The role of lung biopsy for diagnosis and prognosis of interstitial lung disease in systemic sclerosis: a systematic literature review.

BACKGROUND: The prognostic and theragnostic role of histopathological subsets in systemic sclerosis interstitial lung disease (SSc-ILD) have been largely neglected due to the paucity of treatment options and the risks associated with surgical lung biopsy. The novel drugs for the treatment of ILDs and the availability of transbronchial cryobiopsy provide a new clinical scenario making lung biopsy more feasible and a pivotal guide for treatment. The aim of our study was to investigate the usefulness of lung biopsy in SSc ILD with a systematic literature review (SLR). METHODS: PubMed, Embase and Cochrane databases were searched up to June 30, 2023. Search terms included both database-specific controlled vocabulary terms and free-text terms relating to lung biopsy and SSc-ILD diagnostic and prognosis. The SLR was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Studies were selected according to the PEO (population, exposure, and outcomes) framework and Quality assessment of diagnostic accuracy studies (QUADAS) were reported. RESULTS: We selected 14 articles (comprising 364 SSc-ILD patients). The paucity and heterogeneity of the studies prevented a systematic analysis. Diffuse cutaneous SSc was present in 30-100% of cases. Female predominance was observed in all studies (ranging from 64 to 100%). Mean age ranged from 42 to 64 years. Mean FVC was 73.98 (+/-17.3), mean DLCO was 59.49 (+/-16.1). Anti-Scl70 antibodies positivity was detected in 33% of cases (range: 0-69.6). All patients underwent surgical lung biopsies, and multiple lobes were biopsied in a minority of studies (4/14). Poor HRCT-pathologic correlation was reported with HRCT-NSIP showing histopathologic UIP in up to 1/3 of cases. Limited data suggest that SSc-UIP patients may have a worse prognosis and response to immunosuppressive treatment compared to other histopathologic patterns. CONCLUSIONS: The data from this SLR clearly show the paucity and heterogeneity of the studies reporting lung biopsy in SSc ILD. Moreover, they highlight the need for further research to address whether the lung biopsy can be helpful to refine prognostic prediction and guide therapeutic choices.

Descripción epidemiológica de la patología social y de salud mental en una sala de internación clínica de un hospital publico especializado en pediatría / Epidemiological description of social pathology and mental health in a clinical hospital ward of a public hospital specialized in pediatrics

En la actualidad, existe un notable incremento en las patologías relacionadas con problemáticas sociales y de salud mental. La problemática social da cuenta de la existencia de situaciones familiares que ponen en riesgo a los niños, como situaciones de maltrato, violencia u omisión de cuidados de los mismos. Los problemas de salud mental hacen referencia a niños que padecen desordenes mentales que los llevan a la psicosis, intentos de suicidio, depresión, o trastornos del ánimo y del humor. Estas patologías son susceptibles de comorbilidades clínicas como la obesidad ya que las características familiares, las psiquiátricas y los aspectos psicológicos, entre ellos la ansiedad, han sido descritos en la producción y mantenimiento de la misma. Objetivo: Describir las características epidemiológicas de pacientes hospitalizados en una sala de internación general del Hospital de Niños Sor María Ludovica de La Plata con problemática en cuanto a patología Social y de Salud mental, durante un periodo de 18 meses. Material y métodos: Estudio descriptivo retrospectivo. Se analizaron 61 historias clínicas de ingresos 35 por patología de salud mental y problemática social en la sala 3 de Clínica Pediátrica durante un periodo de 18 meses. Resultados: El 78,6% fueron de sexo femenino y el 80 % mayores de 10 años. La mayoría provenía del Gran La Plata (90%). El 85% ingresaron en buen estado general o alcanzaron la estabilidad clínica en las primeras 72 horas de internación. Estas internaciones fueron prolongadas comparadas con el promedio de internación hospitalaria general. En ellas intervinieron múltiples servicios (promedio de 3 servicios por paciente y de 2 a 6 interconsultas). En un porcentaje importante (88%) se caracterizó a la familia como disfuncional o de riesgo. Conclusión: Se evidenció un predominio de hospitalizaciones por cuestiones sociales o de salud mental en pacientes de sexo femenino y del grupo de adolescentes. Los diagnósticos clínicos de ingreso se superpusieron a la problemática social y de salud mental demostrando la complejidad de estas patologías y la necesidad del trabajo interdisciplinario

