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In the United States, Latino youth experience disproportionately higher rates of teen pregnancy and sexually transmitted infections (STIs) than non-Latino Whites. As a result, organizations serving Latino youth seek culturally appropriate evidence-based prevention programs that promote sexual abstinence and condom use. ¡Cuídate! is an efficacious HIV sexual risk reduction program for Latino youth aged 13-18. The program incorporates cultural beliefs that are common among Latino youth and associated with sexual risk behavior, and uses these beliefs to frame abstinence and condom use as culturally accepted and effective ways to prevent unintended pregnancy and STIs, including HIV/AIDS. ¡Cuídate! has been successfully delivered in community agencies and after-school programs but has not been integrated into an existing school curriculum. This brief case study describes efforts to implement ¡Cuídate! in a predominantly Latino urban high school in Denver. Ninety-three youth participated in the program from October 2007 to May 2008. ¡Cuídate! was adapted to accommodate the typical class period by delivering program content over a larger number of sessions and extending the total amount of time of the program to allow for additional activities. Major challenges of program implementation included student recruitment and the 'opt in' policy for participation. Despite these challenges, ¡Cuídate! was implemented with minor adaptations in a school setting. [ABSTRACT FROM AUTHOR]

Nos proponemos en este trabajo indagar qué ventajas puede suponer para la enseñanza de la gramática del español como lengua extranjera o segunda lengua la consideración de los recursos gramaticales desde los puntos de vista de la lingüística cognitiva por un lado y de la pragmática por otro. Plantearemos la descripción de unos cuantos casos bastante representativos de la gramática del español a la luz de la concepción cognitivo-funcionalista e intentaremos sacar conclusiones de cara a la práctica pedagógica centrada en la gramática, sobre todo en lo que se refiere a su presentación a estudiantes extranjeros.

Background: CD44 is a cell-surface transmembrane glycoprotein that participates in the regulation of many cellular processes, including cell division, adhesion, migration and stem-like characteristics. CD63 is involved in the exocytosis process., Objective: To evaluate the relationship between CD44 and CD63 expression and clinicopathological features, including tumor-infiltrating lymphocytes (TILs), phosphoinositide 3-kinase (PIK3CA) mutation and survival., Methodology: CD44 and CD63 were stained in samples from 101 breast cancer cases from Peruvian women., Results: Median age was 52 years, most were most were grade-3 (68%), estrogen receptor (ER)+ (64%) and stage II-III (92%). Median ki67 was 30%, median stromal TIL was 30% and PIK3CA mutation was found in 49%. Longer survival was associated with earlier stages ( p = 0.016), lower ki67 ( p = 0.023), ER+ ( p = 0.034), luminal phenotype ( p = 0.029) and recurrence ( p < 0.001). CD44 was classified as high cell density staining in 57% and high intensity in 55%. High CD44 density was associated with younger age ( p = 0.043), triple-negative phenotype ( p = 0.035) and shorter survival ( p = 0.005). High CD44 expression was associated with short survival ( p = 0.005). High CD63 cell density was found in 56% of cases and was associated with ER-positive ( p = 0.045), low TIL levels ( p = 0.007), Luminal-A ( p = 0.015) and low CD44 intensity ( p = 0.032)., Conclusion: CD44 expression was associated with aggressive features and low CD63 density staining., Competing Interests: The authors declare that they have no conflict of interest., (© the authors; licensee ecancermedicalscience.)

Background: The influence of Helicobacter-pylori ( H. pylori ) infection and the characteristics of gastric cancer (GC) on tumor-infiltrating lymphocyte (TIL) levels has not been extensively studied. Analysis of infiltrating-immune-cell subtypes as well as survival is necessary to obtain comprehensive information., Aim: To determine the rates of deficient mismatch-repair (dMMR), HER2-status and H. pylori infection and their association with TIL levels in GC., Methods: Samples from 503 resected GC tumors were included and TIL levels were evaluated following the international-TILs-working-group recommendations with assessment of the intratumoral (IT), stromal (ST) and invasive-border (IB) compartments. The density of CD3, CD8 and CD163 immune cells, and dMMR and HER2-status were determined by immunohistochemistry (IHC). H. pylori infection was evaluated by routine histology and quantitative PCR (qPCR) in a subset of samples., Results: dMMR was found in 34.4%, HER2+ in 5% and H. pylori -positive in 55.7% of samples. High IT-TIL was associated with grade-3 ( P = 0.038), while ST-TIL with grade-1 ( P < 0.001), intestinal-histology ( P < 0.001) and no-recurrence ( P = 0.003). dMMR was associated with high TIL levels in the ST ( P = 0.019) and IB ( P = 0.01) compartments, and ST-CD3 ( P = 0.049) and ST-CD8 ( P = 0.05) densities. HER2- was associated with high IT-CD8 ( P = 0.009). H. pylori -negative was associated with high IT-TIL levels ( P = 0.009) when assessed by routine-histology, and with high TIL levels in the 3 compartments ( P = 0.002-0.047) and CD8 density in the IT and ST compartments ( P = 0.001) when assessed by qPCR. A longer overall survival was associated with low IT-CD163 ( P = 0.003) and CD8/CD3 ( P = 0.001 in IT and P = 0.002 in ST) and high IT-CD3 ( P = 0.021), ST-CD3 ( P = 0.003) and CD3/CD163 ( P = 0.002)., Conclusion: TIL levels were related to dMMR and H. pylori -negativity. Low CD8/CD3 and high CD163/CD3 were associated with lower recurrence and longer survival., Competing Interests: Conflict-of-interest statement: The authors have no financial relationships to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To evaluate the relationship between circulating tumor DNA (ctDNA) presence and tumor features including tumor-infiltrating lymphocyte (TIL) levels in Peruvian breast cancer patients., Materials and Methods: This was a prospective study conducted at the Instituto Nacional de Enfemedades Neoplasicas, Peru. We evaluated level of TIL and PIK3CA mutations in ctDNA. Clinical characteristics, including outcome data, were collected from the patient file. Survival was calculated from the date of blood sample drawn to the event time. Data collected were analyzed using SPSS software version 25., Results: We analyzed plasma samples from 183 breast cancer patients. most cases were of Luminal-B (44.8%) phenotype and stage II (41.5%), and median stromal TIL was 30%. PIK3CA mutation in ctDNA was detected in 35% cases (most with E545K) and was associated with lower TIL level (p=0.04). PIK3CA in ctDNA tended to be associated with advanced stages (p=0.09) in the whole series and with higher recurrence rates (p=0.053) in the non-metastatic setting. Patients with presence of PIK3CA in ctDNA tended to have shorter survival (p=0.083)., Conclusion: Presence of PIK3CA mutation in ctDNA was frequently found in our Peruvian breast cancer series, was associated with lower TIL levels and tended to predict poor outcomes.

