Correction: Méndez-Blanco et al. Stabilization of Hypoxia-Inducible Factors and BNIP3 Promoter Methylation Contribute to Acquired Sorafenib Resistance in Human Hepatocarcinoma Cells. Cancers 2019, 11, 1984.

In the original publication [...].

EGFR-mutated advanced lung cancer. Data from a single institution, the Hospital of Leon, in Spain.

INTRODUCTION: 10-16% of non-small cell lung cancer (NSCLC) cases have the epidermal growth factor receptor (EGFR) amplified and/or mutated. Studies show that EGFR tyrosine kinase inhibitors (TKIs) significantly prolong progression-free survival (PFS) in patients with advanced NSCLC compared to those treated with platinum-based chemotherapy (CT) doublets. Our aim is to perform a real-world survival analysis of patients treated with TKI as first-line therapy at the Hospital of Leon (CAULE) in Spain. The impact on global survival rates and responses to clinical and histopathological factors were also analyzed. MATERIAL AND METHODS: We retrospectively reviewed patients diagnosed with EGFR-mutated NSCLC who received treatment with EGFR-TKI in the Department of Oncology at the University of Leon Health Center complex between March 2011 and June 2018. Data was analyzed with Kaplan-Meier and Cox regression models to show overall survival (OS), progression-free survival (PFS), and the associated variables. RESULTS: 53 patients were included in the study, 50% (n = 27) were treated with gefitinib, 32% (n = 18) with erlotinib and 10% (n = 6) with afatinib. The median OS and PFS were 27.7 months (95% CI: 21-33.8 months) and 18 months (95% CI 14.25-21.89 months), respectively. The variables associated with OS and with PFS were exon19 deletion as a protective factor and presence of extrathoracic metastasis as a risk factor. The most frequent adverse effects were rash, diarrhea, asthenia, and conjunctivitis. CONCLUSIONS: Real-world analysis of this data confirms that treatment with TKI is beneficial for patients diagnosed with EGFR-mutated NSCLC. Our OS outcomes were similar to those reported in clinical trials.

Relationship between Aldehyde Dehydrogenase, PD-L1 and Tumor-Infiltrating Lymphocytes with Pathologic Response and Survival in Breast Cancer.

Aldehyde dehydrogenase 1A1 (ALDH1A1) is a cancer stem cell (CSC) marker related to clinical outcomes in breast cancer (BC). The aim of this study was to analyze the relationship between ALDH1A1, programmed death ligand 1 (PD-L1) and tumor-infiltrating lymphocytes (TILs) in triple negative (TN) and human epidermal growth factor receptor 2-positive (HER2+) BC tumors, and its association with clinicopathological characteristics and outcomes. A retrospective, historical cohort study of patients diagnosed with early or locally advanced BC treated with neoadjuvant chemotherapy was conducted. ALDH1A1, PD-L1 expression and TILs were assessed using immunohistochemistry. A total of 75 patients were analyzed (42.7% TN, 57.3% HER2+ tumors). ALDH1A1+ was related to HTILs (p = 0.005) and PD-L1+ tumors (p = 0.004). ALDH1A1+ tumors presented higher CD3+ (p = 0.008), CD4+ (p = 0.005), CD8+ (p = 0.003) and CD20+ (p = 0.006) TILs. ALDH1A1+ (p = 0.018), PD-L1+ (p = 0.004) and HTILs (p < 0.001) were related to smaller tumors. ALDH1A1+ was related to pathologic complete response (pCR) (p = 0.048). At the end of the follow-up (54.4 [38.3−87.6] months), 47 patients (62.7%) remained disease-free, and 20 (26.7%) had died. HTILs were related to improved disease-free survival (p = 0.027). ALDH1A1+ was related to PD-L1+ and HITLs, that might be related to higher pCR rates with neoadjuvant therapy.

Health-related quality of life with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive metastatic breast cancer: Patient-reported outcomes in the PEARL study.

