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Introduction: The release of neutrophil extracellular traps (NETs) is a key factor contributing to the severity of acute respiratory distress syndromes (ARDS). Identifying potential new pathways that can be targeted to modulate this pathological process will offer insights and open up new treatment possibilities for managing this condition. Aim: To evaluate if cyclic nucleotides stimulators are capable of modulating NETs release in vitro. Methods: We stimulated healthy neutrophils with phorbol myristate acetate (PMA) or serum from severe COVID-19 patients (n = 15) as a model of ARDS condition in the presence and in absence of three different cyclic nucleotides stimulators drugs: the guanylyl cyclase activator cinaciguat (0.5 μg/mL, 1 μg/mL and 5 μg/mL), the phosphodiesterase 5 (PDE5) inhibitor sildenafil (10 μM, 50μM and 100 μM) or the inhibitor of phosphodiesterase-3 (PDE-3) milrinone (100 μM, 250 μM and 500 μM). Cell incubation images were captured using Incucyte after a duration of 1.5 hours. The number of cells that underwent netosis and those that did not were determined and the percentage of netosis was calculated. Images were analyzed by fluorescence. Results: In PMA-stimulated neutrophils, cinaciguat reduced NETs release by 35% at 1μM and 49% at 5μM, but not at the lower concentration of 0.5μM. Sildenafil reduced NETs release by 14% at 50 μM and 62% at 100 μM, but showed no effect at the lower concentration of 10 μM. Milrinone reduced NETs release by 51% at 500μM but not at the lower concentrations of 100 μM and 250 μM. When neutrophils were stimulated with COVID-19 serum, cinaciguat at 5μM reduced NETs release by 30%, sildenafil at 100μM by 19%, and milrinone at 500 μM by 24%, but there was no effect at the lower concentrations of all three drugs. Conclusion: Cinaciguat, sildenafil and milrinone were capable of “in vitro” reducing netosis induced by PMA and COVID-19 serum. Such findings indicate an involvement of cGMP and cAMP in modulating NETs formation and highlight the potential of targeting the production of these cyclic nucleotides as a novel approach for treating ARDS and other inflammatory conditions associated with excessive NETs release.

Introdução: A púrpura trombocitopênica trombótica adquirida (PTTa) tem alta morbimortalidade, sendo o rápido diagnóstico e o tratamento adequado essenciais para o prognóstico dos pacientes. As evidências epidemiológicas e clínicas da PTT são derivadas de registros norte-americanos e europeus. Não há dados brasileiros de apresentação clínica, acesso e resposta ao tratamento ou prognóstico. Objetivo: Investigar o perfil epidemiológico e clínico de pacientes com PTT no Brasil. Métodos: Trata-se de um estudo ambispectivo de coorte, multicêntrico, em que os dados dos pacientes tratados em centros de referência foram coletados utilizando a Plataforma REDcap. Foram analisados evolução clínica, resposta ao tratamento, prognóstico e mortalidade de casos com diagnóstico no período de maio de 2018 a maio de 2023. Para o diagnóstico de PTT foi considerado PLASMIC score maior ou igual a 6 pontos ou dosagem de ADAMTS13 inferior a 10% ou equivalente. Resultados: Completou-se 60 casos, distribuídos em 7 centros, 5 da região sudeste (SP, ES e RJ), um da região nordeste (CE) e um da região sul (PR). A mediana de idade foi de 36 anos (IQR 25 -46), 77% mulheres, 8% haviam episódios prévios de PTT e 6% tinham uma condição clínica subjacente, como doenças reumatológicas, oncológicas ou infecciosas. Quanto à clínica na admissão: 63% apresentavam sangramento leve, 20% febre, 63% alterações neurológicas graves (sintomas focais, confusão mental, convulsão ou coma), 18% sintomas digestivos (náusea, vômitos ou diarreia), 37% elevação de transaminases hepáticas, 20% piora renal (2% necessidade de diálise), 15% elevação de troponina e 8% instabilidade hemodinâmica. Sangramentos e sintomas neurológicos foram os de aparecimento mais precoces, 9 (IQR 4 – 16) e 11 dias (IQR 4-18) antes da hospitalização. A dosagem da atividade da ADAMTS13 estava disponível em 36 casos (60%), sendo todas abaixo compatíveis com PTT. Em relação ao tratamento: 89.7% realizaram plasmaferese (iniciada em média 1 dia após a internação), 95% corticosteroides, 43% rituximabe e 5% caplacizumabe. A mediana de dias de plasmaferese foi 8 (5 -13) e de tempo de internação 13 (IQR 7-28.5); 24% dos pacientes foram inicialmente refratários, 73% tiveram remissão clínica ao final do tratamento e 15% exacerbação da PTT, 17% dos pacientes foram a óbito. Foram associados ao risco de óbito a idade (p = 0.003); diarreia (OR 6.7 95% CI 1.1 - 40.1; p = 0.04) e instabilidade hemodinâmica na admissão (OR 10.3 (95% CI 1.5 - 72.8; p = 0.02). Total de 22 pacientes finalizaram 12 meses de seguimento, com 6 casos de recidiva (4 nos primeiros 6 meses), 7 casos com sequelas neurológicas (cefaleia crônica), 3 com sequelas cardiovasculares (hipertensão) e 2 psiquiátricas (ansiedade, depressão). O uso de rituximabe na fase aguda da PTT mostrou-se como o principal fator associado à ausência de recidiva nos 6 meses seguintes ao tratamento (p < 0,001). Discussão/Conclusão: A distribuição de sexo e idade foi semelhante à de outras coortes (Registro Francês, Oklahoma, Japonês, Harvard), sugerindo que essas características da PTT são consistentes entre populações geograficamente distintas. Em comparação com as coortes mais recentes, observamos um tempo prolongado para o diagnóstico (acima de 10 dias), uma alta prevalência de sintomas neurológicos graves e colapso cardiovascular já ao diagnóstico, tempo prolongado para a recuperação plaquetária acima de 10 dias) e duração da internação, e uma alta mortalidade relacionada ao quadro agudo.