Objective: To evaluate the frequency distribution of viral infections in Peruvian Breast Cancer (BC) lesions and its association with clinicopathological features. Additionally, a prospective evaluation of p16 and Tumor-infiltrating lymphocytes (TIL) levels were performed for developing a comprehensive analysis., Methods: Detection of high risk- human papillomavirus (HR- HPV) through qPCR was performed in 447 BC and 79 non-cancer frozen samples. Paired paraffin samples from 238 BC were stained with Human cytomegalovirus (HCMV) and p16 immunohistochemistry. TIL was calculated in 397 BC cases., Results: HCMV was positive in 72.5%. HR- HPV was detected in 2.9% of BC and 1.3% of non-malignant samples. P16+ was found in 28.15% and median TIL percentage was 30. HR- HPV infection was associated with non-ductal histology (p=0.003) and p16+ (p=0.017). Positive P16+ was associated with higher T stage (p=0.022), grade (p=0.009), TIL level (p=0.002), and triple-negative phenotype (p=0.021)., Conclusion: HCMV is frequent, but HR- HPV infection is unusual in Peruvian BC. P16+ is associated with HR- PVH infection, high TIL and aggressive features.

Triple-negative breast cancer (TNBC) is a highly complex, heterogeneous disease and historically has limited treatment options. It has a high probability of disease recurrence and rapid disease progression despite adequate systemic treatment. Immunotherapy has emerged as an important alternative in the management of this malignancy, showing an impact on progression-free survival and overall survival in selected populations. In this review we focused on immunotherapy and its current relevance in the management of TNBC, including various scenarios (metastatic and early -neoadjuvant, adjuvant-), new advances in this subtype and the research of potential predictive biomarkers of response to treatment., Competing Interests: Conflict-of-interest statement: None to declare., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Breast cancer (BC) frequency in males is extremely low and tumor features vary from its female counterpart. Breast cancer clinical and pathological features differ by race in women. Tumor infiltrating lymphocyte (TIL) levels, mismatch repair (MMR) protein loss, androgen receptor (AR) expression, and PIK3CA gene mutations are predictive biomarkers of response to biological therapy in female BC. There is limited information about clinical and pathological features as well as predictive biomarkers in males of non-Caucasian races with BC., Aim: To investigate clinicopathological features and biomarkers of BC tumors in males and their prognostic value in Peruvian population., Methods: This study looked at a single-institution series of 54 Peruvian males with invasive BC who were diagnosed from Jan 2004 to June 2018. Standard pathological features, TIL levels, MMR proteins, AR immunohistochemistry staining, and PIK3CA gene mutations were prospectively evaluated in cases with available paraffin material. Percentage of AR and estrogen receptor (ER) positive cells was additionally calculated by software after slide scanning. Statistical analyses included association tests, intraclass correlation test and Kaplan Meier overall survival curves., Results: The median age was 63 years and most cases were ER-positive (85.7%), HER2 negative (87.2%), Luminal-A phenotype (60%) and clinical stage II (41.5%) among our male breast tumors. Median TIL was 10% and higher levels tended to be associated with Luminal-B phenotype and higher grade. AR-positive was found in 85.3% and was correlated with ER (intraclass index of 0.835, P < 0.001). Loss of MMR proteins was found in 15.4% and PIK3CA mutation (H1047R) in 14.3% (belonged to the Luminal-A phenotype). Loss of MMR proteins was associated with AR-negative ( P = 0.018) but not with ER ( P = 0.43) or TIL ( P = 0.84). Early stages ( P < 0.001) and lower grade ( P = 0.006) were associated with longer overall survival. ER status, phenotype, AR status, TIL level, MMR protein loss nor PIK3CA mutation was not associated with survival ( P > 0.05)., Conclusion: Male BC is usually ER and AR positive, and Luminal-A. MMR loss and PIK3CA mutations are infrequent. Stage and grade predicted overall survival in our South American country population., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls., Competing Interests: Competing interestsA.E. is on the Roche advisory board and has reported honoraria from Amgen, Novartis and Roche. A.J.L. is a consultant for BMS, Merck, AZ/Medimmune, and Genentech. R.S. reports research funding from Roche, Puma, Merck; advisory board and consultancy for BMS; travel funding from Roche, Merck, and Astra Zeneca. S.G. reports Lab research funding from Lilly, Clinical research funding from Eli Lilly and Novartis and is a Paid advisor to Eli Lilly, Novartis, and G1 Therapeutics. J.v.d.L. is member of the scientific advisory boards of Philips, the Netherlands and ContextVision, Sweden and receives research funding from Philips, the Netherlands and Sectra, Sweden. S.A. reports Research funding to institution from Merck, Genentech, BMS, Novartis, Celgene and Amgen and is an uncompensated consultant /steering committee member for Merck, Genentech and BMS. T.O.N. has consulted for Nanostring and received compensation and has intellectual property rights/ownership interests from Bioclassifier LLC [not related to the subject material under consideration]. S.L. receives research funding to institution from Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology, Pfizer and Eli Lilly, has acted as consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca and Roche-Genentech and acted as consultant (paid to her institution) to Aduro Biotech. S.R.L. has received travel and educational funding from Roche/Ventana. A.M. is an equity holder in Elucid Bioimaging and in Inspirata Inc., a scientific advisory consultant for Inspirata Inc, has served as a scientific advisory board member for Inspirata Inc, Astrazeneca, Bristol Meyers-Squibb and Merck, has sponsored research agreements with Philips and Inspirata Inc, is involved in a NIH U24 grant with PathCore Inc, and 3 different R01 grants with Inspirata Inc. and his technology has been licensed to Elucid Bioimaging and Inspirata Inc. G.C. is on the advisory boards of Roche, BMS, Pfizer, Seattle Genetics and Ellipsis, and reports personal fees from Roche, BMS, Pfizer, Seattle Genetics, and Ellipsis, outside of the submitted work. J.H. is the director and owner of Vivactiv Ltd. J.H. is the director and owner of Slide Score B.V. F.P.L. reports funding from Astrazeneca, BMS, Roche, MSD, Pfizer, Novartis, Sanofi, Eli Lilly. J.B. reports consultancies from Insight Genetics, BioNTech AG, Biotheranostics, Pfizer, RNA Diagnostics and OncoXchange, research funding from Thermo Fisher Scientific, Genoptix, Agendia, NanoString Technologies, Stratifyer GmbH and Biotheranostics, applied for patents, including Jan 2017: Methods and Devices for Predicting Anthracycline Treatment Efficacy, US utility—15/325,472; EPO—15822898.1; Canada—not yet assigned; Jan 2017: Systems, Devices and Methods for Constructing and Using a Biomarker, US utility—15/328,108; EPO—15824751.0; Canada—not yet assigned; Oct 2016: Histone gene module predicts anthracycline benefit, PCT/CA2016/000247; Dec 2016: 95‐Gene Signature of Residual Risk Following Endocrine Treatment, PCT/CA2016/000304; Dec 2016: Immune Gene Signature Predicts Anthracycline Benefit, PCT/CA2016/000305. M.A.S. reports consulting work for Achilles Therapeutics. C.S. reports receipt of grants/research support from Pfizer, AstraZeneca, BMS and Ventana; receipt of honoraria, consultancy, or SAB Member fees from Pfizer, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, AstraZeneca, Illumina, Sarah Canon Research Institute, Genentech, Roche-Ventana, GRAIL, Medicxi; Advisor for Dynamo Therapeutics; Stock shareholder in Apogen Biotechnologies, Epic Bioscience, GRAIL; Co-Founder & stock options in Achilles Therapeutics. A.H.B. is the co-founder and CEO of PathAI. J.K. is an employee of PathAI. D.D. is on the advisory board for Oncology Analytics, Inc, and a consultant for Novartis. D.L.R. is on the advisory board of Amgen, Astra Zeneca, Cell Signaling Technology, Cepheid, Daiichi Sankyo, GSK, Konica/Minolta, Merck, NanoString, Perkin Elmer, Ventana, Ultivue; receives research support from Astra Zeneca, Cepheid, Navigate BioPharma, NextCure, Lilly, Ultivue; instrument support from Ventana, Akoya/Perkin Elmer, NanoString; paid consultant for Biocept; received travel honoraria from BMS, founder and equity holder for PixelGear and received royalty from Rarecyte. A.T. reports benefits from ICR’s Inventors Scheme associated with patents for one of PARP inhibitors in BRCA1/2 associated cancers, as well as honoraria from Pfizer, Vertex, Prime Oncology, Artios, honoraria and stock in InBioMotion, honoraria and financial support for research from AstraZeneca, Medivation, Myriad Genetics and Merck Serono. This work includes contributions from, and was reviewed by, individuals at the FDA. This work has been approved for publication by the agency, but it does not necessarily reflect official agency policy. Certain commercial materials and equipment are identified in order to adequately specify experimental procedures. In no case does such identification imply recommendation or endorsement by the FDA, nor does it imply that the items identified are necessarily the best available for the purpose. This work includes contributions from, and was reviewed by, individuals who received funding from the National Institutes of Health, the U.S. Department of Veterans Affairs and the Department of Defense. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the U.S. Department of Veterans Affairs, the Department of Defense, or the United States Government., (© The Author(s) 2020.)

