Modeling Glutaric Aciduria Type I in human neuroblastoma cells recapitulates neuronal damage that can be rescued by gene replacement.

Glutaric Aciduria type I (GA1) is a rare neurometabolic disorder caused by mutations in the GDCH gene encoding for glutaryl-CoA dehydrogenase (GCDH) in the catabolic pathway of lysine, hydroxylysine and tryptophan. GCDH deficiency leads to increased concentrations of glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body fluids and tissues. These metabolites are the main triggers of brain damage. Mechanistic studies supporting neurotoxicity in mouse models have been conducted. However, the different vulnerability to some stressors between mouse and human brain cells reveals the need to have a reliable human neuronal model to study GA1 pathogenesis. In the present work we generated a GCDH knockout (KO) in the human neuroblastoma cell line SH-SY5Y by CRISPR/Cas9 technology. SH-SY5Y-GCDH KO cells accumulate GA, 3-OHGA, and glutarylcarnitine when exposed to lysine overload. GA or lysine treatment triggered neuronal damage in GCDH deficient cells. SH-SY5Y-GCDH KO cells also displayed features of GA1 pathogenesis such as increased oxidative stress vulnerability. Restoration of the GCDH activity by gene replacement rescued neuronal alterations. Thus, our findings provide a human neuronal cellular model of GA1 to study this disease and show the potential of gene therapy to rescue GCDH deficiency.

Treatment of COVID-19 pneumonia with low-dose radiotherapy plus standard of care versus standard of care alone in frail patients : The SEOR-GICOR IPACOVID comparative cohort trial.

PURPOSE: To assess the efficacy of lung low-dose radiotherapy (LD-RT) in the treatment of patients with COVID-19 pneumonia. MATERIALS AND METHODS: Ambispective study with two cohorts to compare treatment with standard of care (SoC) plus a single dose of 0.5 Gy to the whole thorax (experimental prospective cohort) with SoC alone (control retrospective cohort) for patients with COVID-19 pneumonia not candidates for admission to the intensive care unit (ICU) for mechanical ventilation. RESULTS: Fifty patients treated with LD-RT were compared with 50 matched controls. Mean age was 85 years in both groups. An increase in arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (PAFI) in the experimental LD-RT-treated group compared to the control group could not be found at 48 h after LD-RT, which was the primary endpoint of the study. However, PAFI values significantly improved after 1 month (473 vs. 302 mm Hg; p < 0.0001). Pulse oxymetric saturation/fraction of inspired oxygen (SAFI) values were also significantly higher in LD-RT-treated patients than in control patients at 1 week (405 vs. 334 mm Hg; p = 0.0157) and 1 month after LD-RT (462 vs. 326 mm Hg; p < 0.0001). All other timepoint measurements of the respiratory parameters were similar across groups. Patients in the experimental group were discharged from the hospital significantly earlier (23 vs. 31 days; p = 0.047). Fifteen and 26 patients died due to COVID-19 pneumonia in the experimental and control cohorts, respectively (30% vs. 48%; p = 0.1). LD-RT was associated with a decreased odds ratio (OR) for 1­month COVID-19 mortality (OR = 0.302 [0.106-0.859]; p = 0.025) when adjusted for potentially confounding factors. Overall survival was significantly prolonged in the LD-RT group compared to the control group (log-rank p = 0.027). No adverse events related to radiation treatment were observed. CONCLUSION: Treatment of frail patients with COVID-19 pneumonia with SoC plus single-dose LD-RT of 0.5 Gy improved respiratory parameters, reduced the period of hospitalization, decreased the rate of 1­month mortality, and prolonged actuarial overall survival compared to SoC alone.

Incidental appendectomy in surgical treatment of ileocolic intussusception in children. Is it safe to perform? / Apendicectomía incidental en el tratamiento quirúrgico de la intususcepción ileocólica en niños. ¿Es segura?

