Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management

The assessment of hormone receptors (HRs) and human epidermal growth factor receptor (HER)-2 is necessary to select patients who are candidates for hormonal and anti-HER-2 therapy. The evaluation of these parameters is generally carried out in primary tumors and it is not clear if reassessment in metastatic lesions might have an impact on patient management. The primary aim of this analysis was to compare HER-2 and HR status in primary tumors versus metastatic sites in breast cancer patients. PATIENTS AND METHODS: Seventy-five patients with available samples from primary tumors and paired metastases were included. HER-2 status was evaluated by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH); HR status was assessed by IHC. RESULTS: Nineteen percent of primary tumors were HER-2 positive; 77% were HR positive. Sites of biopsied or resected metastases were: locoregional soft tissues (n = 30), liver (n = 20), central nervous system (n = 5), bone (n = 5), pleura (n = 4), distant soft tissues (n = 3), abdomen (stomach, colon, peritoneum) (n = 3), bronchus (n = 3), and bone marrow (n = 2). For paired metastases, the HER-2 status was unchanged in 84% of cases; two patients changed from positive to negative, while 10 patients converted from negative to positive (agreement, 84%; kappa = 0.5681). A change in HR status was observed in 16 cases (21%): nine cases from positive to negative and seven cases from negative to positive (agreement, 78.7%; kappa = 0.4158). CONCLUSIONS: Further studies are necessary to better define the level of discordance in HER-2 or HR status between primary tumors and paired metastases. However, a biopsy of metastatic disease can be recommended, if feasible with minimal invasiveness, because treatment options might change for a significant proportion of patient

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

Beta-Blocker Use in Older Hospitalized Patients Affected by Heart Failure and Chronic Obstructive Pulmonary Disease: An Italian Survey From the REPOSI Register

Beta (β)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to β2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective β1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge (admission, 36.9% vs. 51.3%; discharge, 38.0% vs. 51.7%). In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD (adj. OR, 95% CI: 0.50, 0.37-0.67), while the diagnosis of COPD was not associated with the choice of selective β1-BB (adj. OR, 95% CI: 1.33, 0.76-2.34). Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a β1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations

Pesticides in the environment: analysis, occurrence, impact and recommendations for their attenuation

