Human Gut Microbiota Composition Associated with International Travels.

OBJECTIVE: The objective of this study was to evaluate whether long stays in non-European countries influence the composition, diversity, and dynamics of gut microbiota, considering the potential impact of travelling, close contact with new people, and consumption of water and food. METHODS: Two prospective cohorts were analyzed: (i) A longitudinal cohort comprising long-term travellers who provided fecal samples before and after their travels. (ii) A cohort consisting of long-term travellers and recently arrived migrants from non-European countries, which was compared with non-traveller controls. Each participant self-collected fecal samples and provided demographic and epidemiological data. Microbiota was characterized through 16S rRNA gene sequencing. RESULTS: The longitudinal cohort comprised 17 subjects. A trend toward higher bacterial diversity was observed after travelling (Shannon index 3.12vs3.26). When comparing 84 travellers/migrants with 97 non-travellers, a confirmed association of higher diversity levels with travelling was observed (Phylogenetic diversity: 22.1vs20.9). Specific genera enriched in travellers' gut microbiota were identified, including Escherichia/Shigella, Bacteroides, and Parabacteroides. The analysis revealed three major clusters with profound differences in their bacterial composition, which exhibited differential distribution between travellers and non-travellers (Adonis P<0.001; R2=30.6%). Two clusters were more frequently observed in travellers: The first cluster, characterized by dominance of Escherichia/Shigella, exhibited the lowest levels of richness and diversity. The second cluster, dominated by Faecalibacterium and Bacteroides, displayed the highest richness and diversity patterns. CONCLUSION: These findings highlight the diverse impact of international travel on gut microbiota composition and underscore the importance of considering microbiota resilience and diversity in understanding the health implications.

Proposal and Validation of a New Index to Assess the Difficulty of Lower Third Molar Extraction.

There is no current consensus on the parameters that determine the difficulty of mandibular third molar extraction in terms of the time required, which is essential to prevent complications and optimize the time of the intervention. This study aims to obtain, using the mathematical method of multiple linear regression, an equation that allows estimating the extraction time of a lower third molar according to its complexity, as well as to validate this equation in a sample of external wisdom teeth. METHODS: A prospective cohort study on a sample of patients of the Master of Oral Surgery of the University of Seville in which multiple linear regression coefficients were calculated with a subsequent validation study of the results in the sample of patients operated in the Hospital Palmaplanas of Mallorca. RESULTS: The regression line obtained after applying the statistical methodology to the cohort of patients from the University of Seville obtained significant dependent variables such as depth, roots, and odontosection. Once applied to the cohort of patients from the Palmaplanas Hospital in Mallorca, a regression coefficient was obtained between the data received and the estimated 0.770. CONCLUSIONS: The formula proposed in this article presents significant validity in the prediction of the surgical time of extraction of the lower third molars included.

Comparative prebiotic potential of galacto- and fructo-oligosaccharides, native inulin, and acacia gum in Kenyan infant gut microbiota during iron supplementation.

Iron fortification to prevent anemia in African infants increases colonic iron levels, favoring the growth of enteropathogens. The use of prebiotics may be an effective strategy to reduce these detrimental effects. Using the African infant PolyFermS gut model, we compared the effect of the prebiotics short-chain galacto- with long-chain fructo-oligosaccharides (scGOS/lcFOS) and native inulin, and the emerging prebiotic acacia gum, a branched-polysaccharide-protein complex consisting of arabinose and galactose, during iron supplementation on four Kenyan infant gut microbiota. Iron supplementation did not alter the microbiota but promoted Clostridioides difficile in one microbiota. The prebiotic effect of scGOS/lcFOS and inulin was confirmed during iron supplementation in all investigated Kenyan infant gut microbiota, leading to higher abundance of bifidobacteria, increased production of acetate, propionate, and butyrate, and a significant shift in microbiota composition compared to non-supplemented microbiota. The abundance of the pathogens Clostridium difficile and Clostridium perfringens was also inhibited upon addition of the prebiotic fibers. Acacia gum had no effect on any of the microbiota. In conclusion, scGOS/lcFOS and inulin, but not acacia gum, showed a donor-independent strong prebiotic potential in Kenyan infant gut microbiota. This study demonstrates the relevance of comparing fibers in vitro prior to clinical studies.