Objetivos: O objetivo deste estudo é avaliar se há aumento do risco trombótico em pacientes portadores de trombocitopenia imune (PTI), especialmente nos pacientes submetidos à esplenectomia. Métodos: Estudo de coorte, retrospectivo, unicêntrico, com pacientes acima de 18 anos diagnosticados com PTI e que foram atendidos entre os anos de 2005 e 2021. Foi realizada análise descritiva de dados demográficos e clínicos, além de descrição do desfecho através da frequência de trombose no grupo submetido à esplenectomia (expostos) e não submetido à esplenectomia (não expostos), pareados por sexo, idade e tempo de diagnóstico, com comparação entre esses valores. Foram excluídos os casos de PTI secundária doenças infecciosas, neoplasia, imunodeficiência comum variável ou lúpus eritematoso sistêmico. Resultados: Foram incluídos 152 pacientes não esplenectomizados e 90 pacientes esplenectomizados. Em ambos os grupos houve predominância de pacientes do sexo feminino (75.5% e 78%), com mediana de idade à admissão de 34 e 32 anos respectivamente. A presença de hipertensão arterial sistêmica foi mais frequente no grupo esplenectomizado (27.7% vs. 16.6% p = 0.032). Não houve diferença estatística em relação à presença de anticorpos antifosfolípides entre os dois grupos e foi encontrada uma maior tendência à presença de fator antinuclear no grupo não esplenectomizado (28% vs. 18.1%; p = 0.07). Dos 242 pacientes, 226 (93%) necessitaram de ao menos uma linha de tratamento. Em relação ao desfecho, a trombose ocorreu em 13 pacientes esplenectomizados (14.4%) contra 7 pacientes não esplenectomizados (4.6%). Portanto, a esplenectomia aumentou em três vezes o risco de trombose (OR 3.6, 95% CI 1.3 – 9.1; p = 0.01). Este risco permaneceu após ajuste para sexo, idade, presença de anticorpos antifosfolípides e comorbidades. Dos 13 pacientes que apresentaram trombose no grupo esplenectomizado, houve predominância de tromboembolismo venoso (TEV) em 53.7% dos pacientes e trombose esplâncnica em 38.4%, sendo que um paciente teve trombose arterial e venosa concomitantemente. Oito desses eventos foram considerados provocados, sendo 5 dos 13 eventos (38.5%) associados à esplenectomia (< 90 dias). A mediana de contagem plaquetária no momento da trombose foi de 172.000/mm3 (IQR 33.5 – 367). Já em relação ao grupo não esplenectomizado, sete (4.6%) pacientes apresentaram trombose, sendo cinco eventos venosos (71.4%) e dois eventos arteriais (28.6%). Houve maior prevalência de TEV (57%). A maioria dos eventos foi não provocado (71.4%) e a mediana de contagem plaquetária ao desenvolvimento de trombose foi de 184000/mm3 (IQR 60 – 295). Discussão: Na nossa coorte, foi encontrado que a esplenectomia aumenta em três vezes o risco de desenvolvimento de trombose. Nos últimos anos vem sendo descritos eventos trombóticos venosos e arteriais em pacientes portadores de PTI, entretanto a causa de hipercoagulabilidade destes pacientes ainda é desconhecida. Considera-se que a própria doença leva a um risco trombótico aumentado, em especial quando associada a alguns tratamentos, como esplenectomia, e a fatores pessoais, como presença de comorbidades cardiovasculares e anticorpos antifosfolípides. Conclusão: A esplenectomia, apesar de ser um tratamento bem tolerado e com possibilidade de remissão duradoura da PTI à longo prazo, leva a um risco trombótico persistentemente aumentado em pacientes portadores de PTI.

