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Carlos Camps Herrero,1 Antonio Antón Torres,2 Juan Jesús Cruz-Hernández,3 Alfredo Carrato,4 Manuel Constenla,5 Eduardo Díaz-Rubio,6 Margarita Feyjoo Saus,7 Jesus Garcia-Foncillas,8 Pere Gascón,9 Vicente Guillem101Jefe de Servicio de Oncología Médica, Consorcio Hospital General Universitario, Valencia, Spain; 2Jefe del Servicio de Oncología Médica, Hospital Universitario Miguel Servet, Zaragoza, Spain; 3Jefe del Servicio de Oncología Médica, Hospital Universitario De Salamanca-IBSAL, Salamanca, Spain; 4Jefe del Servicio de Oncología Médica, Hospital Universitario Ramón y Cajal, Madrid, Spain; 5Jefe de Servicio de Oncología, Complejo Hospitalario Universitario de Pontevedra, Pontevedra, Spain; 6Jefe del Servicio de Oncología Médica, Hospital Universitario Clínico San Carlos, Madrid, Spain; 7Jefe del Servicio de Oncología Médica, Hospital La Moraleja, Madrid, Spain; 8Jefe de Servicio de Oncología Médica, Hospital Universitario “Fundación Jiménez Díaz”, Madrid, Spain; 9Jefe del Servicio de Oncología Médica, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, Spain; 10Jefe del Servicio de Oncología Médica, Instituto Valenciano de Oncología, Valencia, SpainPurpose: There is a lack of standards for the diagnosis, assessment and management of breakthrough cancer pain (BTcP). La Fundación ECO (the Foundation for Excellence and Quality in Oncology) commissioned a study to establish a consensus and lay the foundations for the appropriate management of BTcP in oncology patients.Patients and methods: A modified Delphi survey comprising two rounds was used to gather and analyze data, which was conducted over the Internet. Each statement that reached a consensus with the respondents was defined as a median consensus score (MED) of ≥7, and agreement among panelists as an interquartile range (IQR) of ≤3.Results: In total, 69 medical oncologists responded, with a broad consensus that BTcP implied exacerbations of high-intensity pain, as opposed to moderate pain. Furthermore, they concurred that appropriate diagnostic equipment is needed, and that rapid-onset fentanyl formulations should be the preferred treatment for BTcP management. The panelists agreed that a lack of appropriate information and training to attend to patients, as well as limited patient visitation rights, were barriers to effective BTcP management. Regarding gaps in detected knowledge, the panelists were unsure of the measures necessary to assess the burden of the disease on the patient’s quality of life and associated medication costs. Alongside this, there was a lack of awareness of the technical specifics of the different formulations of rapid-onset fentanyl.Conclusion: These results represent the current status of BTcP management. They may inform recommendations and provide a framework for future research.Keywords: breakthrough pain, rapid-onset opioids, fentanyl, medical oncology, pain management

BackgroundTalimogene laherparepvec (T-VEC), a first-in-class oncolytic viral immunotherapy, enhances tumor-specific immune activation. T-VEC combined with atezolizumab, which blocks inhibitor T-cell checkpoints, could provide greater benefit than either agent alone. Safety/efficacy of the combination was explored in patients with triple negative breast cancer (TNBC) or colorectal cancer (CRC) with liver metastases.MethodsIn this phase Ib, multicenter, open-label, parallel cohort study of adults with TNBC or CRC with liver metastases, T-VEC (106 then 108 PFU/ml; ≤4 ml) was administered into hepatic lesions via image-guided injection every 21 (±3) days. Atezolizumab 1200 mg was given on day 1 and every 21 (±3) days thereafter. Treatment continued until patients experienced dose-limiting toxicity (DLT), had complete response, progressive disease, needed alternative anticancer treatment, or withdrew due to an adverse event (AE). The primary endpoint was DLT incidence, and secondary endpoints included efficacy and AEs.ResultsBetween 19 March 2018 and 6 November 2020, 11 patients with TNBC were enrolled (safety analysis set: n = 10); between 19 March 2018 and 16 October 2019, 25 patients with CRC were enrolled (safety analysis set: n = 24). For the 5 patients in the TNBC DLT analysis set, no patient had DLT; for the 18 patients in the CRC DLT analysis set, 3 (17%) had DLT, all serious AEs. AEs were reported by 9 (90%) TNBC and 23 (96%) CRC patients, the majority with grade ≥3 [TNBC, 7 (70%); CRC, 13 (54%)], and 1 was fatal [CRC, 1 (4%)]. Evidence of efficacy was limited. Overall response rate was 10% (95% confidence interval 0.3-44.5) for TNBC; one (10%) patient had a partial response. For CRC, no patients had a response; 14 (58%) were unassessable.ConclusionsThe safety profile reflected known risks with T-VEC including risks of intrahepatic injection; no unexpected safety findings from addition of atezolizumab to T-VEC were observed. Limited evidence of antitumor activity was observed.