Screw reactor design for potato peel pretreatment using the steam explosion.

In this article we can observe the scanning by the literature for the pretreatment of steam explosion applied to lignocellulose biomass. A comparison of the chemical and physical characterization of potato peel as a lignocellulose biomass. Besides, the innovative design of a continuous reactor for the potato peel steam explosion process is shown, with specific temperature and pressure conditions on a pilot scale, detailing its parts. Finally, a finite element analysis was performed where stress results were obtained from the reactor material, severity factor, structural analysis and thermal analysis, providing a panorama of the reactor's behavior with the conditions specific.

The Cardiovascular Event Risk Associated with Tyrosine Kinase Inhibitors and the Lipid Profile in Patients with Chronic Myeloid Leukemia.

BACKGROUND: Second- and third-generation tyrosine kinase inhibitors (TKIs) are now available to treat chronic-phase chronic myeloid leukemia (CP-CML) in the first and second line. However, vascular adverse events (VAEs) have been reported for patients with CML treated with some TKIs. METHODS: We retrospectively evaluated the cumulative incidence (CI) and cardiovascular risk for 210 patients included in the Canarian Registry of CML. RESULT: With a mean follow up of 6 years, 19/210 (9.1%) patients developed VAEs, all of whom presented at least one cardiovascular risk factor at diagnosis. The mean time to VAE presentation was 54 months from the start of TKI treatment. We found a statistically significant difference between the CI for nilotinib-naïve vs. nilotinib-treated patients (p = 0.005), between dasatinib-naïve and dasatinib-treated patients (p = 0.039), and for patients who received three lines of treatment with first-line imatinib vs. first-line imatinib (p < 0.001). From the multivariable logistic regression analyses, the Framingham risk score (FRS) and patients with three lines of TKI with first-line imatinib were the only variables with statistically significant hazard ratios for VAE development. Significant increases in HDL-C and total cholesterol may also be predictive for VAE. CONCLUSIONS: In conclusion, it is important to estimate the cardiovascular risk at the diagnosis of CML as it can help determine whether a patient is likely to develop a VAE during TKI treatment.

Long-term continuous cultivation of Kenyan infant fecal microbiota using the host adapted PolyFermS model.

Appropriate in vitro models to investigate the impact of novel nutritional strategies on the gut microbiota of infants living in rural Africa are scarce. Here, we aimed to develop such a continuous gut fermentation model based on the PolyFermS platform, which allows controlled and stable long-term cultivation of colon microbiota in conditions akin the host. Nine immobilized Kenyan infant fecal microbiota were used as inoculum for continuous PolyFermS colon models fed with medium mimicking the weaning infant diet. Fructo-oligosaccharides (FOS) supplementation (1, 4 and 8 g/L) and cultivation pH (5.8 and 6.3) were investigated stepwise. Conditions providing a close match between fecal and in vitro microbiota (pH 5.8 with 1 g/L FOS) were selected for investigating long-term stability of four Kenyan infant PolyFermS microbiota. The shared fraction of top bacterial genera between fecal and in vitro microbiota was high (74-89%) and stable during 107 days of continuous cultivation. Community diversity was maintained and two distinct fermentation metabolite profiles of infant fecal microbiota were observed. Three propiogenic and one butyrogenic metabolite profile of infant fecal microbiota established from day 8 onwards and stayed stable. We present here the first rationally designed continuous cultivation model of African infant gut microbiota. This model will be important to assess the effect of dietary or environmental factors on the gut microbiota of African infants with high enteropathogen exposure.

Long-term continuous cultivation of Kenyan infant fecal microbiota using the host adapted PolyFermS model.