BACKGROUND: Surgical treatment of ileo-colic intussusception (ICI) has been reported as the second cause of emergency laparotomy in children. The performance of incidental appendectomy after surgical reduction is currently controversial. The aim is to analyse the outcomes of performing incidental appendectomy after surgical ICI reduction with or without associated bowel resection. MATERIALS AND METHODS: A retrospective study was performed in patients with ICI episodes, who underwent surgical treatment in our institution between 2005-2019. Patients were divided in two groups according to the performance of associated appendectomy (AA group) or not (NA group). Subsequently, a stratified analysis was performed according to the need for bowel resection in both groups. Demographic variables, intraoperative findings, surgical time, hospital stay, postoperative complications and recurrences were analysed. RESULTS: A total of 101 patients (77 AA group; 24 NA group) were included, without differences in demographics or intraoperative findings. A total of 36 bowel resections were performed (24 group AA; 10 group NA), with no differences in surgical time (55.7 min in group AA vs. 61.2 min in group NA; p = 0.587) or hospital stay (median 5 days in both groups). There were also no differences in postoperative complications or recurrences between the two groups. Stratified analysis showed that bowel resection increases operative time, hospital stay and postoperative complications, regardless of whether associated appendectomy was performed or not. CONCLUSIONS: Incidental appendectomy during surgical treatment of ICI in children is a safe procedure that does not increase operative time, hospital stay, postoperative complications or recurrence.

OBJETIVO: El tratamiento quirúrgico de la intususcepción ileocólica (IIC) es la segunda causa más frecuente de laparotomía de urgencia en niños. La realización de una apendicectomía incidental tras la reducción quirúrgica sigue siendo motivo de controversia. El objetivo de este trabajo es analizar los resultados obtenidos al llevar a cabo una apendicectomía incidental tras la reducción quirúrgica de una IIC con o sin resección intestinal asociada. MATERIAL Y METODO: Se realizó un estudio retrospectivo en pacientes con episodios de IIC sometidos a tratamiento quirúrgico en nuestro centro entre 2005 y 2019. Los pacientes se dividieron en dos grupos según se llevara a cabo apendicectomía asociada (grupo AA) o no (grupo NA). Posteriormente, se elaboró un análisis estratificado según la necesidad de practicar resección intestinal en ambos grupos. Se analizaron las variables demográficas, los hallazgos intraoperatorios, el tiempo quirúrgico, la estancia hospitalaria, las complicaciones posoperatorias y las recidivas. RESULTADOS: Se incluyeron un total de 101 pacientes (77 en el grupo AA, y 24 en el grupo NA), sin diferencias en las características demográficas ni en los hallazgos intraoperatorios. Se practicaron un total de 36 resecciones intestinales (24 en el grupo AA; 10 en el grupo NA), sin diferencias en el tiempo quirúrgico (55,7 min en el grupo AA frente a 61,2 min en el grupo NA; p = 0,587) ni en la estancia hospitalaria (mediana de 5 días en ambos grupos). Tampoco se registraron diferencias en términos de complicaciones posoperatorias o recidivas entre los dos grupos. El análisis estratificado mostró que la resección intestinal incrementa el tiempo quirúrgico, la estancia hospitalaria y las complicaciones posoperatorias, con independencia de si se lleva a cabo apendicectomía asociada o no. CONCLUSION: La apendicectomía incidental durante el tratamiento quirúrgico de la IIC en niños es un procedimiento seguro que no aumenta el tiempo quirúrgico, la estancia hospitalaria, las complicaciones posoperatorias ni las posibilidades de recidiva.

Publisher Correction: Feasibility and effects of enhanced recovery vs. conventional care after emergency colon surgery for patients with left colon perforation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Feasibility and effects of enhanced recovery vs. conventional care after emergency colon surgery for patients with left colon perforation.

The impact of an enhanced recovery after surgery (ERAS) programme in emergency colorectal surgery has not yet been reported. The objective of this study was to evaluate the feasibility and the results of patients included in an ERAS protocol following emergency colon surgery for left colon perforation. For this purpose, patients with a low to moderate risk of mortality, according to a Peritonitis Severity Score (PSS), and treated with an ERAS protocol (ERAS group) after emergency surgery for left colon perforation were compared for a period of 40 months (March 2014-June 2017) with a control group of patients treated with conventional care (CC group) during the 38 months prior to implementation of the new ERAS protocol (January 2011-February 2014). The main endpoint was 90-day postoperative morbidity according to the Clavien-Dindo classification. Secondary endpoints included length of postoperative hospital stay, 90-day readmission rate, protocol compliance and mortality. Fifty patients were included in the study, 29 in the ERAS group and 21 in the CC group. There were no significant differences between the groups in the demographic data or in the operative characteristics. A reduction in the incidence of postoperative complications (20.7% vs. 38%; p > 0.05) and in the postoperative hospital stay (7.7 + /- 3.85 vs. 10.9 + /- 5.6 days; p = 0.009) were observed in the ERAS group. The 90-day readmission rate did not differ significantly between the two groups (2 vs. 1). No 90-day mortality was observed in either group. The ERAS group showed better results than the CC group in protocol compliance. We conclude that ERAS protocols are feasible and help to reduce morbidity and length of hospital stay without adversely affecting the rate of readmission or mortality.