Currently, there is a notable increase in pathologies related to social problems and mental health. The social problem accounts for the existence of family situations that put children at risk, such as situations of abuse, violence or lack of care for them. Mental health problems refer to children who suffer from mental disorders that lead to psychosis, suicide attempts, depression, or mood and mood disorders. These pathologies are susceptible to clinical comorbidities such as obesity since family characteristics, psychiatric and psychological aspects, including anxiety, have been described in its production and maintenance. Objectives: To describe the epidemiological characteristics of patients hospitalized in a general hospitalization room of the Sor María Ludovica Children's Hospital of La Plata with problems in terms of Social pathology and mental health, during a period of 18 months. Material and methods: Descriptive-retrospective study. 61 medical records of admissions for mental health pathology and social problems were analyzed in room 3 of Clínica Pediátrica during a period of 18 months. Results: 78.6% were female and 80% were older than 10 years. The majority came from Gran La Plata (90%). 85% were admitted in good general condition or achieved clinical stability in the first 72 hours of hospitalization. These hospitalizations were prolonged compared to the average general hospital stay. They involved multiple services (average of 3 services per patient and 2 to 6 interconsultations). In a significant percentage (88%) the family was characterized as dysfunctional or with social risk. Conclusion: A predominance of hospitalizations for social or mental health issues was evidenced in female patients and in the adolescent group. The admission diagnoses were superimposed on the social and mental health problems, demonstrating the complexity of these pathologies and the need for interdisciplinary work

Is systemic inflammation a missing link between periodontitis and hypertension? Results from two large population-based surveys.

OBJECTIVE: The primary objective was to investigate the relationship between periodontitis and hypertension in two independent large surveys. The secondary objective was to ascertain whether systemic inflammation had a mediation effect in the association. METHODS: This cross-sectional study analysed representative samples of the US (n = 3460; NHANES 2009/10) and Korean (n = 4539; 2015 KNHANES VI-3) populations. The association between periodontitis (exposure), hypertension (outcome) and inflammatory markers [C-reactive protein (CRP) and white blood cell counts (WBC)] (mediators) was assessed using multivariate linear and logistic regression models and mediation analysis. RESULTS: Participants with periodontitis were more likely to have hypertension (NHANES: OR = 1.3, 95% CI: 1.0-1.6, P = 0.025; KNHANES: OR = 1.2, 95% CI: 1.0-1.4, P = 0.041) and actual systolic blood pressure ≥ 140 mmHg (NHANES: OR = 1.6, 95% CI: 1.1-2.3, P < 0.001; KNHANES: OR = 1.3, 95% CI :1.0-1.6, P < 0.031) than those without the disease. These associations were independent of age, gender, BMI, education level, smoking, alcohol consumption, creatinine, physical activity, presence of other comorbidities and confirmed in participants not taking antihypertensive medications. Diagnosis of periodontitis was directly associated with WBC (in both surveys: NHANES: ß ± SE = 0.3 ± 0.1, P < 0.004; KNHANES: ß ± SE = 0.3 ± 0.1, P < 0.001) and with CRP levels (in one survey: NHANES: ß ± SE = 0.1 ± 0.03, P < 0.007; KNHANES: ß ± SE = 0.1 ± 0.04, P > 0.213). Mediation analyses confirmed that CRP acted as a mediator in the association between periodontitis and hypertension in both populations (mediated effect: NHANES: ß ± SE = 0.010 ± 0.003, P < 0.001; KNHANES: ß ± SE = 0.003 ± 0.001, P = 0.015). WBC acted as a mediator in the KNHANES (mediated effect: ß ± SE = 0.004 ± 0.001, P = 0.004) whilst in the NHANES, its effect was dependent of CRP inclusion in the model (mediated effect WBC + CRP: ß ± SE = 0.002 ± 0.001, P = 0.001). CONCLUSIONS: These findings suggest that periodontitis is closely linked to hypertension and systemic inflammation is, in part, a mediator of this association.

Feasibility of voxel-based Dose Painting for recurrent Glioblastoma guided by ADC values of Diffusion-Weighted MR imaging.