Appropriate in vitro models to investigate the impact of novel nutritional strategies on the gut microbiota of infants living in rural Africa are scarce. Here, we aimed to develop such a continuous gut fermentation model based on the PolyFermS platform. Eight immobilized Kenyan infant fecal microbiota were used as inoculum for continuous PolyFermS colon models fed with medium mimicking the weaning infant diet. Fructo-oligosaccharides (FOS) supplementation (1, 4 and 8 g/L) and cultivation pH (5.8 and 6.3) were stepwise investigated. Conditions providing a close match between fecal and in vitro microbiota (pH 5.8 with 1 g/L FOS) were selected for investigating long-term stability of four Kenyan infant PolyFermS microbiota. The shared fraction of top bacterial genera between fecal and in vitro microbiota was high (74-89%) and stable during 107 days of continuous cultivation. Community diversity was maintained, and two distinct fermentation metabolite profiles, propiogenic and butyrogenic, of infant fecal microbiota established from day 8 onwards and stayed stable. We present here the first rationally designed and accurate continuous cultivation model of African infant gut microbiota. This model will be important to assess the effect of dietary or environmental factors on the gut microbiota of African infants with high enteropathogen exposure.

A Systematic Review and Meta-Analysis of Systemic and Local Antibiotic Therapy in the Surgical Treatment of Peri-Implantitis.

(1) Background: Given the existing controversy regarding the use of antibiotics in the treatment of peri-implantitis, this systematic review and meta-analysis aim to ascertain how beneficial the role of systemic and local antibiotics is in peri-implant surgical therapy, considering the harmful effects that they represent and the abuse of antibiotics in terms of global health. (2) Methods: To determine the therapeutic efficacy of the administration of antibiotics in the surgical treatment of peri-implantitis in terms of probing pocket depth (PPD) and bleeding on probing (BoP), electronic and manual bibliographic searches were carried out in the Embase and PubMed databases, collecting data that related to before and after treatment. (3) Results: The adjunctive use of local antibiotics provides significant improvements in PPD (MD = 1.29; 95% CI: 0.56 to 2.02; p ≤ 0.0006; I2 = 0%) when compared with surgical treatment alone. No significant differences were found in the other subgroup; that is, the use of systemic antibiotics did not significantly improve PPD changes in the surgical treatment of peri-implantitis (MD = 0.40; 95% CI: -0.15 to 0.95; p = 0.15; I2 = 0). (4) Conclusions: The use of local antibiotics in the surgical treatment of peri-implantitis seems to offer treatment improvements in terms of PPD and BoP, unlike that observed with the use of systemic antibiotics. However, these results should be taken with caution as they also depend on the type of surgical technique used, whether regenerative or resective. More research is needed on this topic to understand the role of local and systemic antibiotics in the treatment of peri-implantitis.

GLORIA: phase III, open-label study of adagloxad simolenin/OBI-821 in patients with high-risk triple-negative breast cancer.

Triple-negative breast cancer (TNBC) has the highest rate of distant metastasis and poorest overall survival among breast cancer subtypes. In a phase II study, adagloxad simolenin (AdaSim), a synthetic Globo H conjugate vaccine administered with adjuvant OBI-821, was shown to induce IgM and IgG anti-Globo H humoral responses in patients with metastatic breast cancer overexpressing the glycosphingolipid Globo H. GLORIA is an ongoing phase III, randomized, open-label clinical trial to evaluate the safety and efficacy of AdaSim and the quality of life (QoL) of patients receiving AdaSim plus standard of care (SOC) versus SOC alone in high-risk, early-stage TNBC. The primary end point is invasive progression-free survival; secondary end points include overall survival, QoL, breast cancer-free interval, distant disease-free survival, safety, and tolerability.

Patients with triple-negative breast cancer generally do very poorly with the current available therapies. A vaccine with a totally different mechanism of action is being investigated in these patients to see how they do with this new therapy. This trial is a very early investigation and is currently ongoing. Clinical Trial Registration: NCT03562637 (ClinicalTrials.gov).

Frecuencia de Patologías y Condiciones de Lengua Observadas en Población Pediátrica