BACKGROUND: The PEARL study showed that palbociclib plus endocrine therapy (palbociclib/ET) was not superior to capecitabine in improving progression-free survival in postmenopausal patients with metastatic breast cancer resistant to aromatase inhibitors, but was better tolerated. This analysis compared patient-reported outcomes. PATIENTS AND METHODS: The PEARL quality of life (QoL) population comprised 537 patients, 268 randomised to palbociclib/ET (exemestane or fulvestrant) and 269 to capecitabine. Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23 and EQ-5D-3L questionnaires. Changes from the baseline and time to deterioration (TTD) were analysed using linear mixed-effect and stratified Cox regression models, respectively. RESULTS: Questionnaire completion rate was high and similar between treatment arms. Significant differences were observed in the mean change in global health status (GHS)/QoL scores from the baseline to cycle 3 (2.9 for palbociclib/ET vs. -2.1 for capecitabine (95% confidence interval [CI], 1.4-8.6; P = 0.007). The median TTD in GHS/QoL was 8.3 months for palbociclib/ET versus 5.3 months for capecitabine (adjusted hazard ratio, 0.70; 95% CI, 0.55-0.89; P = 0.003). Similar improvements for palbociclib/ET were also seen for other scales as physical, role, cognitive, social functioning, fatigue, nausea/vomiting and appetite loss. No differences were observed between the treatment arms in change from the baseline in any item of the EQ-5D-L3 questionnaire as per the overall index score and visual analogue scale. CONCLUSION: Patients receiving palbociclib/ET experienced a significant delay in deterioration of GHS/QoL and several functional and symptom scales compared with capecitabine, providing additional evidence that palbociclib/ET is better tolerated. TRIAL REGISTRATION NUMBER: NCT02028507 (ClinTrials.gov). EUDRACT STUDY NUMBER: 2013-003170-27.

Previously diagnosed cancer and mortality after ST-segment elevation acute myocardial infarction treated with primary angioplasty.

OBJECTIVE: We investigated if a previous cancer diagnosis influences the outcome of patients with STEMI treated with primary coronary intervention (PCI). BACKGROUND: ST-segment myocardial infarction (STEMI) and a history of cancer can coexist because both have a high incidence and prevalence. METHODS: Prospective cohort observational study, The primary end-point was total mortality. RESULTS: We included 917 patients, 53 of them (5.8%) were cancer survivors. During follow-up (median, 643 days [interquartile range, 258 to 1,015 days]), 100 patients died, 88 (10.2%) patients without a cancer diagnosis and 12 (22.6%) patients with a previous cancer diagnosis, which was significantly different (log-rank test = 8.4, p = .004). Cancer patients were older (73.4 (11.5) vs. 65.2 (13.8) years, p < .001), with a lower prevalence of previous stroke (1.1% vs. 2.2%, p = .002). Their hemoglobin concentration was also lower (13.4 (2.1) vs. 14.4 (1.7) g/L, p = .001). A trend towards a lower use of coronary stents in cancer survivors was noted (p = .061). Cancer was associated with a high probability of death (HR = 2.37, 95% confidence interval [CI] 1.30-4.34, p = .005). When confounding variables were included, this association was no longer significant (HR = 1.63, 95% CI 0.84-3.18, p = .150). CONCLUSIONS: Patients with a previous cancer diagnosis who had an acute STEMI treated by primary PCI did not seem to have a worse prognosis. The difference in the crude mortality rate can be explained by the baseline differences between both groups. Previous cancer diagnosis should not be included in the clinical decision process when a patient is having an acute STEMI.

Stabilization of Hypoxia-Inducible Factors and BNIP3 Promoter Methylation Contribute to Acquired Sorafenib Resistance in Human Hepatocarcinoma Cells.