PURPOSE: Glioblastoma Multiforme (GBM) is the most common malignant brain tumor and frequently recurs in the same location after radiotherapy. Intensive treatment targeting localized lesion is required to improve GBM outcome, but dose escalation using conventional methods is limited by healthy tissue tolerance. Helical Tomotherapy (HT) Dose Painting (DP) treatments were simulated to safely deliver high doses in the recurrent regions. MATERIALS AND METHODS: Apparent Diffusion Coefficient (ADC) data from five recurrent GBM were retrospectively considered for planning. Hypo-fractionated (25-50Gy, 5 fractions) voxel-based prescriptions were opportunely converted to personalized structured-based dose maps to create DP plans with a commercial Treatment Planning System. Optimized plans were generated and analyzed in terms of plan conformity to dose prescription (Q0.90-1.10), tolerance of the healthy tissues (DMAX), and dosimetry accuracy of the deliverable plans (γ-index). RESULTS: Only three of the five cases could receive a safe retreatment without violating the maximum critical organs dose constraints. The conformity of the simulated plans was between 40.9% and 79.9% (Q0.90-1.10), their delivery time was in the range of 38.3-63.6min, while the dosimetry showed γ-index of 82.4-92.4%. CONCLUSIONS: This study proved the ability of our method to simulate personalized, deliverable and dosimetrically accurate DPBN plans. HT hypo-fractionated treatments guided by ADC maps can be realized and applied to deliver high doses in the GBM recurrent regions, although there are some critical issues related to low Q0.90-1.10 values, to exceeding of healthy-tissue dose constraints for some patients and long delivery times.

Monitoring a CuO gas sensor at work: an advanced in situ X-ray absorption spectroscopy study.

X-ray absorption near edge structure (XANES) and electrical measurements were used to elucidate the local structure and electronic changes of copper(II) oxide (CuO) nanostructures under working conditions. For this purpose, a sample holder layout was developed enabling the simultaneous analysis of the spectroscopic and electrical properties of the sensor material under identical operating conditions. The influence of different carrier gases (e.g., air and N2) on the CuO nanostructures behavior under reducing conditions (H2 gas) was studied to analyze how a particular gas atmosphere can modify the oxidation state of the sensor material in real time.

Síndrome de burnout en médicos de Terapias Intensivas de General Roca y Cipolletti / Burnout syndrome in doctors of Intensive Therapies General Roca and Cipolletti

Objetivo: Conocer la existencia del síndrome de burnout en médicos intensivistas de General Roca y Cipolletti, y correlacionarlo con factores de estrés laboral. Diseño: Encuesta a los médicos intensivistas de adultos, pediátricos y neonatólogos, de General Roca y Cipolletti, utilizando el Maslach Burnout Inventory Manual (MBI), la encuesta hospitalaria de estrés/satisfacción laboral (HCJSSQ) y una autoevaluación del nivel de estrés/satisfacción. Se identificaron los profesionales que están por encima de la mediana en agotamiento emocional y despersonalización, y por debajo en realización personal. La presencia de las tres dimensiones definió la existencia del síndrome. Se correlacionaron las encuestas con el coeficiente de Pearson, vinculando el burnout con los factores que provocan estrés. Resultados: Respondieron 52 intensivistas (92% del total); 12 presentaron burnout (21,4%), en su mayoría, mujeres (58,33%). Cinco (41,7%) de ellos consideraron al estrés intenso; 6 (50%), moderado y uno (8,33%), leve. Casi el 60% de los afectados no reconoció su existencia. Los intensivistas de instituciones públicas, de terapias pediátricas/neonatoló- gicas y de Cipolletti manifestaron más afectación. Los factores que provocan estrés fueron: falta de tiempo, mayor complejidad tecnológica, necesidad de cubrir guardias y dar malas noticias, amenaza de litigio, restricciones institucionales, conflictos con el equipo de trabajo, falta de autonomía, exceso de responsabilidad y sensación de no hacer bien la tarea. Un factor de satisfacción fue el trabajo en equipo. Conclusión: Se evidenció el rol institucional en la prevención, el reconocimiento y el empleo de estrategias de abordaje orientadas al afectado y a mejorar el clima organizacional, las condiciones laborales, la comunicación y el trabajo en equipo.(AU)

