Preventing alpelisib-related hyperglycaemia in HR+/HER2-/PIK3CA-mutated advanced breast cancer using metformin (METALLICA): a multicentre, open-label, single-arm, phase 2 trial.

Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/PIK3CA-mutated advanced breast cancer (ABC). Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL [<5.6 mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140 mg/dL [5.6-7.8 mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively. Findings: 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P = 0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2). Interpretation: In HR+/HER2-/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia. Funding: Novartis Pharmaceuticals.

Noninvasive detection of microsatellite instability in patients with endometrial cancer.

The analysis of mismatch repair proteins in solid tissue is the standard of care (SoC) for the microsatellite instability (MSI) characterization in endometrial cancer (EC). Uterine aspirates (UAs) or circulating-DNA (cfDNA) samples capture the intratumor heterogeneity and provide a more comprehensive and dynamic molecular diagnosis. Thus, MSI analysis by droplet-digital PCR (ddPCR) in UAs and cfDNA can provide a reliable tool to characterize and follow-up the disease. The UAs, paraffin-embedded tumor tissue (FFPE) and longitudinal plasma samples from a cohort of 90 EC patients were analyzed using ddPCR panel and compared to the SoC. A high concordance (96.67%) was obtained between the analysis of MSI markers in UAs and the SoC. Three discordant cases were validated as unstable by ddPCR on FFPE samples. Besides, a good overall concordance (70.27%) was obtained when comparing the performance of the ddPCR assay on UAs and cfDNA in high-risk tumors. Importantly, our results also evidenced the value of MSI analysis to monitor the disease evolution. MSI evaluation in minimally invasive samples shows great accuracy and sensitivity and provides a valuable tool for the molecular characterization and follow-up of endometrial tumors, opening new opportunities for personalized management of EC.

Real-world safety and effectiveness of maintenance niraparib for platinum-sensitive recurrent ovarian cancer: A GEICO retrospective observational study within the Spanish expanded-access programme.

AIM: To describe patient characteristics, effectiveness and safety in a real-world population treated with niraparib in the Spanish expanded-access programme. PATIENTS AND METHODS: This retrospective observational study included women with platinum-sensitive recurrent high-grade serous ovarian cancer who received maintenance niraparib within the Spanish niraparib expanded-access programme. Eligible patients had received ≥2 previous lines of platinum-containing therapy, remained platinum-sensitive after the penultimate line of platinum and had responded to the most recent platinum-containing therapy. Niraparib dosing was at the treating physician's discretion (300 mg/day fixed starting dose or individualised starting dose [ISD] according to baseline body weight and platelet count). Safety, impact of dose adjustments, patient characteristics and effectiveness were analysed using data extracted from medical records. RESULTS: Among 316 eligible patients, 80% had BRCA wild-type tumours and 66% received an ISD. Median niraparib duration was 7.8 months. The most common adverse events typically occurred within 3 months of starting niraparib. Median progression-free survival was 8.6 (95% confidence interval [CI] 7.6-10.0) months. One- and 2-year overall survival rates were 86% (95% CI 81-89%) and 65% (95% CI 59-70%), respectively. Dose interruptions, dose reductions, haematological toxicities and asthenia/fatigue were less common with ISD than fixed starting dose niraparib, but progression-free survival was similar irrespective of dosing strategy. Subsequent therapy included platinum in 71% of patients who received further treatment. CONCLUSION: Outcomes in this large real-world dataset of niraparib-treated patients are consistent with phase III trials, providing reassuring evidence of the tolerability and activity of niraparib maintenance therapy for platinum-sensitive recurrent ovarian cancer. GOV REGISTRATION: NCT04546373.

Open-label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors: the GREKO (GRanulosa Et KetOconazole) trial, GETHI 2011-03.

