Chemotherapy remains as the only systemic treatment option available for basal-like breast cancer (BC) patients. Preclinical models and several phase II studies suggested that platinum salts are ...active drugs in this BC subtype though there is no randomized study supporting this hypothesis. This study investigates if the addition of carboplatin to a combination of an alkylating agent together with anthracyclines and taxanes is able to increase the efficacy in the neoadjuvant treatment context. Patients with operable breast cancer and immunophenotypically defined basal-like disease (ER-/PR-/HER2- and cytokeratin 5/6+ or EGFR+) were recruited. Patients were randomized to receive EC (epirubicin 90 mg/m
2
plus cyclophosphamide 600 mg/m
2
for 4 cycles) followed either by D (docetaxel 100 mg/m
2
× 4 cycles; EC–D) or DCb (docetaxel 75 mg/m
2
plus carboplatin AUC 6 × 4 cycles; EC–DCb). The primary end point was pathological complete response (pCR) in the breast following the Miller and Payne criteria. Ninety-four patients were randomized (46 EC–D, 48 EC–DCb). pCR rate in the breast was seen in 16 patients (35 %) with EC–D and 14 patients (30 %) with EC–DCb (
P
value = 0.61). pCR in the breast and axilla was seen in 30 % of patients in both arms. The overall clinical response rate was 70 % (95 % CI 56–83) in the EC–D arm and 77 % (95 % CI 65–87) in the EC–DCb arm. Grade 3/4 toxicity was similar in both arms. The addition of carboplatin to conventional chemotherapy with EC–D in basal-like breast cancer patients did not improve the efficacy probably because they had already received an alkylating agent. These findings should be taken into consideration when developing new agents for this disease.
To compare different methods in order to assess adherence and persistence with oral endocrine therapy in women diagnosed with breast cancer (BC) in Catalonia.
This study covered all women newly ...diagnosed with stage I, II or IIIa BC and positive hormone receptors at six hospitals in Catalonia (Spain) in 2004. Adherence was assessed on the basis of physician report and patient self-report using a telephone questionnaire. Persistence was measured by refill prescriptions. We used the Kappa index to compare adherence measures and logistic regression to evaluate adherence-related risk factors.
The study covered a total of 692 women. Adherence ranged from 92% (self-report) to 94.7% (physician report), depending on the measure used; persistence was 74.7% at 5 years of follow-up. Low concordance between measures was observed (Kappa range: 0.018-0.267). Patients aged 50-74 years showed higher adherence than those aged <50 years. Adherence was also associated with: adjuvant chemotherapy and sequential hormonal therapy.
Concordance between the different measures was remarkably low, indicating the need for further research. Adherence is an issue in the management of BC patients taking oral drugs, and should be assessed in clinical practice.
Background: The aim of the study was to analyse the toxicity and health related quality of life (HRQoL) of breast cancer patients treated with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) and ...TAC (docetaxel, doxorubicin, cyclophosphamide) with and without primary prophylactic G-CSF (PPG). Patients and methods: This was a phase III study to compare FAC and TAC as adjuvant treatment of high-risk node-negative breast cancer patients. After the entry of the first 237 patients, the protocol was amended to include PPG in the TAC arm due to the high incidence of febrile neutropenia. A total of 1047 evaluable patients from 49 centres in Spain, two in Poland and four in Germany were included in the trial. Side-effects and the scores of the EORTC QLQ-C30 and QLQ BR-23 questionnaires were compared in the three groups (FAC, TAC pre-amendment and TAC post-amendment). Results: The addition of PPG to TAC significantly reduced the incidence of neutropenic fever, grade 2–4 anaemia, asthenia, anorexia, nail disorders, stomatitis, myalgia and dysgeusia. Patient QoL decreased during chemotherapy, more with TAC than FAC, but returned to baseline values afterwards. The addition of PPG to TAC significantly reduced the percentage of patients with clinically relevant Global Health Status deterioration (10 or more points over baseline value) at the end of chemotherapy (64% versus 46%, P < 0.03). Conclusions: The addition of PPG significantly reduces the incidence of neutropenic fever associated with TAC chemotherapy as well as that of some TAC-induced haematological and extrahaematological side-effects. The HRQoL of patients treated with TAC is worse than that of those treated with FAC but improves with the addition of PPG, particularly in the final part of chemotherapy treatment.
