Electrochemical Characterization of the Encapsulation and Release of 5-Fluorouracil in Nanocarriers Formed from Soy Lecithin Vesicles.

5-Fluorouracil (5-FU) is an antineoplastic agent known for its low bioavailability and limited cellular penetration, often resulting in adverse effects on healthy cells. Thus, finding vehicles that enhance bioavailability, enable controlled release, and mitigate adverse effects is crucial. The study focuses on encapsulating 5-FU within soy lecithin vesicles (SLVs) and assessing its impact on the carrier's properties and functionality. Results show that incorporating 5-FU does not affect SLVs' size or polydispersity, even postlyophilization. Liberation of 5-FU from SLVs requires system disruption rather than spontaneous release, with an encapsulation efficiency of approximately 43% determined using Square Wave Voltammetry. Cytotoxicity assays on colorectal cancer cells reveal SLV-based delivery's significant efficacy, surpassing free drug solution effects with 45% cell viability after 72 h vs 73% viability. The research addresses 5-FU's limited bioavailability by creating a biocompatible nanocarrier for efficient drug delivery, highlighting SLVs as promising for targeted cancer therapy due to sustained antiproliferative effects and improved cellular uptake. The study underscores the importance of tailored drug delivery systems in enhancing therapeutic outcomes and suggests SLV/5-FU formulations as a potential advancement in cancer treatment strategies.

Prognostic value of EndoPredict test in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer screened for the randomized, double-blind, phase III UNIRAD trial.

BACKGROUND: The purpose of this study was to evaluate the prognostic value of the multigene EndoPredict test in prospectively collected data of patients screened for the randomized, double-blind, phase III UNIRAD trial, which evaluated the addition of everolimus to adjuvant endocrine therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. PATIENTS AND METHODS: Patients were classified into low or high risk according to the EPclin score, consisting of a 12-gene molecular score combined with tumor size and nodal status. Association of the EPclin score with disease-free survival (DFS) and distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier estimates. The independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics. RESULTS: EndoPredict test results were available for 768 patients: 663 patients classified as EPclin high risk (EPCH) and 105 patients as EPclin low risk (EPCL). Median follow-up was 70 months (range 1-172 months). For the 429 EPCH randomized patients, there was no significant difference in DFS between treatment arms. The 60-month relapse rate for patients in the EPCL and EPCH groups was 0% and 7%, respectively. Hazard ratio (HR) supposing continuous EPclin score was 1.87 [95% confidence interval (CI) 1.4-2.5, P < 0.0001]. This prognostic effect remained significant when assessed in a Cox model adjusting on tumor size, number of positive nodes and tumor grade (HR 1.52, 95% CI 1.09-2.13, P = 0.0141). The 60-month DMFS for patients in the EPCL and EPCH groups was 100% and 94%, respectively (adjusted HR 8.10, 95% CI 1.1-59.1, P < 0.0001). CONCLUSIONS: The results confirm the value of EPclin score as an independent prognostic parameter in node-positive, hormone receptor-positive, HER2-negative early breast cancer patients receiving standard adjuvant treatment. EPclin score can be used to identify patients at higher risk of recurrence who may warrant additional systemic treatments.

Efficacy of olaparib in advanced cancers with germline or somatic mutations in BRCA1, BRCA2, CHEK2 and ATM, a Belgian Precision tumor-agnostic phase II study.

BACKGROUND: The Belgian Precision initiative aims to maximize the implementation of tumor-agnostic next-generation sequencing in patients with advanced cancer and enhance access to molecularly guided treatment options. Academic tumor-agnostic basket phase II studies are part of this initiative. The current investigator-driven trial aimed to investigate the efficacy of olaparib in advanced cancers with a (likely) pathogenic mutation (germline or somatic) in a gene that plays a role in homologous recombination (HR). PATIENTS AND METHODS: This open-label, multi-cohort, phase II study examines the efficacy of olaparib in patients with an HR gene mutation in their tumor and disease progression on standard of care. Patients with a somatic or germline mutation in the same gene define a cohort. For each cohort, a Simon minimax two-stage design was used. If a response was observed in the first 13 patients, 14 additional patients were included. Here, we report the results on four completed cohorts: patients with a BRCA1, BRCA2, CHEK2 or ATM mutation. RESULTS: The overall objective response rate across different tumor types was 11% in the BRCA1-mutated (n = 27) and 21% in the BRCA2-mutated (n = 27) cohorts. Partial responses were seen in pancreatic cancer, gallbladder cancer, endocrine carcinoma of the pancreas and parathyroid cancer. One patient with a BRCA2 germline-mutated colon cancer has an ongoing complete response with 19+ months on treatment. Median progression-free survival in responding patients was 14+ months (5-34+ months). The clinical benefit rate was 63% in the BRCA1-mutated and 46% in the BRCA2-mutated cohorts. No clinical activity was observed in the ATM (n = 13) and CHEK2 (n = 14) cohorts. CONCLUSION: Olaparib showed efficacy in different cancer types harboring somatic or germline mutations in the BRCA1/2 genes but not in ATM and CHEK2. Patients with any cancer type harboring BRCA1/2 mutations should have access to olaparib.