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin-stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Aim: To correlate levels of tumor-infiltrating lymphocytes (TIL) evaluated using the International Immuno-Oncology Biomarker Working Group methodology, and both density of tumor-infiltrating immune cell and clinicopathological features in different malignancies. Methods: 209 pathological samples from gastric cancer, cervical cancer (CC), non-small-lung cancer, cutaneous melanoma (CM) and glioblastoma were tested for TIL in hematoxylin eosin, and density of CD3 + , CD4 + , CD8 + , CD20 + , CD68 + and CD163 + cells by digital analysis. Results: TIL levels were higher in invasive margin compartments (IMC). TIL in IMC, intratumoral and stromal compartments predicted survival. CC and gastric cancer had higher TIL in intratumoral; CC and CM had higher TIL in stromal compartment and IMC. CM had the highest density of lymphocyte and macrophage populations. CD20 density was associated with survival in the whole series. Conclusion: Standardized evaluation of TIL levels may provide valuable prognostic information in a spectrum of different malignancies.

Objective: To evaluate the correlation between the presence of H. pylori in paired samples of tap water and gastric cancer (GC) lesion in Lima city (Peru)., Material and Methods: Gastric tissue and tap-water samples were prospectively collected from 82 Gastric Cancer who lived in Lima. HspA and ureA genes were evaluated by qPCR in the samples.  Results: The median age of patients with GC was 63 years, 52.4% were men and stage-II in 36.6%. A home-living time> 10 years was reported in 84.1% of patients. Boiling water treatment was indicated in 85.4% of cases. H. pylori was detected in 69.5% of gastric tissues and in 12.2% of analyzed tap-water. There was no differences in gastric infection rates among those with or without water contamination (70% vs. 69.4%, p=0.971). Conclusion & Impact: H. pylori was found in tap-water samples, however, detection rates were lower than in gastric cancer samples. Other sources of infection transmission should be investigated.