Objective: To establish the occurrence of burnout syndrome in critical care physicians from General Roca and Ciplolletti, and correlate it with factors found in work-related stress. Design: A survey involving all adult, pediatric and neonatal critical care physicians in General Roca and Cipolletti. The Maslach Burnout Inventory Manual (MBI) questionnaire, the Hospital Consultants Job Stress & Satisfaction questionnaire (HCJSSQ) and an auto-evaluation of stress and satisfaction levels were used. The investigation identified professionals of above-average emotional exhaustion and depersonalisation, and below-average personal achievement. The presence of these three indicators defined the existence of the syndrome. The questionnaires were correlated using the Pearson coefficient to link burnout with factors causing stress. Results: Fifty-two critical care physicians responded to the survey (92% of the target group): 12 presented burnout (21.4%), the majority being women (58.33%). Five (41.7%) of them considered their stress to be "severe", 6 (50%) "moderate" and 1 (8.33%) "mild". Almost 60% of those affected were unaware of its presence. Critical care physicians working in public institutions, in pediatric/neonatal care and in Cipolletti were the most affected. Correlating stress-inducing factors: lack of time, high levels of technological complexity, need to cover ER/A&E and deliver bad news, threat of litigation, institutional restrictions, conflicts within a team, lack of autonomy, excess responsibility and the feeling of underperforming. Teamwork was a factor in deriving satisfaction. Conclusion: The role played by the institution was identified as a factor in the prevention and recognition, and the use of hands-on strategies aimed at the sufferer and at improving the organisational climate, working conditions, communication and teamwork(AU)

Breast-conservative surgery with and without radiotherapy in patients aged 55-75 years with early-stage breast cancer: a prospective, randomized, multicenter trial analysis after 108 months of median follow-up.

OBJECTIVES: Breast-conserving therapy (BCT), including postoperative whole breast irradiation (WBI), is generally accepted as the treatment of choice for most patients with early-stage breast cancer. The question whether WBI is mandatory in all patients remains one of the most controversial issues in BCT. To answer this question, a randomized, prospective, multicentre study was launched in January 2001. Primary endpoints of the study were to assess the cumulative incidence of in-breast-recurrences (IBR) and overall survival (OAS) after conservative surgery (BCS) with or without WBI. METHODS: From January 2001 until December 2005, 749 patients with unifocal infiltrating breast cancer up to 25 mm, 0-3 positive axillary lymph nodes, no extensive intraductal component or lymphvascular invasion from 11 centres in Italy, were randomly assigned to BCS+WBI (arm 1:373 patients) or BCS alone (arm 2:376 patients). Treatment arms were well balanced in terms of baseline characteristics. Systemic adjuvant therapy was administered according to the institutional policies. Kaplan-Meier method was used for survival analysis and log-rank test to evaluate the difference between the two arms. RESULTS (Last analysis 31.12.2012): After median follow-up of 108 months, 12 (3.4%) IBR were observed in arm 1 and 16 (4.4%) in arm 2. OAS was 81.4% in arm 1 and 83.7% in arm 2. There was no statistically significant difference regarding IBR and death in the two treatment groups. CONCLUSIONS: These data are promising and suggest that WBI after BCS can be omitted in selected patients with early stage breast cancer without exposing them to an increased risk of local recurrence and death. Longer follow-up is needed to further consolidate these results.

Controlled synthesis of layered Sn3O4 nanobelts by carbothermal reduction method and their gas sensor properties.

This paper reports both the controlled synthesis of Sn3O4 nanobelts by carbothermal reduction method and the gas sensor properties of these nanostructures. The synthesized material was characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy and gas sensor measurements. The results showed that the Sn3O4 nanobelts grow in a layered way and the careful control of experimental parameters is fundamental for stabilization of the correct phase. From the gas sensor measurements using oxygen as analyte gas, it was observed that the Sn3O4 nanobelts exhibit n-type behavior and both the sensitivity and the response time are dependent on the oxygen concentration. A model based on molecules adsorption was proposed to illustrate the mechanism of gas detection of these nanostructures. In summary, these results indicate that Sn3O4 nanobelts synthesized by carbothermal reduction method are promising to be applied as gas sensors.

Ultrasound in sialadenitis.

The salivary glands are located superficially and are therefore easily accessible to ultrasound (US) examination, particularly if a high-frequency probe designed for small parts is used. Hence, US examination of these organs is widely applied particularly in non-neoplastic pathologies. In this way, it is possible to obtain adequate images without the use of ionizing radiation or complex instrumentation such as magnetic resonance imaging. However, US examination requires an expert clinical knowledge and familiarity with the normal and pathological US anatomy of the area. Limitations and pitfalls linked to US examination of this area should also be kept in mind.

