 multiplet, such that its ground-state doublet is composed of m_{J}=±3/2, giving these doublets a dipole-octupole (DO) character with local Ising anisotropy. Its magnetic susceptibility shows weak antiferromagnetic correlations with θ_{CW}=-0.4(2) K, leading to a naive expectation of an all-in, all-out ordered state at low temperatures. Instead, our low-energy inelastic neutron scattering measurements show a dynamic quantum spin ice state, with suppressed scattering near |Q|=0, and no long-range order at low temperatures. This is consistent with recent theory predicting symmetry-enriched U(1) quantum spin liquids for such DO doublets decorating the pyrochlore lattice. Finally, we show that disorder, especially oxidation of powder samples, is important in Ce_{2}Zr_{2}O_{7} and could play an important role in the low-temperature behavior of this material.

Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer.

Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors is driven by amplification or mutation of HER2. This paper reviews the role of HER2 amplification as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type. While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established. Indeed, independent studies documented substantial clinical benefit in patients treated with biomarker-driven HER2-targeted therapies, with an impact on response rates and duration of response that compared favorably with immunotherapy and other examples of precision oncology. HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of metastatic CRC patients.

Dynamic molecular analysis and clinical correlates of tumor evolution within a phase II trial of panitumumab-based therapy in metastatic colorectal cancer.

Background: Mutations in rat sarcoma (RAS) genes may be a mechanism of secondary resistance in epidermal growth factor receptor inhibitor-treated patients. Tumor-tissue biopsy testing has been the standard for evaluating mutational status; however, plasma testing of cell-free DNA has been shown to be a more sensitive method for detecting clonal evolution. Materials and methods: Archival pre- and post-treatment tumor biopsy samples from a phase II study of panitumumab in combination with irinotecan in patients with metastatic colorectal cancer (mCRC) that also collected plasma samples before, during, and after treatment were analyzed for emergence of mutations during/post-treatment by next-generation sequencing and BEAMing. Results: The rate of emergence of tumor tissue RAS mutations was 9.5% by next-generation sequencing (n = 21) and 6.3% by BEAMing (n = 16). Plasma testing of cell-free DNA by BEAMing revealed a mutant RAS emergence rate of 36.7% (n = 39). Exploratory outcomes analysis of plasma samples indicated that patients who had emergent RAS mutations at progression had similar median progression-free survival to those patients who remained wild-type at progression. Serial analysis of plasma samples showed that the first detected emergence of RAS mutations preceded progression by a median of 3.6 months (range, -0.3 to 7.5 months) and that there did not appear to be a mutant RAS allele frequency threshold that could predict near-term outcomes. Conclusions: This first prospective analysis in mCRC showed that serial plasma biopsies are more inclusive than tissue biopsies for evaluating global tumor heterogeneity; however, the clinical utility of plasma testing in mCRC remains to be further explored. ClinicalTrials.gov Identifier: NCT00891930.

Diagnostic relevance of IgE sensitization profiles to eight recombinant Phleum pratense molecules.

BACKGROUND: Grass pollen-related seasonal allergic rhinoconjunctivitis (SARg) is clinically heterogeneous in severity, comorbidities, and response to treatment. The component-resolved diagnostics disclosed also a high heterogeneity at molecular level. Our study aimed at analyzing the characteristics of the IgE sensitization to Phleum pratense molecules and investigating the diagnostic relevance of such molecules in childhood. METHODS: We examined 1120 children (age 4-18 years) with SARg. Standardized questionnaires on atopy were acquired through informatics platform (AllergyCARD™). Skin prick tests were performed with pollen extracts. Serum IgE to airborne allergens and eight P. pratense molecules (rPhl p 1, rPhl p 2, rPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11, rPhl p 12) were tested by ImmunoCAP FEIA. RESULTS: The analysis of IgE responses against eight P. pratense molecules showed 87 profiles. According to the number of molecules recognized by IgE, the more complex profiles were characterized by higher serum total IgE, higher grass-specific serum IgE, and higher number and degree of sensitization to pollens. The most frequent IgE sensitization profile was the monomolecular Phl p 1. Sensitization to Phl p 7 was a reliable biomarker of asthma, whereas Phl p 12 of oral allergy syndrome. Sensitization to Phl p 7 was associated with a higher severity of SARg, and complex profiles were associated with longer disease duration. CONCLUSIONS: In a large pediatric population, the complexity of IgE sensitization profiles against P. pratense molecules is related to high atopic features although useless for predicting the clinical severity. The detection of serum IgE to Phl p 1, Phl p 7, and Phl p 12 can be used as clinical biomarkers of SARg and comorbidities. Further studies in different areas are required to test the impact of different IgE molecular profiles on AIT response.