Introdução: A SAF é uma doença sistêmica imunomediada caracterizada por trombose arterial ou venosa recorrente ou morbidades obstétricas acompanhadas por anticorpos antifosfolipídeos. A metabolômica permite a compreensão da função dos metabólitos no organismo, fornecendo informações sobre as vias biológicas que são comprometidas pela doença ou levam a alterações relacionadas a ela. Objetivo: Diagnosticar o TEV por meio da metabolômica em pacientes trombóticos sem SAF e com SAF primária Trombótica (SAF-T), comparando com o Controle Saudável (CS). Material e métodos: Pacientes com trombose arterial ou venosa atendidos no ambulatório do Hemocentro da Unicamp entre 2009 e 2020. Os critérios de exclusão foram: SAF secundária, infecção, doença reumatológica, renal, hepática e uso de corticosteroides. Foram selecionados 3 grupos de pacientes: evento venoso ou arterial sem SAF (TEV) (n = 32), SAF-T (n = 32) e CS (n = 32). O diagnóstico de SAF-T foi confirmado com perfil antifosfolípide, seguindo os guidelines do ISTH e SCLI. Os pacientes selecionados foram pareados por idade e sexo com os grupos TEV e controle. No momento da inclusão, foram obtidas informações clínicas e amostras de soro, os quais foram posteriormente analisadas por Ressonância Magnética Nuclear (1H-NMR). Resultados e discussão: Nos grupos VTE e CS, a maior parte foi composta por mulheres, enquanto na SAF-T por homens. Os pacientes com eventos arteriais representaram 12,5% no SAF-T e 3,1% no TEV. Os eventos trombóticos foram considerados como provocados em 25% SAF-T e 64,5% TEV. Os fatores de risco transitório menor foram observados em 71,4% SAF-T e 65% TEV. Fatores de risco transitório maior foram observados em 14,3% SAF-T e 25% TEV. Fatores de risco persistente foram observados em 14,3% SAF-T e 10% TEV. A localização dos eventos trombóticos foi: membros inferiores proximais 43,8% SAF-T e 59,4% TEV, e TEP 21,9% SAF-T e 43,8% TEV. Nos pacientes do SAF-T 87,5% e 6,3% do TEV estavam sob anticoagulação perene, e aqueles com trombose arterial prévia utilizavam ainda a aspirina como tratamento. Na metabolômica, o grupo TEV apresentou concentrações reduzidas de creatinina, glicose, lisina e glutamina, e concentrações aumentadas de valina, treonina, histidina e tirosina quando comparado ao CS. O grupo SAF-T apresentou concentrações reduzidas de lipídios, valina, lisina e glutamina e concentrações aumentadas de isoleucina e treonina (p < 0,002) em relação ao CS. Comparando os grupos TEV e SAF-T, não houve diferença estatisticamente significativa. Ao avaliar o subgrupo de pacientes triplo-positivos (n = 9) de SAF-T e pareá-lo com o grupo de TEV foi possível verificar maiores quantidades de glicose, lisina, glutamato, tirosina, 3-hidroxi-butirato e metileno de lipídios neste subgrupo, enquanto o grupo de pacientes com TEV apresentou maiores quantidades de glicerol, lipídios, valina, isoleucina, fenilalanina e colina. Conclusão: As mudanças nos metabólitos indicaram alterações importantes nas vias metabólicas da glicólise, ciclo TCA, metabolismo de lipídios e metabolismo de aminoácidos de cadeia ramificada (BCAA), envolvendo mecanismos complexos de patogênese da SAF-T e TEV. Estes metabólitos podem ser potenciais biomarcadores para diferenciar pacientes com SAF-T e TEV, incluindo o parâmetro do perfil antifosfolípide para pacientes com SAF.