PRECISION: the Belgian molecular profiling program of metastatic cancer for clinical decision and treatment assignment.

PRECISION is an initiative from the Belgian Society of Medical Oncology (BSMO) in collaboration with several stakeholders, encompassing four programs that aim to boost genomic and clinical knowledge with the ultimate goal to offer patients with metastatic solid tumors molecularly guided treatments. The PRECISION 1 study has led to the creation of a clinico-genomic database. The Belgian Approach for Local Laboratory Extensive Tumor Testing (BALLETT) and GeNeo studies will increase the number of patients with advanced cancer that have comprehensive genotyping of their cancer. The PRECISION 2 project consists of investigator-initiated phase II studies aiming to provide access to a targeted drug for patients whose tumors harbor actionable mutations in case the matched drug is not available through reimbursement or clinical trials in Belgium.

Impact of the line of treatment on progression-free survival in patients treated with T-DM1 for metastatic breast cancer.

BACKGROUND: Trastuzumab emtansine (T-DM1) is indicated as second-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic or unresectable locally advanced breast cancer, after progression on trastuzumab and a taxane-based chemotherapy. We wished to determine if the line of treatment in which T-DM1 is administered has an impact on progression-free survival (PFS) and in particular, if prior treatment with capecitabine/lapatinib or pertuzumab modifies PFS of further treatment with T-DM1. PATIENTS AND METHODS: We performed a multicenter retrospective study in 3 Belgian institutions. We evaluated PFS with T-DM1 in patients treated for HER2 positive metastatic or locally advanced unresectable breast cancer between January 1, 2009 and December 31, 2016. RESULTS: We included 51 patients. The median PFS was 9.01 months. The line of treatment in which T-DM1 (1st line, 2nd line, 3rd line or 4+ lines) was administered had no influence on PFS (hazard ratio 0.979, CI95: 0.835-1.143). There was no significant difference in PFS whether or not patients had received prior treatment with capecitabine/lapatinib (9.17 vs 5.56 months, p-value 0.875). But, patients who received pertuzumab before T-DM1 tended to exhibit a shorter PFS (3.55 months for T-DM1 after pertuzumab vs 9.50 months for T-DM1 without pretreatment with pertuzumab), even if this difference was not statistically significant (p-value 0.144). CONCLUSION: Unlike with conventional chemotherapy, the line of treatment in which T-DM1 is administered does not influence PFS in our cohort of patients with advanced HER2-positive breast cancer.

Flexible care in breast cancer.

Treatment of patients with cancer in hospitals or clinics is resource-intensive and imposes a burden on patients. 'Flexible care' is a term that can be used to describe treatment administered outside the oncology ward, oncological outpatient clinic or office-based oncologist setting. Programmes that reduce travel burden by bringing cancer treatment to the patient's home, workplace or closer to the patient's home, in the form of satellite clinics or mobile cancer units, expand treatment capacity and are well received. Clinical trial data show that, compared with intravenous administration, subcutaneous (s.c.) administration of trastuzumab is preferred by patients with breast cancer (BC), saves healthcare professionals' (HCPs) time, reduces drug preparation and administration time and reduces direct and indirect costs. As such, s.c. trastuzumab is well suited to flexible care. The results of a Belgian study (BELIS) show that home administration of s.c. trastuzumab is feasible and preferred by patients with BC. Numerous programmes and pilot studies in Europe show that s.c. trastuzumab can be administered effectively in the patient's home, in primary care settings or local hospitals. Such programmes require planning, training, careful patient selection and technology to link patients, caregivers and specialists in oncology clinics. Once these elements are in place, flexible care offers patients with BC a choice of how treatment may be delivered and lead to improved quality of life, while reducing pressure on HCPs and hospitals. The concept of flexible care is particularly relevant amid the COVID-19 pandemic where guidelines have been developed encouraging remote care.