Background: Endocrine therapy-based neoadjuvant treatment for luminal breast cancer allows efficient testing of new combinations before surgery. The activation of the phosphatidylinositol-3-kinase (PI3K) pathway is a known mechanism of resistance to endocrine therapy. Taselisib is an oral, selective PI3K inhibitor with enhanced activity against PIK3CA-mutant cancer cells. The LORELEI trial tested whether taselisib in combination with letrozole would result in an increased proportion of objective responses and pathological complete responses., Methods: In this multicentre, randomised, double-blind, parallel-cohort, placebo-controlled phase 2, study, we enrolled postmenopausal women (aged ≥18 years) with histologically confirmed, oestrogen receptor (ER)-positive, HER2-negative, stage I-III, operable breast cancer, from 85 hospitals in 22 countries worldwide. To be eligible, patients had have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1, adequate organ function, and had to have evaluable tumour tissue for PIK3CA genotyping. Patients were randomly assigned (1:1) by means of a permuted block algorithm (block size of four) via an interactive voice or web-based response system, to receive letrozole (2·5 mg/day orally, continuously) with either 4 mg of oral taselisib or placebo (on a 5 days-on, 2 days-off schedule) for 16 weeks, followed by surgery. Randomisation was stratified by tumour size and nodal status. Site staff, patients, and the sponsor were masked to treatment assignment. Coprimary endpoints were the proportion of patients who achieved an objective response by centrally assessed breast MRI and a locally assessed pathological complete response in the breast and axilla (ypT0/Tis, ypN0) at surgery in all randomly assigned patients and in patients with PIK3CA-mutant tumours. Analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02273973, and is closed to accrual., Findings: Between Nov 12, 2014, and Aug 12, 2016, 334 participants were enrolled and randomly assigned to receive letrozole and placebo (n=168) or letrozole and taselisib (n=166). Median follow-up was 4·9 months (IQR 4·7-5·1). The study met one of its primary endpoints: the addition of taselisib to letrozole was associated with a higher proportion of patients achieving an objective response in all randomly assigned patients (66 [39%] of 168 patients in the placebo group vs 83 [50%] of 166 in the taselisib group; odds ratio [OR] 1·55, 95% CI 1·00-2·38; p=0·049) and in the PIK3CA-mutant subset (30 [38%] of 79 vs 41 [56%] of 73; OR 2·03, 95% CI 1·06-3·88; p=0·033). No significant differences were observed in pathological complete response between the two groups, either in the overall population (three [2%] of 166 in the taselisib group vs one [1%] of 168 in the placebo group; OR 3·07 [95% CI 0·32-29·85], p=0·37) or in the PIK3CA-mutant cohort (one patient [1%) vs none [0%]; OR not estimable, p=0·48). The most common grade 3-4 adverse events in the taselisib group were gastrointestinal (13 [8%] of 167 patients), infections (eight [5%]), and skin-subcutaneous tissue disorders (eight [5%]). In the placebo group, four (2%) of 167 patients had grade 3 or worse vascular disorders, two (1%) had gastrointestinal disorders, and two (1%) patients had grade 3 or worse infections and infestations. There was no grade 4 hyperglycaemia and grade 3 cases were asymptomatic. Serious adverse events were more common in the taselisib group (eight [5%] patients with infections and seven [4%] with gastrointestinal effects) than in the placebo group (one [1%] patient each with grade 3 postoperative wound and haematoma infection, grade 4 hypertensive encephalopathy, grade 3 acute cardiac failure, and grade 3 breast pain). One death occurred in the taselisib group, which was not considered to be treatment-related., Interpretation: The increase in the proportion of patients who achieved an objective response from the addition of taselisib to endocrine therapy in a neoadjuvant setting is consistent with the clinical benefit observed in hormone receptor-positive, HER2-negative, metastatic breast cancer., Funding: Genentech and F Hoffmann-La Roche., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Helicobacter pylori (HP) and Epstein Barr virus (EBV) infections induce chronic gastritis (CG) and are accepted carcinogenics of gastric cancer (GC). Our objective for this study was to determine the prevalence of these agents and clinicopathological features of GC and CG associated with the infection., Patients and Methods: A single-center cohort of 375 Peruvian patients with GC and 165 control subjects with CG were analyzed. Evaluation of HP and EBV genes was performed through quantitative polymerase chain reaction., Results: Prevalence of HP was 62.9% in the whole population and 60.8% in the GC subset. The cagA gene was detected in 79.9%; vacAs1 and vacAm1 alleles in 41.6% and 60.7%, respectively; and concurrent expression of vacAs1 and vacAm1 in 30.4% of infected patients in the whole series. The prevalence of EBV was 14.1% in the whole population and was higher in GC ( P < .001). Coinfection of HP and EBV was found in 7.8% and was also higher in GC in univariate ( P < .001) and multivariate ( P = .011) analyses. Infection rates of HP and EBV were not associated with a geographic location in the whole series. Few clinicopathological features have been associated with infectious status., Conclusion: Prevalence of HP infection and virulent strains are high in the Peruvian population. Infection by EBV was more frequent in patients with GC.

Purpose: This study aims to evaluate the association between composition of tumor-infiltrating lymphocytes (TIL) and expression of p16 in acral lentiginous melanoma (ALM), and their impact on prognosis., Materials and Methods: A cohort of 148 surgical pathology specimens of ALM was studied. TIL were evaluated by immunohistochemical detection of CD3 and CD8, along with CD20, CD4, CD68, and CD163 in a subset of 43 cases. p16 protein expression was also investigated in all the cases., Results: The median age was 66 years, median Breslow thickness was 6.0 mm, grade III TIL was found in 28.4% and lymph nodes were involved in 54.2%. Breslow thickness (p < 0.001), stage I-II (p < 0.001), negative lymph nodes (p < 0.001) and < 10% p16 (p = 0.01) were associated with longer survival. Grade III of TIL was associated with thinner Breslow thickness (p = 0.008) and lower mitosis (p = 0.047). A higher density of CD3 TIL was associated with male gender (p = 0.008), thinner Breslow thickness (p = 0.047), negative lymph node (p = 0.031), early stage (p = 0.046), and p16 nuclear expression of > 10% (p = 0.045). Higher CD8 TIL was associated with > p16 (p = 0.03). Survival analysis found that longer survival had a trend to be associated with high TIL (p = 0.090). Levels of CD3+ and CD8+ cells were correlated with those of CD4+, CD20+, CD68+ and CD163+ immune cells., Conclusions: Higher levels of TIL tend to be associated with better overall survival in ALM. Loss of expression of p16 is associated with lower levels of CD3+ and CD8+ TIL, indicating a probable relationship between p16 and TIL immune response in ALM .

Aim: Evaluation of features related to infiltrating immune cell level in glioblastoma., Methods: Tumor-infiltrating lymphocytes (TILs) through H&E staining, and TILs (CD3, CD4, CD8 and CD20) and macrophage (CD68 and CD163) levels through immunohistochemistry were evaluated through digital analysis., Results: CD68 (9.1%), CD163 (2.2%), CD3 (1.6%) and CD8 (1.6%) had the highest density. Higher CD4 + was associated with unmethylated MGMT (p = 0.016). Higher CD8 + was associated with larger tumoral size (p = 0.027). Higher CD163 + was associated with higher age (p = 0.044) and recursive partitioning analysis = 4. Women (p < 0.05), total resection (p < 0.05), MGMT-methylation (p < 0.001), radiotherapy (p < 0.001), chemotherapy (p < 0.001) and lower CD4 + (p < 0.05) were associated with longer overall survival., Conclusion: Macrophages are more frequent than TILs. Some subsets are associated with clinical features.