A method for gamma/neutron event classification based on frequency-domain analysis for mixed radiation environments is proposed. In contrast to the traditional charge comparison method for pulse-shape discrimination, which requires baseline removal and pulse alignment, our method does not need any preprocessing of the digitized data, apart from removing saturated traces in sporadic pile-up scenarios. It also features the identification of neutron events in the detector’s full energy range with a single device, from thermal neutrons to fast neutrons, including low-energy pulses, and still provides a superior figure-of-merit for classification.The proposed frequency-domain analysis consists of computing the fast Fourier transform of a triggered trace and integrating it through a simplified version of the transform magnitude components that distinguish the neutron features from those of the gamma photons. Owing to this simplification, the proposed method may be easily ported to a real-time embedded deployment based on Field-Programmable Gate Arrays or Digital Signal Processors. We target an off-the-shelf detector based on a small CLYC (Cs2LiYCl6:Ce) crystal coupled to a silicon photomultiplier with an integrated bias and preamplifier, aiming at lightweight embedded mixed radiation monitors and dosimeter applications.

Abstract Background Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille’s heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking. Methods The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action. Results We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration. Conclusions Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.

Atomic-scale imaging using scanning probe microscopy is a pivotal method for investigating the morphology and physico-chemical properties of nanostructured surfaces. Time resolution represents a significant limitation of this technique, as typical image acquisition times are on the order of several seconds or even a few minutes, while dynamic processes—such as surface restructuring or particle sintering, to be observed upon external stimuli such as changes in gas atmosphere or electrochemical potential—often occur within timescales shorter than a second. In this article, we present a fully redesigned field programmable gate array (FPGA)-based instrument that can be integrated into most commercially available standard scanning probe microscopes. This instrument not only significantly accelerates the acquisition of atomic-scale images by orders of magnitude but also enables the tracking of moving features such as adatoms, vacancies, or clusters across the surface (“atom tracking”) due to the parallel execution of sophisticated control and acquisition algorithms and the fast exchange of data with an external processor. Each of these measurement modes requires a complex series of operations within the FPGA that are explained in detail.

Abstract Background Disinfection by-products in drinking water are chemical contaminants that have been associated with cancer and other adverse effects. Exposure occurs from consumption of tap water, inhalation and dermal absorption. Methods We determined the relationship between socioeconomic status and exposure to disinfection by-products in 1271 controls from a multicentric bladder cancer case-control study in Spain. Information on lifetime drinking water sources, swimming pool attendance, showering-bathing practices, and socioeconomic status (education, income) was collected through personal interviews. Results The most highly educated subjects consumed less tap water (57%) and more bottled water (33%) than illiterate subjects (69% and 17% respectively, p-value = 0.003). These differences became wider in recent time periods. The time spent bathing or showering was positively correlated with attained educational level (p < 0.001). Swimming pool attendance was more frequent among highly educated subjects compared to the illiterate (odds ratio = 3.4; 95% confidence interval 1.6-7.3). Conclusions The most highly educated subjects were less exposed to chlorination by-products through ingestion but more exposed through dermal contact and inhalation in pools and showers/baths. Health risk perceptions and economic capacity may affect patterns of water consumption that can result in differences in exposure to water contaminants.

Abstract Background The Int7G24A variant of transforming growth factor-beta receptor type I (TGFBR1) has been shown to increase the risk for kidney, ovarian, bladder, lung and breast cancers. Its role in colorectal cancer (CRC) has not been established. The aims of this study were to assess the association of TGFBR1*Int7G24A variant with CRC occurrence, patient age, gender, tumour location and stage. Methods We performed a case-control study with 504 cases of sporadic CRC; and 504 non-cancerous age, gender and ethnically matched controls. Genotyping analysis was performed using allelic discrimination assay by real time PCR. Results The Int7G24A variant was associated with increased CRC incidence in an additive model of inheritance (P for trend = 0.005). No significant differences were found between Int7G24A genotypes and tumour location or stage. Interestingly, the association of the Int7G24A variant with CRC risk was significant in men (odds ratio 4.10 with 95% confidence intervals 1.41-11.85 for homozygous individuals; P for trend = 0.00023), but not in women. We also observed an increase in susceptibility to CRC for individuals aged less than 70 years. Conclusion Our data suggest that the Int7G24A variant represents a risk factor for CRC in the male Spanish population.