Anti-invasive effects and proapoptotic activity induction by the rexinoid IIF and valproic acid in combination on colon cancer cell lines.

In this study, we investigated the antiproliferative and anti-invasive mechanism action of sodium valproate (VPA), an inhibitor of histone deacetylase (HDAC) activity, in combination with the rexinoid 6-OH-11-O-hydroxyphenanthrene (IIF), a ligand of retinoid X receptor (RXR), in the HT-29 and LoVo colon cancer cell lines. VPA inhibited HDAC-1 and increased RXRγ expression. VPA and IIF reduced viability in a dose- and time-dependent manner. The combined use of VPA and IIF enhanced the apoptosis induction. In particular, the BCL2 level decreased, while levels of BAX, cleaved caspase-3 and caspase-9 increased. The same treatment also reduced invasiveness of HT-29 cell line through the inhibition of metalloproteinase-9 (MMP9) expression, and MMP9 and MMP2 activity, with an increase of tissue inhibitors of MMPs TIMP1 and TIMP2. In conclusion, VPA and IIF have strong proapoptotic and anti-invasive effects in the HT-29 colon cancer cell line and their effects are enhanced when used together.

Combined modality treatment for patients with locally advanced pancreatic adenocarcinoma.

BACKGROUND: Radiofrequency ablation (RFA) is an emerging treatment for patients with locally advanced pancreatic carcinoma, and can be combined with radiochemotherapy and intra-arterial plus systemic chemotherapy. METHODS: This observational study compared two groups of patients with locally advanced pancreatic carcinoma treated with either primary RFA (group 1) or RFA following any other primary treatment (group 2). RESULTS: Between February 2007 and May 2010, 107 consecutive patients were treated with RFA. There were 47 patients in group 1 and 60 in group 2. Median overall survival was 25·6 months. Median overall survival was significantly shorter in group 1 than in group 2 (14·7 versus 25·6 months; P = 0·004) Patients treated with RFA, radiochemotherapy and intra-arterial plus systemic chemotherapy (triple-approach strategy) had a median overall survival of 34·0 months. CONCLUSION: RFA after alternative primary treatment was associated with prolonged survival. This was further extended by use of a triple-approach strategy in selected patients. Further evaluation of this approach seems warranted.

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells.

Recent literature highlights the importance of pro-inflammatory cytokines in the biology of breast cancer stem cells (CSCs), unraveling differences with respect to their normal counterparts. Expansion of mammospheres (MS) is a valuable tool for the in vitro study of normal and cancer mammary gland stem cells. Here, we expanded MSs from human breast cancer and normal mammary gland tissues, as well from tumorigenic (MCF7) and non-tumorigenic (MCF10) breast cell lines. We observed that agonists for the retinoid X receptor (6-OH-11-O-hydroxyphenanthrene), retinoic acid receptor (all-trans retinoic acid (RA)) and peroxisome proliferator-activated receptor (PPAR)-γ (pioglitazone (PGZ)), reduce the survival of MS generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells. This phenomenon is paralleled by the hampering of pro-inflammatory Nuclear Factor-κB (NF-κB)/Interleukin-6 (IL6) axis that is hyperactive in breast cancer-derived MS. The hindrance of such pathway associates with the downregulation of MS regulatory genes (SLUG, Notch3, Jagged1) and with the upregulation of the differentiation markers estrogen receptor-α and keratin18. At variance, the PPARα agonist Wy14643 promotes MS formation, upregulating NF-κB/IL6 axis and MS regulatory genes. These data reveal that nuclear receptors agonists (6-OH-11-O-hydroxyphenanthrene, RA, PGZ) reduce the inflammation dependent survival of breast CSCs and that PPARα agonist Wy14643 exerts opposite effects on this phenotype.

Low dose fractionated cisplatin plus gemcitabine for elderly patients with advanced non small cell lung cancer: a retrospective analysis.