[eng] The assessment of pesticide occurrence in different environmental compartments has become a matter of outstanding importance since its effects on exposed organisms may be considered a warning on the potential risk these substances may pose to human health. In this context, and in the framework of this doctoral thesis, the presence and fate of 52 pesticides and transformation products were evaluated in surface water, groundwater, and sediments from four river basins, and the associated environmental risk was assessed. In addition, the performance of a fungi-based bioremediation technique for the removal of pesticides was evaluated. The methods developed are based on the use of advanced extraction techniques such as on-line solid-phase extraction, pressurized liquid extraction, and QuEChERS extraction, and analyte determination with liquid chromatography coupled to tandem mass spectrometry. The use of an isotope-dilution approach ensured the reliability of the results and the satisfactory performance of the methodologies in terms of accuracy, precision, linearity, sensitivity and matrix effect. The most relevant pesticides detected in agricultural areas (Ebro River Delta, Ter River) were the herbicides widely used in rice cultivation bentazone, MCPA and propanil, while in urban and industrial areas like the lower Llobregat River basin, the most relevant pesticides were bromoxynil, diuron, linuron and terbutryn, used for both agricultural and non-agricultural purposes. In the sediments of the Llobregat River and the fish samples collected from the Adige River, most of the pesticides found are currently banned, which suggest their persistence in the environment. The assessment of the environmental risk highlighted the role of pesticides as relevant stressors in the aquatic environment. The degradation of selected pesticides by the fungus T. versicolor point at this organism as an efficient, green and economic alternative for pesticide removal during water treatment. Further pesticide pollution attenuation was attempted by contributing to the design of participatory multi-actor events to increase the awareness of farmers and stakeholders on the issue of environmental pollution by pesticides, involving them in the decision-making processes for the implementation of mitigation measures and best management practices aimed at reducing pesticide release into the environment.[spa] La evaluación de la presencia de plaguicidas en los diferentes compartimentos ambientales es de gran importancia ya que sus efectos en los organismos expuestos pueden considerarse una advertencia del riesgo potencial que estas sustancias pueden suponer para la salud humana. En este contexto, en el marco de esta tesis doctoral se ha estudiado la presencia y destino de 52 pesticidas y productos de transformación en aguas superficiales, subterráneas, sedimentos y biota de cuatro cuencas hidrográficas, y se ha evaluado el riesgo ambiental asociado. Además, se ha valorado la eficacia de una técnica de biorremediación basada en hongos para eliminar plaguicidas seleccionados. Los métodos desarrollados se basan en el uso de técnicas avanzadas de extracción como son la extracción en fase sólida (SPE) on line automatizada, la extracción mediante líquidos presurizados (PLE) seguida de purificación del extracto mediante SPE, y la extracción con QuEChERS para la preconcentración de los plaguicidas en agua, sedimento, y biota, respectivamente, y la determinación de los compuestos mediante cromatografía de líquidos acoplada a espectrometría de masas en tándem. El uso de dilución isotópica para la cuantificación garantiza la fiabilidad de los resultados y el rendimiento satisfactorio de los métodos desarrollados en términos de exactitud, precisión, linealidad y efecto de la matriz. La sensibilidad de los métodos desarrollados posibilita la evaluación de los plaguicidas seleccionados a los niveles de los estándares de calidad ambiental marcados por la Comisión Europea en el ámbito de la política de aguas. Los plaguicidas más relevantes detectados en las áreas agrícolas investigadas fueron los herbicidas bentazona, MCPA y propanil, ampliamente utilizados en el cultivo del arroz en el delta del río Ebro. El río Ter, también afectado por actividades agrícolas intensivas, resultó contaminado en menor medida por bentazona y MCPA. En áreas urbanas e industriales como la cuenca baja del río Llobregat, los compuestos más ubicuos y abundantes fueron bromoxinilo, diurón, linurón y terbutrina, utilizados tanto con fines agrícolas como no agrícolas. En esta zona, muchos de los plaguicidas encontrados superaban el límite de 100 ng/L establecido por la Unión Europea para plaguicidas individuales en aguas destinadas al consumo humano. En los sedimentos del río Llobregat y las muestras de peces recogidas en el río Adige, los plaguicidas presentan propiedades físico-químicas que los hacen más propensos a acumularse en sedimentos o bioacumularse en la biota. La mayoría de los pesticidas detectados en estas matrices están actualmente prohibidos, lo cual sugiere su persistencia en el medio ambiente. Diclorvos e irgarol superaron las concentraciones máximas admisibles establecidas por la Comunidad Europea como normas de calidad ambiental para compuestos prioritarios en aguas superficiales, mientras que los límites máximos aceptables de detección (LODs) establecidos en la Lista de Observación europea fueron superados por acetamiprid, imidacloprid, tiacloprid y metiocarb. La evaluación del riesgo ambiental ha destacado el papel de los plaguicidas como estresores relevantes en el medio acuático. Además, la co-ocurrencia de plaguicidas resulta en un aumento del riesgo en los diversos compartimentos ambientales estudiados, lo que hace necesaria la adopción de medidas para atenuar la contaminación ambiental por plaguicidas. Con este propósito, se exploró la capacidad del hongo T. versicolor para degradar malatión, acetamiprid e imidacloprid. Los resultados apuntan a este organismo como una alternativa eficaz, ecológica y económica para la eliminación de pesticidas del agua. Por otro lado, se diseñaron eventos participativos con el fin de aumentar la conciencia de los agricultores y otras partes interesadas sobre el problema de la contaminación ambiental por plaguicidas, involucrándolos en los procesos de toma de decisiones para motivar la implementación de medidas de mitigación destinadas a reducir la liberación de plaguicidas al medio ambiente

Pesticides in the environment: analysis, occurrence, impact and recommendations for their attenuation