Latina women in the U.S. have relatively low breast cancer incidence compared to Non-Latina White (NLW) or African American women but are more likely to be diagnosed with the more aggressive "triple negative" breast cancer (TNBC). Latinos in the U.S. are a heterogeneous group originating from different countries with different cultural and ancestral backgrounds. Little is known about the distribution of tumor subtypes in Latin American regions. Clinical records of 303 female Peruvian patients, from the Peruvian National Cancer Institute, were analyzed. Participants were diagnosed with invasive breast cancer between 2010 and 2015 and were identified as residing in either the Selva or Sierra region. We used Fisher's exact test for proportions and multivariable Cox Proportional Hazards Models to compare overall survival between regions. Women from the Selva region were more likely to be diagnosed with TNBC than women from the Sierra region (31% vs. 14%, p = 0.01). In the unadjusted Cox model, the hazard of mortality was 1.7 times higher in women from the Selva than the Sierra (p = 0.025); this survival difference appeared to be largely explained by differences in the prevalence of TNBC. Our results suggest that the distribution of breast cancer subtypes differs between highly Indigenous American women from two regions of Peru. Disentangling the factors that contribute to this difference will add valuable information to better target prevention and treatment efforts in Peru and improve our understanding of TNBC among all women. This study demonstrates the need for larger datasets of Latin American patients to address differences between Latino subpopulations and optimize targeted prevention and treatment., Competing Interests: The authors have declared that no competing interests exist.

Around 2% of early breast cancer cases treated with axillary lymph node dissection (ALND) underwent axillary recurrence (AR) and it has a deleterious effect in prognosis. Different scenarios have incorporated Sentinel Lymph Node (SLN) Biopsy (SLNB) instead of ALND as part of the standard treatment and more effective systemic treatment has also been incorporated in routine management after first curative surgery and after regional recurrence. However, there is concern about the effect of SLNB alone over AR risk and how to predict and treat AR. SLN biopsy (SLNB) has been largely accepted as a valid option for SLN-negative cases, and recent prospective studies have demonstrated that it is also safe for some SLN-positive cases and both scenarios carry low AR rates. Different studies have identified clinicopathological factors related to aggressiveness as well as high-risk molecular signatures can predict the development of locoregional recurrence. Other publications have evaluated factors affecting prognosis after AR and find that time between initial treatment and AR as well as tumor aggressive behavior influence patient survival. Retrospective and prospective studies indicate that treatment of AR should include local and systemic treatment for a limited time., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: To evaluate the prognostic value of tumor-infiltrating lymphocytes (TILs) and Ki67 in brain metastasis lesions, and the effect of adding them to variables of graded prognostic assessment score., Patients & Methods: Clinicopathological information from 111 medical charts of brain metastasis patients was obtained, and TIL distribution (n = 84), Ki67 index (n = 79) and CD3 TIL (n = 64) were prospectively evaluated., Results: Most frequent TIL pattern was perivascular (67.8%), and median Ki67 and CD3 TIL percents were 30 and 4.8%, respectively. Ki67 ≥15 was associated with shorter survival (p = 0.018) but CD3 TIL was not (p = 0.870). The highest graded prognostic assessment score was not associated with survival (p = 0.648), however, those with low Ki67 and high score was associated with better outcome (p = 0.007)., Conclusion: High Ki67 index in brain metastasis carries a worse prognosis.

Aim: To investigate the survival impact of clinicopathological factors, including pathological complete response (pCR) and tumor-infiltrating lymphocytes (sTIL) levels according to subtypes, in breast cancer (BC) patients who received neo-adjuvant chemotherapy (NAC)., Methods: We evaluated 435 BC patients who presented and received NAC at the Instituto Nacional de Enfermedades Neoplasicas from 2003 to 2014. sTIL was analyzed as the proportion of tumor stroma occupied by lymphocytes, and was prospectively evaluated on hematoxylin and eosin-stained sections of the preNAC core biopsy. pCR was considered in the absence of infiltrating cancer cells in primary tumor and axillary lymph nodes. Analysis of statistical association between clinical pathological features, sTIL, pCR and survival were carried out using SPSSvs19., Results: Median age was 49 years (range 24-84 years) and the most frequent clinical stage was IIIB (58.3%). Luminal A, Luminal B, HER2-enriched and (triple-negative) TN phenotype was found in 24.6%, 37.9%, 17.7% and 19.8%, respectively. pCR was observed in 11% and median percentage of sTIL was 40% (2%-95%) in the whole population. pCR was associated to Ct1-2 ( P = 0.045) and to high sTIL ( P = 0.029) in the whole population. There was a slight trend towards significance for sTIL ( P = 0.054) in Luminal A. sTIL was associated with grade III ( P < 0.001), no-Luminal A subtype ( P < 0.001), RE-negative ( P < 0.001), PgR-negative ( P < 0.001), HER2-positive ( P = 0.002) and pCR ( P = 0.029) in the whole population. Longer disease-free survival was associated with grade I-II ( P = 0.006), cN0 ( P < 0.001), clinical stage II ( P = 0.004), ER-positive ( P < 0.001), PgR-positive ( P < 0.001), luminal A ( P < 0.001) and pCR ( P = 0.002). Longer disease-free survival was associated with grade I-II in Luminal A ( P < 0.001), N0-1 in Luminal A ( P = 0.045) and TNBC ( P = 0.01), clinical stage II in Luminal A ( P = 0.003) and TNBC ( P = 0.038), and pCR in TNBC ( P < 0.001). Longer overall survival was associated with grade I-II ( P < 0.001), ER-positive ( P < 0.001), PgR-positive ( P < 0.001), Luminal A ( P < 0.001), cN0 ( P = 0.002) and pCR ( P = 0.002) in the whole population. Overall survival was associated with clinical stage II ( P = 0.017) in Luminal A, older age ( P = 0.042) in Luminal B, and pCR in TNBC ( P = 0.005)., Conclusion: Predictive and prognostic values of clinicopathological features, like pCR and sTIL, differ depending on the evaluated molecular subtype.

Purpose: O 6 -methylguanine-DNA methyltransferase ( MGMT ) promoter methylation predicts the outcome and response to alkylating chemotherapy in glioblastoma. The aim of this study is to evaluate the prevalence of MGMT methylation in Peruvian glioblastoma cases., Patients and Methods: We evaluated retrospectively 50 cases of resected glioblastoma during the period 2008-2013 at Instituto Nacional de Enfermedades Neoplasicas in Peru. Samples consisted of paraffin embedded and frozen tumour tissue. MGMT -promoter methylation status and the expression level of MGMT gene were evaluated by methylation-specific PCR and real-time PCR, respectively., Results: Unmethylated, methylated and partially methylated statuses were found in 54%, 20% and 26% of paraffin-embedded samples, respectively. Methylation status was confirmed in the Virgen de la Salud Hospital and frozen samples. There was an association between the status of MGMT -promoter methylation and the level of gene expression ( p = 0.001). Methylation was associated with increased progression-free survival ( p = 0.002) and overall survival (OS) ( p < 0.001)., Conclusion: MGMT -promoter methylation frequency in Peruvian glioblastoma is similar to that reported in other populations and the detection test has been standardised.