Objectives: To test for specific anthropometric parameters to predict perioperative outcomes after thermal ablation (TA) for renal cell carcinoma (RCC)., Materials and Methods: Retrospective single center (2008-2022) analysis of 538 T1a-b RCC patients treated with TA. We tested for specific anthropometric parameters, namely skin to tumor distance (STTD), perirenal fat thickness (PFT), median psoas muscle axial area (PMAA) and median paravertebral muscle axial area (PVMAA), to predict TRIFECTA achievement: (1) absence of CLAVIEN-DINDO≥ 3 complications; (2) complete ablation; (3) absence of ≥ 30% decrease in eGFR. Univariable (ULRM) and multivariable logistic regression models (MLRM) were used for testing TRIFECTA achievement., Results: Overall, 103 patients (19%) did not achieve TRIFECTA. Of all anthropometric factors, only lower PMAA was associated with no TRIFECTA achievement (10 vs. 11 cm 2 , P = .02). However, ULRMs and MLRMs did not confirmed the aforementioned association. We than tested for the 3 specific TRIFECTA items. In separate ULRM and MLRM predicting incomplete ablation, both continuously coded STTD (Odds Ratio [OR]: 1.02; CI: 1.01-1.03; P = .02) and STTD strata (STTD > 10 cm; OR: 2.1; CI: 1.1-4.1; P = .03) achieved independent predictor status. Conversely, in separate ULRM and MLRM predicting CLAVIEN-DINDO ≥3 complications, both continuously coded PFT (OR: 1.04; CI: 1.01-1.07; P = .01) and PFT strata (PFT ≥ 14 mm; OR: 3.3; CI: 1.6-10.2; P = .003) achieved independent predictor status. Last, none of the anthropometric parameters were associated with eGFR decrease ≥ 30%., Conclusion: None of the tested anthropometric parameters predicted TRIFECTA achievement. However, when the 3 specific TRIFECTA items were tested, STTD and PFT were associated with, respectively, incomplete ablation and CLAVIEN-DINDO ≥ 3 complications., Competing Interests: Disclosure None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Study Objective: More than 13 million laparoscopic procedures are performed globally every year. The LevaLap 1.0 device may facilitate safe abdominal access when using the Veress needle for initial abdominal insufflation during laparoscopic surgery. We undertook this study to test the hypothesis that use of the LevaLap 1.0 would increase the distance from the abdominal wall to underlying viscera and the retroperitoneum, including from major vessels., Design: Prospective cohort study., Setting: Referral center., Patients: Eighteen patients scheduled to undergo an interventional radiology procedure under general anesthesia and muscle relaxation., Interventions: Application of the LevaLap 1.0 device on the umbilicus and on Palmer's point, during computed tomography scanning., Measurements: Distance from the abdominal wall to the underlying bowel and to retroperitoneal blood vessels and more distant intra-abdominal organs before and after vacuum was applied to the LevaLap 1.0., Main Results: The device did not significantly increase the distance from the abdominal wall to the immediate underlying bowel. Alternatively, the LevaLap 1.0 created a significant increase in the distance between the abdominal wall at the access point and more distant intra-abdominal organs at the umbilicus and at Palmer's point (mean ± SD: +3.91 ± 2.32 cm, p = .001, and +3.41 ± 3.12 cm, p = .001, respectively). At the umbilicus, the device increased the distance between the abdominal wall and the anterior wall of the vena cava by +5.32 ± 1.22 cm (p = .004) or the anterior wall of the aorta by 5.49 ± 1.40 cm (p = .004). At Palmer's point, the device increased the distance between the anterior abdominal wall and the colon and/or small bowel by 2.13 ± 1.81 cm (p = .023). No adverse events were reported., Conclusions: The LevaLap 1.0 increased the distance between abdominal wall and major retroperitoneal blood vessels by >5 cm, promoting safer access during Veress needle insufflation when performing laparoscopic surgery., (Copyright © 2023 AAGL. Published by Elsevier Inc. All rights reserved.)

Objectives: To test TRIFECTA achievement [1) absence of CLAVIEN-DINDO ≥3 complications; 2) complete ablation; 3) absence of ≥30% decrease in eGFR] and local recurrence rates, according to tumor size, in patients treated with thermal ablation (TA: radiofrequency [RFA] and microwave ablation [MWA]) for small renal masses., Methods: Retrospective analysis (2008-2020) of 432 patients treated with TA (RFA: 162 vs. MWA: 270). Tumor size was evaluated as: 1) continuously coded variable (cm); 2) tumor size strata (0.1-2 vs. 2.1-3 vs. 3.1-4 vs. >4 cm). Multivariable logistic regression models and a minimum P-value approach were used for testing TRIFECTA achievement. Kaplan-Meier plots depicted local recurrence rates over time., Results: Overall, 162 (37.5%) vs. 140 (32.4%) vs. 82 (19.0%) vs. 48 (11.1%) patients harboured, respectively, 0.1 to 2 vs. 2.1 to 3 vs. 3.1 to 4 vs. >4 cm tumors. In multivariable logistic regression models, increasing tumor size was associated with higher rates of no TRIFECTA achievement (OR:1.11; P< 0.001). Using a minimum P-value approach, an optimal tumor size cut-off of 3.2 cm was identified (P< 0.001). In multivariable logistic regression models, 3.1 to 4 cm tumors (OR:1.27; P< 0.001) and >4 cm tumors (OR:1.49; P< 0.001), but not 2.1 to 3 cm tumors (OR:1.05; P= 0.3) were associated with higher rates of no TRIFECTA achievement, relative to 0.1 to 2 cm tumors. The same results were observed in separate analyses of RFA vs. MWA patients. After a median (IQR) follow-up time of 22 (12-44) months, 8 (4.9%), 8 (5.7%), 11 (13.4%), and 5 (10.4%) local recurrences were observed in tumors sized 0.1 to 2 vs. 2.1 to 3 vs. 3.1 to 4 vs. >4 cm, respectively (P= 0.01)., Conclusion: A tumor size cut-off value of ≤3 cm is associated with higher rates of TRIFECTA achievement and lower rates of local recurrence over time in patients treated with TA for small renal masses., Competing Interests: Conflicts of interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give patients, health professionals, managers and policymakers a guide to essential care throughout the patient journey. Pancreatic cancer is an increasing cause of cancer mortality and has wide variation in treatment and care in Europe. It is a major healthcare burden and has complex diagnosis and treatment challenges. Care must be carried out only in pancreatic cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals detailed here. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Arachidonic acid (AA) is a fatty acid involved in the modulation of several ion channels. Previously, we reported that AA activates the high conductance Ca 2+ - and voltage-dependent K + channel (BK) in vascular smooth muscle depending on the expression of the auxiliary β1 subunit. Here, using the patch-clamp technique on BK channel co-expressed with β1 subunit in a heterologous cell expression system, we analyzed whether AA modifies the three functional modules involved in the channel gating: the voltage sensor domain (VSD), the pore domain (PD), and the intracellular calcium sensor domain (CSD). We present evidence that AA activates BK channel in a direct way, inducing VSD stabilization on its active configuration observed as a significant left shift in the Q-V curve obtained from gating currents recordings. Moreover, AA facilitates the channel opening transitions when VSD are at rest, and the CSD are unoccupied. Furthermore, the activation was independent of the intracellular Ca 2+ concentration and reduced when the BK channel was co-expressed with the Y74A mutant of the β1 subunit. These results allow us to present new insigths in the mechanism by which AA modulates BK channels co-expressed with its auxiliary β1 subunit., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Tumorigenesis is a complex and dynamic process involving different cellular and non-cellular elements composed of tumor microenvironment (TME). The interaction of TME with cancer cells is responsible for tumor development, progression and drug resistance. TME consists of non malignant cells of the tumor such as cancer associated fibroblasts (CAFs), endothelial cells and pericytes composing tumor vasculature, immune and inflammatory cells, bone marrow derived cells, and the extracellular matrix (ECM) establishing a complex cross-talk with tumor. These interactions contribute towards proliferation and invasion of the tumor by producing growth factors, chemokines and matrix-degrading enzymes. ECM is a complex system containing macromolecules with distinctive physical, biochemical and biomechanical properties. During tumorigenesis this system is deregulated favoring the generation of tumorigenic microenvironment enhancing tumor-associated angiogenesis and inflammation. An important step of anticancer treatment is the identification of the biological alterations present in TME in order to target these key molecular players. Multitargeted approaches, providing a simultaneous inhibition of TME components, may offer a more efficient way to treat cancer. In this manuscript we overview the function of each components of TME and the treatments targeting the key players., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Molecular profiling of metastatic disease may greatly influence the systemic therapy recommended by oncologists and chosen by patients, allowing treatment to be more targeted. Comprehensive care of patients with advanced breast cancer now includes percutaneous image-guided biopsy if this has the potential to influence systemic treatment [1]. Interventional radiologists can contribute significantly to the care of patients affected by breast cancer, in diagnostic and supportive procedures and importantly also in treatment. Interventional radiologists carry out image guided percutaneous biopsies not only of the primary tumour but also of metastases. They insert percutaneous ports and tunnelled central venous catheters. They ablate painful bone metastases, and can treat or prevent pathological fractures. Most importantly they can ablate liver metastases in patients with limited or oligometastatic disease. The inhomogeneity and variety of cell populations in metastatic tumours from breast cancer, which is an important consideration in systemic therapy, is not an important consideration in the treatment of metastatic tumours using percutaneous ablative techniques, which are the major focus of this article. The treatment of primary tumours in the breast is also being explored, but is considered in its infancy at this stage., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: The purpose of the study was to evaluate the feasibility of irradiation after prostatectomy in the presence of asymptomatic pelvic lymphocele., Patients and Methods: The inclusion criteria for this study were: (1) patients referred for postoperative (adjuvant or salvage) intensity modulated radiotherapy (IMRT; 66-69 Gy in 30 fractions); (2) detection of postoperative pelvic lymphocele at the simulation computed tomography [CT] scan; (3) no clinical symptoms; and (4) written informed consent. Radiotherapy toxicity and occurrence of symptoms or complications of lymphocele were analyzed. Dosimetric data (IMRT plans) and the modification of lymphocele volume during radiotherapy (cone beam CT [CBCT] scan) were evaluated., Results: Between January 2011 and July 2013, in 30 of 308 patients (10%) treated with radiotherapy after prostatectomy, pelvic lymphocele was detected on the simulation CT. The median lymphocele volume was 47 cm(3) (range, 6-467.3 cm(3)). Lymphocele was not included in planning target volume (PTV) in 8 cases (27%). Maximum dose to lymphocele was 57 Gy (range, 5.7-73.3 Gy). Radiotherapy was well tolerated. In all but 2 patients, lymphoceles remained asymptomatic. Lymphocele drainage-because of symptom occurrence-had to be performed in 2 patients during IMRT and in one patient, 7 weeks after IMRT. CBCT at the end of IMRT showed reduction in lymphocele volume and position compared with the initial data (median reduction of 37%), more pronounced in lymphoceles included in PTV., Conclusion: Radiotherapy after prostatectomy in the presence of pelvic asymptomatic lymphocele is feasible with acceptable acute and late toxicity. The volume of lymphoceles decreased during radiotherapy and this phenomenon might require intermediate radiotherapy plan evaluation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: The complication rate, loco-regional responses and length of hospital stay were analyzed in patients with liver and kidney cancer older than 70years treated with interventional oncology procedures. The findings from the older population were compared with the younger patients (<70years) to detect any difference not related to chance., Materials and Methods: Prospectively collected data on patients who underwent hepatic artery embolization (with or without radiofrequency ablation) and kidney radiofrequency ablation were retrospectively analyzed. Complication rates, loco-regional responses and length of hospital stay for patients older and younger than 70 were compared., Results: 163 patients were treated, 66 (40.5%) older and 97 (59.5%) younger than 70years. The complication rate in patients older than 70 was 4.5% (3/66 pts) versus 3.1% (3/97 pts) (p=0.69) in the younger age-group. The complication rates for the liver embolization group, liver embolization plus radiofrequency and kidney radiofrequency group were 2/90 pts (2.2%), 2/42 pts (4.8%) and 2/31 pts (6.5%), respectively (p=0.46). Median hospital stay was three nights in both older and younger patients. Response rates were not significantly influenced by age., Conclusion: Liver embolization with or without radiofrequency and renal radiofrequency are safe and effective in older patients. Age alone should not be considered a contraindication to treatment in carefully selected patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Biopsy of metastatic site of disease can influence treatment decisions, but its impact on survival remains uncertain., Patients and Methods: One-hundred patients with first metachronous liver metastases (LM) from breast cancer (BC) who underwent liver biopsy between 1999 and 2009 were identified. One-hundred matched control patients with LM from BC and no biopsy were selected., Results: Liver biopsy had no statistically significant impact on survival when comparing biopsied patients to controls [HR 0.82 (95% CI 0.58-1.16)]. Patients with early metastasis (within 3 years) undergoing liver biopsy had a better survival [HR 0.60 (95% CI 0.38-0.97)] compared to those who did not. Liver biopsy had no statistically significant impact on survival in patients with late LM (after 3 years) [HR 1.09 (95% CI 0.69-1.74)]. We observed that 18 out of 100 biopsied patients (18.0%) had a conversion of predictive factors which allowed adjusting for therapy, specifically new expression of ER (n=5), overexpression of HER2 (n=12) or both (n=1). Fourteen out of 18 (77.8%) received anti-HER2 treatment for the first time at the time of metastasis and 3 others (16.7%) received hormone therapy. Those 18 patients showed a better survival compared to the other 82 biopsied patients [HR 0.55 (95% CI 0.28-1.10)] and compared to the 13 biopsied patients with disappearance of features which predicted responsiveness to a given treatment [HR 0.19 (95% CI 0.06-0.62)]., Conclusions: Liver biopsy can impact survival of patients with early metastases from BC. Discordance between primary and distant lesions can offer the patients new treatment options., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Currently, the acquisition of tissue from metastatic deposits is not recommended as a routine practice. Our aim was to evaluate the discordance rate of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) receptor status between primary tumor and liver metastases and its potential impact on treatment choice., Patients and Methods: We retrospectively analyzed a database including 1250 ultrasound-guided liver biopsies carried out at the European Institute of Oncology from August 1999 to March 2009. ER, PgR, and HER2 status were determined by immunohistochemistry and/or FISH. Differences between proportions were evaluated using Fisher's exact test., Results: We identified 255 consecutive patients with matched primary and liver tissue samples. Changes in ER status were observed in 37 of 255 patients (14.5%). Changes in PgR status were observed in 124 of 255 patients (48.6%). Changes in HER2 status were observed in 24 of 172 assessable patients (13.9%). We observed a discordance in receptor status (ER, PgR, and HER2) between primary tumor and liver metastases, which led to change in therapy for 31 of 255 of patients (12.1%)., Conclusions: Biopsy of metastases for reassessment of biological features should be considered in all patients, when safe and easy to carry out, since it is likely to impact treatment choice.