The aim of the study was to evaluate safety and efficacy of gemcitabine-cisplatin in elderly patients with advanced non small cell lung cancer (NSCLC). This study included 59 patients aged >70 years consecutively admitted to our Department. treatment consisted of gemcitabine 1000 mg/m(2) on days 1 and 8, and low-dose fractionated cisplatin 20 mg/m(2) on days 1, 2, 3 of a 21-day cycle. Toxicity was graded according to the world Health Organization (WHO) criteria.A total of 281 cycles was administered. Hematological toxicities of grade 3 and 4 were seen in 17% and 5% of patients, respectively. Grade 3 gastrointestinal toxicity was 3%, grade 2 neuropathy was 2%. Twenty-nine partial responses with an objective response rate of 49% were obtained. No complete responses were observed. The median progression-free survival (PFS) and overall survival (OS) were 7.8 and 15.5 months respectively. Cisplatin-based combination chemotherapy at low doses appears to be safe and active in older patients with advanced NSCLC.

(-)-Epigallocatechin-3-gallate downregulates Pg-P and BCRP in a tamoxifen resistant MCF-7 cell line.

We investigated the anticancer effect of EGCG treatment on a breast carcinoma cell line resistant to tamoxifen (MCF-7Tam cells). As there are no reports about the molecular mechanisms implicated in EGCG treatment of tamoxifen resistant breast carcinoma cells, we studied the effects of EGCG treatment on three plasma membrane proteins that are involved in the mechanism of drug-resistance: Multidrug Resistance Protein (MRP1), P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). EGCG treatment (10-100 microg/ml for 24-72 hours) caused cell growth inhibition and dose-dependent apoptosis: after 100 microg/ml EGCG treatment for 24 hours, Bax expression increased and Bcl2 expression decreased (p<0.05). Coherently, Annexin V-FITC apoptosis assay detected a significant increase in labelled cells (p<0.05). EGCG did not affect MRP1: in contrast, 100 microg/ml EGCG administration caused P-gp decrease to 53% of control cells (p<0.001) and this effect was not due to downregulation of P-gp gene expression. EGCG induced P-gp decrease even when MG132, a strong proteasome inhibitor, was given together with EGCG to MCF-7Tam cells. EGCG treatment also inhibited BCRP activity: mRNA transcription and protein level did not change after treatment, but mitoxantrone test demonstrated a strong inhibition of BCRP activity (p<0.001). In conclusion, the present results showed that EGCG could down-regulate the activity of two molecules that play a key role in drug metabolism and transport and that are highly expressed in tamoxifen resistant breast carcinoma cells. The interaction of EGCG and drugs used in the therapy of estrogen sensitive breast carcinoma ought to be subject of studies and the potential use of EGCG in drug-resistant diseases ought to be better considered.

Gynecomastia in two young men with histories of prolonged use of anabolic androgenic steroids.

The aim of this report is to highlight the risk of anabolic androgenic steroid-induced gynecomastia in young men involved in nonagonistic sports and the role of ultrasonography in its diagnosis. The authors describe two cases of gynecomastia in nonprofessional weight lifters with histories of AAS use. In both cases, the diagnosis was based on patient history and clinical findings, but the sonographic examination confirmed the clinical suspicion and excluded the presence of other types of disease associated with mammary-gland enlargement in men.

Conservative surgery with and without radiotherapy in elderly patients with early-stage breast cancer: a prospective randomised multicentre trial.

Breast conserving therapy (BCT) including postoperative irradiation of the remaining breast tissue is generally accepted as the best treatment for the majority of patients with early-stage breast cancer. The question is whether there is a necessity for irradiating all patients. Between 2001 and 2005, 749 women aged 55-75 years with infiltrating breast carcinoma were randomly assigned to breast conservative surgery, with or without radiotherapy (RT), to evaluate the incidence of in-breast recurrence (IBR). After 5 years of median follow-up, the cumulative incidence of IBR was 2.5% in the surgery-only arm and 0.7% in the surgery plus RT arm. There are no differences in terms of overall survival and distant disease-free survival. The preliminary evaluation suggests that breast irradiation after conservative surgery can be avoided without exposing these patients to an increased risk of distant-disease recurrence. Prolonged follow-up will further clarify the possible risks and late sequelae potentially induced by breast RT.

Enhanced effects of PPARgamma ligands and RXR selective retinoids in combination to inhibit migration and invasiveness in cancer cells.