BACKGROUND: Granulosa cell ovarian tumor (GCT) is characterized by a pathognomonic mutation in the FOXL2 gene (402 C > G) that leads to an overactivation of steroidogenesis. CYP17 is a key enzyme in such process and can be inhibited by ketoconazole. METHODS: We designed a phase II clinical trial to assess the efficacy of ketoconazole in advanced GCT and conducted several in vitro studies to support the clinical findings. RESULTS: From October 1st 2012 to January 31st 2014, six evaluable patients were recruited in ten hospitals of the Spanish Group for Transversal Oncology and Research in Orphan and Infrequent Tumors" (GETTHI). FOXL2 (402C > G) mutation was confirmed in three; two cases were wild type and it could not be assessed in one. No objective response by RECIST was observed, but five cases achieved stable disease longer than 12 months. Median progression-free survival was 14.06 months (CI 95% 5.43-22.69) for the whole study population (3.38 and 13.47 months for wild-type cases and 14.06, 20.67 and 26.51 for those with confirmed FOXL2 mutation). Median overall survival was 22·99 months (CI 95% 8.99-36.99). In vitro assays confirmed the activity of ketoconazole in this tumor and suggested potential synergisms with other hormone therapies. CONCLUSION: Ketoconazole has shown activity in advanced GCT in clinical and in vitro studies. Based on these data, an orphan designation was granted by the European Medicines Agency for ketoconazole in GCT (EU/3/17/1857). GOV IDENTIFIER: NCT01584297.

Red Blood Cells Protein Profile Is Modified in Breast Cancer Patients.

Metastasis is the primary cause of death for most breast cancer (BC) patients who succumb to the disease. During the hematogenous dissemination, circulating tumor cells interact with different blood components. Thus, there are microenvironmental and systemic processes contributing to cancer regulation. We have recently published that red blood cells (RBCs) that accompany circulating tumor cells have prognostic value in metastatic BC patients. RBC alterations are related to several diseases. Although the principal known role is gas transport, it has been recently assigned additional functions as regulatory cells on circulation. Hence, to explore their potential contribution to tumor progression, we characterized the proteomic composition of RBCs from 53 BC patients from stages I to III and IV, compared with 33 cancer-free controls. In this work, we observed that RBCs from BC patients showed a different proteomic profile compared to cancer-free controls and between different tumor stages. The differential proteins were mainly related to extracellular components, proteasome, and metabolism. Embryonic hemoglobins, not expected in adults' RBCs, were detected in BC patients. Besides, lysosome-associated membrane glycoprotein 2 emerge as a new RBCs marker with diagnostic and prognostic potential for metastatic BC patients. Seemingly, RBCs are acquiring modifications in their proteomic composition that probably represents the systemic cancer disease, conditioned by the tumor microenvironment.

Laboratory Cross-Comparison and Ring Test Trial for Tumor BRCA Testing in a Multicenter Epithelial Ovarian Cancer Series: The BORNEO GEICO 60-0 Study.

Germline and tumor BRCA testing constitutes a valuable tool for clinical decision-making in the management of epithelial ovarian cancer (EOC) patients. Tissue testing is able to identify both germline (g) and somatic (s) BRCA variants, but tissue preservation methods and the widespread implementation of NGS represent pre-analytical and analytical challenges that need to be managed. This study was carried out on a multicenter prospective GEICO cohort of EOC patients with known gBRCA status in order to determine the inter-laboratory reproducibility of tissue sBRCA testing. The study consisted of two independent experimental approaches, a bilateral comparison between two reference laboratories (RLs) testing 82 formalin-paraffin-embedded (FFPE) EOC samples each, and a Ring Test Trial (RTT) with five participating clinical laboratories (CLs) evaluating the performance of tissue BRCA testing in a total of nine samples. Importantly, labs employed their own locally adopted next-generation sequencing (NGS) analytical approach. BRCA mutation frequency in the RL sub-study cohort was 23.17%: 12 (63.1%) germline and 6 (31.6%) somatic. Concordance between the two RLs with respect to BRCA status was 84.2% (gBRCA 100%). The RTT study distributed a total of nine samples (three commercial synthetic human FFPE references, three FFPE, and three OC DNA) among five CLs. The median concordance detection rate among them was 64.7% (range: 35.3-70.6%). Analytical discrepancies were mainly due to the minimum variant allele frequency thresholds, bioinformatic pipeline filters, and downstream variant interpretation, some of them with consequences of clinical relevance. Our study demonstrates a wide range of concordance in the identification and interpretation of BRCA sequencing data, highlighting the relevance of establishing standard criteria for detecting, interpreting, and reporting BRCA variants.