Purpose: Acral lentiginous melanoma (ALM) is a poor prognosis subtype and is the most prevalent in non-Caucasian populations. The presence of tumor infiltrating lymphocytes (TILs) has been associated with poor prognosis in melanoma. A large cohort of ALM cases was studied to determine status of TIL and its association with outcome., Methods: All patients with cutaneous melanoma presenting from 2005 to 2012 at Instituto Nacional de Enfermedades Neoplasicas in Peru were retrospectively identified. Clinicopathological information was obtained from the medical charts. A prospective evaluation of TIL was performed. Analysis of association between ALM and clinicopathological features including TIL as well as survival analysis compared the outcome of ALM to whole group and extremity NALM was performed., Results: 537 ALM from a total of 824 cutaneous melanoma cases were studied. Older age (p = 0.022), higher Breslow (p = 0.008) and ulceration (p < 0.001) were found to be more frequent in ALM. Acral had worse overall survival (OS) compared with the whole group (p = 0.04). Clinical stage (CS) I-II patients had a median OS of 5.3 (95% CI 4.3-6.2) for ALM and 9.2 (95% CI 5.0-7.0) for extremity NALM (p = 0.016). Grade 0 (absence of TIL), I, II and III were found in 7.5, 34.5, 32.1, and 25.9%, respectively. Lower TIL grade was associated with larger tumor size (p = 0.003), higher Breslow (p = 0.001), higher Clark level (p = 0.007), higher CS (p = 0.002), extremity location (p = 0.048), histological subtype ALM (p = 0.024) and better OS (p = 0.001)., Conclusions: ALM is highly prevalent in Peru and carries poor outcome. Lower TIL levels were associated with poor outcome and ALM.

Histone deacetylase 8 (HDAC8) is a well-characterized member of the class I acetyl-lysine deacetylase (HDAC) family. Previous work has shown that the efficiency of HDAC8-catalyzed deacetylation of a methylcoumarin peptide varies depending on the identity of the divalent metal ion in the HDAC8 active site. Here we demonstrate that both HDAC8 activity and substrate selectivity for a diverse range of peptide substrates depend on the identity of the active site metal ion. Varied deacetylase activities of Fe(II)- and Zn(II)-HDAC8 toward an array of peptide substrates were identified using self-assembled monolayers for matrix-assisted laser desorption ionization (SAMDI) mass spectrometry. Subsequently, the metal dependence of deacetylation of peptides of biological interest was measured using an in vitro peptide assay. While Fe(II)-HDAC8 is generally more active than Zn(II)-HDAC8, the Fe(II)/Zn(II) HDAC8 activity ratio varies widely (from 2 to 150) among the peptides tested. These data provide support for the hypothesis that HDAC8 may undergo metal switching in vivo that, in turn, may regulate its activity. However, future studies are needed to explore the identity of the metal ion bound to HDAC8 in cells under varied conditions.

We report four cases of glioblastoma in the pineal region. The patients presented a severe headache and vomiting. Brain imaging showed a heterogeneously enhanced tumor in the pineal region with obstructive hydrocephalus. Case 3 developed a subependymal dissemination. The patient went to ventricular-peritoneal shunt and subtotal or total resection and radiotherapy with/without chemotherapy. Cases 1 and 2 received radiation and died 8 and 11 later months. Cases 3 and 4 completed radiotherapy and chemotherapy, and survived 28 and 31 months after the initial diagnosis. Glioblastoma in the pineal region carry a poor prognosis and require neurooncology teams.

Aim: To determine influence of neoadjuvant-chemotherapy (NAC) over tumor-infiltrating-lymphocytes (TIL) in triple-negative-breast-cancer (TNBC)., Methods: TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de Enfermedades Neoplasicas from 2005 to 2010. Immunohistochemistry staining for CD3, CD4, CD8 and FOXP3 was performed in tissue microarrays (TMA) sections. Evaluation of H/E in full-face and immunohistochemistry in TMA sections was performed in pre and post-NAC samples. STATA software was used and P value < 0.05 was considered statistically significant., Results: Higher TIL evaluated in full-face sections from pre-NAC tumors was associated to pathologic-complete-response (pCR) ( P = 0.0251) and outcome ( P = 0.0334). TIL evaluated in TMA sections showed low level of agreement with full-face sections (ICC = 0.017-0.20) and was not associated to pCR or outcome. TIL in post-NAC samples were not associated to response or outcome. Post-NAC lesions with pCR had similar TIL levels than those without pCR ( P = 0.6331). NAC produced a TIL decrease in full-face sections ( P < 0.0001). Percentage of TIL subpopulations was correlated with their absolute counts. Higher counts of CD3, CD4, CD8 and FOXP3 in pre-NAC samples had longer disease-free-survival (DFS). Higher counts of CD3 in pre-NAC samples had longer overall-survival. Higher ratio of CD8/CD4 counts in pre-NAC was associated with pCR. Higher ratio of CD4/FOXP3 counts in pre-NAC was associated with longer DFS. Higher counts of CD4 in post-NAC samples were associated with pCR., Conclusion: TIL in pre-NAC full-face sections in TNBC are correlated to longer survival. TIL in full-face differ from TMA sections, absolute count and percentage analysis of TIL subpopulation closely related., Competing Interests: Conflict-of-interest statement: To our knowledge, no conflict of interest exists.

Background: The presence of tumor-infiltrating lymphocytes (TILs) in breast tumors is prognostic and predictive, suggesting that TILs may be an important biomarker. Recently, an international TILs working group formulated consensus recommendations for TIL evaluation. The current study was performed to determine interobserver agreement using that methodology., Methods: Tumor-infiltrating lymphocytes were assessed on a single hematoxylin and eosin (H&E)-stained slide obtained from the core biopsy of 75 triple-negative breast cancers. Four pathologists independently reviewed each slide and evaluated stromal TILs (sTILs) and intratumoral TIL (iTILs). The kappa statistic was used to estimate interobserver agreement for identification of sTILs, and the intraclass correlation coefficient (ICC) was used to estimate the agreement among observers for iTILs. Cases with poor agreement were reviewed to identify pathologic factors that may contribute to the lack of agreement., Results: The kappa statistic for sTIL evaluation was 0.57 (standard error, 0.04). For iTILs, the ICC calculated to determine internal consistency within raters was 0.65 (95 % confidence interval [CI] 0.56-0.74; p < 0.0001), and the ICC calculated to determine agreement among raters was 0.62 (95 % CI 0.50-0.72; p < 0.0001). In 10 cases (13 %), there was not agreement between three of four pathologists. The pathologic features contributing to difficulty in TIL enumeration included marked individual tumor cell necrosis or apoptosis, the presence of reactive plasma cells mimicking tumor cells, plasmatoid tumor cells, and accurate quantification of TILs in specimens with focal areas of heavy immune infiltrate., Conclusion: Acceptable agreement in TIL enumeration was observed, suggesting that the proposed methodology can be used to facilitate the use of TILs as a biomarker in research and clinical trial settings.