Despite sorafenib effectiveness against advanced hepatocarcinoma (HCC), long-term exposure to antiangiogenic drugs leads to hypoxic microenvironment, a key contributor to chemoresistance acquisition. We aimed to study the role of hypoxia in the development of sorafenib resistance in a human HCC in vitro model employing the HCC line HepG2 and two variants with acquired sorafenib resistance, HepG2S1 and HepG2S3, and CoCl2 as hypoximimetic. Resistant cells exhibited a faster proliferative rate and hypoxia adaptive mechanisms, linked to the increased protein levels and nuclear translocation of hypoxia-inducible factors (HIFs). HIF-1α and HIF-2α overexpression was detected even under normoxia through a deregulation of its degradation mechanisms. Proapoptotic markers expression and subG1 population decreased significantly in HepG2S1 and HepG2S3, suggesting evasion of sorafenib-mediated cell death. HIF-1α and HIF-2α knockdown diminished resistant cells viability, relating HIFs overexpression with its prosurvival ability. Additionally, epigenetic silencing of Bcl-2 interacting protein 3 (BNIP3) was observed in sorafenib resistant cells under hypoxia. Demethylation of BNIP3 promoter, but not histone acetylation, restored BNIP3 expression, driving resistant cells' death. Altogether, our results highlight the involvement of HIFs overexpression and BNIP3 methylation-dependent knockdown in the development of sorafenib resistance in HCC. Targeting both prosurvival mechanisms could overcome chemoresistance and improve future therapeutic approaches.

Broad consensus on the optimal sequence for the systemic treatment of metastatic breast cancer: results from a survey of Spanish medical oncologists.

Objective: The aim of this survey conducted by 20 leading Spanish oncologists was to analyze the concurrence between Spanish clinical practice and the recently published definition of the optimal sequence for the systemic treatment of metastatic breast cancer (MBC) according to patient profiles. Methods: A self-administered questionnaire was developed, divided into five sections comprising 34 specific questions related to sequential treatments, plus three additional general questions. Respondents were asked to justify negative answers. Participants were recruited randomly by invitation out of a total of 619 oncologists. The questionnaire was sent and collected via e-mail between October 2015 and May 2016. A total of 191 completed questionnaires were received. Results: Overall, 70% of oncologists would keep the three patient profiles exactly as proposed (hormone receptor-positive and HER2-negative, HER2-positive, and triple negative breast cancer). Affirmative answers to questions regarding treatment sequences for these patient profiles (1-34) ranged from 77.8-99.5%, with an average of 90.9% of oncologists being in agreement with the recommended sequential treatments. The lowest degree of consensus was observed for endocrine treatments in pre-menopausal women and for chemotherapy options in hormone-resistant patients, whilst the highest degree of consensus was reached for targeted therapies in HER2-positive patients and for endocrine therapy in post-menopausal women. In their comments, participants revealed a number of economic constraints that prevented them from implementing some of the best treatment options. Conclusions: In conclusion, despite the complexity of MBC treatment, there is general agreement on the optimal treatment sequences.

Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors.

Sorafenib, a multikinase inhibitor with antiproliferative, antiangiogenic, and proapoptotic properties, constitutes the only effective first-line drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Despite its capacity to increase survival in HCC patients, its success is quite low in the long term owing to the development of resistant cells through several mechanisms. Among these mechanisms, the antiangiogenic effects of sustained sorafenib treatment induce a reduction of microvessel density, promoting intratumoral hypoxia and hypoxia-inducible factors (HIFs)-mediated cellular responses that favor the selection of resistant cells adapted to the hypoxic microenvironment. Clinical data have demonstrated that overexpressed HIF-1α and HIF-2α in HCC patients are reliable markers of a poor prognosis. Thus, the combination of current sorafenib treatment with gene therapy or inhibitors against HIFs have been documented as promising approaches to overcome sorafenib resistance both in vitro and in vivo. Because the depletion of one HIF-α subunit elevates the expression of the other HIF-α isoform through a compensatory loop, targeting both HIF-1α and HIF-2α would be a more interesting strategy than therapies that discriminate among HIF-α isoforms. In conclusion, there is a marked correlation between the hypoxic microenvironment and sorafenib resistance, suggesting that targeting HIFs is a promising way to increase the efficiency of treatment.

