Morbilidad relacionada con el momento de la linfadenectomía por afectación del ganglio centinela en el melanoma: Una puntualización a su evidencia / Morbidity Associated With the Timing of Lymphadenectomy for Sentinel Lymph Node Metastasis in Melanoma: A Clarification Concerning the Available Evidence

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Mitotic rate as an important prognostic factor in cutaneous malignant melanoma.

BACKGROUND: Recently, the quantification of mitoses in cutaneous melanoma has been discharged from the main prognostic variables of the TNM classification. OBJECTIVE: To investigate the prognostic value of the presence of mitoses in primary cutaneous melanoma and to establish the number of mitoses per mm2 that may have prognostic significance. METHODS: A retrospective observational study was performed on 141 patients treated for cutaneous melanoma, who were assessed by the same pathologist, and who had a minimum follow-up of 2 years. Clinical, epidemiological, histopathological and follow-up variables were gathered and compared with the number of mitoses to distinguish the significance of differences by means of univariate, multivariate, and survival analyses. RESULTS: The cut-off level related to a better sensitivity and specificity was 1.50 mitoses per mm2. The presence of two or more mitoses/mm2 showed a better relationship with prognostic variables and both the overall and disease-free survival than the presence of 1 or more mitoses/mm2. This happens especially in melanomas thicker than 0.8 mm and it could affect the staging in cases with Breslow between 1 and 2 mm. CONCLUSIONS: A mitotic rate of two or more mitoses per mm2 in cutaneous melanoma should be considered as a more accurate prognostic factor than one or more mitoses per mm2, particularly in tumors equal or greater than 0.8 mm in thickness.

Usefulness of lymphocyte-to-monocyte, neutrophil-to-monocyte and neutrophil-to-lymphocyte ratios as prognostic markers in breast cancer patients treated with neoadjuvant chemotherapy

Background. Nowadays, neoadjuvant chemotherapy (nCT) in breast cancer is more and more standardized, not only in advanced tumours but also in those for which there is an attempt to achieve breast-conserving surgery. In literature, we can find evidences of the relationship between several types of tumours and systemic inflammatory response. Our objective is to analyse the prognostic value of blood parameters (lymphocytes, neutrophils, monocytes, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-monocyte ratio (NMR) and neutrophil-to-lymphocyte ratio (NLR) in breast cancer (BC) patients treated with nCT. Methods. A retrospective cohort of 150 breast cancer patients treated with nCT and subsequently with surgery was analysed. Data about the patients, histology, response to chemotherapy and peripheral blood values of lymphocytes, monocytes and neutrophils was collected, and used to calculate the LMR, NMR and NLR. Univariate and multivariate analyses were performed for the variables to see the relationship of the ratios to disease-free survival (DFS) and overall survival (OS). Results. Patients with high LMR (≥5.46) and low NLR (<3.33) were associated with a lower percentage of relapse (P = 0.048 and P = 0.015, respectively) and, above all, NLR was associated with a better survival (P = 0.024), being those factors that predict a good progress. Conclusion. High LMR and low NLR can be considered as favourable prognostic factors in BC patients treated with nCT (AU)

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Usefulness of lymphocyte-to-monocyte, neutrophil-to-monocyte and neutrophil-to-lymphocyte ratios as prognostic markers in breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Nowadays, neoadjuvant chemotherapy (nCT) in breast cancer is more and more standardized, not only in advanced tumours but also in those for which there is an attempt to achieve breast-conserving surgery. In literature, we can find evidences of the relationship between several types of tumours and systemic inflammatory response. Our objective is to analyse the prognostic value of blood parameters (lymphocytes, neutrophils, monocytes, lymphocyte-to-monocyte ratio (LMR), neutrophil-to-monocyte ratio (NMR) and neutrophil-to-lymphocyte ratio (NLR) in breast cancer (BC) patients treated with nCT. METHODS: A retrospective cohort of 150 breast cancer patients treated with nCT and subsequently with surgery was analysed. Data about the patients, histology, response to chemotherapy and peripheral blood values of lymphocytes, monocytes and neutrophils was collected, and used to calculate the LMR, NMR and NLR. Univariate and multivariate analyses were performed for the variables to see the relationship of the ratios to disease-free survival (DFS) and overall survival (OS). RESULTS: Patients with high LMR (≥5.46) and low NLR (<3.33) were associated with a lower percentage of relapse (P = 0.048 and P = 0.015, respectively) and, above all, NLR was associated with a better survival (P = 0.024), being those factors that predict a good progress. CONCLUSION: High LMR and low NLR can be considered as favourable prognostic factors in BC patients treated with nCT.