Unexpected tryptic cleavage has been characterized at modified K48 residues in polyubiquitins. In particular, the tryptic products of all seven of the lysine-linked dimers of ubiquitin and of three trimers-linear Ub-(48)Ub-(48)Ub, linear Ub-(63)Ub-(63)Ub, and the branched trimer [Ub]2-(6,48)Ub-have been analyzed. In addition to the peptide products expected under commonly used tryptic conditions, we observe that peptides are formed with an unexpected ε-glycinylglycinyl-Lys carboxyl terminus when the site of linkage is Lys48. Trypsin from three different commercial sources exhibited this aberration. Initial cleavage at R74 is proposed in a distal ubiquitin to produce a glycinylglycinyl-lysine residue which is bound by trypsin.

Better knowledge of the biology of breast cancer has allowed the use of new targeted therapies, leading to improved outcome. High-throughput technologies allow deepening into the molecular architecture of breast cancer, integrating different levels of information, which is important if it helps in making clinical decisions. microRNA (miRNA) and protein expression profiles were obtained from 71 estrogen receptor-positive (ER(+)) and 25 triple-negative breast cancer (TNBC) samples. RNA and proteins obtained from formalin-fixed, paraffin-embedded tumors were analyzed by RT-qPCR and LC/MS-MS, respectively. We applied probabilistic graphical models representing complex biologic systems as networks, confirming that ER(+) and TNBC subtypes are distinct biologic entities. The integration of miRNA and protein expression data unravels molecular processes that can be related to differences in the genesis and clinical evolution of these types of breast cancer. Our results confirm that TNBC has a unique metabolic profile that may be exploited for therapeutic intervention., (©2015 American Association for Cancer Research.)

26S proteasome, a major regulatory protease in eukaryotes, consists of a 20S proteolytic core particle (CP) capped by a 19S regulatory particle (RP). The 19S RP is divisible into base and lid sub-complexes. Even within the lid, subunits have been demarcated into two modules: module 1 (Rpn5, Rpn6, Rpn8, Rpn9 and Rpn11), which interacts with both CP and base sub-complexes and module 2 (Rpn3, Rpn7, Rpn12 and Rpn15) that is attached mainly to module 1. We now show that suppression of RPN11 expression halted lid assembly yet enabled the base and 20S CP to pre-assemble and form a base-CP. A key role for Regulatory particle non-ATPase 11 (Rpn11) in bridging lid module 1 and module 2 subunits together is inferred from observing defective proteasomes in rpn11-m1, a mutant expressing a truncated form of Rpn11 and displaying mitochondrial phenotypes. An incomplete lid made up of five module 1 subunits attached to base-CP was identified in proteasomes isolated from this mutant. Re-introducing the C-terminal portion of Rpn11 enabled recruitment of missing module 2 subunits. In vitro, module 1 was reconstituted stepwise, initiated by Rpn11-Rpn8 heterodimerization. Upon recruitment of Rpn6, the module 1 intermediate was competent to lock into base-CP and reconstitute an incomplete 26S proteasome. Thus, base-CP can serve as a platform for gradual incorporation of lid, along a proteasome assembly pathway. Identification of proteasome intermediates and reconstitution of minimal functional units should clarify aspects of the inner workings of this machine and how multiple catalytic processes are synchronized within the 26S proteasome holoenzymes., (© 2015 The Author(s).)

Aim: This retrospective study determined features associated with brain metastasis (BM) in women with breast cancer., Patients & Methods: A total of 215 initially early breast cancer cases were included. We reviewed files and CT scan images of BM., Results: Median age was 47 years and most of our cases were stage III (58.6%), grade III (62.8%), ER negative (62.3%) and nonluminal (59.1%). Median survival after BM was 4 months. Nonluminal, extracranial disease, time to CNS shorter than 15 months, >three brain lesions and poor breast-graded prognostic assessment and recursive partitioning analysis scores were associated with shorter survival. Adding extracranial disease to breast-graded prognostic assessment score also predicted survival after BM. Radiation response was assessed in 57 patients and response tended to be associated with nonluminal phenotype but not with survival., Conclusion: Factors associated with both initial tumor and clinical features at BM time are associated with shorter survival in our Latinas population.

Purpose: Mammography is the cornerstone of breast cancer (BC) evaluation. This report investigates whether breast density (BD) and mammographic features of the tumor can provide information on both BC susceptibility to chemotherapy and other clinicopathologic features of locally advanced BC (LA BC)., Materials and Methods: We evaluated mammography films and clinicopathological information of patients with LA BC who received neoadjuvant chemotherapy (NAC) followed by tumor resection at the Instituto Nacional de Enfermedades Neoplásicas (INEN) from 2000 to 2011., Results: We selected 494 LA BC cases. Most cases were at clinical tumor stage 4 (48.5%), node stage 1 (58.8%) and had high histologic grade (53.3%). BI-RADS 1, 2, 3, and 4 BD were found in 16.9%, 22%, 35.7% and 25.1% of patients, respectively. High BD has been associated with younger age (p<0.001), obesity (p=0.017) and no skin infiltration (T3 vs T4) (p=0.018). An association between dusty microcalcifications and HER2 group, as well as between casting microcalcifications and TN BC group (p=0.05) was found. NAC included anthracyclines and taxanes in 422 (85.5%) cases. Miller-Payne pathologic responses 4 and 5 (pCR) in the primary lesion and absence of axillary lymph nodes involvement were found in 15.3% of cases and were associated with younger age (p<0.001) and HG-3 lesions (p<0.001), but not with mammographic images., Conclusion: Mammographic features are associated with specific clinicopathological features of pre-NAC BC lesions but do not predict pCR. The implications and biological reasons for these findings require further study., (Copyright © 2014 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.)