Organised since 1990 in France, cancer genetics has been strengthened since 2003 by the programme "Plan Cancer" which resulted in an improvement of the organisation of activities. The aim of this review is to present an update of the estimation of the needs of the population in this field for the next ten years, provided by a group of experts mandated by the French National Cancer Institute. Identification and management of major hereditary predispositions to cancer have a major impact on decrease in mortality and incidence. Sensitivity of criteria for the detection of BRCA1/2 mutations could be substantially improved by enlarging the indication for genetic testing to isolated cases of ovarian cancer occurring before 70 years and to familial cases occurring after this age limit. In the Lynch syndrome, the present criteria would have an excellent sensitivity for the detection of mutations in the mismatch repair (MMR) genes if the pre-screening of tumours on microsatellite instability (MSI) phenotype was effective, but these criteria are actually poorly applied. However, genetic testing should not be proposed to all the patients affected by tumours belonging to the spectrum of major predispositions and a fortiori to unaffected persons unless an affected relative has been identified as a carrier. The prescription of tests should continue to be strictly controlled and organised, in patients as well as in at-risk relatives. The enlargement of criteria and the improvement in the spreading of recommendations should result in an increase of genetic counselling activity and of the prescriptions of tests by a factor 2 to 4, and to a lesser extent in the clinical management of at risk persons. In a near future, it appears important to mandate experts on specific issues such as the determinants of the lack of effective application of tumour screening for MSI phenotype, the recommendations for the identification and the management of MYH-associated polyposis, or the predictive value of tumour characteristics for the identification of BRCA1/2 mutations. The expected increase in cancer genetics activity will need an optimal organisation to increase the throughput. Such measures will help in facing up to new predispositions that will probably be identified in common cancers.

Background: Central venous access is extensively used in oncology, though practical information from randomized trials on the most convenient insertion modality and site is unavailable., Methods: Four hundred and three patients eligible for receiving i.v. chemotherapy for solid tumors were randomly assigned to implantation of a single type of port (Bard Port, Bard Inc., Salt Lake City, UT), through a percutaneous landmark access to the internal jugular, a ultrasound (US)-guided access to the subclavian or a surgical cut-down access through the cephalic vein at the deltoid-pectoralis groove. Early and late complications were prospectively recorded until removal of the device, patient's death or ending of the study., Results: Four hundred and one patients (99.9%) were assessable: 132 with the internal jugular, 136 with the subclavian and 133 with the cephalic vein access. The median follow-up was 356.5 days (range 0-1087). No differences were found for early complication rate in the three groups {internal jugular: 0% [95% confidence interval (CI) 0.0% to 2.7%], subclavian: 0% (95% CI 0.0% to 2.7%), cephalic: 1.5% (95% CI 0.1% to 5.3%)}. US-guided subclavian insertion site had significantly lower failures (e.g. failed attempts to place the catheter in agreement with the original arm of randomization, P = 0.001). Infections occurred in one, three and one patients (internal jugular, subclavian and cephalic access, respectively, P = 0.464), whereas venous thrombosis was observed in 15, 8 and 11 patients (P = 0.272)., Conclusions: Central venous insertion modality and sites had no impact on either early or late complication rates, but US-guided subclavian insertion showed the lowest proportion of failures.

Background: To analyze the influence of the prothrombotic gene mutation factor V G1691A (factor V Leiden) and prothrombin G20210A on the risk of a first episode of catheter-related deep venous thrombosis (DVT) in a group of patients with breast cancer treated with chemotherapy., Patients and Methods: Between January 1999 and February 2001, the occurrence of a first symptomatic DVT was investigated in a cohort of 300 consecutive patients with locally advanced or metastatic breast cancer treated at a single institution with fluorouracil-based chemotherapy, administered continuously through a totally implanted access port. A nested case-control study included 25 women (cases) with catheter-related DVT and 50 controls without DVT matched with cases for age, identical chemotherapy, stage of disease and prognostic features. The G1691A factor V and G20210A prothrombin mutation genotypes were analyzed., Results: Five cases [20%; 95% confidence interval (CI) 9% to 39%)] and two controls (4%; 95% CI 1% to 14%) were heterozygous carriers of G1691A factor V (P = 0.04). The age-adjusted odds ratio for catheter-related DVT was 6.1 (95% CI 1.1-34.3). Only one patient (case) had the G20210A prothrombin gene mutation. Time from start of chemotherapy infusion to DVT was not significantly different between patients with (median 31 days) and without (median 43 days) G1691A factor V mutation (P = 0.6)., Conclusions: Factor V Leiden carriers with locally advanced or metastatic breast cancer have an increased risk of developing catheter-related DVT during chemotherapy.