Experience with eribulin in HR+/HER2- metastatic breast cancer, including a male.

Numerous patient- and disease-related factors must be considered when deciding a treatment approach for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. Hormone therapy (HT) is generally the first option in the absence of compelling reasons for chemotherapy (e.g., rapidly progressive visceral disease). After failure of first-choice HT, alternative HT options are usually attempted until hormone resistance occurs and chemotherapy becomes the treatment of choice. The first two patients presented herein experienced prolonged disease control with third-line eribulin after two lines of HT. The third report involves a case of male breast cancer which typically presents as the HR+/HER2- phenotype. Eribulin in the second line provided prolonged clinical improvement and was well tolerated.

Melatonin enhances sorafenib actions in human hepatocarcinoma cells by inhibiting mTORC1/p70S6K/HIF-1α and hypoxia-mediated mitophagy.

The antiangiogenic effects of sustained sorafenib treatment in hepatocellular carcinoma (HCC) lead to the occurrence of hypoxia-mediated drug resistance resulting in low therapy efficiency and negative outcomes. Combined treatments with coadjuvant compounds to target the hypoxia-inducible factor-1α (HIF-1α) represent a promising therapeutic approach through which sorafenib efficiency may be improved. Melatonin is a well-documented oncostatic agent against different cancer types. Here, we evaluated whether melatonin could enhance sorafenib cytotoxicity and overcome the hypoxia-mediated resistance mechanisms in HCC. The pharmacological melatonin concentration (2 mM) potentiated the oncostatic effects of sorafenib (5 µM) on Hep3B cells even under hypoxia. Melatonin downregulated the HIF-1α protein synthesis through the inhibition of the mammalian target of rapamycin complex 1 (mTORC1)/ribosomal protein S6 kinase beta-1 (p70S6K)/ribosomal protein S6 (RP-S6) pathway, although the indole enhanced Akt phosphorylation by the mTORC1/C2 negative feedback. Furthermore, melatonin and sorafenib coadministration reduced the HIF-1α-mitophagy targets expression, impaired autophagosome formation and subsequent mitochondria and lysosomes colocalization. Together, our results indicate that melatonin improves the Hep3B sensitivity to sorafenib, preventing HIF-1α synthesis to block the cytoprotective mitophagy induced by the hypoxic microenvironment, an important element of the multifactorial mechanisms responsible for the chemotherapy failure.

Shift work and colorectal cancer risk in the MCC-Spain case-control study.

Objectives Shift work that involves circadian disruption has been associated with a higher cancer risk. Most epidemiological studies to date have focused on breast cancer risk and evidence for other common tumors is limited. We evaluated the risk for colorectal cancer (CRC) in relation to shift work history in a population-based case-control study in Spain. Methods This analysis included 1626 incident CRC cases and 3378 randomly selected population controls of both sexes, enrolled in 11 regions of Spain. Sociodemographic and lifestyle information was assessed in face-to-face interviews. Shift work was assessed in detail throughout lifetime occupational history. We estimated the risk of colon and rectal cancer associated with rotating and permanent shift work (ever, cumulative duration, age of first exposure) using unconditional logistic regression analysis adjusting for potential confounders. Results Having ever performed rotating shift work (morning, evening and/or night) was associated with an increased risk for CRC [odds ratio (OR) 1.22, 95% confidence interval (95% CI) 1.04-1.43], as compared to day workers. Having ever worked permanent night shifts (≥3 nights/month) was not associated with CRC risk (OR 0.79, 95% CI 0.62-1.00). OR increased with increasing lifetime cumulative duration of rotating shift work (P-value for trend 0.005) and were highest among subjects in the top quartiles of exposure (3 rdquartile, 20-34 years, OR 1.38, 95%CI 1.06-1.81; 4 thquartile, ≥35 years, OR 1.36, 95% CI 1.02-1.79). Conclusions These data suggest that rotating shift work may increase the risk of CRC especially after long-term exposures.