Effects of radiotherapy on plasma energy metabolites in patients with breast cancer who received neoadjuvant chemotherapy.

PURPOSE: Neoadjuvant chemotherapy (NACT) is employed in patients with breast cancer (BC) with the aim of reducing tumor burden and improving surgical outcomes. We evaluated the levels of energy metabolites pre- and post-radiotherapy (RT) in breast cancer (BC) patients who previously received NACT and investigated the alterations of these metabolites in relation to the patient achieving a pathologic complete response to NACT. MATERIALS AND METHODS: We included 37 BC patients who were treated with NACT following surgery and analyzed the concentrations of energy balance-related metabolites using targeted metabolomics before and one month after the end of RT. The control group was composed of 44 healthy women. RESULTS: Pre-radiotherapy, patients had significant decreases in the plasma levels of 12 metabolites. RT corrected these alterations and the improvement was superior in patients with a pathologic complete response. CONCLUSION: Our results highlight the importance of metabolism in the outcomes of patients with BC.

Paraoxonase-1 activity in patients with cancer: A systematic review and meta-analysis.

PURPOSE: Paraoxonase-1 (PON1) is a lipolactonase implicated in the elimination of carcinogenic free radicals and in the scavenging mechanisms to maintain oxidative balance. The objective of the present systematic review and meta-analysis was to evaluate possible alterations in serum PON1 activity in patients with cancer. METHODS: A systematic search of the observational studies in humans published in the last 15 years was performed through Medline databases following the PRISMA and STARLITE statements. Further, a keyword-based computerized search with restrictions on publication date, and a meta-analysis of case-control studies was performed. RESULTS: In total, 23 studies were included most of which reported decreased PON1 activity in patients with cancer. This could indicate impaired defense ability against oxidative stress with potential implications in cell proliferation, promotion of genetic instability, and alterations in cellular sensitivity to chemotherapy. CONCLUSION: This systematic review and meta-analysis confirms a consistent association between cancer and decreased serum PON1 activities. These findings may open fruitful lines of research with clinical relevance, and an understanding of molecular alterations underlying carcinogenesis.

Mapping of the circulating metabolome reveals α-ketoglutarate as a predictor of morbid obesity-associated non-alcoholic fatty liver disease.

BACKGROUND: Obesity severely affects human health, and the accompanying non-alcoholic fatty liver disease (NAFLD) is associated with high morbidity and mortality. Rapid and non-invasive methods to detect this condition may substantially improve clinical care. METHODS: We used liquid and gas chromatography-quadruple time-of-flight-mass spectrometry (LC/GC-QTOF-MS) analysis in a non-targeted metabolomics approach on the plasma from morbidly obese patients undergoing bariatric surgery to gain a comprehensive measure of metabolite levels. On the basis of these findings, we developed a method (GC-QTOF-MS) for the accurate quantification of plasma α-ketoglutarate to explore its potential as a novel biomarker for the detection of NAFLD. RESULTS: Plasma biochemical differences were observed between patients with and without NAFLD indicating that the accumulation of lipids in hepatocytes decreased ß-oxidation energy production, reduced liver function and altered glucose metabolism. The results obtained from the plasma analysis suggest pathophysiological insights that link lipid and glucose disturbances with α-ketoglutarate. Plasma α-ketoglutarate levels are significantly increased in obese patients compared with lean controls. Among obese patients, the measurement of this metabolite differentiates between those with or without NAFLD. Data from the liver were consistent with data from plasma. Clinical utility was assessed, and the results revealed that plasma α-ketoglutarate is a fair-to-good biomarker in patients (n=230). Other common laboratory liver tests used in routine application did not favourably compare. CONCLUSION: Plasma α-ketoglutarate is superior to common liver function tests in obese patients as a surrogate biomarker of NAFLD. The measurement of this biomarker may potentiate the search for a therapeutic approach, may decrease the need for liver biopsy and may be useful in the assessment of disease progression.

Joint research towards a better radiation protection-highlights of the Fifth MELODI Workshop.