What is the prognostic impact of FDG PET in locally advanced head and neck squamous cell carcinoma treated with concomitant chemo-radiotherapy? A systematic review and meta-analysis.

PURPOSE: Evidence is conflicting on the prognostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in head and neck squamous cell carcinoma. The aim of our study was to determine the impact of semiquantitative and qualitative metabolic parameters on the outcome in patients managed with standard treatment for locally advanced disease. METHODS: A systematic review of the literature was conducted. A meta-analysis was performed of studies providing estimates of relative risk (RR) for the association between semiquantitative metabolic parameters and efficacy outcome measures. RESULTS: The analysis included 25 studies, for a total of 2,223 subjects. The most frequent primary tumour site was the oropharynx (1,150/2,223 patients, 51.7%). According to the available data, the majority of patients had stage III/IV disease (1,709/1,799, 94.9%; no information available in four studies) and were treated with standard concurrent chemoradiotherapy (1,562/2,009 patients, 77.7%; only one study without available information). A total of 11, 8 and 4 independent studies provided RR estimates for the association between baseline FDG PET metrics and overall survival (OS), progression-free survival (PFS) and locoregional control (LRC), respectively. High pretreatment metabolic tumour volume (MTV) was significantly associated with a worse OS (summary RR 1.86, 95% CI 1.08-3.21), PFS (summary RR 1.81, 95% CI 1.14-2.89) and LRC (summary RR 3.49, 95% CI 1.65-7.35). Given the large heterogeneity (I2 > 50%) affecting the summary measures, no cumulative threshold for an unfavourable prognosis could be defined. No statistically significant association was found between SUVmax and any of the outcome measures. CONCLUSION: FDG PET has prognostic relevance in the context of locally advanced head and neck squamous cell carcinoma. Pretreatment MTV is the only metabolic variable with a significant impact on patient outcome. Because of the heterogeneity and the lack of standardized methodology, no definitive conclusions on optimal cut-off values can be drawn.

How to improve effectiveness of pegvisomant treatment in acromegalic patients.

PURPOSE: Pegvisomant (PEGV) treatment in acromegaly patients resistant to somatostatin analogues is less effective in the real life than in clinical trials. This is a multicenter, observational, retrospective, longitudinal study. The aim was to detect characteristics which improve long-term PEGV effectiveness. METHODS: 87 acromegalic patients treated with PEGV have been enrolled in seven referral Italian centres. PEGV was administered for up to 4 years, at doses up titrated until IGF-1 normalization or to ≥ 30 mg/day. The rate of patients who reached IGF-1 normalization at last visit has been calculated. RESULTS: IGF-1 was normalized in 75.9% of patients after 1 year and in 89.6% at last visit. Disease control was associated with lower baseline GH, IGF-1 and IGF-1 xULN and was more frequent when baseline IGF-1 was < 2.7 × ULN (p < 0.02). PEGV dose was dependent on baseline IGF-1 > 2.7 × ULN (p < 0.05) and doses > 1.0 mg/BMI/day were administered more frequently when baseline IGF-1 was > 2.0 × ULN (p = 0.03). PEGV resistance was associated with higher BMI (p = 0.006) and was more frequent when BMI was > 30 kg/m2 (p = 0.07). There were no significant differences between patients treated with monotherapy or combined treatment. IGF-1 normalization, PEGV dose and rate of associated treatment were similar between males and females. PEGV effectiveness was independent from previous management. Diabetic patients needed higher doses of PEGV than non-diabetic ones. CONCLUSIONS: PEGV effectiveness improves when up titration is appropriate. Higher PEGV doses at start and a more rapid up-titration are necessary in patients with obesity and/or IGF-1 > 2.7 × ULN.

Lipid-lowering therapy of everolimus-related severe hypertriglyceridaemia in a pancreatic neuroendocrine tumour (pNET).

WHAT IS KNOWN AND OBJECTIVE: Hypertriglyceridaemia (HTG) is a potentially serious side effect of everolimus therapy. We here report a case of severe HTG in an everolimus-treated patient and provide recommendations for its management. CASE SUMMARY: The patient was a 70-year-old woman, being treated with everolimus for a pancreatic neuroendocrine tumour (pNET). She developed severe HTG to a maximum of 969 mg/dL after 22 months of therapy. Treatment with fenofibrate rapidly normalized triglyceride (TG) levels. WHAT IS NEW AND CONCLUSION: Severe HTG may occur in everolimus-treated patients. Prescription of the appropriate therapy can allow patients to continue this medication.