RESUMEN: Las patologías y condiciones linguales constituyen una proporción considerable del total de lesiones de la mucosa oral. Los estudios epidemiológicos que describen su frecuencia en la población pediátrica son escasos y variables. El objetivo de este estudio fue establecer la frecuencia de patologías y condiciones de lengua en niños atendidos en la Facultad de Odontología de la Universidad de Chile. Se realizó un estudio observacional, descriptivo y de corte transversal donde se examinaron pacientes pediátricos de 4 a 13 años de ambos sexos. De un total de 179 pacientes, un 53 % presentó al menos una patología o condición lingual. El rango etario de 11 a 13 años presentó un mayor OR de presentar lesiones y/o condiciones linguales al ser comparado con los otros rangos etarios (valor p<0,05). La patología o condición lingual más frecuente fue la lengua saburral (39 %), seguida por la lengua fisurada (15 %), la hipertrofia de papilas linguales (5 %) y la lengua geográfica (3 %). La ubicación más frecuente fue la base lingual con un 59 % del total de ubicaciones registradas. En base a la escasa evidencia que existe y a la alta frecuencia encontrada en esta investigación, se debe destacar la importancia del conocimiento de las patologías y condiciones linguales en niños. A través de este estudio, se sientan bases para futuras investigaciones que ayuden a odontólogos a reconocer, diagnosticar y tratar estas condiciones cuando sea necesario.

ABSTRACT: Lingual pathologies and conditions constitute a considerable proportion of the total lesions of the oral mucosa.The epidemiological studies that describe its frequency in the pediatric population are limited and variable. The objective of this study was to establish the frequency of pathologies and lingual conditions in children attended at the Faculty of Dentistry of the University of Chile. An observational, descriptive and cross-sectional study was carried out where pediatric patients between 4 and 13 years of both sexes were examined. Of a total of 179 patients, 53 % had at least one pathology or lingual condition. The age range of 11 to 13 years presented a higher OR of presenting lesions and/or lingual conditions when compared with the other age ranges (p value <0.05). The most frequent pathology or lingual condition was coated tongue (39 %), fast due to the fissured tongue (15 %), the hypertrophy of the lingual papillae (5 %) and the geographic tongue (3 %). The most frequent location was the lingual base with 59 % of the total frequency registered. Based on the little evidence that exists and the high frequency found in this research, the importance of knowledge of pathologies and lingual conditions in children should be highlighted. Through this study, foundations are laid for future investigations that help dentists recognize, diagnose, and treat these conditions when necessary.

Roux-en-Y gastric bypass-induced bacterial perturbation contributes to altered host-bacterial co-metabolic phenotype.

BACKGROUND: Bariatric surgery, used to achieve effective weight loss in individuals with severe obesity, modifies the gut microbiota and systemic metabolism in both humans and animal models. The aim of the current study was to understand better the metabolic functions of the altered gut microbiome by conducting deep phenotyping of bariatric surgery patients and bacterial culturing to investigate causality of the metabolic observations. METHODS: Three bariatric cohorts (n = 84, n = 14 and n = 9) with patients who had undergone Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) or laparoscopic gastric banding (LGB), respectively, were enrolled. Metabolic and 16S rRNA bacterial profiles were compared between pre- and post-surgery. Faeces from RYGB patients and bacterial isolates were cultured to experimentally associate the observed metabolic changes in biofluids with the altered gut microbiome. RESULTS: Compared to SG and LGB, RYGB induced the greatest weight loss and most profound metabolic and bacterial changes. RYGB patients showed increased aromatic amino acids-based host-bacterial co-metabolism, resulting in increased urinary excretion of 4-hydroxyphenylacetate, phenylacetylglutamine, 4-cresyl sulphate and indoxyl sulphate, and increased faecal excretion of tyramine and phenylacetate. Bacterial degradation of choline was increased as evidenced by altered urinary trimethylamine-N-oxide and dimethylamine excretion and faecal concentrations of dimethylamine. RYGB patients' bacteria had a greater capacity to produce tyramine from tyrosine, phenylalanine to phenylacetate and tryptophan to indole and tryptamine, compared to the microbiota from non-surgery, normal weight individuals. 3-Hydroxydicarboxylic acid metabolism and urinary excretion of primary bile acids, serum BCAAs and dimethyl sulfone were also perturbed following bariatric surgery. CONCLUSION: Altered bacterial composition and metabolism contribute to metabolic observations in biofluids of patients following RYGB surgery. The impact of these changes on the functional clinical outcomes requires further investigation. Video abstract.

Long-term PM2.5 exposure before diagnosis is associated with worse outcome in breast cancer.