Tumor suppressor SET9 guides the epigenetic plasticity of breast cancer cells and serves as an early-stage biomarker for predicting metastasis.

During the course of cancer progression, neoplastic cells undergo dynamic and reversible transitions between multiple phenotypic states, and this plasticity is enabled by underlying shifts in epigenetic regulation. Our results identified a negative feedback loop in which SET9 controls DNA methyltransferase-1 protein stability, which represses the transcriptional activity of the SET9 promoter in coordination with Snail. The modulation of SET9 expression in breast cancer cells revealed a connection with E2F1 and the silencing of SET9 was sufficient to complete an epigenetic program that favored epithelial-mesenchymal transition and the generation of cancer stem cells, indicating that SET9 plays a role in modulating breast cancer metastasis. SET9 expression levels were significantly higher in samples from patients with pathological complete remission than in samples from patients with disease recurrence, which indicates that SET9 acts as a tumor suppressor in breast cancer and that its expression may serve as a prognostic marker for malignancy.

Targeting the epigenetics of the DNA damage response in breast cancer.

Cancer is as much an epigenetic disease as it is a genetic disease, and epigenetic alterations in cancer often serve as potent surrogates for genetic mutations. Because the epigenetic factors involved in the DNA damage response are regulated by multiple elements, therapies to target specific components of the epigenetic machinery can be inefficient. In contrast, therapies aimed at inhibiting the methionine cycle can indirectly inhibit both DNA and protein methylation, and the wide variety of genes and pathways that are affected by these methylations make this global strategy very attractive. In the present study, we propose an adjuvant therapy that targets the epigenetics of the DNA damage response in breast cancer cells and that results in efficient apoptosis and a reduction in distant metastases in vivo. We observed that a combined therapy designed to uncouple adenosine metabolism using dipyridamole in the presence of a new synthetic antifolate, 3-O-(3,4,5-trimethoxybenzoyl)-(-)-catechin, simultaneously and efficiently blocked both the folic cycle and the methionine cycle in breast cancer cells and sensitized these cells to radiotherapy. The treatment impeded the recruitment of 53BP1 and BRCA1 to the chromatin regions flanking DNA double-strand breaks and thereby avoided the DNA damage responses in breast cancer cells that were exposed to ionizing radiation. In addition, this hypomethylating therapy was also efficient in reducing the self-renewal capability of breast cancer-initiating cells and induced reversion of mesenchymal phenotypes in breast cancer cells.

Superparamagnetic iron oxide as a tracer for sentinel node biopsy in breast cancer: A comparative non-inferiority study.

AIMS: The gold standard for detection of Sentinel Lymph Nodes (SLN) is a combined radioisotope and blue dye breast injection, using a gamma probe (GP). A new, non-radioactive method was developed, using a tracer (Sienna+(®)) of superparamagnetic iron oxide (SPIO) nanoparticles and a manual magnetometer (SentiMag(®)) (SM). The IMAGINE study was designed to show the non-inferiority of SM compared to GP, for the detection of SLN in breast cancer patients with SLN biopsy indication. METHODS: From November 2013 to June 2014, 181 patients were recruited, and 321 nodes were excised and assessed ex-vivo. Readings from both SM and GP devices were recorded during transcutaneous, intraoperative, and ex-vivo detection attempts. RESULTS: At the patient level, ex-vivo detection rates (primary variable) with SM and GP were 97.8% and 98.3% (concordance rate 99.4%). Transcutaneous and intraoperative detection rates were 95.5% vs 97.2%, and 97.2% vs 97.8% for SM and GP respectively (concordance rates > 97%). At the node level, intraoperative and ex-vivo detection rates were 92.5% vs 89.3% and 91.0% vs 86.3% for SM and GP respectively. In all cases the non-inferiority of SM compared to SM was shown by ruling out a predefined non-inferiority margin of 5%. CONCLUSIONS: Our study showed the non-inferiority of SM as compared to GP. Moreover, the ex-vivo and intraoperative detection rates at the node level were slightly higher with SM.

