Conflicting data on the role of total virus- and protein-specific cytotoxic-T-lymphocyte (CTL) responses in the control of human immunodeficiency virus (HIV) disease progression exist. We present data generated from a Peruvian cohort of untreated, clade B-infected subjects, demonstrating that the proportion of Gag-specific, and in particular p24-reactive, CTL responses among the total virus-specific CTL activity is associated with individuals' CD4 counts and viral loads. Analyses in a second cohort in the United States confirm these findings and point towards a dominant role of Gag-specific immunity in effective control of HIV infection, providing important guidance for HIV vaccine development.
Norovirus was a significant cause of AGE in this community, especially among children <2 years of age. Inclusion of vomiting in the case definition resulted in a 20% improvement for detection of norovirus cases.
Background: Prosigna™ (PAM50) is a standardized test that measures the expression levels of 50 classifier genes in formalin-fixed paraffin-embedded (FFPE) breast tissue tumor samples. It provides subtype classification based on the fundamental biology of an individual patient’s tumor (referred to as "intrinsic subtyping"), as well as a prognostic score (referred to as "risk of recurrence [ROR] score") that predicts the probability of distant recurrence over 10 years. This decision impact study examines whether the Prosigna™ test influences both physician and patient adjuvant treatment selection, beyond standard immunohistochemistry (IHC) testing. Methods: The analytic sample was comprised of postmenopausal women with node-negative, estrogen-receptor positive (ER+), HER2 negative (HER2-), early-stage breast cancer with tumors <5 cm (T1-T2). FFPE surgical specimens were analyzed using Prosigna™ in a central laboratory. Patients were classified according to the intrinsic tumor subtype (i.e., Luminal A, Luminal B, HER2-enriched, basal-like) and ROR score (low, intermediate or high risk groups). The primary endpoint was the effect of the Prosigna™ test on oncologists’ treatment recommendations, and the actual treatment received by patients (hormonal therapy [HT], chemotherapy [CT], chemotherapy and hormonal therapy [CHT]). All samples were analyzed in two independent laboratories to measure site-to-site concordance. Prosigna™ subtypes were compared with IHC intrinsic subtypes based on the St. Gallen 2013 criteria (cut-points: PgR≥20% and Ki67≥14%). Results: A total of 200 patients met eligibility criteria and were enrolled in the study between June 2013 and January 2014. According to Prosigna™ results, intrinsic tumor subtypes of these patients were distributed as follows: 129 Luminal A (64.5%), 66 Luminal B (33.0%), 3 HER2-enriched (1.5%) and 2 basal-like (1.0%). Modifications to the adjuvant treatment recommendations by ROR score can be seen in the following table: Change in physician pre- to post- Prosigna recommendation Low ROR (N=101), N (%)Intermediate ROR (N=66), N (%)High ROR (N=33), N (%)TOTAL (N=200), N (%)HT to CHT0 (0.0)8 (12.1)10 (30.3)18 (9.0)CHT to HT11 (10.9)9 (13.6)0 (0.0)20 (10.0)TOTAL11 (10.9)17 (25.7)10 (30.3)38 (19.0) Treatment decisions changed for 19.0% of all patients: 10.0% and 9.0% of patients went from CHT to HT and HT to CHT, respectively. The percentage of patients who received chemotherapy in the low, intermediate and high risk groups was 5%, 36% and 88%, respectively. Both the central and each local laboratory analyzed the samples using IHC. We found 60% concordance between central IHC and Prosigna™ intrinsic subtypes (Kappa=0.2365). Prosigna™ results were consistent across labs (Kappa = 0.89). Conclusions: The Prosigna™ test can be reliably performed in hospital laboratories to provide useful information beyond standard clinical-pathological variables that oncologists can use to optimize adjuvant treatment decisions in clinical practice. Subtype determined using IHC is not an interchangeable proxy for subtype determined by Prosigna™. *Two last authors have contributed equally to the study. Citation Format: Miguel Martín, Milagros González-Rivera, Serafín Morales, Juan de la Haba, Lucía González-Cortijo, Luis Manso, Joan Albanell, Antonio González-Martín, Sónia González, Angels Arcusa, Luis de la Cruz-Merino, Federico Rojo, Maria Vidal, Uxue Goicoechea, Patricia Galván, Rosalía Caballero, Eva Carrasco, Steven Michalopoulos, John Hornberger, Aleix Prat. Prospective study of the impact of the Prosigna™ assay on adjuvant clinical decision-making in women with estrogen receptor-positive, HER2-negative, node-negative breast cancer: A GEICAM study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-10.