Memoria presentada para optar al título de Doctora por la Universidad de Barcelona.-- Tutor académico: Dr. Francisco Javier Santos Vicente.[EN] The assessment of pesticide occurrence in different environmental compartments has become a matter of outstanding importance since its effects on exposed organisms may be considered a warning on the potential risk these substances may pose to human health. In this context, and in the framework of this doctoral thesis, the presence and fate of 52 pesticides and transformation products were evaluated in surface water, groundwater, and sediments from four river basins, and the associated environmental risk was assessed. In addition, the performance of a fungi-based bioremediation technique for the removal of pesticides was evaluated. The methods developed are based on the use of advanced extraction techniques such as on-line solid-phase extraction, pressurized liquid extraction, and QuEChERS extraction, and analyte determination with liquid chromatography coupled to tandem mass spectrometry. The use of an isotope-dilution approach ensured the reliability of the results and the satisfactory performance of the methodologies in terms of accuracy, precision, linearity, sensitivity and matrix effect. The most relevant pesticides detected in agricultural areas (Ebro River Delta, Ter River) were the herbicides widely used in rice cultivation bentazone, MCPA and propanil, while in urban and industrial areas like the lower Llobregat River basin, the most relevant pesticides were bromoxynil, diuron, linuron and terbutryn, used for both agricultural and non-agricultural purposes. In the sediments of the Llobregat River and the fish samples collected from the Adige River, most of the pesticides found are currently banned, which suggest their persistence in the environment. The assessment of the environmental risk highlighted the role of pesticides as relevant stressors in the aquatic environment. The degradation of selected pesticides by the fungus T. versicolor point at this organism as an efficient, green and economic alternative for pesticide removal during water treatment. Further pesticide pollution attenuation was attempted by contributing to the design of participatory multi-actor events to increase the awareness of farmers and stakeholders on the issue of environmental pollution by pesticides, involving them in the decision-making processes for the implementation of mitigation measures and best management practices aimed at reducing pesticide release into the environment.[ES] La evaluación de la presencia de plaguicidas en los diferentes compartimentos ambientales es de gran importancia ya que sus efectos en los organismos expuestos pueden considerarse una advertencia del riesgo potencial que estas sustancias pueden suponer para la salud humana. En este contexto, en el marco de esta tesis doctoral se ha estudiado la presencia y destino de 52 pesticidas y productos de transformación en aguas superficiales, subterráneas, sedimentos y biota de cuatro cuencas hidrográficas, y se ha evaluado el riesgo ambiental asociado. Además, se ha valorado la eficacia de una técnica de biorremediación basada en hongos para eliminar plaguicidas seleccionados. Los métodos desarrollados se basan en el uso de técnicas avanzadas de extracción como son la extracción en fase sólida (SPE) on line automatizada, la extracción mediante líquidos presurizados (PLE) seguida de purificación del extracto mediante SPE, y la extracción con QuEChERS para la preconcentración de los plaguicidas en agua, sedimento, y biota, respectivamente, y la determinación de los compuestos mediante cromatografía de líquidos acoplada a espectrometría de masas en tándem. El uso de dilución isotópica para la cuantificación garantiza la fiabilidad de los resultados y el rendimiento satisfactorio de los métodos desarrollados en términos de exactitud, precisión, linealidad y efecto de la matriz. La sensibilidad de los métodos desarrollados posibilita la evaluación de los plaguicidas seleccionados a los niveles de los estándares de calidad ambiental marcados por la Comisión Europea en el ámbito de la política de aguas. Los plaguicidas más relevantes detectados en las áreas agrícolas investigadas fueron los herbicidas bentazona, MCPA y propanil, ampliamente utilizados en el cultivo del arroz en el delta del río Ebro. El río Ter, también afectado por actividades agrícolas intensivas, resultó contaminado en menor medida por bentazona y MCPA. En áreas urbanas e industriales como la cuenca baja del río Llobregat, los compuestos más ubicuos y abundantes fueron bromoxinilo, diurón, linurón y terbutrina, utilizados tanto con fines agrícolas como no agrícolas. En esta zona, muchos de los plaguicidas encontrados superaban el límite de 100 ng/L establecido por la Unión Europea para plaguicidas individuales en aguas destinadas al consumo humano. En los sedimentos del río Llobregat y las muestras de peces recogidas en el río Adige, los plaguicidas presentan propiedades físico-químicas que los hacen más propensos a acumularse en sedimentos o bioacumularse en la biota. La mayoría de los pesticidas detectados en estas matrices están actualmente prohibidos, lo cual sugiere su persistencia en el medio ambiente. Diclorvos e irgarol superaron las concentraciones máximas admisibles establecidas por la Comunidad Europea como normas de calidad ambiental para compuestos prioritarios en aguas superficiales, mientras que los límites máximos aceptables de detección (LODs) establecidos en la Lista de Observación europea fueron superados por acetamiprid, imidacloprid, tiacloprid y metiocarb. La evaluación del riesgo ambiental ha destacado el papel de los plaguicidas como estresores relevantes en el medio acuático. Además, la co-ocurrencia de plaguicidas resulta en un aumento del riesgo en los diversos compartimentos ambientales estudiados, lo que hace necesaria la adopción de medidas para atenuar la contaminación ambiental por plaguicidas. Con este propósito, se exploró la capacidad del hongo T. versicolor para degradar malatión, acetamiprid e imidacloprid. Los resultados apuntan a este organismo como una alternativa eficaz, ecológica y económica para la eliminación de pesticidas del agua. Por otro lado, se diseñaron eventos participativos con el fin de aumentar la conciencia de los agricultores y otras partes interesadas sobre el problema de la contaminación ambiental por plaguicidas, involucrándolos en los procesos de toma de decisiones para motivar la implementación de medidas de mitigación destinadas a reducir la liberación de plaguicidas al medio ambiente.This PhD thesis has been financially supported by the European Union through the research projects WaterProtect (Horizon 2020 - Research and Innovation Framework Programme, No. 727450), GLOBAQUA (Seventh Framework Programme (FP7), No. 265264), and SOLUTIONS (FP7, No. 603437), and by the Ministry of Economy and Competitiveness (MINECO) through the BECAS project (Spanish State Research Agency and European Regional Development Fund (ERDF), CTM2016-75587-C2-2-R). The work conducted within this thesis has been also partially funded by the Government of Catalonia (2017 SGR 01404 and SGR 00014) and the Spanish Ministry of Science and Innovation (Project CEX2018-000794)