Antiplatelet effect of new lipophilic hydroxytyrosol alkyl ether derivatives in human blood.

PURPOSE: To investigate the in vitro antiplatelet and anti-inflammatory effects of five alkyl hydroxytyrosol (HT) ether derivatives in human whole blood and compare these effects with those of HT. METHODS: Blood samples from healthy volunteers were incubated with HT and HT alkyl ether derivatives (ethyl, butyl, hexyl, octyl and dodecyl). Maximum intensity of platelet aggregation was induced with collagen, arachidonic acid or ADP. Calcium-induced thromboxane B(2) and nitric oxide production, LPS-induced prostaglandin E(2) and nitric oxide production and LPS-induced interleukin 1ß production were measured. RESULTS: All compounds inhibited platelet aggregation, thromboxane B(2) and inflammatory mediators in a concentration-dependent manner. The concentrations of each compound that inhibited the corresponding variable by 50 % compared to control samples (IC(50)) were in the range of 10(-7)-10(-6) M for HT hexyl ether; for the other compounds, these values were in the range of 10(-5) M. The IC(50) for thromboxane B(2) production was in the range of 10(-4) M. The effects of HT alkyl ether derivatives were greater than those of HT. These compounds increased nitric oxide production. There was no direct relationship between the effects of these compounds and alkyl chain length. Maximum effects were observed in the C4-C6 range. CONCLUSIONS: Alkyl ether derivatives of HT exert antiplatelet and anti-inflammatory effects that are greater than those of HT.

Neuroprotective effect of alkyl hydroxytyrosyl ethers in rat brain slices subjected to a hypoxia-reoxygenation model.

The aim of the present study was to investigate the antioxidant and possible neuroprotective and antioxidant effects of five alkyl hydroxytyrosyl (HT) ethers (ethyl, butyl, hexyl, octyl and dodecyl) in rat brain slices. None of the compounds modified lipid peroxidation or glutathione concentrations (GSH) in oxygenated samples. The effects of oxidative stress were investigated with ferrous salts to induce lipid peroxidation and diethylmaleate (DEM) to reduce GSH. All compounds inhibited lipid peroxidation with an inhibitory concentration 50% (IC(50)) one tenth that of HT. These compounds, especially the butyl derivative, prevented GSH depletion after incubation with DEM. We also explored the neuroprotective effect of these compounds in an experimental model of hypoxia-reoxygenation in rat brain slices. All compounds showed neuroprotective and antioxidant effects. Our results established a relationship between these effects and the length of the carbon chain (maximum effect in the range of C4-C8).

Preparation and antioxidant activity of tyrosyl and homovanillyl ethers.

Preparation of tyrosyl and homovanillyl lipophilic derivatives was carried out as a response to the food industry's increasing demand for new synthetic lipophilic antioxidants. Tyrosyl and homovanillyl ethers were synthesized in high yields by a three-step procedure starting from tyrosol (Ty) and homovanillic alcohol (HMV). The antioxidant activity of these new series of alkyl tyrosyl and homovanillyl ethers was evaluated by the Rancimat test in a lipophilic food matrix and by the FRAP, ABTS and ORAC assays and compared to free Ty and HMV as well as two antioxidants widely used in the food industry, butylhydroxytoluene (BHT) and α-tocopherol. The results pointed out the higher activity of homovanillyl series in comparison with tyrosyl series with all the assayed methods. However, while both synthetic series were less antioxidant than BHT and α-tocopherol in a lipophilic matrix after their Rancimat test evaluation, homovanillyl alkyl ethers showed the best reducing power and radical scavenging activity of all evaluated compounds. This batch of synthetic lipophilic compounds, derived from biologically active compounds such as Ty and HMV, provide interesting and potentially bioactive compounds.