Purpose: To determine the frequency of PIK3CA mutations in a Peruvian cohort with HER2-amplified and triple negative breast cancers (TNBC)., Methods: We analyzed two cohorts of 134 primary non-metastatic breast cancer patients from Peru. Cohorts consisted of 51 hormone receptors (+)/HER2-amplified breast tumor patients surgically resected as first treatment included in the ALTTO trial (ALTTO cohort) and 81 TNBC patients with residual disease after neoadjuvant treatment (neoadjuvant cohort). Genomic DNA was extracted from paraffin-embedded tumor samples. Samples from the ALTTO and neoadjuvant cohorts were taken at biopsies and from residual tumors, respectively. PIK3CA mutations were detected by sequencing DNA fragments obtained by PCR amplification of exons and their flanking introns. All of the detected PIK3CA mutations were confirmed in a second independent run of sample testing., Results: PIK3CA mutations were present in 21/134 cases (15.7%). Mutations in exon 9 and 20 were present in 10/134 (7.5%) and 11/134 (8.2%), respectively. No cases had mutations in both exons. Mutations in exon 9 consisted of E545A (seven cases), E545K (two cases) and E545Q (one case); while in exon 20, mutations consisted of H1047R (10 cases) and H1047L (one case). Compared to TNBC patients, HER2-amplified patients were more likely to have PIK3CA mutated (23% vs 9.6%; P=0.034). There were no associations between mutational status of PIK3CA with estrogen receptor status (P=0.731), progesterone receptor status (P=0.921), age (P=0.646), nodal status (P=0.240) or histological grade (P=1.00). No significant associations were found between PIK3CA mutational status and clinicopathological features., Conclusions: We found a similar frequency of PIK3CA mutations to that reported in other series. Although we did not include HR+/HER2 patients, those with HER2-amplified tumors were more likely to present PIK3CA mutations compared to patients with triple negative tumors., (Copyright © 2014 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.)

Zebu (Bos indicus) crossbred beef cows (Droughtmaster) were maintained long-term (16 months) on standard nutrition (SN) or improved nutrition (IN). Cows on IN had better body condition and greater (P<0.05) circulating concentrations of leptin than cows on SN (0.7±0.1n/ml and 1.7±0.1n/ml, respectively). There were no outstanding differences between SN and IN cows in basal number of ovarian follicles (≤4mm, 5-8mm, and ≥9mm) and there were also no differences in number of oocytes recovered by oocyte pick-up. Cows on IN had a greater (P<0.05) number of total follicles after stimulation with FSH than cows on SN. Oocytes from cows on IN had greater (P<0.05) lipid content than cows on SN (-0.23±0.16 and 0.20±0.18 arbitrary units, respectively) and oocytes of the former cows also tended to have more active mitochondria, although this was not significant. Cows on IN showed a positive relationship (R(2)=0.31, P<0.05) between plasma leptin and oocyte lipid content. Lipids are utilized by oocytes during high energy consumptive processes including fertilization and early cleavage. The greater lipid content of oocytes from IN cows could therefore confer a reproductive advantage. The present study has shown relationships between nutrition, body condition, circulating leptin, and oocyte lipid content, but a clear cause-and-effect requires further investigation in the cow., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Bovine oocytes that stain with brilliant cresyl blue (BCB) have a relatively higher developmental competence. The aim of the present study was to investigate the relationships among BCB staining, lipid content, and active mitochondria. Bovine oocytes (N = 133) with at least three layers of cumulus cells were segregated as BCB retained (BCB+) or metabolized (BCB-) and then stained for active mitochondria (Mitotracker Red) and lipid (Bodipy), with analysis by confocal microscopy. The BCB+ oocytes (N = 45) contained approximately 26% more cytoplasmic lipid than BCB- oocytes (N = 26-27; P < 0.05). Staining for active mitochondria did not differ between the groups. In BCB- oocytes but not BCB+ oocytes, lipid content correlated with active mitochondrial staining (r = 0.48; P < 0.05). Diameter correlated with lipid content for BCB+ oocytes (r = 0.46; P < 0.05), but not for BCB- oocytes (r = 0.16; P > 0.05). Irrespective of BCB staining, both lipid and active mitochondrial content correlated with diameter. In conclusion, the higher lipid content of BCB+ bovine oocytes might provide a cellular and functional basis for their greater developmental competence., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Unlabelled: INTRODUCTION Breast cancer (BC) becomes more aggressive throughout disease progression. Clinical stage is correlated with patient outcome. We hypothesised that BC molecular subtypes are associated with a poor prognosis in advanced clinical stages. We analysed the distribution and behaviour of molecular subtypes at different BC tumour size and variation of molecular subtype in recurrent lesions., Patients and Methods: We studied 1647 consecutive patients with non-metastatic invasive and microinvasive (Tmi) BC treated from January 1997 to December 2007. Patients were categorised by tumour size and molecular subtype. A chi-square method was used for multiple group comparisons. Kaplan-Meier product limit method was used to calculate overall survival and disease-free survival., Results: Median follow-up was 7.2 years. For patients with invasive BC the median age was 56 years. Four hundred and fifteen patients recurred and 225 died. Larger tumours were more frequently of triple-negative (TN) subtype than small ones or Tmi lesions. Any molecular subtype change from primary tumour to recurrent lesions is more likely to happen from a good prognosis to a subtype of worse prognosis than the opposite. Larger tumours of luminal A, luminal B and TN, but not HER2 subtype, are more likely to carry aggressive markers and to have worse outcomes than small ones., Conclusion: We found accumulation of TN subtype, migration to a poor prognosis subtype and increasing aggressiveness of luminal and TN subtypes throughout tumour progression. Tumours belonging to the HER2 subtype behave aggressively regardless of the primary size.

The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway mediates the effects of a variety of extracellular signals in a number of cellular processes including cell growth, proliferation, and survival. The alteration of integrants of this pathway through mutation of its coding genes increases the activation status of the signaling and can thus lead to cellular transformation. The frequent dysregulation of the PI3K/Akt pathway in breast cancer (BC) and the mediation of this pathway in different processes characteristically implicated in tumorigenesis have attracted the interest of this pathway in BC; however, a more comprehensive understanding of the signaling intricacies is necessary to develop clinical applications of the modulation of this pathway in this pathology. We review a series of experiments examining the contribution of alteration of integrants of this signaling network to human BC and we make an update of the information about the effect of the modulation of this pathway in this cancer.

Resistance to chemotherapy is a complex and very frequent problem in the treatment of breast cancer. It is associated with a poor prognosis and short overall survival. We report a patient with advanced breast cancer without response to anthracyclines or taxanes but who controlled the disease for 15 months with the combination of ixabepilone and capecitabine.

Pazopanib, a tyrosine kinase inhibitor targeted to angiogenesis, has been tested in preclinical and clinical trials and has shown promising activity against a variety of solid tumors, such as renal cancer, all of which are related to the angiogenic pathway. It has a safety profile related to this mechanism of action. Diarrhea, hypertension, hair depigmentation and nausea are the most common side effects. Pazopanib is currently under evaluation as monotherapy and in combination with some potentially synergistic agents of proven activity.