Prospective multicentre study on barbed reposition pharyngoplasty standing alone or as a part of multilevel surgery for sleep apnoea.

OBJECTIVES: The aim of this study was to demonstrate in a prospective multicentre study that Barbed Reposition Pharyngoplasty (BRP) procedure is safe and effective in management of obstructive sleep apnoea/hypopnea syndrome (OSAHS) patients. DESIGN: Prospective study. SETTING: Multicentre study. PARTICIPANTS: Patients suffering from obstructive sleep apnoea. MAIN OUTCOMES MEASURES: Values of postoperative apnoea-hypopnea index (AHI), oxygen desaturation index (ODI), epworth sleepiness scale (ESS). RESULTS: 111 Barbed Reposition Pharyngoplasty procedures standing alone or as a part of multilevel surgery for OSAHS, performed between January and September 2016, were analysed in 15 different centres. The average hospitalisation period was 2.5 ± 0.5 days. The mean patient age was 46.3 ± 10.5 years. The average body mass index at the time of the procedure was 27.9 ± 3.2, and the majority of the patients were men (83%). The mean preoperative and postoperative apnoea/hypopnea index was 33.4 ± 19.5 and 13.5 ± 10.3, respectively (P < .001). The mean preoperative and postoperative ESS score was 10.2 ± 4.5 and 6.1 ± 3.6, respectively (P < .001). The mean preoperative and postoperative ODI were 29.6 ± 20.7 and 12.7 ± 10.8, respectively (P < .001). CONCLUSIONS: Patients undergoing BRP standing alone or as part of a multilevel approach for the treatment of OSAHS have a reasonable expectation for success with minimal morbidity.

Distal Akin osteotomy for hallux valgus interphalangeus.

BACKGROUND: The aim of this study was to assess clinical and radiological outcomes in patients who underwent distal Akin osteotomy for hallux valgus interphalangeus (HVI). METHODS: A series of 15 consecutive patients (17 feet) was retrospectively reviewed. All the patients were preoperatively and post-operatively evaluated with a physical and radiographic assessment (HVI angle). Satisfaction has been assessed through a satisfaction survey, the scale used consisted in three possible choice: very satisfied, satisfied, not satisfied. RESULTS: Among 15 patients the 52.9% (9 patients) stated to be "very satisfied", the 41.2% (7 patients) "satisfied" and just a 5.9% (one patient) was "not satisfied". The mean HVI value decreased from 24.9°±7.8° preoperatively to 13.1°±5.8° postoperatively at last follow up (p<0.05). CONCLUSIONS: Based on these findings we can conclude that the distal Akin osteotomy can be considered safe and effective in the surgical correction of symptomatic HVI deformities.

Tracking a CAD-ALK gene rearrangement in urine and blood of a colorectal cancer patient treated with an ALK inhibitor.

BACKGROUND: Monitoring response and resistance to kinase inhibitors is essential to precision cancer medicine, and is usually investigated by molecular profiling of a tissue biopsy obtained at progression. However, tumor heterogeneity and tissue sampling bias limit the effectiveness of this strategy. In addition, tissue biopsies are not always feasible and are associated with risks due to the invasiveness of the procedure. To overcome these limitations, blood-based liquid biopsy analysis has proven effective to non-invasively follow tumor clonal evolution. PATIENTS AND METHODS: We exploited urine cell-free, trans-renal DNA (tr-DNA) and matched plasma circulating tumor DNA (ctDNA) to monitor a metastatic colorectal cancer patient carrying a CAD-ALK translocation during treatment with an ALK inhibitor. RESULTS: Using a custom next generation sequencing panel we identified the genomic CAD-ALK rearrangement and a TP53 mutation in plasma ctDNA. Sensitive assays were developed to detect both alterations in urine tr-DNA. The dynamics of the CAD-ALK rearrangement in plasma and urine were concordant and paralleled the patient's clinical course. Detection of the CAD-ALK gene fusion in urine tr-DNA anticipated radiological confirmation of disease progression. Analysis of plasma ctDNA identified ALK kinase mutations that emerged during treatment with the ALK inhibitor entrectinib. CONCLUSION: We find that urine-based genetic testing allows tracing of tumor-specific oncogenic rearrangements. This strategy could be effectively applied to non-invasively monitor tumor evolution during therapy. The same approach could be exploited to monitor minimal residual disease after surgery with curative intent in patients whose tumors carry gene fusions. The latter could be implemented without the need of patient hospitalization since urine tr-DNA can be self-collected, is stable over time and can be shipped at specified time-points to central labs for testing.