PURPOSE: Increasingly epidemiological evidence supports that environmental factors are associated with breast cancer (BC) outcomes after a BC diagnosis. Although evidence suggests that air pollution exposure is associated with higher mortality in women with BC, studies investigating potential mechanisms have been lacking. METHODS: We evaluated women with BC (N = 151) attended at the National Cancer Institute-Mexico from 2012 to 2015. We calculated 1-year average exposures to particulate matter < 2.5 µm (PM2.5) at home address before diagnosis. We used linear and logistic regression models to determine the associations between PM2.5 exposure and BC aggressiveness (tumor size, molecular phenotype). RESULTS: Average annual PM2.5 exposure of this population was 23.0 µg/m3 [standard deviation (SD)]: 1.90 µg/m3]. PM2.5 levels were positively correlated with tumor size at diagnosis (r = 0.22; p = 0.007). Multivariable linear models had a similar inference [risk ratio (RR): 1.32; 95% confidence interval (95% CI): 1.04, 1.674]. We did not observe differences in this association by age or menopause status. Further, women with triple-negative BC (TNBC) had significantly higher PM2.5 levels compared with other phenotypes (p = 0.015). Multivariable-adjusted logistic regression models assessing the association between PM2.5 and tumor size had a similar inference (RR 1.41; 95% CI 1.05, 1.89) overall for all ages and also for women who were ≤ 50 years old at diagnosis (RR 1.63; 95% CI 1.036, 2.57). CONCLUSIONS: Our findings suggest a significant association between long-term PM2.5 exposure and BC aggressiveness based on tumor size and phenotype, as well as a worse outcome.

A Phase I, Open-label, Dose-escalation, and Cohort Expansion Study to Evaluate the Safety and Immune Response to Autologous Dendritic Cells Transduced With AdGMCA9 (DC-AdGMCAIX) in Patients With Metastatic Renal Cell Carcinoma.

Expression of carbonic-anhydrase IX (CAIX) in clear cell renal cell carcinoma (RCC) makes it an attractive vaccine target. We developed a fusion-gene construct, granulocyte-macrophage (GM) colony-stimulating factor+CAIX, delivered by an adenoviral vector (Ad) into autologous dendritic cells (DCs) in this phase 1 study. The injected immature DCs were expected to stimulate an antigen-specific immune response against CAIX expressing RCC. Three dose-escalation cohorts (5, 15, and 50×10 cells/administration) were injected intradermally q2wk×3 doses based on a 3+3 design. The primary objective was the safety of the injections. Secondary objectives were immune responses using enzyme-linked immunosorbent spot, a serum biomarker panel, and clinical response. Fifteen patients with metastatic RCC were enrolled, and 9 patients received all 3 doses. No serious adverse events were seen. There were 3 (33%) patients with grade 1 fatigue, 1 of whom subsequently experienced grade 2 fatigue. One patient (11%) experienced grade 1-2 leukopenia. Only 1 patient (11%) experienced grade 2 flu-like symptoms. Of the 9 patients who received treatment, 1 expired of progressive disease, 2 patients were lost to follow-up and 6 patients are alive. Of the 6 patients, 5 have progressive disease, and 1 has completed treatment with stable disease at 27 months follow-up. Immune response measurements appeared more robust in higher dose cohorts, which appeared to be related to patients with stable disease at 3 months. These early data show that autologous immature DC-AdGMCAIX can be safely given to metastatic RCC patients without any serious adverse events with CAIX-specific immune response elicited by the treatment. These preliminary data support further study of Ad-GMCAIX, particularly with combination therapies that may enhance clinical activity.

Review of evidence based clinical practice guidelines developed in Latin America and Caribbean during the last decade: an analysis of the methods for grading quality of evidence and topic prioritization.