ResumenSe estudió la actividad inmunoduladora sobre cultivos de linfocitos T humanos de sangre periférica. Se evaluó la producción de IFN−γ inducida por los extractos metanólicos (EM) de los ecotipos blanco, negro, rojo y morado de Lepidium peruvianum (conocida también como Lepidium meyenii Walp.) maca. Luego de cultivar los linfocitos con los respectivos EM de maca durante 14 horas sólo el EM del ecotipo morado indujo la producción significativa de IFN−γ cuantificada mediante Elispot. El extracto metanólico del ecotipo morado de maca posee propiedades inmunoestimuladoras importantes, desencadenando la activación de linfocitos T humanos.Palabras Clave: Lepidium peruvianum, Lepidium meyenii, ecotipos de maca, maca, inmunomodulación por maca, Interferón−γ. AbstractThe immunomodulatory activity was studied in function of the production of γ−IFN induced by the methanolic extracts (ME) of the white, black, red and purple ecotypes of Lepidium peruvianum, Chacón (at present Lepidium meyenii Walp.) maca, on cultures of human T lymphocytes obtained of periferic blood. After cultivating the lymphocytes with the respective ME of maca during 14 hours, only the ME of the purple ecotype induced the significant production of IFN−γ by Elispot quantified. The methanolic extract of the purple ecotype of maca possesses important immunostimulatory properties triggering the activation of the human T lymphocytes.
Background. In HER2+/HR+ breast cancer (BC), CDK4/6 inhibition combined with anti-HER2 therapy is currently being explored in phase II/III trials. However, we and others have shown that Luminal A and B subtypes (i.e. luminal disease) defined by gene expression only represent 30-50% in this group. Identification of the luminal subtype in HER2+/HR+ disease might be important since the median IC50 of palbociclib in HER2+ BC cell lines falling into the luminal subtype is lower than in non-luminal HER2+ cell lines (47.5 vs. 300 nM; Finn BCR 2011). Here, we explored, for the first time, the efficacy (progression-free survival [PFS]) of palbociclib and trastuzumab and its association with subtype in HER2+/HR+ BC. Methods. PATRICIA is an exploratory, prospective, open-label, multicenter phase II trial in advanced HER2+ BC. Patients (pts) had received 2-4 prior lines of anti-HER2-based regimens. Treatment consisted of trastuzumab 6 mg/kg every 3w and palbociclib 200 mg daily for 2w and 1w off. The study was based on a Simon 2-stage design comprising 3 cohorts: ER-negative cohort A (still recruiting) and ER+ cohorts B1 and B2 (both completed). Patients in cohort B2 also received letrozole by randomization. Safety run-in phase was made for first 12 pts. For stage 1 to be successful, at least 6 pts of 15 had to be progression-free at 6 months (PFS6) in each cohort. In stage 2, up to 46 pts per cohort will be included to show a PFS6 >50%. As a secondary objective, research-based PAM50 intrinsic subtype was performed from FFPE samples using the nCounter platform. Estimates of PFS were from Kaplan-Meier curves. Univariate Cox regression analyses evaluating luminal subtype, age, performance status, treatment line, type of biopsy and endocrine treatment were evaluated. Results. Thirty-one pts with HER2+/HR+ disease were recruited in stage 1 in cohorts B1 (n=16) and B2 (n=15). Median age was 59.8y, and median number of prior lines was 3.0. The rate of PFS6 was 40.0% (6/15) and 53.3% (8/15) in cohorts B1 and B2, respectively. A total of 26 (83.9%) tumors samples (15 primary and 11 metastatic tumors) were profiled. Subtype distribution was as follows: 46.2% HER2-enriched, 23.1% Luminal B, 19.2% Luminal A and 11.5% Normal-like. Median PFS in this subgroup of patients with PAM50 data was 3.71 months. Compared to non-luminal disease, luminal disease showed a statistically significantly longer median PFS (10.37 vs. 3.53 months, p-value=0.023). The PFS hazard ratio of luminal versus non-luminal groups was 0.34 (95% CI 0.13-0.92, p-value=0.033). In addition, Luminal A signature score, as a continuous variable, was also found associated with PFS (adjusted hazard ratio=0.54, 0.31-0.92, p-value=0.023). No clinical-pathological variable was found associated with PFS. Conclusion. PAM50 subtype predicts PFS in HER2+/HR+ advanced BC treated with palbociclib and trastuzumab. Patients with non-luminal disease might not derive a large benefit from this treatment strategy concordant with the preclinical in vitro data. Our results might have important implications for current and future clinical trials evaluating CDK4/6 inhibitors in HER2+/HR+ disease. Citation Format: Ciruelos E, Villagrasa P, Paré L, Oliveira M, de la Peña L, Pernas S, Cortés J, Soberino J, Adamo B, Vazquez S, Martínez N, Perelló A, Bermejo B, Martínez E, Garau I, Melé M, Morales S, Galvan P, Pascual T, Nuciforo P, Gonzalez X, Prat A. PAM50 intrinsic subtype predicts survival outcome in HER2-positive/hormone receptor-positive metastatic breast cancer treated with palbociclib and trastuzumab: a correlative analysis of the PATRICIA (SOLTI 13-03) trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-19.
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