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OBJECTIVE: Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that the pretreatment molecular profiles of diagnostic biopsies can predict patient benefit from chemotherapy and define molecular bases of innate chemoresistance. DESIGN: We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as extreme outliers on chemotherapy (survival <6 m in rapid progressors, RP; survival >23 m in long survivors, LS). Diagnostic biopsies were characterised by digital pathology, then subjected to whole-transcriptome profiling of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumour-infiltrating myeloid cells was performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in multiple cohorts of resected cancers. Signatures were also characterised using in vitro cell lines, in vivo mouse models and single cell RNA-sequencing data. RESULTS: Pretreatment transcriptome profiles differentiated patients who would become RPs or LSs on chemotherapy. Biologically, this signature originated from altered tumour-myeloid dynamics, implicating tumour-induced immune tolerogenicity with poor response to chemotherapy. The central role of the liver microenviroment was confrmed by the association of the RPLS transcriptome signature with clinical outcome in iCCA but not extrahepatic CCA, and in liver metastasis from colorectal cancer, but not in the matched primary bowel tumours. CONCLUSIONS: The RPLS signature could be a novel metric of chemotherapy outcome in iCCA. Further development and validation of this transcriptomic signature is warranted to develop precision chemotherapy strategies in these settings.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Animales , Ratones , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Perfilación de la Expresión Génica , Transcriptoma , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/metabolismoRESUMEN
BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent liver cancer. The overall survival of iCCA and other biliary tract cancers (BTC) remains poor. Recently, the ABC-06 trial reported the superiority of FOLFOX vs clinical observation as a second-line treatment. Still, the survival benefit was less than expected. We hypothesized that the pattern of progression of iCCA can drive post-progression survival (PPS), similar to hepatocellular carcinoma. METHODS: Multicentre retrospective evaluation of consecutive iCCA patients who progressed after frontline systemic treatment with gemcitabine as monotherapy or in combination with platinum. Radiological assessment of progression was evaluated according to RECIST 1.1. The progression pattern was divided according to the presence/absence of new extrahepatic lesions (NEH). RESULTS: We included 206 patients from 5 centres. The median OS was 14.1 months and its independent predictors (hazard ratio [HR], 95% confidence interval [CI]) were previous surgery 0.699 [0.509-0.961], performance status >2.445 [1.788-3.344], permanent first-line discontinuation 16.072 [5.102-50.633], registration of ascites 2.226 [1.448-3.420] or bilirubin >3 mg/dl 3.004 [1.935-4.664] during the follow-up, and disease progression 2.523 [1.261-5.050]. The appearance of NEH independently predicted OS 2.18 [1.55-3.06] in patients with radiological progression. Amongst 138 patients eligible for second-line treatment, PPS was 16.8 and 5.9 months in cases without and with NEH, respectively (P = .001). Progression owing to NEH lesions was an independent predictor of PPS 1.873 [1.333-2.662], together with performance status, time to progression to the frontline treatment, bilirubin >3 mg/dl and ascites. CONCLUSIONS: PPS of iCCA is influenced by progression pattern, with important implications for second-line trial design and analysis.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Neoplasias Hepáticas , Neoplasias de los Conductos Biliares/diagnóstico por imagen , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/diagnóstico por imagen , Colangiocarcinoma/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
Aims: To investigate the influence of various concomitant medications on outcomes in patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation. Materials & methods: The authors retrospectively identified 246 patients from 2003 to 2018, collecting demographic and clinicopathological data of interest. Odds ratio (OR) was used to assess the association between concomitant drugs and outcomes. Results: The authors found an association between statins and a Dworak regression grade of 3-4 (OR = 8.78; p = 0.01). Furthermore, statins were significantly associated with more frequent chemoradiation-related toxicity (OR = 2.39; p = 0.0098) and chemotherapy dose reduction or discontinuation (OR = 2.26; p = 0.03). Conclusion: Despite higher frequency of radiotherapy and chemotherapy interruption or dose reduction, the concomitant use of statins during neoadjuvant chemoradiation proved to be associated with better tumor regression.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Neoplasias Primarias Secundarias , Neoplasias del Recto , Quimioradioterapia/efectos adversos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Terapia Neoadyuvante/efectos adversos , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/patología , Neoplasias del Recto/patología , Estudios RetrospectivosRESUMEN
In this paper, the use of a phase-sensitive optical time-domain reflectometry (Ï-OTDR) sensor for the detection of the Lamb waves excited by a piezoelectric transducer in an aluminum plate, is investigated. The system is shown to detect and resolve the Lamb wave in distinct regions of the plate, opening the possibility of realizing structural health monitoring (SHM) and damage detection using a single optical fiber attached to the structure. The system also reveals the variations in the Lamb wave resulting from a change in the load conditions of the plate. The same optical fiber used to detect the Lamb waves has also been employed to realize distributed strain measurements using a Brillouin scattering system. The method can be potentially used to replace conventional SHM sensors such as strain gauges and PZT transducers, with the advantage of offering several sensing points using a single fiber.