Experimental data from in vitro and in vivo models indicate that peroxisome proliferator-activated receptor (PPAR) ligand activation regulates differentiation and induces cell growth arrest and apoptosis in a variety of cancer types. Thiazolidinediones such as ciglitazone (CGZ) constitute the most well-known synthetic ligands for PPARgamma. We previously reported a remarkable antitumor effect of the retinoid 6-OH-11-O-hydroxyphenantrene (IIF), synthetic retinoid X receptors (RXRs) agonist, on many cancer cell lines. Since PPARs bind to DNA as heterodimers with RXRs, in this study we investigated if IIF potentiates the antitumoral properties of the PPARgamma ligand CGZ in glioblastoma U87MG and melanoma G361 cells. Our results show that either IIF or CGZ inhibited cell growth and tissue invasion ability, but these properties were enhanced by using IIF and CGZ in combined treatment. Since matrix metalloproteinases (MMPs) play a major role in tumor cell invasion, we analyzed the effect of IIF and CGZ on MMP2 and MMP9 activity and expression. The addition of IIF to CGZ resulted in a decrease of MMP2 and MMP9 expression and activity, higher than when each agent was used alone. Furthermore, treatment with IIF and/or CGZ enhanced PPARgamma expression but both agents in combined treatment caused the maximum efficiency. Finally, we demonstrated that IIF can potentiate PPARgamma trascriptional activity induced by CGZ, by evaluation of peroxisome proliferator-responsive element transactivation. In conclusion, these findings suggest that the RXR selective retinoid IIF, in combination with the PPARgamma ligand CGZ, may provide a therapeutic advantage in cancer treatment.

Growth inhibition and proapoptotic activity induction by IIF and valproic acid on RA-resistant leukemia cells.

All-trans retinoic acid (RA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). Nevertheless, most of these patients develop RA resistance and relapse. In an attemp to mimic clinical conditions for the treatment of leukemia, a stably RA-resistant subclone of the human promyelocytic leukemia cell line HL60 (HL60-R) was developed to study the antiproliferative and proapoptotic effect of the retinoid IIF (6-OH-11-O-hydroxyphenantrene) in comparison with RA. Moreover whether the inhibitor of histone deacetylase (HDAC) activity, valproic acid (VPA), could enhance sensitivity to retinoids in HL60-R cells was evaluated. Finally, the effect of IIF on the expression of multidrug resistance-associated protein 1 (MRP1) and P-glycoprotein (P-gp) was evaluated. It was found that IIF strongly suppressed cell proliferation (as measured by growth curves) and induced apoptosis (as measured by DNA fragmentation and Annexin V detection assays), while RA was practically ineffective. The addition of VPA to IIF accentuated the antiproliferative effect of IIF alone and increased apoptosis; the combination of VPA with RA allowed growth arrest. Moreover IIF caused a reduction of transmembrane transporter expression, particularly of P-gp, as shown by Western blotting. Our results suggest that IIF may be useful in controlling the proliferation of RA-resistant leukemia cells, especially in combination with an HDAC inhibitor, such as VPA.

Inhibitory effects of retinoic acid and IIF on growth, migration and invasiveness in the U87MG human glioblastoma cell line.

Glioblastomas, the most malignant and prevalent brain tumors which remain incurable, are characterized by both extensive proliferation and invasive growth. We previously reported a remarkable antitumoral effect of the retinoid 6-OH-11-O-hydroxyphenantrene (IIF) on neuroblastoma, leukemia and colon carcinoma cells. In this study we examined the effect of IIF on proliferation, apoptosis and cell invasion in the human glioblastoma cell line U87MG, in comparison with all-trans-retinoic acid (RA). Our results showed that both retinoids induced cell growth inhibition and apoptosis in a dose- and time-dependent manner. We also demonstrated that the invasive ability of glioblastoma cells decreased after treatment with IIF or RA. Since cell invasion involves a complex system of tightly regulated proteases, matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of MMPs (TIMPs), we analysed the effect of IIF on MMP and TIMP expression in comparison with RA. Treatment with both retinoids resulted in a marked decrease of MMP2 and MMP9 expression and of lytic activity of MMP2. In addition, exposure to IIF led to enhanced expression of TIMP2. Collectively, our results demonstrated the effectiveness of both IIF and RA in inhibiting proliferation, cell migration, and the invasive potential of glioblastoma U87MG cells. Notably, the anticancer activity of IIF, on the whole, was more pronounced than that of RA. Therefore, these findings, besides providing further evidence that IIF may be a powerful tool in the development of cancer treatments, suggest that IIF may have therapeutic potential against the invasiveness of brain tumors.