Aggressive behavior in cattle is associated with a polymorphism in the MAOA gene promoter.

Molecular mechanisms underlying aggressive behavior are primitive and similar among the subphylum Vertebrata. In humans, a primary goal in the study of aggression is to determine the neurobehavioral molecular factors triggering violence. Although several species have been used to study agonistic responses, researchers are limited by the difficulty of artificially inducing aggression in animals not selected for it. Conversely, the Lidia cattle breed has been selected since the eighteenth century to display agonistic responses based on traits such as aggressiveness, ferocity and mobility, all of them showing significant heritability values. This intensive selection may have driven shifts in specific allele frequencies. In a previous analysis across the autosomes, we revealed long-term selection regions including genes involved in behavioral development. In the present study, we focus on mapping recent signatures of selection associated with aggressiveness at chromosome X, by comparing Lidia cattle samples with two non-specialized Spanish breeds showing tamed behavior. The most significant markers peaked around the monoamine oxidase A (MAOA) gene, and thus the associations of three functionally important regions located near the promoter of this gene were further investigated. A polymorphism consisting of a variable number of tandem repeats of the nucleotide 'C' (BTX:105,462,494) and displaying lower number of repetitions in the Lidia breed when compared with the tamed breeds was detected. In silico analyses predicted that the g.105,462,494delsinsC variant may code for the Sp1 binding motif, one of the major transcription factors controlling the core promoter and expression of the MAOA gene in humans.

Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer.

Background: Palbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety of chemotherapy and letrozole-palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC. Patients and methods: NeoPAL (UCBG10/4, NCT02400567) is a randomised, parallel, non-comparative phase II study. Patients with ER-positive, HER2-negative, Prosigna®-defined luminal B, or luminal A and node-positive, stage II-III breast cancer, not candidate for breast-conserving surgery, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks, or to FEC100 (5FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)×3 21-day courses followed by docetaxel 100 mg/m2×3 21-day courses. Primary end point was residual cancer burden (RCB 0-I rate). Secondary end points included clinical response, proliferation-based markers, and safety. Results: Overall, 106 patients were randomised [median Prosigna® ROR Score 71 (22-93)]. RCB 0-I was observed in four and eight patients in LETPAL [7.7% (95% CI 0.4-14.9)] and chemotherapy [15.7% (95% CI 5.7-25.7)] arms, respectively. Pathological complete response rates were 3.8% and 5.9%. Clinical response (75%) and breast-conserving surgery rates (69%) were similar in both arms. Preoperative Endocrine Prognostic Index 0 scores (breast cancer-specific survival) were observed in 17.6% and 8.0% of patients in LETPAL and chemotherapy arms, respectively. Safety profile was as expected, with 2 versus 17 serious adverse events (including 11 grade 4 serious AEs in the chemotherapy arm). Conclusion: LETPAL combination was associated with poor pathological response but encouraging clinical and biomarker responses in Prosigna®-defined high-risk LBC. Contemporary chemotherapy regimen was associated with poor pathological and biomarker responses, with a much less favourable safety profile. LETPAL combination might represent an alternative to chemotherapy in early high-risk LBC. Clinical Trial Number: NCT02400567.

Detection of selection signatures for agonistic behaviour in cattle.

The identification of genomic regions including signatures of selection produced by domestication and its subsequent artificial selection processes allows the understanding of the evolution of bovine breeds. Although several studies describe the genomic variability among meat or milk production cattle breeds, there are limited studies orientated towards bovine behavioural features. This study is focused on mapping genomic signatures of selection which may provide insights of differentiation between neutral and selected polymorphisms. Their effects are studied in the Lidia cattle traditionally selected for agonistic behaviour compared with Spanish breeds showing tamed behaviour. Two different approaches, BayeScan and SelEstim, were applied using genotypic 50K SNP BeadChip data. Both procedures detected two genomic regions bearing genes previously related to behavioural traits. The frequencies of the selected allele in these two regions in Lidia breed were opposite to those found in the tamed breeds. In these genomic regions, several putative genes associated with enriched metabolic pathways related to the behavioural development were identified, as neurochondrin gene (NCDN) or glutamate ionotropic receptor kainate type subunit 3 (GRIK3) both located at BTA3 or leucine-rich repeat and Ig domain containing 2 (LINGO2) and phospholipase A2-activating protein (PLAA) at BTA8.

Dissection of ancestral genetic contributions to Creole goat populations.