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Fibras Ópticas , TransductoresRESUMEN
Objectives: The ABC-06 and the NIFTY trials recently established the role of second-line chemotherapy (2L) in patients with advanced biliary tract cancer (BTC). Our real-world study aimed to explore 2L in BTC patients aged ≥ 70 years old and to compare their outcomes with younger subjects. Methods: Institutional registries across three academic medical centers were retrospectively reviewed. The Kaplan−Meier methods were used to estimate survival, and the log-rank test was used to make comparisons. Results: A total of 190 BTC patients treated with 2L were identified and included in the analysis. Among them, 52 (27.3%) were aged ≥ 70 years (range 70−87 years). No statistically significant differences in both median overall survival (mOS) and median progression-free survival (mPFS) were recorded between the elderly and younger patients. Absolute lymphocyte count < 1000/mmc (p < 0.001) and albumin level < 3 g/dL (p < 0.001) were independently associated with worse prognoses. Conclusions: The results of this real-world study suggest that for patients aged ≥ 70 years, 2L could be equally effective for younger patients with survival outcomes aligned to those from the ABC-06 and NIFTY trials. The delivery of 2L should be carefully evaluated and monitored in this patient subset.
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Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Anciano , Humanos , Neoplasias del Sistema Biliar/tratamiento farmacológico , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Pronóstico , Resultado del TratamientoRESUMEN
INTRODUCTION: Pazopanib, a tyrosine kinase inhibitor (TKI), is a standard treatment for various tumours, including metastatic non-adipocytic soft-tissue sarcomas. In literature, erythrocytosis has been described as a TKI-related condition. CASE REPORT: A 59-year-old man underwent surgical removal of a sub-scapular mass consistent with myxofibrosarcoma. After distant relapse, he first started chemotherapy, and then Pazopanib. He was found to have increased levels of hemoglobin (Hb) and hematocrit (Hct). He was asymphtomatic, with no history of pulmonary disease nor smoking habit. Erythropoietin (EPO) level was higher than normal. A polycythemia vera was ruled out.Management & outcome: The patient started a prophylactic therapy with lysine acetylsalicylate, and we observed a reduction of Hb, but not Hct. Due to disease progression, we interrupted Pazopanib. After a week from drug discontinuation, Hb levels got back to the normal range, Hct was lowering. We decided not to perform phlebotomy, considering the declining trend in Hb and Hct values and the absence of symptoms. DISCUSSION: We postulated a Pazopanib-related secondary erythrocytosis, since Hb and Hct levels increased from baseline during treatment, then normalized when Pazopanib was discontinued. We used the Naranjo Nomogram to assess the correlation between the adverse effect and Pazopanib, the correlation was "Probable", a score of 5. To the best of our knowledge, this is the first case report of Pazopanib-related secondary polycythemia in a patient with sarcoma. It is important to pay attention to blood count and to any symptoms potentially related to erythrocytosis in patients treated with TKIs.