Use of non-steroidal anti-inflammatory drugs and risk of breast cancer: The Spanish Multi-Case-control (MCC) study.

BACKGROUND: The relationship between non-steroidal anti-inflammatory drug (NSAID) consumption and breast cancer has been repeatedly studied, although the results remain controversial. Most case-control studies reported that NSAID consumption protected against breast cancer, while most cohort studies did not find this effect. Most studies have dealt with NSAIDs as a whole group or with specific drugs, such aspirin, ibuprofen, or others, but not with NSAID subgroups according to the Anatomical Therapeutic Chemical Classification System; moreover, scarce attention has been paid to their effect on different tumor categories (i.e.: ductal/non-ductal, stage at diagnosis or presence of hormonal receptors). METHODS: In this case-control study, we report the NSAID - breast cancer relationship in 1736 breast cancer cases and 1895 healthy controls; results are reported stratifying by the women's characteristics (i.e.: menopausal status or body mass index category) and by tumor characteristics. RESULTS: In our study, NSAID use was associated with a 24 % reduction in breast cancer risk (Odds ratio [OR] = 0.76; 95 % Confidence Interval [CI]: 0.64-0.89), and similar results were found for acetic acid derivatives, propionic acid derivatives and COXIBs, but not for aspirin. Similar results were found in postmenopausal and premenopausal women. NSAID consumption also protected against hormone + or HER2+ cancers, but not against triple negative breast cancers. The COX-2 selectivity showed an inverse association with breast cancer (i.e. OR < 1), except in advanced clinical stage and triple negative cancers. CONCLUSION: Most NSAIDs, but not aspirin, showed an inverse association against breast cancer; this effect seems to be restricted to hormone + or HER2+ cancers.

[Mechanism of action and preclinical development of afatinib]. / Mecanismo de acción y desarrollo preclínico de afatinib.

Afatinib, together with gefitinib and erlotinib, is approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). This is an irreversible inhibitor of the ErbB family, acting on EGFR (HER1, ErbB1), ErbB2 (HER2) and ErbB4 (HER4). Covalent attachment to cysteine residues in the catalytic domain of EGFR, HER2 and ErbB4 inhibits the tyrosine kinase activity (TKIs) of these receptors, decreasing auto- and transphosphorylation between ErbB dimers, and thus blocking the activity of downstream signalling pathways related to growth and apoptosis suppression. In preclinical models, this has resulted in a reduction in tumour size. Furthermore, due to its mechanism of action, afatinib may be more potent than the first-generation EGFR TKIs (gefitinib and erlotinib) and may even be able to overcome acquired resistance to such treatments. Finally, because of the demonstrated synergism with other chemotherapeutic and target agents, it could be interesting to enhance its clinical development in combination with other drugs.

Modulation of Autophagy by Sorafenib: Effects on Treatment Response.

The multikinase inhibitor sorafenib is, at present, the only drug approved for the treatment of hepatocellular carcinoma (HCC), one of the most lethal types of cancer worldwide. However, the increase in the number of sorafenib tumor resistant cells reduces efficiency. A better knowledge of the intracellular mechanism of the drug leading to reduced cell survival could help to improve the benefits of sorafenib therapy. Autophagy is a bulk cellular degradation process activated in a broad range of stress situations, which allows cells to degrade misfolded proteins or dysfunctional organelles. This cellular route can induce survival or death, depending on cell status and media signals. Sorafenib, alone or in combination with other drugs is able to induce autophagy, but cell response to the drug depends on the complex integrative crosstalk of different intracellular signals. In cancerous cells, autophagy can be regulated by different cellular pathways (Akt-related mammalian target of rapamycin (mTOR) inhibition, 5' AMP-activated protein kinase (AMPK) induction, dissociation of B-cell lymphoma 2 (Bcl-2) family proteins from Beclin-1), or effects of some miRNAs. Inhibition of mTOR signaling by sorafenib and diminished interaction between Beclin-1 and myeloid cell leukemia 1 (Mcl-1) have been related to induction of autophagy in HCC. Furthermore, changes in some miRNAs, such as miR-30α, are able to modulate autophagy and modify sensitivity in sorafenib-resistant cells. However, although AMPK phosphorylation by sorafenib seems to play a role in the antiproliferative action of the drug, it does not relate with modulation of autophagy. In this review, we present an updated overview of the effects of sorafenib on autophagy and its related activation pathways, analyzing in detail the involvement of autophagy on sorafenib sensitivity and resistance.