Improved fully automated method for the determination of medium to highly polar pesticides in surface and groundwater and application in two distinct agriculture-impacted areas.

It is possible to consult this version in open access at the following web address: arXiv:2011.11639Water is an essential resource for all living organisms. The continuous and increasing use of pesticides in agricultural and urban activities results in the pollution of water resources and represents an environmental risk. To control and reduce pesticide pollution, reliable multi-residue methods for the detection of these compounds in water are needed. In this context, the present work aimed at providing an analytical method for the simultaneous determination of trace levels of 51 target pesticides in water and applying it to the investigation of the target pesticides in two agriculture-impacted areas of interest. The method developed, based on an isotopic dilution approach and on-line solid-phase extraction-liquid chromatography-tandem mass spectrometry, is fast, simple, and to a large extent automated, and allows the analysis of most of the target compounds in compliance with European regulations. Application of the method to the analysis of selected water samples collected at the lowest stretches of the two largest river basins of Catalonia (NE Spain), Llobregat and Ter, revealed the presence of a wide suite of pesticides in the Llobregat basin, some of them at concentrations above the water quality standards (irgarol and dichlorvos) or the acceptable method detection limits (methiocarb, imidacloprid, and thiacloprid), and much cleaner waters in the Ter River basin. Risk assessment of the pesticide concentrations measured in the Llobregat River indicated high risk due to the presence of irgarol, dichlorvos, methiocarb, azinphos ethyl, imidacloprid, and diflufenican (hazard quotient (HQ) values>10), and moderate potential risk in the Ter River, associated to the occurrence of bentazone and irgarol (HQ > 1).This work has received funding from the European Union's Horizon 2020 - Research and Innovation Framework Programme (WaterProtect project, No. 727450), the Spanish State Research Agency (AEI) and the European Regional Development Fund (ERDF) (BECAS project, CTM2016-75587-C2-2-R), the Spanish Ministry of Science and Innovation (Project CEX2018-000794-S), and the Government of Catalonia (2017 SGR 01404). Vinyet Solà from CUADLL and Francesc Camps Saguè from IRTA are acknowledged for their help in the collection of samples from the Llobregat River and the Ter River, respectively.Peer reviewe

KI67 AS A PREDICTOR OF RESPONSE AND LONG TERM SURVIVAL IN HORMONE RECEPTOR POSITIVE/HER2 NEGATIVE BREAST CANCER PATIENTS TREATED WITH PREOPERATIVE CHEMOTHERAPY