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Fibroma/tratamiento farmacológico , Fibrosarcoma/tratamiento farmacológico , Policitemia/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Sulfonamidas/efectos adversos , Inhibidores de la Angiogénesis/efectos adversos , Fibroma/diagnóstico , Fibrosarcoma/diagnóstico , Humanos , Indazoles , Masculino , Persona de Mediana Edad , Policitemia/diagnóstico , Neoplasias de los Tejidos Blandos/tratamiento farmacológicoRESUMEN
BACKGROUND: An accurate risk-stratification is key to optimize the benefit-to-risk ratio of palliative treatment in advanced biliary cancer. We aimed at assessing the impact of the prognostic nutritional index (PNI) on survival and treatment response in advanced biliary cancer (ABC) receiving first-line chemotherapy. METHODS: Medical records of ABC treated with standard chemotherapy at the Modena Cancer Centre were retrospectively reviewed for variables deemed of potential interest, including the PNI. Univariate and multivariate analyses were performed to investigate the association between the covariates and overall survival (OS). RESULTS: 114 ABC fulfilled the inclusion criteria and made up the training cohort. A PNI cut-off value of 36.7 was established using the receiver operating characteristic (ROC) analysis. At both the univariate and the multivariate analysis, low PNI value (<36.7) was associated with shorter OS (P = .0011), together with increased NLR (P = .0046) and ECOG >1 (P < .0001). The median OS was 5.4 vs 12.1 months in the low- vs high PNI-group. Moreover, a PNI value >36.7 resulted in a higher disease control in patients treated with gemcitabine/platinum combination (61.4% vs 34.3%). These results were validated in an independent cohort of 253 ABC. CONCLUSIONS: We demonstrated and externally validated a prognostic role for the PNI in ABC treated with first-line chemotherapy. Although the PNI turned out to be predictive in the subset of patients receiving platinum/gemcitabine combination, future prospective confirmation is needed.
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Neoplasias , Evaluación Nutricional , Humanos , Pronóstico , Curva ROC , Estudios RetrospectivosRESUMEN
PURPOSE: BRAF mutations represent the main negative prognostic factor for metastatic colorectal cancer and a supposed negative predictive factor of response to standard chemotherapy. We have explored survival difference in right-sided colon cancer (RCC) patients according to BRAF mutations, with the aim to identify any predictive factors of response to targeted-based therapy. METHODS: A retrospective study of RCC patients, with BRAF known mutation status, treated with chemotherapy (CT) from October 2008 to June 2019 in 5 Italian centers, was conducted. RESULTS: We identified 207 advanced RCC patients: 20.3% BRAF mutant and 79.7% BRAF wild type (wt). BRAF-mutant cancers were more likely to be pT4 (50.0% v 25.7%, p = 0.016), undifferentiated (71.4% v 44.0%, p = 0.004), KRAS wt (90.5% v 38.2%, p < 0.001), and MSI-H (41.7% v 16.2%, p = 0.019) tumors, with synchronous (52.4% v 31.5%, p = 0.018) and peritoneal metastases (38.1% v 22.4%, p = 0.003). Median overall survival (OS) was 16 v 27 months in BRAF mutant and BRAF wt (P = 0.020). In first-line setting, BRAF-mutant showed a 2ys OS of 80% in clinical trials, 32% in anti-VEGF, 14% in epidermial growth factor receptor (EGFR), and 0% in chemotherapy alone regimens (P = 0.009). BRAF-mutant patients demonstrated worse survival, regardless of targeted therapy administered. However, survival difference was statistically significant in the anti-EGFR-treated subgroup (16 v 28 months, P = 0.005 in BRAF mutant v BRAF wt, respectively). CONCLUSIONS: Our study demonstrated that BRAF status makes the difference in treatment's outcome. Therefore, the anti-EGFR should not be excluded in all advanced RCC but considered on a case-by-case basis.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Receptores ErbB , Humanos , Mutación/genética , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Estudios RetrospectivosRESUMEN
An investigation was carried out on rhizosphere bacteria to determine if they may be associated with perennial crops affected by nonspecific decline, a phenomenon that is difficult to diagnose and prevent. Esca disease of grapevine was chosen for this case study because of its easy foliar symptom identification. Ribosomal DNA fingerprint analysis by polymerase chain reaction - denaturing gradient gel electrophoresis (PCR-DGGE), quantitative PCR (qPCR), and rDNA amplicon sequencing by next-generation sequencing (NGS) were adopted to investigate the bacterial communities associated with grapevines, which were selected for the presence and absence of external foliar symptoms in 11 vineyards. According to PCR-DGGE and qPCR, bacterial communities differed in site of origin (vineyards), but not between symptomatic and asymptomatic plants, whereas qPCR gave a significantly higher presence of total bacteria and Pseudomonas spp. in asymptomatic plants. NGS confirmed no difference between symptomatic and asymptomatic plants, apart from a few minor genera (<0.5%) such as Salinibacterium, Flavobacterium, Nocardia, and Janthinobacterium, which were, in all cases, higher in asymptomatic plants and whose functional role should be the object of further investigation. The fact that total bacteria and Pseudomonas were more abundant in the rhizosphere of asymptomatic grapevines and that some bacterial genera were associated with the latter, represents a new element when investigating the multiple-origin phenomenon such as esca disease of grapevine.