Mecanismo de acción y desarrollo preclínico de afatinib / Mechanism of action and preclinical development of afatinib

Afatinib, junto con gefitinib y erlotinib, está aprobado para el tratamiento de primera línea del cáncer de pulmón de célula no pequeña avanzado con mutaciones activadoras del receptor del factor de crecimiento epidérmico (EGFR). Se trata de un inhibidor irreversible de la familia ErbB, que actúa sobre EGFR (HER1, ErbB1), ErbB2 (HER2) y ErbB4 (HER4). Su unión covalente a los residuos de cisteína en el dominio catalítico de EGFR, HER2 y ErbB4, inhibe la actividad tirosincinasa (ITK) de estos receptores, disminuyendo la auto y la transfosforilación entre los dímeros ErbB y bloqueando, por tanto, la actividad de diferentes vías de señalización intracelular relacionadas con el crecimiento y la supresión de la apoptosis celular. En los modelos preclínicos, esto se ha traducido en una reducción del tamaño tumoral. Además se sugiere que por su mecanismo de acción podría ser más potente que los EGFR ITK de primera generación (gefitinib y erlotinib) e incluso podría ser capaz de revertir la resistencia adquirida a dichos tratamientos. Por último, el sinergismo demostrado con otros agentes diana y quimioterápicos lo convierten en un fármaco de interés para potenciar su desarrollo clínico en combinación (AU)

Afatinib, together with gefitinib and erlotinib, is approved for first-line treatment of advanced non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR). This is an irreversible inhibitor of the ErbB family, acting on EGFR (HER1, ErbB1), ErbB2 (HER2) and ErbB4 (HER4). Covalent attachment to cysteine residues in the catalytic domain of EGFR, HER2 and ErbB4 inhibits the tyrosine kinase activity (TKIs) of these receptors, decreasing auto- and transphosphorylation between ErbB dimers, and thus blocking the activity of downstream signalling pathways related to growth and apoptosis suppression. In preclinical models, this has resulted in a reduction in tumour size. Furthermore, due to its mechanism of action, afatinib may be more potent than the first-generation EGFR TKIs (gefitinib and erlotinib) and may even be able to overcome acquired resistance to such treatments. Finally, because of the demonstrated synergism with other chemotherapeutic and target agents, it could be interesting to enhance its clinical development in combination with other drugs (AU)

Nab-Paclitaxel in Metastatic Breast Cancer: Defining the Best Patient Profile.

Around 40% of patients with breast cancer will present with a recurrence of the disease. Chemotherapy is recommended for patients with recurrent hormone-independent or hormone-refractory breast cancer and almost all patients with metastatic breast cancer (MBC) receive chemotherapy during their medical history. Nanoparticle albuminbound (nab)-paclitaxel is a solvent-free, 130-nanometer particle formulation of paclitaxel. Nab-paclitaxel can be administered to all patients for whom the treatment choice is a taxane. In this review, 6 patient profiles for which nabpaclitaxel may be particularly useful are described and analyzed: (i) as first-line treatment of MBC, (ii) as second-line treatment of MBC after oral chemotherapy, (iii) after a standard taxane, (iv) as third-line treatment after a standard taxane and oral chemotherapy, (v) for patients with HER2-positive MBC and (vi) for patients with intolerance to standard taxanes. Nab-paclitaxel is a rational treatment choice for patients with MBC in different settings, as well as for those with prior exposure to a standard taxane.