Purpose: Breast cancer is a heterogeneous disease, and newer technologies have identified different molecular classes with distinct behaviour. In particular, hormone receptor positive tumors can be classified as luminal A or luminal B subtypes. Luminal A is a true endocrine dependent disease, generally characterized by high hormone receptor expression, low proliferation and HER2 negativity. Luminal B tumors show a more aggressive phenotype, expressed as a higher proliferation and/or HER2 positivity. It is known that hormone receptor positive tumors are less likely to achieve a pathologic complete response (pCR) after preoperative chemotherapy. Aim of the present analysis was to discriminate, on the basis of tumor proliferation as measured by Ki67, patients with hormone receptor positive/HER2 negative tumors with different probability of obtaining a pCR, and with different long term outcome. Patients and Methods: 274 consecutive stage II-III breast cancer patients treated with preoperative chemotherapy were evaluated. Patients were classified as having hormone receptor positive tumors in case of ER and/or PgR >/= 10%. On the basis of immunohistochemical characteristic, patients were classified as follows: Luminal A, in case of hormone receptor positivity, HER2 negativity, and Ki67<15% (16%); Ki67-Luminal B, in case of hormone receptor positivity, HER2 negativity and Ki67 >/= 15% (37%); HER2-Luminal B in case of hormone receptor positivity and HER2 positivity (19%); HER2, in case of hormone receptor negativity and HER2 positivity (8%); triple negative, in case of hormone receptor negativity and HER2 negativity (20%) Results: Patients characteristics were as follows: median age 50 yrs (range: 27-76); clinical stage: IIA 35.7%, IIB 42.3%, III 22%. After a median of 4 courses of preoperative chemotherapy, 46% of the patients underwent conservative surgery. A pCR, as defined as absence of infiltrating tumor in both breast and axillary lymph-nodes, was observed in 28 patients (10.2%). All hormone receptor positive patients received adjuvant hormonal therapy for 5 years after surgery. The probability of obtaining a pCR was significantly lower in patients with hormone receptor positive tumors: 6.8% vs 17.5% in hormone receptor negative, p=0.010. No pCR was observed in the 40 patients classified as having Luminal A tumor; two pCRs only were observed among the 89 patients classified as having Ki67-Luminal B tumors. Patients in the Ki67-Luminal B group had significantly shorter disease-free survival (DFS) as compared with Luminal A patients (5-yr DFS 63% vs 86%, p= 0.0061). The 5-yr overall survival in Ki67-Luminal B group was 88% versus 93% in the Luminal A group. However, with 14 events only, this difference was not statistically significant. Conclusions: In this analysis, patients with Ki67-Luminal B have a worse DFS as compared to patients with Luminal A disease. Due to the limited number of events, no differences in the probability of obtaining a pCR were observed between Luminal A and Ki67-Luminal B tumors

Tumori ginecologici

Introduzione: Le neoplasie ginecologiche, ovvero le neoplasie che insorgono nell’apparato riproduttivo femminile sono, con più di un milione di nuovi casi all’anno il secondo tipo di neoplasia più diffuso nel mondo dopo il carcinoma della mammella e la prima causa di morte con circa 500.000 decessi annui. In Italia, con 14.949 nuovi casi e 5.719 decessi all’anno rappresentano il terzo tipo di neoplasia più diffuso dopo il carcinoma della mammella e del colon-retto e la quarta causa di morte dopo il carcinoma della mammella, del colon-retto e del polmone (GLOBOCAN 2008). I cinque tipi più frequenti di neoplasie ginecologiche sono il carcinoma della cervice uterina, il carcinoma del corpo dell’utero, il carcinoma dell’ovaio, il carcinoma della vulva ed il carcinoma della vagina. Sebbene spesso si tenda a raggruppare questo tipo di neoplasie con il termine di neoplasie ginecologiche, è opportuno ricordare che ognuna di queste neoplasie costituisce un’entità unica, che esordisce con segni e sintomi propri e che presenta prognosi e possibilità terapeutiche differenti. Tutte le donne sono a rischio di sviluppare una neoplasia ginecologica, ma il rischio tende ad incrementare in rapporto all’età. Tra i fattori di rischio, l’unico agente con un rapporto etiopatogenetico certo è l’HPV per il carcinoma della cervice uterina e per alcuni carcinomi della vulva e della vagina. I segni e sintomi più comuni di esordio delle neoplasie ginecologiche sono il sanguinamento vaginale anomalo, intermestruale o post-coitale, il dolore pelvico o addominale, il cambiamento dell’alvo, il bruciore in sede vulvo-vaginale. Il trattamento delle neoplasie ginecologiche si basa sulla chirurgia, sulla chemioterapia e sulla radioterapia, le cui modalità di impiego e finalità sono stabiliti solo dopo un’accurata stadiazione di malattia