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Microbiota , Enfermedades de las Plantas/microbiología , Rizosfera , Vitis/microbiología , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , ADN Bacteriano/genética , Granjas , Microbiota/genética , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADNRESUMEN
The optimization of production processes has always been one of the cornerstones for manufacturing companies, aimed to increase their productivity, minimizing the related costs. In the Industry 4.0 era, some innovative technologies, perceived as far away until a few years ago, have become reachable by everyone. The massive introduction of these technologies directly in the factories allows interconnecting the resources (machines and humans) and the entire production chain to be kept under control, thanks to the collection and the analyses of real production data, supporting the decision making process. This article aims to propose a methodological framework that, thanks to the use of Industrial Internet of Things-IoT devices, in particular the wearable sensors, and simulation tools, supports the analyses of production line performance parameters, by considering both experimental and numerical data, allowing a continuous monitoring of the line balancing and performance at varying of the production demand. A case study, regarding a manual task of a real manufacturing production line, is presented to demonstrate the applicability and the effectiveness of the proposed procedure.
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Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is a heterogeneous disease, which can be classified into different subtypes, characterized by specific molecular and morphological alterations. In this context, BRAF mutations are found in about 10% of CRC patients and define a particular subtype, characterized by a dismal prognosis, with a median survival of less than 12 months. Chemotherapy plus bevacizumab is the current standard therapy in first-line treatment of BRAF-mutated metastatic CRC (mCRC), with triplet (FOLFOXIRI) plus bevacizumab as a valid option in patients with a good performance status. BRAF inhibitors are not so effective as compared to melanoma, because of various resistance mechanisms. However, the recently published results of the BEACON trial will establish a new standard of care in this setting. This review provides insights into the molecular underpinnings underlying the resistance to standard treatment of BRAF-mutated CRCs, with a focus on their molecular heterogeneity and on the research perspectives both from a translational and a clinical point of view.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Masculino , Melanoma/tratamiento farmacológico , Mutación , Pronóstico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismoRESUMEN
This study aimed at investigating the degree of interference of high soil copper (Cu) contamination when an old vineyard is converted into a protected area. This study was performed within an intensive agricultural system; it was organized into a two-factorial nested design to analyze the impact of management (conventional vs re-naturalized orchard) and position within each orchard (tree-rows and strips). Chemical and biochemical properties along with bacterial and fungal communities, evaluated with PCR-DGGE starting from total soil DNA, were analyzed. Total Cu was localized in tree rows in the old vineyard at 1000 mg kg(-1) of soil, whereas it did not exceed 80 mg kg(-1) soil in the other treatments. Total organic carbon and all biochemical properties significantly improved in re-naturalized compared to conventionally cultivated site, while no significant differences were observed between tree row and strip. Moreover, a higher extractable carbon-extractable nitrogen (Cext-to-Next) ratio in the re-naturalized (19.3) site than in the conventionally managed site (10.2) indicated a shift of soil system from C-limited to N-limited, confirming a successful ecological restoration. Deep improvement of soil biochemical properties exceeded the negative impact of Cu contamination. A shift of bacterial community composition as well as increased bacterial diversity in Cu contaminated treatment indicated a bacterial response to Cu stress; to the contrary, soil fungi were less susceptible than bacteria, though an overall reduction of fungal DNA was detected. Findings suggest that ecological restoration of highly polluted agricultural soils leads to overcoming the reduction of soil functionalities linked to Cu contamination and opens interesting perspectives for mitigating Cu stress in agricultural soils with strategies based on conservative agriculture.