Melatonin Activates Endoplasmic Reticulum Stress and Apoptosis in Rats with Diethylnitrosamine-Induced Hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is one of the most lethal human cancers worldwide because of its high incidence, its metastatic potential and the low efficacy of conventional treatment. Inactivation of apoptosis is implicated in tumour progression and chemotherapy resistance, and has been linked to the presence of endoplasmic reticulum stress. Melatonin, the main product of the pineal gland, exerts anti-proliferative, pro-apoptotic and anti-angiogenic effects in HCC cells, but these effects still need to be confirmed in animal models. Male Wistar rats in treatment groups received diethylnitrosamine (DEN) 50 mg/kg intraperitoneally twice/once a week for 18 weeks. Melatonin was given in drinking water at 1 mg/kg/d, beginning 5 or 12 weeks after the start of DEN administration. Melatonin improved survival rates and successfully attenuated liver injury, as shown by histopathology, decreased levels of serum transaminases and reduced expression of placental glutathione S-transferase. Furthermore, melatonin treatment resulted in a significant increase of caspase 3, 8 and 9 activities, polyadenosine diphosphate (ADP) ribose polymerase (PARP) cleavage, and Bcl-associated X protein (Bax)/Bcl-2 ratio. Cytochrome c, p53 and Fas-L protein concentration were also significantly enhanced by melatonin. Melatonin induced an increased expression of activating transcription factor 6 (ATF6), C/EBP-homologous protein (CHOP) and immunoglobulin heavy chain-binding protein (BiP), while cyclooxygenase (COX)-2 expression decreased. Data obtained suggest that induction of apoptosis and ER stress contribute to the beneficial effects of melatonin in rats with DEN-induced HCC.

[Municipal distribution and trend of the incidence of breast cancer in the health area of León, Spain (1996-2010)]. / Tendencia y distribución municipal de la incidencia de cáncer de mama en el área de salud de León (1996-2010).

BACKGROUND: Breast cancer is the most common amongst women. The aim of this study was to analyze the incidence and geographical distribution of breast cancer in the health area of León. METHODS: We designed an observational descriptive study that included women enrolled in the Hospital Tumor Registry of the Centro Asistencial Universitario in León with a diagnosis of breast malignant neoplasm (ICD-9: 174, ICD-10: 50) between 01/01/1996 and 31/12/2010 and resident in the health area of León. To study the spatial distribution, we estimated municipal relative risks (RR) smoothed by fitting the Besag, York and Mollié model and the posterior probability (PP) of RR > 1 using Bayesian methods. RESULTS: A total of 2379 cases were included. The number of new cases and the crude incidence rate have both increased in every triennium, from 72,7 (1996-1998) to 101,5 (2008-2010) per 100,000 women. The age adjusted rates per 100,000 women (European standard population) increased from 58,0 during the first triennium to 69,4 during the last one. An average annual increase of 1,3% was observed. Several municipalities from the health area of León showed risks higher than a 10%. The PP were higher than 0.9 only in the municipality of León. CONCLUSION: The observed rates are among the lowest in our country. Nevertheless, the number of cases and the incidence rates have increased progressively.

Tendencia y distribución municipal de la incidencia de cáncer de mama en el área de salud de León (1996-2010) (AU) / Municipal distribution and trend of the incidence of breast cancer in the health area of León, Spain (1996-2010)