A genome-wide cell-free DNA methylation analysis identifies an episignature associated with metastatic luminal B breast cancer.

Breast cancers of the luminal B subtype are frequent tumors with high proliferation and poor prognosis. Epigenetic alterations have been found in breast tumors and in biological fluids. We aimed to profile the cell-free DNA (cfDNA) methylome of metastatic luminal B breast cancer (LBBC) patients using an epigenomic approach to discover potential noninvasive biomarkers. Plasma cfDNA was analyzed using the Infinium MethylationEpic array in a cohort of 14 women, including metastatic LBBC patients and nontumor controls. The methylation levels of cfDNA and tissue samples were validated with droplet digital PCR. The methylation and gene expression data of 582 primary luminal breast tumors and 79 nontumor tissues were obtained from The Cancer Genome Atlas (TCGA). We found an episignature of 1,467 differentially methylated CpGs that clearly identified patients with LBBC. Among the genes identified, the promoter hypermethylation of WNT1 was validated in cfDNA, showing an area under the ROC curve (AUC) of 0.86 for the noninvasive detection of metastatic LBBC. Both paired cfDNA and primary/metastatic breast tumor samples showed hypermethylation of WNT1. TCGA analysis revealed significant WNT1 hypermethylation in the primary tumors of luminal breast cancer patients, with a negative association between WNT1 methylation and gene expression. In this proof-of-principle study, we discovered an episignature associated with metastatic LBBC using a genome-wide cfDNA methylation approach. We also identified the promoter hypermethylation of WNT1 in cfDNA as a potential noninvasive biomarker for luminal breast cancer. Our results support the use of EPIC arrays to identify new epigenetic noninvasive biomarkers in breast cancer.

Use of image analysis to evaluate morphometric measurements of broiler breast fillets affected by the woody breast condition.

The objective of this study was to investigate the relationships between morphometric measurements and woody breast (WB) severity in breast fillets using image processing as an objective detection method for WB. Breast fillets were collected and categorized as normal (NORM), mild (MILD), moderate (MOD), and severe (SEV). Compression force and energy increased as WB severity increased alongside a decrease in severity through fillet regions (P < 0.05). Length and caudal thickness were highest in SEV and MOD groups (P < 0.05), and cranial thickness increased as WB severity increased (P < 0.05). The aerial area was the smallest in NORM fillets, while the planar area increased from NORM to MOD (P < 0.05). Fillet curvatures were highest in SEV and MOD fillets (P < 0.05). All measured parameters expressed strong correlation to WB scores (P < 0.05) except width. The results from this study may provide a basis for further assessment of the potential incorporation of these measurements into vision grading systems that may allow processors to sort fillets by WB severity in commercial plants. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-022-05525-x.

Improving the Management of Endometrial Cancer Patients through the Use of Liquid Biopsy Analyses: A Case Report.

Endometrial cancer (EC) is the 4th most common neoplasm of the female genital tract, with 15-20% of patients being of high risk of recurrence which leads to a significant decrease in patient survival. Current therapeutic options for patients with EC are poor, being the combined therapy of carboplatin and paclitaxel the standard of care, with limited efficacy. Therefore, new therapeutic options and better monitoring tools are needed to improve the management of the disease. In the current case report, we showcase the value of liquid biopsy analyses in a microsatellite instability EC patient with initially good prognosis that however underwent rapid progression disease within 6 months post-surgery; through the study of plasma cfDNA/ctDNA dynamics to assess the tumour evolution during treatment, as well as the study of the uterine aspirate as a valuable sample that captures the intra-tumour heterogeneity that allows a comprehensive genomic profiling of the disease to identify potential therapeutic options. Furthermore, preclinical models were generated at the time of tumour progression to assess the efficacy of the identified targeted therapies.