Goats have played a key role as source of nourishment for humans in their expansion all over the world in long land and sea trips. This has guaranteed a place for this species in the important and rapid episode of livestock expansion triggered by Columbus' arrival in the Americas in the late 1400s. The aims of this study are to provide a comprehensive perspective on genetic diversity in American goat populations and to assess their origins and evolutionary trajectories. This was achieved by combining data from autosomal neutral genetic markers obtained in more than two thousand samples that encompass a wide range of Iberian, African and Creole goat breeds. In general, even though Creole populations differ clearly from each other, they lack a strong geographical pattern of differentiation, such that populations of different admixed ancestry share relatively close locations throughout the large geographical range included in this study. Important Iberian signatures were detected in most Creole populations studied, and many of them, particularly the Cuban Creole, also revealed an important contribution of African breeds. On the other hand, the Brazilian breeds showed a particular genetic structure and were clearly separated from the other Creole populations, with some influence from Cape Verde goats. These results provide a comprehensive characterisation of the present structure of goat genetic diversity, and a dissection of the Iberian and African influences that gave origin to different Creole caprine breeds, disentangling an important part of their evolutionary history. Creole breeds constitute an important reservoir of genetic diversity that justifies the development of appropriate management systems aimed at improving performance without loss of genomic diversity.

Genomic diversity and population structure of Mexican and Spanish bovine Lidia breed.

The Lidia bovine breed is distinguished for its low genetic exchangeability given its selection on aggressive behavior, its management uniqueness and its subdivided structure. In this study, we present a comprehensive genome-wide analysis of genetic diversity, population structure and admixture of 468 animals from Mexican and Spanish Lidia breed populations and 64 samples belonging to 10 Spanish native and American-creole breeds using 37 148 single nucleotide polymorphisms. We found similar average inbreeding values in the Lidia breed, with different distributions within groups; variability of inbreeding values among Spanish lineages was significant and no differences were found among the Mexican sub-populations. Together, the high FIS of the lineages and the behavior of the runs of homozygosity are consequences of the lineage's small effective population sizes, contributing to their inbreeding increase. Population admixture analysis discarded any influence on the genetic structure of the Lidia populations from the Spanish native and American-creole breeds. In addition, both Lidia populations depicted different genetic origins, with the exception of some Mexican individuals whose origins traced back to recent Spanish importations.

Genetic diversity of the Mexican Lidia bovine breed and its divergence from the Spanish population.

Lidia bovine breed exists since the XIV century in the Iberian Peninsula. These animals were initially produced for meat but some, showing an aggressive behaviour which difficulted their management, were used to participate in popular traditional and social events. A specialization of the breed giving rise to the original Lidia population is documented in Spain since mid-XVIII century. Following the same tradition than in the Spanish population, Mexico used aggressive animals at the beginning of the XX century until two families of breeders started importing Lidia breed bovines from Spain with the aim of specializing their production. Each family (Llaguno and González) followed different breeding managements, and currently, most of the Lidia Mexican population derives from the Llaguno line. Although genetic structure and diversity of the Spanish population have been studied (using autosomal microsatellite markers, Y chromosome DNA markers and mitochondrial DNA sequences), the Mexican population is not analysed. The aim of the study was to assess both the genetic structure and diversity of the Mexican Lidia breed and its relationship with the original Spanish population using the same molecular tools. A total of 306 animals belonging to 20 breeders issued from both existing Mexican families were genotyped, and the genetic information was compared to the previously existing Spanish information. Slightly higher levels of genetic diversity in Mexican population were found when comparing to the Spanish population, and the variability among populations accounted for differences within them showing mean values of 0.18 and 0.12, respectively. Animals from the Mexican breeders, belonging to each of the two families, clustered together, and there was little evidence of admixture with the Spanish population. The analysis of Y chromosome diversity showed a high frequency of the H6 haplotype in the Mexican population, whereas this haplotype is rare in the Spanish, which is only found in the Miura (100%) and Casta Navarra (38%) lineages. Mitochondrial DNA revealed similar haplotypic pattern in both Spanish and Mexican populations, which is in accordance with most of the Mediterranean bovine breeds. In conclusion, as the Mexican Lidia population had initially a small number of founders and its current population has been reared isolated from their Spanish ancestors since a long time, these bottleneck effects and a combination of mixed cattle origin are the factors that might erase any trace of the Spanish origin of this population.

Candidate gene analysis of osteochondrosis in Spanish Purebred horses.