MELODI is the European platform dedicated to low-dose radiation risk research. From 7 October through 10 October 2013 the Fifth MELODI Workshop took place in Brussels, Belgium. The workshop offered the opportunity to 221 unique participants originating from 22 countries worldwide to update their knowledge and discuss radiation research issues through 118 oral and 44 poster presentations. In addition, the MELODI 2013 workshop was reaching out to the broader radiation protection community, rather than only the low-dose community, with contributions from the fields of radioecology, emergency and recovery preparedness, and dosimetry. In this review, we summarise the major scientific conclusions of the workshop, which are important to keep the MELODI strategic research agenda up-to-date and which will serve to establish a joint radiation protection research roadmap for the future.

Cancer driver-passenger distinction via sporadic human and dog cancer comparison: a proof-of-principle study with colorectal cancer.

Herein we report a proof-of-principle study illustrating a novel dog-human comparison strategy that addresses a central aim of cancer research, namely cancer driver-passenger distinction. We previously demonstrated that sporadic canine colorectal cancers (CRCs) share similar molecular pathogenesis mechanisms as their human counterparts. In this study, we compared the genome-wide copy number abnormalities between 29 human and 10 canine sporadic CRCs. This led to the identification of 73 driver candidate genes (DCGs), altered in both species, and with 27 from the whole genome and 46 from dog-human genomic rearrangement breakpoint (GRB) regions, as well as 38 passenger candidate genes (PCGs), altered in humans only and located in GRB regions. We noted that DCGs significantly differ from PCGs in every analysis conducted to assess their cancer relevance and biological functions. Importantly, although PCGs are not enriched in any specific functions, DCGs possess significantly enhanced functionality closely associated with cell proliferation and death regulation, as well as with epithelial cell apicobasal polarity establishment/maintenance. These observations support the notion that, in sporadic CRCs of both species, cell polarity genes not only contribute in preventing cancer cell invasion and spreading, but also likely serve as tumor suppressors by modulating cell growth. This pilot study validates our novel strategy and has uncovered four new potential cell polarity and colorectal tumor suppressor genes (RASA3, NUPL1, DENND5A and AVL9). Expansion of this study would make more driver-passenger distinctions for cancers with large genomic amplifications or deletions, and address key questions regarding the relationship between cancer pathogenesis and epithelial cell polarity control in mammals.

Multifunctional targets of dietary polyphenols in disease: a case for the chemokine network and energy metabolism.

Chronic, non-acute inflammation is behind conditions that represent most of the disease burden in humans and is clearly linked to immune and metabolic mechanisms. The convergence of pathways involving the immune response, oxidative stress, increased circulating lipids and aberrant insulin signaling results in CCL2-associated macrophage recruitment and altered energy metabolism. The CCL2/CCR2 pathway and the energy sensor AMP-activated protein kinase (AMPK) are attractive therapeutic targets as a part of preventive management of disease. Several effects of polyphenols are useful in this scenario, including a reduction in the activities of cytokines and modulation of cellular metabolism through histone deacetylase inhibitors, AMPK activators, calorie-restriction mimetics or epigenetic regulators. Research is currently underway to develop orally active drugs with these effects, but it is convenient to examine more closely what we are eating. If a lack of relevance in terms of toxicity and substantial effectiveness are confirmed, plant-derived components may provide useful druggable components and dietary supplements. We consider therapeutic actions as a combination of synergistic and/or antagonistic interactions in a multi-target strategy. Hence, improvement in food through enrichment with polyphenols with demonstrated activity may represent a major advance in the design of diets with both industrial and sanitary value.

MicroRNA-24 regulates XIAP to reduce the apoptosis threshold in cancer cells.

MicroRNAs have been implicated as important mediators of cancer cell homeostasis, and accumulating data suggest compelling roles for them in the apoptosis pathway. X-linked inhibitor of apoptosis protein (XIAP) is a potent caspase inhibitor and an important barrier to apoptotic cell death, but the mechanisms that determine the diverse range of XIAP expression seen in cancer remains unclear. In this study, we present evidence that miR-24 directly targets the 3'UTR of the XIAP messenger RNA (mRNA) to exert translational repression. Using a heuristic algorithm of bioinformatics analysis and in vitro screening, we identified miR-24 as a candidate regulator of XIAP expression. Array comparative genomic hybridization and spectral karyotype analysis reveal that genomic copy number loss at the miR-24 locus is concordant with the loss of endogenous miR-24 in cancer cells. Using a luciferase construct of the XIAP 3'UTR, we showed that miR-24 specifically coordinates to the XIAP mRNA. Interference with miR-24's binding of the critical seed region, resulting from site-directed mutagenesis of the 3'UTR, significantly abrogated miR-24's effects on XIAP expression. Moreover, miR-24 overexpression can overcome apoptosis resistance in cancer cells via downregulation of XIAP expression, and the resulting cancer cell death induced by tumor necrosis factor-related apoptosis-inducing ligand is executed by the canonical caspase-mediated apoptosis pathway. In summary, our data suggest a novel mechanism by which miR-24 directly modulates XIAP expression level and consequently the apoptosis threshold in cancer cells.