Assessment of meat quality distributions of breast fillets with woody breast condition in the raw and cooked state.

The objective of this study was to determine meat quality distributions and assess hardness distributions in raw and cooked breast fillets with the woody breast (WB) condition, in addition to evaluating the relationship between water properties and WB severity. A total of 90 breast fillets were collected and categorized as normal (NORM), mild (MILD) and severe (SEV). Breast weight, drip loss, compression measurements, cook loss, shear and texture profile analysis (TPA) values were measured for each sample by fillet location (cranial to caudal) and sampling depth (cranial-superficial, cranial-internal, middle-superficial, and middle-internal) in the raw and cooked meat state. Low-field NMR relaxation measurements were also collected for both the raw and cooked fillets. Results indicate that severe WB expressed increased hardness, a higher water content (bound water and free water) and reduced meat quality attributes in raw and cooked meat. Breast fillet hardness and meat quality distributions were unevenly distributed between fillets, compression measurements were higher mainly in the cranial region, and progressively decreased toward the caudal region for both raw and cooked fillets. Shear force and energy values were higher in the cranial region than in the middle region, and TPA values were higher in superficial regions rather than internal portions. Additionally, low-field NMR could be used to predict WB through variation in water properties as thermal processing reduces water distributing abilities in affected fillets.

Quality properties of chicken meatballs prepared with varying proportions of woody breast meat.

The objective of this study was to explore the effect of woody breast (WB) on quality characteristics of chicken meatballs paired with the feasibility of its inclusion. Cook loss (CL), color (CIE L*, a*, b*), texture (hardness, springiness, chewiness and resilience), low-field NMR (bound water, immobilized water, and free water), microstructure, and sensory characteristics of chicken meatballs with different WB inclusion levels (0%, 25%, 50%, 75%, 100%) were analyzed. The results showed that the impairment of product quality traits such as CL, color, texture (hardness, chewiness), free water, microstructure, and sensory scores (appearance, organization, total score) increased as the percentage of WB meat increased in the product formulation, particularly when the WB incorporation level exceeded 25%. Indeed, cook loss, L*, a*, b* parameters, bound water, and immobilized water increased when the WB inclusion level was higher than 25% (P ≤ 0.05). However, free water, sensory characteristics, hardness, and chewiness parameters decreased (P ≤ 0.05). The microstructure of chicken meatballs also changed as the proportion of WB meat increased. Even though data suggest that the inclusion of WB meat up to 30% could be feasible to produce acceptable chicken meatballs, the optimal maximum incorporation rate of WB meat into chicken meatball recipes was 25% based on economic feasibility and final overall quality.

Meat quality traits and Blunt Meullenet-Owens Razor Shear characteristics of broiler breast fillets affected by woody breast condition and post-cooking meat temperature.

This study aimed to investigate meat quality attributes, cooking performance, and water properties of woody breast (WB). A total of 48 broiler breast fillets (7 wk, 3 h debone) of 24 normal (NORM) and 24 severe WB (SEV) were collected. Raw meat characteristics (L*, a*, b*, pH, compression force and energy and) along with the blunt blade of the Meullenet-Owens razor shear (BMORS) properties were determined. Cooking time and internal meat temperature were recorded for each fillet every 5 min on each fillet during cooking. Water/moisture properties and shear values of BMORS were determined at different meat temperatures (HOT [68°C], AMBIENT [22°C] and COLD [4°C]) after cooking. SEV fillets showed higher L*, a*, b*, pH, CF, CE, BMORS force, BMORS energy, and peak counts of BMORS values compared to NORM fillets in raw state (P < 0.05). Cooking time was shorter in SEV fillets than NORM fillets (P < 0.0001). Cook loss, total water loss, and moisture loss (HOT, AMBIENT) were greater in SEV fillets than NORM fillets (P < 0.01). PC-BMORS were greater in SEV fillets than NORM fillets (P < 0.05), and all BMORS shear values increased as post-cooking meat temperature decreased (P < 0.05). Positive correlations were observed between WB scores and raw meat characteristics and shear values. There were also significant relationships (P < 0.001) between WB scores and cooking performance measures except moisture loss for COLD treatment. BMORS force and energy were moderately correlated to total water loss, cook loss, and moisture loss (HOT) regardless of meat temperature (P < 0.05); however, PC-BMORS was only correlated to total water loss at COLD and moisture loss (HOT) at all meat temperatures (P < 0.05). These data corroborate the association of WB condition with impaired quality/texture characteristics in raw and cooked fillets; WB also had a significant impact on cooking time, cooking at a faster rate, along with water/moisture loss during and after thermal processing. Results demonstrate that the post-cooking meat temperature plays an important role in shear test values.