Several antioxidants have been shown to reduce lysosomal phospholipidosis, which is a potential mechanism of amiodarone toxicity, and prevent amiodarone toxicity by antioxidant and/or non-antioxidant mechanisms. The aim of this study was to test whether the co-administration of two structurally different antioxidants vitamin E and silymarin with amiodarone can reduce amiodarone-induced lysosomal phospholipidosis, and if yes, by reducing the tissue concentration of amiodarone and desethylamiodarone or by their antioxidant action. To this end, male Fischer 344 rats were treated by gavage once a day for 3 weeks and randomly assigned to the following four experimental groups: 1, control; 2, amiodarone (150 mg/(kg per day)); 3, amiodarone (150 mg/(kg per day)) plus vitamin E (100 mg/(kg per day)); 4, amiodarone (150 mg/(kg per day)) plus silymarin (60 mg/(kg per day)) treated groups. Total plasma phospholipid (PL), liver-conjugated diene, thiobarbituric acid reactive substances (TBARSs), amiodarone and desethylamiodarone concentrations were determined and the extent of lysosomal phospholipidosis in the liver was estimated by a semi-quantitative electron microscopic method. Amiodarone treatment increased significantly the liver-conjugated diene (P<0.001), TBARS (P=0.012), plasma total PL (P<0.001) concentrations compared with control. Antioxidants combined with amiodarone significantly decreased the liver-conjugated diene (P<0.001 for both), TBARS (P=0.016 for vitamin E, P=0.053 borderline for silymarin) and plasma total PL (P=0.058 borderline for vitamin E, P<0.01 for silymarin) concentrations compared with amiodarone treatment alone. Silymarin significantly (P=0.021) reduced liver amiodarone, but only tended to decrease desethylamiodarone concentration; however, vitamin E failed to do so. Amiodarone treatment increased lysosomal phospholipidosis (P<0.001) estimated by semi-quantitative electron microscopic method and both antioxidants combined with amiodarone reduced significantly (P<0.001 for both) the amiodarone-induced lysosomal phospholipidosis. In conclusion, silymarin presumably reduced lysosomal phospholipidosis by both antioxidant action and its liver amiodarone concentration decreasing effect, while vitamin E exerted similar effect by antioxidant action alone. Thus, both antioxidant action and inhibition of tissue uptake of amiodarone might have an important role in the preventative effect of antioxidants against amiodarone toxicity.

Background: A few data are available from analyses of the complications and costs of central venous access ports for chemotherapy. This prospective study deals with the complications and global costs of central venous ports connected to a Groshong catheter for deliverance of long-term chemotherapy., Patients and Methods: Patients with a variety of solid neoplastic diseases requiring chemotherapy who were undergoing placement of implantable ports over a 30-month period (1 October 1994 to 31 March 1997) have been prospectively studied. Follow-up continued until the device was removed or the study was closed (30 September 1997); patients with uneventful implant experience and subsequent follow-ups of less than 180 days were not considered for this study. A single port, constructed of titanium and silicone rubber (Dome Port, Bard Inc., Salt Lake City, USA), was used, connected to an 8 F silastic Groshong catheter tubing (Bard Inc., Salt Lake City, USA). Two-hundred ninety-six devices were placed in the operating room under fluoroscopic control even in the patients treated and monitored in a day-hospital setting: 37 of them were in an angiographic suite. A central venous access form was filled in by the operator after the procedure and all ports were followed prospectively for device-related and overall complications. The average purchase cost of the device was obtained from the hospital charges, based on the costs applied during the 30-month period of the study. Insertion and maintenance costs were estimated by obtaining the charges for an average TIAP implant and its subsequent use; the costs of complication management were assessed analytically. The total cost of each device was defined as the purchase cost plus the insertion cost plus the maintenance cost plus the cost of treatment of the complications, if any. The cost of removing the TIAP was also included in the economic analysis when required by the treatment of the complication., Results: Three hundred thirty-three devices, for a total of 79,178 days in situ, were placed in 328 patients. Five patients received second devices after removal of the first. In all cases the follow-up was appropriate (median 237 days, range 180-732). Early complications included 10 pneumothoraxes (3.4%; six tube-thoracostomies were applied, 1.8%) and six revisions for port and/or catheter malfunction (overall early complications = 16, 4.48%). Late complications comprised five instances of catheter rupture and embolization (1.5%, 0.063 episodes/1000 days of use), five of venous thrombosis (1.5%, 0.063 episodes/1000 days of use), one of pocket infection (0.3%, 0.012 episodes/1000 days of use), and eight of port-related bacteremia (2.4%, 0.101 episodes/1000 days of use). The infections were caused by coagulase-negative Staphylococcus aureus (five cases), Bacillus subtilis (one case), Streptococcus lactaceae (one case) and an unknown agent (one case); port removal was necessary in six of eight cases. The total cost per patient treated for a six-month period, consisting of the costs of purchase and implantation, treatment of early and late complications, and of maintenance of the device, is US$1,970., Conclusions: This study represents the largest published series of patients with totally implantable access ports connected to a Groshong catheter. We have shown that US$2,000 are sufficient to cover six months of chemotherapy in one patient using the most expensive commercially available implantable port. According to the present study, totally implantable access ports connected to a Groshong catheter are associated with high purchase and insertion costs, a low complication rate and low maintenance costs. These data support their increasing use in current oncologic medical practice.