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Ascomicetos/crecimiento & desarrollo , Bacterias/crecimiento & desarrollo , Basidiomycota/crecimiento & desarrollo , Cobre/toxicidad , Contaminación Ambiental/análisis , Restauración y Remediación Ambiental/métodos , Microbiología del Suelo , Contaminantes del Suelo/toxicidad , Agricultura , Ascomicetos/efectos de los fármacos , Ascomicetos/genética , Bacterias/efectos de los fármacos , Bacterias/genética , Basidiomycota/efectos de los fármacos , Basidiomycota/genética , Carbono/análisis , Cobre/química , Ecología , Granjas , Nitrógeno/análisis , Suelo/química , Contaminantes del Suelo/químicaRESUMEN
INTRODUCTION AND OBJECTIVES: To evaluate the oncological and functional outcomes of transperineal laser ablation (TPLA) as the focal therapy for localized prostate cancer (PCa) after a 12-month follow-up. MATERIALS AND METHODS: Patients with low- and intermediate-risk localized PCa were prospectively treated with focal TPLA between July 2021 and December 2022. The inclusion criteria were the following: clinical stage < T2b; PSA < 20 ng/mL; International Society of Urological Pathology (ISUP) grade ≤ 2; MRI-fusion biopsy-confirmed lesion classified as PI-RADS v2.1 ≥ 3. Intra-, peri-, and post-operative data were collected. Variables including age, PSA, prostate volume (PVol), Charlson's Comorbidity Index (CCI), International Prostate Symptom Score (IPSS) with QoL score, International Index of Erectile Function (IIEF-5), International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), and Male Sexual Health Questionnaire-Ejaculatory Dysfunction Short Form (MSHQ-EjD) were collected at baseline and at 3, 6 and 12 months after TPLA. Post-operative mpMRI was performed at 3 and 12 months. Finally, all patients underwent prostatic re-biopsy under fusion guidance at 12 months. The success of this technique was defined as no recurrence in the target treated lesion at the 12-month follow up. RESULTS: Twenty-four patients underwent focal TPLA. Baseline features were age [median 67 years (IQR 12)], PSA [5.7 ng/mL (3.9)], PVol [49 mL (27)], CCI [0 (0)], IPSS [11 (9)], IPSS-QoL [2 (2)], IIEF-5 [21 (6)], ICIQ-SF [0 (7)], MSHQ-EjD ejaculation domain [14 (4)] and bother score [0 (2)]. Median operative time was 34 min (IQR 12). Median visual analogue scale (VAS) 6 h after TPLA was 0 (IQR 1). The post-operative course was regular for all patients, who were discharged on the second post-operative day and underwent catheter removal on the seventh post-operative day. No patient had incontinence at catheter removal. A significant reduction in PSA (p = 0.01) and an improvement in IPSS (p = 0.009), IPSS-QoL (p = 0.02) and ICIQ-SF scores (p = 0.04) compared to baseline were observed at the 3-month follow-up. Erectile and ejaculatory functions did not show any significant variation during the follow-up. No intra- and peri-operative complications were recorded. Three Clavien-Dindo post-operative complications were recorded (12%): grade 1 (two cases of urinary retention) and grade 2 (one case of urinary tract infection). At the 12-month follow-up, eight patients showed mpMRI images referable to suspicious recurrent disease (PIRADS v2.1 ≥ 3). After re-biopsy, 7/24 patients' (29%) results were histologically confirmed as PCa, 3 of which were recurrences in the treated lesion (12.5%). The success rate was 87.5%. CONCLUSIONS: The focal TPLA oncological and functional results seemed to be encouraging. TPLA is a safe, painless, and effective technique with a good preservation of continence and sexual outcomes. Recurrence rate at 12 months was about 12.5%.
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BACKGROUND: This prospective study was created to evaluate the reliability of a new clinical test, which we termed the "loss of extension test" (LOE test). The LOE test investigates the loss of normal maximum passive extension (MPE) of the knee due to an anterior cruciate ligament tear in comparison to the normal MPE of the healthy knee. MATERIALS AND METHODS: The study was divided into two consecutive parts. Part 1 was designed to assess the side-to-side difference in normal MPE in a healthy population. In part 1, 100 healthy adults were enrolled. Part 2 was designed to evaluate the LOE test reliability in injured knees. In part 2, we included 196 selected patients. RESULTS: In part 1, the average side-to-side difference in MPE in the healthy population was not statistically significant. In part 2, the overall average side-to-side difference in MPE of the injured group was 10.1 mm ± 14.1 (min -20; max 60), which was not statistically significant (p = 0.52). An anterior cruciate ligament (ACL) tear was found in 121 knees among 196 patients. The average side-to-side difference in MPE in the ACL-insufficient group was 16.9 mm ± 13.4 (min -20; max 60), which was statistically significant (p < 0.0001). The accuracy of the loss of extension test was 83.7%, its specificity was 93.3%, its sensitivity was 77.7%, its positive predictive value was 95%, and its negative predictive value was 72.2%. CONCLUSIONS: The reliability of the LOE test is comparable to those reported in the literature for the Lachman test and dynamic tests, so the LOE test could represent a useful tool for the diagnosis of the anterior cruciate ligament insufficient knee.