Abstract Background TGF-β receptor type I is a mediator of growth inhibitory signals. TGFBR1*6A (rs11466445) is a common polymorphic variant of the TGF-β receptor I gene and has been associated with tumour susceptibility. Nevertheless, the role of this polymorphism as a risk factor for colorectal cancer is controversial. The aim of this study was to assess the association between TGFBR1*6A and colorectal cancer, age, sex, tumour location and tumour stage in a Spanish population. Methods The case-control study involved 800 Spanish subjects: 400 sporadic colorectal cancer patients and 400 age-, sex-, and ethnic-matched controls. The odds ratio (OR) and 95% confidence interval (95% CI) for the TGFBR1*6A polymorphism were calculated using unconditional logistic regression adjusted for age and sex. Analysis of somatic mutations at the GCG repeat of TGFBR1 exon 1 and germline allele-specific expression were also conducted to obtain further information on the contribution of the TGFBR1*6A allele to CRC susceptibility. Results There was no statistically significant association between the TGFBR1*6A allele and CRC (p > 0.05). The OR was 1.147 (95% CI: 0.799–1.647) for carriers of the TGFBR1*6A allele and 0.878 (95% CI: 0.306–2.520) for homozygous TGFBR1*6A individuals compared with the reference. The frequency of the polymorphism was not affected by age, sex or tumour stage. The TGFBR1*6A allele was more prevalent among colon tumour patients than among rectal tumour patients. Tumour somatic mutations were found in only two of 69 cases (2.9%). Both cases involved a GCG deletion that changed genotype 9A/9A in normal DNA to genotype 9A/8A. Interestingly, these two tumours were positive for microsatellite instability, suggesting that these mutations originated because of a deficient DNA mismatch repair system. Allele-specific expression of the 9A allele was detected in seven of the 14 heterozygous 9A/6A tumour cases. This could have been caused by linkage disequilibrium of the TGFBR1*6A allele with mutations that cause allele-specific expression, as was recently suggested. Conclusion Our results suggest that the TGFBR1*6A allele does not confer an increased risk of colorectal cancer in the Spanish population.

Rationale and objectives: Clinical research is crucial for evaluating new medical procedures and devices. It is important for healthcare units and hospitals to minimize the disruptions caused by conducting clinical studies; however, complex clinical pathways require dedicated recruitment and study designs.This work presents the effective introduction of novel microwave breast imaging (MBI), via MammoWave apparatus, into the clinical routine of an operative screening and diagnostic breast imaging department for conducting a multicentric clinical study. Materials and methods: Microwave breast imaging, using MammoWave apparatus, was performed on volunteers coming from different clinical pathways. Clinical data, comprising demographics and conventional radiologic reports (used as reference standard), was collected; a satisfaction questionnaire was filled by every volunteer. Microwave images were analyzed by an automatic clinical decision support system, which quantified their corresponding features to discriminate between breasts with no relevant radiological findings (NF) and breasts with described findings (WF). Results: Conventional breast imaging (DBT, US, MRI) and MBI were performed and adapted to assure best clinical practices and optimum pathways. 180 volunteers, both symptomatic and asymptomatic, were enrolled in the study. After microwave images' quality assessment, 48 NF (15 dense) and 169 WF (88 dense) breasts were used for the prospective study; 48 (18 dense) breasts suffered from a histology-confirmed carcinoma. An overall sensitivity of 85.8 % in breasts lesions’ detection was achieved by the microwave imaging apparatus. Conclusion: An optimum recruitment strategy was implemented to assess MBI. Future trials may show the clinical usefulness of microwave imaging, which may play an important role in breast screening.