Equine osteochondrosis (OC) is a frequent developmental orthopaedic disease with high economic impact on the equine industry and may lead to premature retirement of the animal as a result of chronic pain and lameness. The genetic background of OC includes different genes affecting several locations; however, these genetic associations have been tested in only one or few populations, lacking the validation in others. The aim of this study was to identify the genetic determinants of OC in the Spanish Purebred horse breed. For that purpose, we used a candidate gene approach to study the association between loci previously implicated in the onset and development of OC in other breeds and different OC locations using radiographic data from 144 individuals belonging to the Spanish Purebred horse breed. Of the 48 polymorphisms analysed, three single nucleotide polymorphisms (SNPs) located in the FAF1, FCN3 and COL1A2 genes were found to be associated with different locations of OC lesions. These data contribute insights into the complex gene networks underlying the multifactorial disease OC, and the associated SNPs could be used in a marker-assisted selection strategy to improve horse health, welfare and competitive lifespan.

Tumor lysis syndrome following trastuzumab and pertuzumab for metastatic breast cancer: a case report.

BACKGROUND: Tumor lysis syndrome is a rare and potentially fatal complication of oncologic treatments, especially in solid tumors. To the best of our knowledge, tumor lysis syndrome has never been reported after trastuzumab and pertuzumab combination therapy. Knowledge of risk factors and active prevention proceedings is of utmost importance to avoid fatal outcomes. CASE PRESENTATION: We present the case of a chemo-naive 58-year-old Belgian woman developing hypovolemic shock and multiple organ failure due to tumor lysis syndrome after a single dose of trastuzumab and pertuzumab in the context of the treatment of a metastatic breast cancer and resulting in fatal outcome despite optimal management. CONCLUSIONS: Considering that targeted cancer therapies become increasingly effective, oncologists should be extremely cautious when treating patients at high risk of tumor lysis syndrome, even if they are not treated with cytotoxic chemotherapy, and determine appropriate prophylaxis.

Conservation priorities of Iberoamerican pig breeds and their ancestors based on microsatellite information.

Criollo pig breeds are descendants from pigs brought to the American continent starting with Columbus second trip in 1493. Pigs currently play a key role in social economy and community cultural identity in Latin America. The aim of this study was to establish conservation priorities among a comprehensive group of Criollo pig breeds based on a set of 24 microsatellite markers and using different criteria. Spain and Portugal pig breeds, wild boar populations of different European geographic origins and commercial pig breeds were included in the analysis as potential genetic influences in the development of Criollo pig breeds. Different methods, differing in the weight given to within- and between-breed genetic variability, were used in order to estimate the contribution of each breed to global genetic diversity. As expected, the partial contribution to total heterozygosity gave high priority to Criollo pig breeds, whereas Weitzman procedures prioritized Iberian Peninsula breeds. With the combined within- and between-breed approaches, different conservation priorities were achieved. The Core Set methodologies highly prioritized Criollo pig breeds (Cr. Boliviano, Cr. Pacifico, Cr. Cubano and Cr. Guadalupe). However, weighing the between- and within-breed components with FST and 1-FST, respectively, resulted in higher contributions of Iberian breeds. In spite of the different conservation priorities according to the methodology used, other factors in addition to genetic information also need to be considered in conservation programmes, such as the economic, cultural or historical value of the breeds involved.

Pathological responses after angiogenesis or EGFR inhibitors in metastatic colorectal cancer depend on the chemotherapy backbone.

BACKGROUND: Optimal preoperative treatment before colorectal cancer metastases (CRCM) resection remains unclear. This study evaluated pathological responses (pR) in CRCM resected after chemotherapy alone or combined with angiogenesis or epidermal growth factor receptor (EGFR) inhibitors. METHODS: Pathological response was retrospectively evaluated on 264 resected metastases from 99 patients. The proportion of responding metastases after different preoperative treatments was reported and compared. Patient's progression-free survival (PFS) and overall survival (OS) were compared based on pR. RESULTS: The combination of anti-angiogenics with oxaliplatin-based chemotherapy resulted in more pR than when they were combined with irinotecan-based chemotherapy (80% vs 50%; P<0.001). Inversely, the combination of EGFR inhibitors with oxaliplatin-based chemotherapy seemed to induce fewer pR than when they were combined with irinotecan-based treatment (53% vs 72%; P=0.049). Overall survival at 5 years was improved for patients with a pR in all resected metastases compared with those who did not achieve a pR (68.5% vs 32.6%; P=0.023) and this response was the only factor predicting OS in a multivariate analysis. CONCLUSION: The chemotherapy partner combined with angiogenesis or EGFR inhibitors influenced pR in resected CRCM. In our exploratory analysis anti-angiogenic/oxaliplatin-based regimens and anti-EGFR/irinotecan-based regimens were associated with the highest pR. Prospective randomised trials should be performed to validate these observations.

Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer.

BACKGROUND: The Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) demonstrated that panitumumab-FOLFOX4 significantly improved progression-free survival (PFS) versus FOLFOX4 as first-line treatment of wild-type (WT) KRAS metastatic colorectal cancer (mCRC), the primary end point of the study. PATIENTS AND METHODS: Patients were randomized 1:1 to panitumumab 6.0 mg/kg every 2 weeks + FOLFOX4 (arm 1) or FOLFOX4 (arm 2). This prespecified final descriptive analysis of efficacy and safety was planned for 30 months after the last patient was enrolled. RESULTS: A total of 1183 patients were randomized. Median PFS for WT KRAS mCRC was 10.0 months [95% confidence interval (CI) 9.3-11.4 months] for arm 1 and 8.6 months (95% CI 7.5-9.5 months) for arm 2; hazard ratio (HR) = 0.80; 95% CI 0.67-0.95; P = 0.01. Median overall survival (OS) for WT KRAS mCRC was 23.9 months (95% CI 20.3-27.7 months) for arm 1 and 19.7 months (95% CI 17.6-22.7 months) for arm 2; HR = 0.88; 95% CI 0.73-1.06; P = 0.17 (68% OS events). An exploratory analysis of updated survival (>80% OS events) was carried out which demonstrated improvement in OS; HR = 0.83; 95% CI 0.70-0.98; P = 0.03 for WT KRAS mCRC. The adverse event profile was consistent with the primary analysis. CONCLUSIONS: In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab-FOLFOX4, with significant improvement in OS observed in an updated analysis of survival in patients with WT KRAS mCRC treated with panitumumab + FOLFOX4 versus FOLFOX4 alone (P = 0.03). These data support a positive benefit-risk profile for panitumumab-FOLFOX4 for patients with previously untreated WT KRAS mCRC. KRAS testing is critical to select appropriate patients for treatment with panitumumab.

Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study.

BACKGROUND: Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. METHODS: Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5)). RESULTS: A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). CONCLUSION: Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.

Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers.

BACKGROUND: This phase II study assessed the safety and efficacy of everolimus, an oral mammalian target of rapamycin inhibitor in advanced transitional carcinoma cell (TCC) after failure of platinum-based therapy. PATIENTS AND METHODS: Thirty-seven patients with advanced TCC received everolimus 10 mg/day until progressive disease (PD) or unacceptable toxicity. The primary end point was the disease control rate (DCR), defined as either stable disease (SD), partial response (PR), or complete response at 8 weeks. Angiogenesis-related proteins were detected in plasma and changes during everolimus treatment were analyzed. PTEN expression and PIK3CA mutations were correlated to disease control. RESULTS: Two confirmed PR and eight SD were observed, resulting in a DCR of 27% at 8 weeks. Everolimus was well tolerated. Compared with patients with noncontrolled disease, we observed in patients with controlled disease a significant higher baseline level of angiopoietin-1 and a significant early plasma decrease in angiopoietin-1, endoglin, and platelet-derived growth factor-AB. PTEN loss was observed only in patients with PD. CONCLUSIONS: Everolimus showed clinical activity in advanced TCC. The profile of the plasma angiogenesis-related proteins suggested a role of the everolimus antiangiogenic properties in disease control. PTEN loss might be associated with everolimus resistance.

Genetic characterization of Latin-American Creole cattle using microsatellite markers.

Genetic diversity in and relationships among 26 Creole cattle breeds from 10 American countries were assessed using 19 microsatellites. Heterozygosities, F-statistics estimates, genetic distances, multivariate analyses and assignment tests were performed. The levels of within-breed diversity detected in Creole cattle were considerable and higher than those previously reported for European breeds, but similar to those found in other Latin American breeds. Differences among breeds accounted for 8.4% of the total genetic variability. Most breeds clustered separately when the number of pre-defined populations was 21 (the most probable K value), with the exception of some closely related breeds that shared the same cluster and others that were admixed. Despite the high genetic diversity detected, significant inbreeding was also observed within some breeds, and heterozygote excess was detected in others. These results indicate that Creoles represent important reservoirs of cattle genetic diversity and that appropriate conservation measures should be implemented for these native breeds in order to minimize inbreeding and uncontrolled crossbreeding.