Metformin: a cheap and well-tolerated drug that provides benefits for viral infections.

OBJECTIVES: Insulin resistance in viral infections is common. We have explored the effectiveness of metformin for alleviating insulin resistance in HIV-infected patients and assessed the relevance of the ataxia-telangiectasia mutated (ATM) rs11212617 variant in the clinical response with the rationale that metformin modulates cellular bioenergetics in an ATM-dependent process. METHODS: HIV-infected patients (n = 385) were compared with controls recruited from the general population (n = 300) with respect to the genotype distribution of the ATM rs11212617 variant and its influence on selected metabolic and inflammatory variables. We also followed up a subset of male patients with HIV and hepatitis C virus (HCV) coinfection (n = 47) who were not receiving antiviral treatment and for whom metformin was prescribed for insulin resistance, which tends to have a higher incidence and severity in coinfected patients. RESULTS: Among the HIV-infected patients, human cytomegalovirus (91.9%) and HCV (62.3%) coinfections were frequent. Selected metabolic and/or inflammatory variables were significantly altered in infected patients. Treatment with metformin in HIV and HCV coinfected patients was well tolerated and significantly increased the sensitivity of peripheral tissues to insulin. The minor allele (C) of the rs11212617 variant was associated with treatment success and may affect the course of insulin resistance in response to metformin (odds ratio 1.21; 95% confidence interval 1.07-1.39; P = 0.005). There were no differences between treated and untreated patients in viral loads or variables measuring immune defence, indicating that toxicity is unlikely. CONCLUSIONS: We provide novel data suggesting that identification of the ATM rs11212617 variant may be important in assessing the glycaemic response to metformin treatment for insulin resistance in HIV-infected patients.

Biodentine(TM) induces TGF-ß1 release from human pulp cells and early dental pulp mineralization.

AIM: To assess the ability of a recently developed tricalcium silicate-based cement (Biodentine™) to induce reparative dentine synthesis and to investigate its capacity to modulate pulp cells TGF-ß1 secretion. METHODOLOGY: Biodentine™ was directly applied onto the dental pulp in an entire human tooth culture model. After various culture periods, the interaction of the material with dental pulp tissue was analysed on tissue sections. The effect of increasing surface area of this material on TGF-ß1 secretion was investigated on pulp cell cultures and compared with that of MTA, calcium hydroxide and Xeno(®) III adhesive resin. After performing artificial injuries on pulp cell cultures, the materials eluates were added for 24 h and then TGF-ß1 secretion was quantified by ELISA. Controls were performed by incubating intact cells with the culture medium, while injured cells TGF-ß1 level was used as the baseline value. RESULTS: Biodentine™ induced mineralized foci formation early after its application. The mineralization appeared under the form of osteodentine and expressed markers of odontoblasts. Biodentine™ significantly increased TGF-ß1 secretion from pulp cells (P < 0.03) independently of the contact surface increase. This increase was also observed with calcium hydroxide and MTA, but not with the resinous Xeno(®) III. The statistical analysis showed statistically significant differences between capping materials and the resinous Xeno(®) III (P < 0.001). CONCLUSIONS: When Biodentine™ was applied directly onto the pulp, it induced an early form of reparative dentine synthesis, probably due to a modulation of pulp cell TGF-ß1 secretion.

Continuous administration of polyphenols from aqueous rooibos (Aspalathus linearis) extract ameliorates dietary-induced metabolic disturbances in hyperlipidemic mice.