Dysbiosis of vaginal microbiota is associated with increased HIV‐1 acquisition, but the underlying cellular mechanisms remain unclear. Vaginal Langerhans cells (LCs) protect against mucosal HIV‐1 ...infection via autophagy‐mediated degradation of HIV‐1. As LCs are in continuous contact with bacterial members of the vaginal microbiome, we investigated the impact of commensal and dysbiosis‐associated vaginal (an)aerobic bacterial species on the antiviral function of LCs. Most of the tested bacteria did not affect the HIV‐1 restrictive function of LCs. However, Prevotella timonensis induced a vast uptake of HIV‐1 by vaginal LCs. Internalized virus remained infectious for days and uptake was unaffected by antiretroviral drugs. P. timonensis‐exposed LCs efficiently transmitted HIV‐1 to target cells both in vitro and ex vivo. Additionally, P. timonensis exposure enhanced uptake and transmission of the HIV‐1 variants that establish infection after sexual transmission, the so‐called Transmitted Founder variants. Our findings, therefore, suggest that P. timonensis might set the stage for enhanced HIV‐1 susceptibility during vaginal dysbiosis and advocate targeted treatment of P. timonensis during bacterial vaginosis to limit HIV‐1 infection.
Synopsis
Vaginal Langerhans cells (LCs) destroy HIV‐1 upon capture, thereby protecting against infection. Investigation of various commensal and dysbiotic bacteria reveals that Prevoptella timonensis selectively subverts these restrictive cells into reservoirs mediating efficient HIV‐1 transmission to target T cells.
P. timonensis, but not other dysbiosis‐associated vaginal bacteria, enhances HIV‐1 uptake in LCs.
P. timonensis transforms LCs into HIV‐1 reservoirs.
HIV‐1 remains infectious for several days in P. timonensis‐exposed LCs.
P. timonensis‐exposed LCs efficiently transmit captured HIV‐1 to target cells.
A particular vaginal dysbiosis‐associated bacterium induces enhanced cellular uptake of HIV‐1 particles that remain infectious over extended periods of time and can be transferred to new target cells.
The effects of reprocessing on the processability of two Acrylonitrile–Butadiene–Styrene (ABS) grade thermoplastic polymers have been investigated. Reprocessing in an injection molding process of a ...low and a high viscosity ABS grade has been done changing operating temperatures and shear rates, design of experiments (DOE) techniques were applied to plan experiments and later analysis. The flow properties of virgin and reprocessed materials have been evaluated by capillary rheology.
Experimental results clearly indicate a qualitatively different behavior of the two polymers upon reprocessing. Low viscosity grade shows a reduction of viscosity upon increasing the number of processing cycles, thus confirming the degradation of this polymer. High viscosity grade, conversely, shows an increase of melt viscosity as the number of injection molding cycles is increased. It has been confirmed that applied shear rates in injection molding process affect material behavior as well as applied temperatures.
We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types.
RNASeqv2 ...data from 10078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy.
In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r>0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%–84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r=0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low=8.31; P<0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response.
Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.
Next-generation sequencing (NGS) of tumour samples is a critical component of personalised cancer treatment, but it requires high-quality DNA samples. Routine neutral-buffered formalin (NBF) fixation ...has detrimental effects on nucleic acids, causing low yields, as well as fragmentation and DNA base changes, leading to significant artefacts.
We have carried out a detailed comparison of DNA quality from matched samples isolated from high-grade serous ovarian cancers from 16 patients fixed in methanol and NBF. These experiments use tumour fragments and mock biopsies to simulate routine practice, ensuring that results are applicable to standard clinical biopsies.
Using matched snap-frozen tissue as gold standard comparator, we show that methanol-based fixation has significant benefits over NBF, with greater DNA yield, longer fragment size and more accurate copy-number calling using shallow whole-genome sequencing (WGS). These data also provide a new approach to understand and quantify artefactual effects of fixation using non-negative matrix factorisation to analyse mutational spectra from targeted and WGS data.
We strongly recommend the adoption of methanol fixation for sample collection strategies in new clinical trials. This approach is immediately available, is logistically simple and can offer cheaper and more reliable mutation calling than traditional NBF fixation.
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