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Lesiones del Ligamento Cruzado Anterior , Traumatismos de la Rodilla/diagnóstico , Examen Físico/métodos , Rango del Movimiento Articular/fisiología , Adolescente , Adulto , Ligamento Cruzado Anterior/fisiopatología , Fenómenos Biomecánicos , Femenino , Humanos , Traumatismos de la Rodilla/fisiopatología , Articulación de la Rodilla/fisiopatología , Masculino , Persona de Mediana Edad , Examen Físico/normas , Estudios Prospectivos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Adulto JovenRESUMEN
AIM: To apply extended ctDNA-based RAS genotyping to clinical criteria for improving the selection of patients eligible for anti-EGFR-based rechallenge in a real-world setting. METHODS: ctDNA testing was prospectively applied to RASwt mCRC progressed after a first-line anti-EGFR-containing regimen and at least one other line. The primary endpoint was the objective response rate. RESULTS: Among ten enrolled patients, the anti-EGFR rechallenge resulted in an objective response rate and disease control rate of 70% and 90%. The median progression-free survival was 11.3 months and overall survival was not reached. Compared with a historical cohort retreated with anti-EGFR agents based on clinical criteria, the ctDNA-driven approach resulted in a higher chance of achieving an objective response and longer survival. CONCLUSIONS: Blood-based RASwt status may enrich metastatic colorectal cancer more likely to benefit from anti-EGFR-based rechallenge. RAS genotyping in ctDNA represents a feasible, fast, and cost-effective tool to be implemented in the clinic for advancing precision medicine.
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Supervivencia sin Progresión , MutaciónRESUMEN
Gastric and gastro-esophageal junction adenocarcinoma (GEA) remains a considerable major public health problem worldwide, being the fifth most common cancer with a fatality-to-case ratio that stands still at 70%. Angiogenesis, which is a well-established cancer hallmark, exerts a fundamental role in cancer initiation and progression and its targeting has been actively pursued as a promising therapeutic strategy in GEA. A wealth of clinical trials has been conducted, investigating anti-angiogenic agents including VEGF-directed monoclonal antibodies, small molecules tyrosine kinase inhibitors and VEGF-Trap agents both in the resectable and advanced setting, reporting controversial results. While phase III randomized trials testing the anti-VEGFR-2 antibody Ramucirumab and the selective VEGFR-2 tyrosine kinase inhibitor Apatinib demonstrated a significant survival benefit in later lines, the shift of angiogenesis inhibitors in the perioperative and first-line setting failed to improve patients' outcome in GEAs. The molecular landscape of disease, together with novel combinatorial strategies and biomarker-selected approaches are under investigation as key elements to the success of angiogenesis blockade in GEA. In this article, we critically review the existing literature on the biological rationale and clinical development of antiangiogenic agents in GEA, discussing major achievements, limitations and future developments, aiming at fully realizing the potential of this therapeutic approach.
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Genetic alterations in CRC have shown a negative predictive and prognostic role in specific target therapies. The onset of immunotherapy has also undergone remarkable therapeutic innovation, although limited to a small subgroup of patients, the MSI-H/dMMR, which represents only 5% of CRC. Research is moving forward to identify whether other biomarkers can predict response to ICIs, despite various limitations regarding expression and identification methods. For this purpose, TMB, LAG3, and PD-L1 expression have been retrospectively evaluated in several solid tumors establishing the rationale to design clinical trials with concurrent inhibition of LAG3 and PD-1 results in a significant advantage in PFS and OS in advanced melanoma patients. Based on these data, there are clinical trials ongoing in the CRC as well. This review aims to highlight what is already known about genetic mutations and genomic alterations in CRC, their inhibition with targeted therapies and immune checkpoints inhibitors, and new findings useful to future treatment strategies.