Linfadenectomía axilar completa frente observación en pacientes con micrometástasis en el ganglio centinela por neoplasia de mama. Resultados preliminares del ensayo clínico multicéntrico AATM 048/13/2000 / Complete axillary lymph node dissection versus clinical follow-up in breast cancer patients with sentinel node micrometastases. Interim analysis of the Spanish multicenter clinical trial. AATM 048/13/2000

Objetivo: Conocer la supervivencia, control o recidiva dela enfermedad, y calidad de vida de las pacientes con micrometástasisen el ganglio centinela no sometidas a vaciamientoaxilar.Pacientes y método: Un ensayo clínico prospectivo aleatorizadoen dos brazos, uno con pacientes con micrometástasis enel ganglio centinela que serían sometidas a observación clínica yotro brazo similar pero con linfadenectomía en un segundotiempo quirúrgico. Las pacientes serían seguidas detalladamentedurante cinco años. La muestra constaría de 176 pacientes porbrazo (total 352) para conseguir solidez estadística.Resultados: Hasta el momento se han incluido 120 pacientes(cabe decir que el estudio se mantiene activo). Descontandolos abandonos (7 en el grupo control y 2 en el experimental)permanecen en el estudio 54 en la rama control y 57en la experimental. En el grupo control se encontraron 8 vaciadospositivos (7 de ellos presentaban únicamente un segundoganglio afectado), mientras que en el grupo experimentalapareció una recidiva axilar local (por palpación, siendo el únicoganglio afectado en la linfadenectomía). La paciente se encuentraen la actualidad libre de enfermedad.El estudio no ha terminado. El tiempo máximo de seguimientoes de 47 meses, insuficiente para concluir. Queda sinembargo, abierto, pues consideramos que la pregunta planteadasigue siendo todavía de actualidad

Objective: To asses the impact of SN technique on thewellbeing and performance status of breast cancer patients,specifically targeting the finding of axillary micrometastatic disease.Patients and method: To achieve such objective, a randomizedprospective clinical trial was devised with two arms. Inone arm, patients with SN micrometastases are the subject ofplain clinical follow-up (experimental arm). In the other arm, patientsare submited for second-sugery completion ALND (controlarm). All patients are intended for a five-year follow-up period,and the accrual goal is 176 patients per arm (352 overall).Results: The study is still in the accrual phase. Up untilnow, 120 patients have been entered. There have been 7withdrawals in the control group and 2 in the experimentalgroup. 54 patients are being followed in the control arm, and57 in the study arm. In the control arm, 8 completion ALNDturned out positive, in seven only with one additional (non-sentinel)lymph-node metastasis. In the study arm, one axillary recurrencehas been observed in a single lymph-node, one yearafter primary surgery. Two years after completion ALND, thepatient is free of disease. This is a still ongoing study. A maximum follow-up periodof 47 months is obviously not enough to draw solid conclusions.It will be open for further accrual as the proposed questionis still in need of a definite answer

The structure of Ski8p, a protein regulating mRNA degradation: Implications for WD protein structure.