The incidence of obesity and related metabolic diseases is increasing globally. Current medical treatments often fail to halt the progress of such disturbances, and plant-derived polyphenols are increasingly being investigated as a possible way to provide safe and effective complementary therapy. Rooibos (Aspalathus linearis) is a rich source of polyphenols without caloric and/or stimulant components. We have tentatively characterized 25 phenolic compounds in rooibos extract and studied the effects of continuous aqueous rooibos extract consumption in mice. The effects of this extract, which contained 25% w/w of total polyphenol content, were negligible in animals with no metabolic disturbance but were significant in hyperlipemic mice, especially in those in which energy intake was increased via a Western-type diet that increased the risk of developing metabolic complications. In these mice, we found hypolipemiant activity when given rooibos extract, with significant reductions in serum cholesterol, triglyceride and free fatty acid concentrations. Additionally, we found changes in adipocyte size and number as well as complete prevention of dietary-induced hepatic steatosis. These effects were not related to changes in insulin resistance. Among other possible mechanisms, we present data indicating that the activation of AMP-activated protein kinase (AMPK) and the resulting regulation of cellular energy homeostasis may play a significant role in these effects of rooibos extract. Our findings suggest that adding polyphenols to the daily diet is likely to help in the overall management of metabolic diseases.

Bilateral inguinal hernia repair: laparoscopic or open approach?

BACKGROUND: The aim of this study was to investigate outcomes in the treatment of bilateral inguinal hernia, comparing the laparoscopic totally extraperitoneal (TEP) and open tension-free mesh repair (LICHT) approaches. METHODS: We performed a prospective controlled non randomized clinical study in 128 patients with bilateral inguinal hernia over a period of 3 years. LICHT was used in 106 cases (53 patients) while TEP was employed in 150 cases (75 patients). The main outcome measurements were: recurrence rate, operating time, hospital stay and postoperative complications. RESULTS: There were three recurrences (2.3%): two in the LICHT group (3.8%) and one (1.3%) in the TEP group P = NS. The TEP procedure was faster than LICHT repair (48.8 ± 10.8 vs. 70.4 ± 11.2 min) P < 0.01. Postoperative complications were more frequent in LICHT group (16%) than TEP group (5.3%) P < 0.01. Hospital stay was significantly shorter in the TEP group (0.6 ± 0.8 vs. 1.3 ± 1.2 days) P < 0.001. CONCLUSIONS: The TEP approach is an effective option for the treatment of bilateral inguinal hernia when performed by experienced surgeons.

[Robotics in pediatric surgery]. / Robótica en cirugía pediátrica.

Despite the extensive use of robotics in the adult population, the use of robotics in pediatrics has not been well accepted. There is still a lack of awareness from pediatric surgeons on how to use the robotic equipment, its advantages and indications. Benefit is still controversial. Dexterity and better visualization of the surgical field are one of the strong values. Conversely, cost and a lack of small instruments prevent the use of robotics in the smaller patients. The aim of this manuscript is to present the controversies about the use of robotics in pediatric surgery.

Phase II clinical trial of liposomal-encapsulated doxorubicin citrate and docetaxel, associated with trastuzumab, as neoadjuvant treatment in stages II and IIIA HER2-overexpressing breast cancer patients. GEICAM 2003-03 study.

BACKGROUND: we previously reported a phase I trial of liposome-encapsulated doxorubicin citrate (LD), docetaxel and trastuzumab as neoadjuvant in stages II and IIIA human epidermal growth factor receptor 2-overexpressing breast cancer patients. This study evaluates the efficacy of this regimen in a phase II trial. PATIENTS AND METHODS: patients were treated with LD 50 mg/m(2) and docetaxel 60 mg/m(2) every 21days associated with standard trastuzumab dose and pegfilgrastim support. RESULTS: fifty-nine patients were enrolled; median age: 48 years (range 24-71 years); premenopausal patients: 36 (61%); 19 patients (32%) presented stage IIIA disease and 40 patients (67%) stage II; histological grades 2-3 tumors: 50 patients (84%) and estrogen receptor-progesterone receptor negative: 28 patients (47%). In all, 27% achieved a pathological complete response in breast and axilla (grade 5-Miller and Payne classification); 15% of patients achieved grade 4. Clinical and radiological response rates were 86% and 81%, respectively. Forty-two patients (71%) underwent breast-conserving surgery. The main grades 3-4 toxic effects were non-febrile neutropenia (29%) and fatigue (8%). Grade 2 left ventricular ejection fraction decline was observed in nine patients. No congestive heart failure was observed. CONCLUSIONS: LD plus docetaxel combination associated with trastuzumab as neoadjuvant is active in breast cancer and entails a favorable cardiotoxicity profile. This regimen is a new treatment option in these patients.