IntroductionWe previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) .MethodsA total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs’ response. Those patients whose IGF1 decreased to

In recent years, the most powerful supercomputers have already reached megawatt power consumption levels, an important issue that challenges sustainability and shows the impossibility of maintaining this trend. To this date, the prevalent approach to supercomputing is dominated by CPUs and GPUs. Given their fixed architectures with generic instruction sets, they have been favored with lots of tools and mature workflows which led to mass adoption and further growth. However, reconfigurable hardware such as FPGAs has repeatedly proven that it offers substantial advantages over this supercomputing approach concerning performance and power consumption. In this survey, we review the most relevant works that advanced the field of heterogeneous supercomputing using FPGAs focusing on their architectural characteristics. Each work was divided into three main parts: network, hardware, and software tools. All implementations face challenges that involve all three parts. These dependencies result in compromises that designers must take into account. The advantages and limitations of each approach are discussed and compared in detail. The classification and study of the architectures illustrate the trade-offs of the solutions and help identify open problems and research lines.

Background and objectiveNeoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care in muscle-invasive bladder cancer (MIBC). Pathological response has been associated with longer survival, but no currently available clinicopathological variables can identify patients likely to respond, highlighting the need for predictive biomarkers. We sought to identify a predictive signature of response to NAC integrating clinical score, taxonomic subtype, and gene expression.Material and methodsFrom 1994 to 2014, pre-treatment tumor samples were collected from MIBC patients (stage T2-4N0/+M0) at two Spanish hospitals. A clinical score was determined based on stage, hydronephrosis and histology. Taxonomic subtypes (BASQ, luminal, and mixed) were identified by immunohistochemistry. A custom set of 41 genes involved in DNA damage repair and immune response was analyzed in 84 patients with the NanoString nCounter platform. Genes related to pathological response were identified by LASSO penalized logistic regression. NAC consisted of cisplatin/methotrexate/vinblastine until 2000, after which most patients received cisplatin/gemcitabine. The capacity of the integrated signature to predict pathological response was assessed with AUC. Overall survival (OS) and disease-specific survival (DSS) were analyzed with the Kaplan-Meier method.ResultsLASSO selected eight genes to be included in the signature (RAD51, IFNγ, CHEK1, CXCL9, c-MET, KRT14, HERC2, FOXA1). The highest predictive accuracy was observed with the inclusion in the model of only three genes (RAD51, IFNɣ, CHEK1). The integrated clinical-taxonomic-gene expression signature including these three genes had a higher predictive ability (AUC=0.71) than only clinical score plus taxonomic subtype (AUC=0.58) or clinical score alone (AUC=0.56). This integrated signature was also significantly associated with OS (p=0.02) and DSS (p=0.02).ConclusionsWe have identified a predictive signature for response to NAC in MIBC patients that integrates the expression of three genes with clinicopathological characteristics and taxonomic subtypes. Prospective studies to validate these results are ongoing.

IntroductionDifferent medical therapies have been developed for pituitary adenomas. However, Non-Functioning Pituitary Neuroendocrine Tumors (NF-PitNET) have shown little response to them. Furthermore, epithelial-mesenchymal transition (EMT) has been linked to resistance to medical treatment in a significant number of tumors, including pituitary adenomas.MethodsWe aimed to evaluate the expression of EMT-related markers in 72 NF-PitNET and 16 non-tumoral pituitaries. To further explore the potential usefulness of medical treatment for NF-PitNET we assessed the expression of somatostatin receptors and dopamine-associated genes.ResultsWe found that SNAI1, SNAI2, Vimentin, KLK10, PEBP1, Ki-67 and SSTR2 were associated with invasive NF-PitNET. Furthermore, we found that the EMT phenomenon was more common in NF-PitNET than in GH-secreting pituitary tumors. Interestingly, PEBP1 was overexpressed in recurrent NF-PitNET, and could predict growth recurrence with 100% sensitivity but only 43% specificity. In parallel with previously reported studies, SSTR3 is highly expressed in our NF-PitNET cohort. However, SSTR3 expression is highly heterogeneous among the different histological variants of NF-PitNET with very low levels in silent corticotroph adenomas.ConclusionNF-PitNET showed an enhanced EMT phenomenon. SSTR3 targeting could be a good therapeutic candidate in NF-PitNET except for silent corticotroph adenomas, which express very low levels of this receptor. In addition, PEBP1 could be an informative biomarker of tumor regrowth, useful for predictive medicine in NF-PitNET.