Ski8p is a 44-kD protein that primarily functions in the regulation of exosome-mediated, 3'--> 5' degradation of damaged mRNA. It does so by forming a complex with two partner proteins, Ski2p and Ski3p, which complete a complex that is capable of recruiting and activating the exosome/Ski7p complex that functions in RNA degradation. Ski8p also functions in meiotic recombination in complex with Spo11 in yeast. It is one of the many hundreds of primarily eukaryotic proteins containing tandem copies of WD repeats (also known as WD40 or beta-transducin repeats), which are short ~40 amino acid motifs, often terminating in a Trp-Asp dipeptide. Genomic analyses have demonstrated that WD repeats are found in 1%-2% of proteins in a typical eukaryote, but are extremely rare in prokaryotes. Almost all structurally characterized WD-repeat proteins are composed of seven such repeats and fold into seven-bladed beta propellers. Ski8p was thought to contain five WD repeats on the basis of primary sequence analysis implying a five-bladed propeller. The 1.9 A crystal structure unexpectedly exhibits a seven-bladed propeller fold with seven structurally authentic WD repeats. Structure-based sequence alignments show additional sequence diversity in the two undetected repeats. This demonstrates that many WD repeats have not yet been identified in sequences and also raises the possibility that the seven-bladed propeller may be the predominant fold for this family of proteins.

The structure of Aip1p, a WD repeat protein that regulates Cofilin-mediated actin depolymerization.

Actin-interacting protein 1 (Aip1p) is a 67-kDa WD repeat protein known to regulate the depolymerization of actin filaments by cofilin and is conserved in organisms ranging from yeast to mammals. The crystal structure of Aip1p from Saccharomyces cerevisiae was determined to a 2.3-A resolution and a final crystallographic R-factor of 0.204. The structure reveals that the overall fold is formed by two connected seven-bladed beta-propellers and has important implications for the structure of Aip1 from other organisms and WD repeat-containing proteins in general. These results were unexpected because a maximum of 10 WD repeats had been reported in the literature for this protein using sequence data. The surfaces of the beta-propellers formed by the D-A and B-C loops are positioned adjacent to one another, giving Aip1p a shape that resembles an open "clamshell." The mapping of conserved residues to the structure of Aip1p reveals dense patches of conserved residues on the surface of one beta-propeller and at the interface of the two beta-propellers. These two patches of conserved residues suggest a potential binding site for F-actin on Aip1p and that the orientation of the beta-propellers with respect to one another plays a role in binding an actin-cofilin complex. In addition, the conserved interface between the domains is mediated by a number of interactions that appear to impart rigidity between the two domains of Aip1p and may make a large substrate-induced conformational change difficult.

Enfisema subcutáneo de miembro inferior como primera manifestación de una dehiscencia colónica / Subcutaneous emphysema of the lower limb as presenting manifestation of colon dehiscence

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[Selective sentinel node biopsy in melanoma using preoperative lymphoscintigraphy location and intraoperative detection gamma probe]. / Biopsia selectiva del ganglio centinela en el melanoma mediante localización con linfogammagrafía preoperatoria y sonda de detección gamma intraoperatoria.

BACKGROUND: The experience in detection of sentinel lymph node in melanoma using preoperative scintigraphy and intraoperative gamma probe is referred. PATIENTS AND METHODS: We studied 60 patients with stage I-II melanoma who underwent sentinel lymph node biopsy performed using 99m-Tc-labelled sulphur colloid as radioactive tracer. A preoperative scintigraphy was performed and intraoperative gamma probe was used to localize the sentinel node in all cases. Scintigraphy results, effectiveness of intraoperative detection (technical efficacy), pathological results, and follow-up have been studied. RESULTS: Preoperative detection was 98.3% and the mean basin detected was 1.17. There were multiple basins especially when melanomas were on the trunk. Technical efficacy was 98.4% and intraoperative detection was more difficult in parotid gland region. HMB-45 immunohistochemical staining was essential in pathological studies, in whom 10% were positives. Lymphadenectomy could be avoided in 90% of the patients. Recurrences were not detected during follow-up and metastases were found only in non biopsied cases. Sentinel node biopsy morbidity was significative lesser than that of lymphadenectomy. CONCLUSIONS: Preoperative scintigraphy and intraoperative gamma probe use to localize sentinel node in melanoma have a high efficacy. They can reveal multiple basins and they allow a more selective surgical approach and a minimal dissection.