BACKGROUND: In the last decade, efforts have been made in Latin America and the Caribbean to advance in the methodological development of evidence based clinical practice guidelines, among other strategies to improve the health provision of services and indicators. OBJECTIVES: To build an evidence map to show the regional GRADE impact in developing clinical practice guidelines and contrast the results with current needs. METHODS: A systematic literature search was conducted in databases, developer's websites, health ministries, repositories and grey literature. Documents were included when they were evidence based clinical practice guidelines developed in Latin American and Caribbean countries in the last decade. Data from the Global Burden of Disease was used to highlight relevant health conditions. RESULTS: Nine thousand seven hundred seventy-six documents were retrieved. 98 guidelines, with specific mention of the use of GRADE methodology were identified. 81% of the guidelines were developed within the last 4 years. 68% are from Colombia, 13% from Peru, 9% from Chile, 3% from Argentina and Costa Rica and Brazil, Honduras and Dominican Republic account 1%. 67% were developed for non-communicable diseases, 10% for communicable diseases, 9% for neonatal pathologies and 5% for maternal problems, 1% injuries and 7% other topics (nutrition, oral health). DISCUSSION: Our findings show a slow and increasing incorporation of the GRADE methodology in the region. GRADE guidelines have been adopted mainly by Colombia and slowly by other countries. Topics for guidelines continue to be comparable to the high-income countries and they don't address communicable diseases or other relevant health issues in the region, such as violence or malnutrition; thus, the evidence based guidelines for clinical practice are only a tool within a complex multimodal strategy to tackle the challenges of the health determinants. CONCLUSIONS: A prioritizing strategy for relevant regional health topics and the use of robust methodological approaches must be in the political agenda in the region. GRADE methods could help to improve the quality and validity of recommendations not only for chronic pathologies but also for ancient and challenging maladies prevalent in the region, as part of a multimodalintersectoral strategy.

A Pilot Trial of the Combination of Transgenic NY-ESO-1-reactive Adoptive Cellular Therapy with Dendritic Cell Vaccination with or without Ipilimumab.

PURPOSE: Transgenic adoptive cell therapy (ACT) targeting the tumor antigen NY-ESO-1 can be effective for the treatment of sarcoma and melanoma. Preclinical models have shown that this therapy can be improved with the addition of dendritic cell (DC) vaccination and immune checkpoint blockade. We studied the safety, feasibility, and antitumor efficacy of transgenic ACT with DC vaccination, with and without CTLA-4 blockade with ipilimumab. PATIENTS AND METHODS: Freshly prepared autologous NY-ESO-1-specific T-cell receptor (TCR) transgenic lymphocytes were adoptively transferred together with NY-ESO-1 peptide-pulsed DC vaccination in HLA-A2.1-positive subjects alone (ESO, NCT02070406) or with ipilimumab (INY, NCT01697527) in patients with advanced sarcoma or melanoma. RESULTS: Six patients were enrolled in the ESO cohort, and four were enrolled in the INY cohort. Four out of six patients treated per ESO (66%), and two out of four patients treated per INY (50%) displayed evidence of tumor regression. Peripheral blood reconstitution with NY-ESO-1-specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Tracking of transgenic T cells to the tumor sites was demonstrated in on-treatment biopsies via TCR sequencing. Multiparametric mass cytometry of transgenic cells demonstrated shifting of transgenic cells from memory phenotypes to more terminally differentiated effector phenotypes over time. CONCLUSIONS: ACT of fresh NY-ESO-1 transgenic T cells prepared via a short ex vivo protocol and given with DC vaccination, with or without ipilimumab, is feasible and results in transient antitumor activity, with no apparent clinical benefit of the addition of ipilimumab. Improvements are needed to maintain tumor responses.

IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System.

PURPOSE: To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. EXPERIMENTAL DESIGN: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/Kb mice within a formal Good Laboratory Practice (GLP)-compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. RESULTS: TCR genetically modified and ex vivo-cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. CONCLUSIONS: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471.

[Prognostic factors in patients with breast cancer and brain metastasis as the first site of recurrence]. / Factores pronósticos en pacientes con cáncer de mama y metástasis cerebral como primer sitio de recurrencia.