Fundamentos: El cáncer de mama es el más frecuente en las mujeres. El objetivo del presente estudio fue analizar la incidencia y distribución geográfica del cáncer de mama invasivo en el área de salud de León (ASL). Métodos: Estudio observacional descriptivo en el que se incluyeron mujeres con diagnóstico de neoplasia maligna de mama (CIE-9:174, CIE-10:C50) del Registro Hospitalario de Tumores del Centro Asistencial Universitario de León, entre 1/1/1996 y 31/12/2010 y con residencia en el ASL. Para el análisis de la distribución espacial se estimaron los riesgos relativos (RR) municipales suavizados mediante el ajuste del modelo de Besag, York y Mollié y sus probabilidades posteriores de que los RR fuesen >1 (PP), utilizando métodos bayesianos. Resultados: Se incluyó un total de 2.379 casos. El número de casos nuevos y las tasas de incidencia brutas en cada trienio fueron de 72,7 (1996-1998) a 101,5 (2008-2010) por 100.000 mujeres. Las tasas a población europea por 100.000 mujeres ascendieron de 58,0 en el primer trienio y a 69,4 en el último. Se observó un incremento anual promedio del 1,3 %. Varios municipios del ASL presentaron riesgos superiores al 10 %. Las PP solo fueron superiores a 0,9 en el municipio de León. Conclusiones: Las tasas observadas son de las más bajas de España. Sin embargo, el número de casos y las tasas de incidencia se incrementaron de manera mantenida en el periodo estudiado (AU)

Background: Breast cancer is the most common amongst women. The aim of this study was to analyze the incidence and geographical distribution of breast cancer in the health area of León. Methods: We designed an observational descriptive study that included women enrolled in the Hospital Tumor Registry of the Centro Asistencial Universitario in León with a diagnosis of breast malignant neoplasm (ICD-9:174, ICD-10:50) between 01/01/1996 and 31/12/2010 and resident in the health area of León. To study the spatial distribution, we estimated municipal relative risks (RR) smoothed by fitting the Besag, York and Mollié model and the posterior probability (PP) of RR > 1 using Bayesian methods. Results: A total of 2379 cases were included. The number of new cases and the crude incidence rate have both increased in every triennium, from 72,7 (1996-1998) to 101,5 (2008-2010) per 100,000 women. The age adjusted rates per 100,000 women (European standard population) increased from 58,0 during the first triennium to 69,4 during the last one. An average annual increase of 1,3 % was observed. Several municipalities from the health area of León showed risks higher than a 10 %. The PP were higher than 0.9 only in the municipality of León. Conclusion: The observed rates are among the lowest in our country. Nevertheless, the number of cases and the incidence rates have increased progressively (AU)

Inhibition of matrix metalloproteinase-9 and nuclear factor kappa B contribute to melatonin prevention of motility and invasiveness in HepG2 liver cancer cells.

Hepatocellular carcinoma (HCC) is one of the most lethal human cancers worldwide because of its high incidence and its metastatic potential. Extracellular matrix degradation by matrix metalloproteinases (MMPs) has been connected with cancer cell invasion, and it has been suggested that inhibition of MMPs by synthetic and natural inhibitors may be of great importance in the HCC therapies. Melatonin, the main product of the pineal gland, exerts antiproliferative, proapoptotic, and antiangiogenic properties in HepG2 human hepatocellular cells, and exhibits anti-invasive and antimetastatic activities by suppressing the enzymatic activity of MMP-9 in different tumor types. However, the underlying mechanism of anti-invasive activity in HCC models has not been fully elucidated. Here, we demonstrate that 1 mm melatonin dosage reduced in IL-1ß-induced HepG2 cells MMP-9 gelatinase activity and inhibited cell invasion and motility through downregulation of MMP-9 gene expression and upregulation of the MMP-9-specific inhibitor tissue inhibitor of metalloproteinases (TIMP)-1. No significant changes were observed in the expression and activity of MMP-2, the other proteinase implicated in matrix collagen degradation, and its tissue inhibitor, TIMP-2. Also, melatonin significantly suppressed IL-1ß-induced nuclear factor-kappaB (NF-κB) translocation and transcriptional activity. In summary, we demonstrate that melatonin modulates motility and invasiveness of HepG2 cell in vitro through a molecular mechanism that involves TIMP-1 upregulation and attenuation of MMP-9 expression and activity via NF-κB signal pathway inhibition.