Abstract Predicting which acromegaly patients could benefit from somatostatin receptor ligands (SRL) is a must for personalized medicine. Although many biomarkers linked to SRL response have been identified, there is no consensus criterion on how to assign this pharmacologic treatment according to biomarker levels. Our aim is to provide better predictive tools for an accurate acromegaly patient stratification regarding the ability to respond to SRL. We took advantage of a multicenter study of 71 acromegaly patients and we used advanced mathematical modelling to predict SRL response combining molecular and clinical information. Different models of patient stratification were obtained, with a much higher accuracy when the studied cohort is fragmented according to relevant clinical characteristics. Considering all the models, a patient stratification based on the extrasellar growth of the tumor, sex, age and the expression of E-cadherin, GHRL, IN1-GHRL, DRD2, SSTR5 and PEBP1 is proposed, with accuracies that stand between 71 to 95%. In conclusion, the use of data mining could be very useful for implementation of personalized medicine in acromegaly through an interdisciplinary work between computer science, mathematics, biology and medicine. This new methodology opens a door to more precise and personalized medicine for acromegaly patients.

To analyze the distribution and factors associated with lack of knowledge about the human papillomavirus (HPV) vaccine among Brazilian adolescents.Cross‐sectional study using the 2019 National School Health Survey among 17,805 Brazilian students of public and private schools, aged 13–17 years. The outcome variable was "lack of knowledge about the HPV vaccine" and the explanatory variables were sociodemographic, behaviors, knowledge, and health conditions. Logistic regression model was used to calculate Odds Ratio (OR) and 95% confidence intervals (95%CI). Spatial analysis techniques were used to determine the formation of clusters in the federated units with similar proportions of adolescents who were unaware of the vaccine. The lack of knowledge about the HPV vaccine was reported by 45.54% of Brazilian students. There was a higher chance of lack of knowledge having had sexual intercourse (OR 1.43; 95% CI 1.20–1.70); attending public school (OR 1.72; 95%CI 1.47–2.02) and located in the Northeast Region (OR 1.35; 95%CI 1.08–1.69). The lower chance of lack of knowledge were female gender (OR 0.41; 95% CI 0.35–0.48), higher maternal education (OR 0.62; 95% CI 0.50–0.77) self‐rated health as Poor/very poor (OR 0.64; 95% CI 0.49–0.86) and receiving contraceptive counseling (OR 0.77; 95% CI 0.65–0.91). The proportion of lack of knowledge about the HPV vaccine was higher with the formation of High–High spatial clusters in the states of Maranhão, Piauí, and Pernambuco. Sociodemographic, health, and behavioral conditions and knowledge of students, as well as school characteristics, were associated with lack of knowledge about the HPV vaccine. A higher frequency of lack of knowledge about the HPV vaccine among adolescents was found in the states of the Northeastern Region. [ABSTRACT FROM AUTHOR]

Atomic-scale imaging using scanning probe microscopy is a pivotal method for investigating the morphology and physico-chemical properties of nanostructured surfaces. Time resolution represents a significant limitation of this technique, as typical image acquisition times are on the order of several seconds or even a few minutes, while dynamic processes—such as surface restructuring or particle sintering, to be observed upon external stimuli such as changes in gas atmosphere or electrochemical potential—often occur within timescales shorter than a second. In this article, we present a fully redesigned field programmable gate array (FPGA)-based instrument that can be integrated into most commercially available standard scanning probe microscopes. This instrument not only significantly accelerates the acquisition of atomic-scale images by orders of magnitude but also enables the tracking of moving features such as adatoms, vacancies, or clusters across the surface ("atom tracking") due to the parallel execution of sophisticated control and acquisition algorithms and the fast exchange of data with an external processor. Each of these measurement modes requires a complex series of operations within the FPGA that are explained in detail. [ABSTRACT FROM AUTHOR]

Machine learning (ML) models have demonstrated discriminative and representative learning capabilities over a wide range of applications, even at the cost of high-computational complexity. Due to their parallel processing capabilities, reconfigurability, and low-power consumption, systems on chip based on a field programmable gate array (SoC/FPGA) have been used to face this challenge. Nevertheless, SoC/FPGA devices are resource-constrained, which implies the need for optimal use of technology for the computation and storage operations involved in ML-based inference. Consequently, mapping a deep neural network (DNN) architecture to a SoC/FPGA requires compression strategies to obtain a hardware design with a good compromise between effectiveness, memory footprint, and inference time. This letter presents an efficient end-to-end workflow for deploying DNNs on an SoC/FPGA by integrating hyperparameter tuning through Bayesian optimization (BO) with an ensemble of compression techniques. [ABSTRACT FROM AUTHOR]