OBJECTIVE: To evaluate the prognostic factors (clinicalpathological characteristics and treatments) in patients with breast cancer and metastasis to central nervous system (CNS) as the first site of the disease. MATERIAL AND METHODS: Kaplan-Meier method and life tables were used to estimate overall survival time over a retrospective cohort of 125 breast cancer patients treated at the Instituto Nacional de Cancerología (INCan) during 2007-2015, who presented metastasis to the CNS as the first site of extension of the disease. The cox proportional hazards model was used to determine the prognosis factors. RESULTS: The median overall survival time was 14.2 months (IC95%: 11.83-26.93). Patients with triple negative (TN), according to inmunohistochemistry analysis classification, had lower survival times (p=0.0004) and had a risk of dying two times (p=0.037) higher than patients with a different immunophenotype (HR: 2.77. 95%CI: 1.10-6.99). The degree of intermediate SBR increases the risk of dying in patients with metastasis (HR 2.76, 95% CI: 1.17-6.51). CONCLUSIONS: CNS metastasis continues to be a poor prognostic factor that reduces survival and affects quality of life. It is recommended to monitor the early presence of clinical neurological manifestations during follow-up for prompt treatment. TN patients have worse prognosis and HER2+ a better control.

OBJETIVO: Evaluar los factores pronósticos (características clínico-patológicas y tratamientos) en las pacientes con cáncer de mama y metástasis al sistema nervioso central (SNC) como primer sitio de afección. MATERIAL Y MÉTODOS: Cohorte retrospectiva, formada por 125 pacientes con cáncer de mama atendidas en el Instituto Nacional de Cancerología durante 2007-2015, quienes presentaron afección en el SNC como primer sitio de metástasis. A través del método Kaplan-Meier y tablas de vida se estimó la supervivencia global. El modelo de riesgos proporcionales de Cox fue utilizado para determinar los factores pronósticos. RESULTADOS: La mediana de supervivencia global fue de 14.2 meses (IC95% 11.8-26.9). Pacientes clasificadas por inmunohistoquímica como triple negativo (TN) presentaron tiempos de supervivencia más cortos (p<0.004) y con dos veces más riesgo de fallecer, en comparación con los otros inmunofenotipos (HR= 2.77; IC95% 1.10-6.99); asimismo, se identificó que un grado intermedio en la escala Scarff-Bloom-Richardson incrementa el riesgo de morir en pacientes con metástasis (HR=2.76; IC95% 1.17-6.51). CONCLUSIONES: La metástasis al SNC continúa siendo un factor de mal pronóstico que reduce la supervivencia y afecta la calidad de vida. Se recomienda vigilar puntualmente la presencia de manifestaciones clínicas neurológicas durante el seguimiento, para una rápida intervención. Las pacientes TN tienen peor pronóstico, y las HER2+ (es decir, con resultado positivo para el receptor 2 del factor de crecimiento humano epidérmico), mejor control a mediano plazo.

Factores pronósticos en pacientes con cáncer de mama y metástasis cerebral como primer sitio de recurrencia / Prognostic factors in patients with breast cáncer and brain metastasis as the first site of recurrence

Resumen: Objetivo: Evaluar los factores pronósticos (características clínico-patológicas y tratamientos) en las pacientes con cáncer de mama y metástasis al sistema nervioso central (SNC) como primer sitio de afección. Material y métodos: Cohorte retrospectiva, formada por 125 pacientes con cáncer de mama atendidas en el Instituto Nacional de Cancerología durante 2007-2015, quienes presentaron afección en el SNC como primer sitio de metástasis. A través del método Kaplan-Meier y tablas de vida se estimó la supervivencia global. El modelo de riesgos proporcionales de Cox fue utilizado para determinar los factores pronósticos. Resultados: La mediana de supervivencia global fue de 14.2 meses (IC95% 11.8-26.9). Pacientes clasificadas por inmunohistoquímica como triple negativo (TN) presentaron tiempos de supervivencia más cortos (p<0.004) y con dos veces más riesgo de fallecer, en comparación con los otros inmunofenotipos (HR= 2.77; IC95% 1.10-6.99); asimismo, se identificó que un grado intermedio en la escala Scarff-Bloom-Richardson incrementa el riesgo de morir en pacientes con metástasis (HR=2.76; IC95% 1.17-6.51). Conclusiones: La metástasis al SNC continúa siendo un factor de mal pronóstico que reduce la supervivencia y afecta la calidad de vida. Se recomienda vigilar puntualmente la presencia de manifestaciones clínicas neurológicas durante el seguimiento, para una rápida intervención. Las pacientes TN tienen peor pronóstico, y las HER2+ (es decir, con resultado positivo para el receptor 2 del factor de crecimiento humano epidérmico), mejor control a mediano plazo.