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Guided wave (GW) structural health monitoring (SHM) systems offer an attractive solution as an in-situ quasi real-time assessment of structural damage, but their sensitivity and efficiency may be impaired under varied environmental and operational conditions. Thus, virtual tests, such as that based on the Finite Element (FE) method, represent a valid approach for simulating and investigating SHM systems, enabling a substantial reduction in experimental campaigns. In this work, GW propagation characteristics in a carbon fibre-reinforced composite plate are studied under a varying temperature condition, representative of the aeronautics application. At first, GW SHM system was physically tested at room temperature (20°C), and the results were used to calibrate and assess the proposed FE modelling approaches, characterised by different element types and mesh sizes. A temperature independent averaged time compensation factor is proposed to mitigate the numerical data dependency on excitation frequency and propagation angle. Two temperature variations (from 20°C to -50°C, and 20°C to 65°C) were experimentally and numerically considered to investigate the effect of varying temperature on the GW. For all test cases, the compensated numerical data was compared to the experimental results, and discussed in terms of dispersion curves, focusing on the zero-order symmetric, S0, and antisymmetric, A0, modes. Results show that both 2D and 3D FE approaches can accurately predict the changes in GW due to varying temperature, with the group velocity of the A0 mode being less sensitive to temperature variations.
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Modelos Teóricos , Ondas Ultrasónicas , Simulación por Computador , TemperaturaRESUMEN
BACKGROUND: Advanced biliary cancers (ABC) are aggressive malignancies with a median overall survival (mOS) <12 months when treated with first-line chemotherapy. Nevertheless, a subset of patients experiencing longer survival has been described in the updated analysis of ABC-02 trial. We aimed to provide a real-world description of ABC long-term survivors (LS), identifying which factors impact on survival. METHODS: Patients diagnosed with ABC at three Institutions between 2002 and 2019, and who survived ≥18 months, were retrospectively identified. We compared them with a control cohort (C) with a mOS <18 months, matched on age, gender, ECOG PS, disease status, primary tumor site, prior surgery, and treatment modality. Their clinical features, treatments, and outcome were analyzed. RESULTS: A total of 78 patients was included, 39 in each group. Both LS and C cohorts had superimposable baseline characteristics, without significant differences. mOS was 29 (95%CI 24.6-33.5) and 9 months (95%CI 6.6-12.9) in the two groups, respectively. After performing a logistic regression analysis, three factors were significantly associated with long-term outcome: low neutrophil-to-lymphocyte ratio (NLR < 3) (Odds Ratio [OR] 0.38), achievement of objective response to treatment (OR 0.16), and the number of lines received (OR 0.29). CONCLUSIONS: We described a considerable subset of ABC experiencing long-term survival with conventional chemotherapy in a real-world scenario. Beyond clinical factors, we identified low NLR as a prognostic determinant that may allow for a more accurate selection of long survivors. While waiting for a deeper molecular characterization of this subgroup, we propose NLR as a stratification factor for daily practice and clinical trials.
Asunto(s)
Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Linfocitos/patología , Neoplasias/patología , Neutrófilos , Pronóstico , Estudios Retrospectivos , SobrevivientesRESUMEN
Background: The role of second-line chemotherapy in advanced biliary cancers (ABCs) has only recently been established in phase III randomized trial and the optimal selection of patients most likely to benefit from it remains challenging. Methods: A cohort of 98 ABC treated second-line chemotherapy was used as a developmental dataset to identify covariates independently associated with overall survival (OS). Kaplan-Meier analysis was used to investigate the association between variables and OS and those retaining statistically significance were combined in a multiplexed score. Results: The following pretreatment variables were independently associated with OS: ECOG PS > 0, peritoneal disease, LDH > 430 UI/L, albumin <3.5 gr/dL, gamma-GT >100 UI/L, sodium <140 mEq/L, absolute lymphocyte count <1000/mmc, and PFS to first-line <6 months. Based on these results, a scoring system was developed that identified three subgroups with statistically different OS: low-risk (mOS 18 months), intermediate-risk (mOS 9.4 months) and high-risk (mOS 2.9 months) (p < 0.001). The prognostic model was both internally and externally validated in a multicentre cohort of 120 ABCs. Conclusion: The Modena score is a multiplexed scoring system capable of accurately risk-stratified ABCs treated with second-line chemotherapy. Based on its reproducibility, usability and generalizability, it has the potential for assisting therapeutic decision-making in the clinic and risk-stratification in future trials.