Abstract: Objective: To evaluate the prognostic factors (clinical-pathological characteristics and treatments) in patients with breast cancer and metastasis to central nervous system (CNS) as the first site of the disease. Materials and methods: Kaplan-Meier method and life tables were used to estimate overall survival time over a retrospective cohort of 125 breast cancer patients treated at the Instituto Nacional de Cancerología (INCan) during 2007-2015, who presented metastasis to the CNS as the first site of extension of the disease. The cox proportional hazards model was used to determine the prognosis factors. Result: The median overall survival time was 14.2 months (IC95%: 11.83-26.93). Patients with triple negative (TN), according to inmunohistochemistry analysis classification, had lower survival times (p=0.0004) and had a risk of dying two times (p=0.037) higher than patients with a different immunophenotype (HR: 2.77. 95%CI: 1.10-6.99). The degree of intermediate SBR increases the risk of dying in patients with metastasis (HR 2.76, 95% CI: 1.17-6.51). Conclusion: CNS metastasis continues to be a poor prognostic factor that reduces survival and affects quality of life. It is recommended to monitor the early presence of clinical neurological manifestations during follow-up for prompt treatment. TN patients have worse prognosis and HER2+ a better control.

Molecular Subtypes and Prognosis in Young Mexican Women With Breast Cancer.

INTRODUCTION: Young age represents an adverse prognostic factor in breast cancer (BC), and young women present with more advanced and aggressive disease. In Latin America, BC is increasing in young women, and there is a lack of information regarding the characteristics and outcomes of this patient population. PATIENTS AND METHODS: We retrospectively analyzed a database of 4315 women treated for BC at a single institution. We compared clinical characteristics, treatment, and survival between women ≤ 40 and > 40 years of age. Survival analyses were performed for each molecular subtype. RESULTS: A total of 662 women (15.3%) were ≤ 40 years old. Younger women had more advanced disease, higher grade, and a larger proportion of luminal B and triple-negative tumors (P < .001). At 5 years, both disease-free and overall survival (OS) were lower in younger women, although there were no differences after adjusting for stage. Five-year OS was worse for young women with hormone receptor-positive, human epidermal growth factor receptor 2-negative subtype (82% vs. 87.1%; P = .03), but not for those with human epidermal growth factor receptor 2-positive or triple-negative disease. This difference can be attributed to luminal B tumors, which showed a worse 5-year OS in younger women (79.1% vs. 85.2%; P = .03). CONCLUSION: Although young Mexican patients with BC have more aggressive disease at presentation than older women, only those with luminal B tumors have a worse survival after adjusting for stage. Strategies aimed at downstaging the disease and at improving the treatment of luminal B tumors in this population are needed.

Real-world outcomes in young women with breast cancer treated with neoadjuvant chemotherapy.

Breast cancer in young women has been shown to have an aggressive behavior and worse prognosis. Studies evaluating young women enrolled in clinical trials of neoadjuvant chemotherapy have shown that age is a determinant factor in the achievement of a pathological complete response (pCR). In this study, we sought to analyze the outcomes of young patients treated with neoadjuvant chemotherapy at a single institution. 1639 patients treated with neoadjuvant chemotherapy were included. 316 patients ≤40 years were compared with 1323 patients aged >40 years regarding the achievement of a pCR (defined as no invasive residual tumor in the breast or lymph nodes). Disease-free survival (DFS) and overall survival were compared between groups according to pCR status and subtype, defined by hormone receptor (HR) and HER2 status. Young women were more likely to have a pCR than their older counterparts (37.4 vs. 26.3 %, P < 0.001). This difference was significant both for HR+/HER2- and triple-negative (TN) tumors. Young age and achieving less than pCR were associated with a greater chance of recurrence for the entire population. Age was not an independent factor for recurrence in TN and HER2+ disease. However, being younger than 40 increased recurrence risk in HR+/HER2- tumors. The achievement of a pCR was not associated with improved DFS in young women with HR+/HER2- tumors. Although young women have a high rate of pCR, they also have a worse prognosis. In a real-world clinical setting, the achievement of a pCR was an independently significant protective factor for recurrence across all subtypes and ages, except for HR+, HER2- disease in young women.