Short-Term Ex Vivo Culture of CTCs from Advance Breast Cancer Patients: Clinical Implications.

BACKGROUND: Circulating tumor cells (CTC) have relevance as prognostic markers in breast cancer. However, the functional properties of CTCs or their molecular characterization have not been well-studied. Experimental models indicate that only a few cells can survive in the circulation and eventually metastasize. Thus, it is essential to identify these surviving cells capable of forming such metastases. METHODS: We isolated viable CTCs from 50 peripheral blood samples obtained from 35 patients with advanced metastatic breast cancer using RosetteSepTM for ex vivo culture. The CTCs were seeded and monitored on plates under low adherence conditions and with media supplemented with growth factors and Nanoemulsions. Phenotypic analysis was performed by immunofluorescence and gene expression analysis using RT-PCR and CTCs counting by the Cellsearch® system. RESULTS: We found that in 75% of samples the CTC cultures lasted more than 23 days, predicting a shorter Progression-Free Survival in these patients, independently of having ≥5 CTC by Cellsearch®. We also observed that CTCs before and after culture showed a different gene expression profile. CONCLUSIONS: the cultivability of CTCs is a predictive factor. Furthermore, the subset of cells capable of growing ex vivo show stem or mesenchymal features and may represent the CTC population with metastatic potential in vivo.

Instrumental texture analysis of chicken patties prepared with broiler breast fillets exhibiting woody breast characteristics.

Potential applications of chicken meat with the woody breast (WB) condition in further processed products could provide processors with alternatives to deal with this meat quality problem. The objective of this study was to evaluate the effect of the use of broiler breast fillets at varying degrees of WB severity and proportions on instrumental texture characteristics of chicken patties. A total of 54 breast fillets were collected from broilers processed as per commercial practices, previously classified based on tactile evaluation in 3 WB categories (normal [NOR]; mild [MIL], and severe [SEV]). Instrumental compression analysis was performed to validate subjective scores. Nine treatments with 6 replicates of chicken patties were prepared: 100% NOR (T1), 67% NOR + 33% MIL (T2), 67% NOR + 33% SEV (T3), 33% NOR + 67% MIL (T4), 33% NOR + 67% SEV (T5), 100% MIL (T6), 67% MIL + 33% SEV (T7), 33% MIL + 67% SEV (T8), and 100% SEV (T9). Instrumental texture profile analysis along with cook loss, color, and dimensional changes was evaluated in cooked patties. Compared with normal samples and excluding treatments T2 and T4, hardness, springiness, and chewiness values of chicken patties decreased (P < 0.05) as WB severity increased in the meat incorporated into the formulation. Patties prepared using mixtures of MIL and SEV fillets (T7 and T8) including T9 had higher levels of cook loss (>26%, P < 0.05) accompanied by significant reductions in diameter (>16%, P < 0.05) and distinguishable color changes (ΔE∗ab > 2) than normal patties. These data suggest that the potential use of WB meat in chicken patties is associated with the degree of WB severity and the incorporation rate. The inclusion of WB fillets at high levels into this product is not recommended owing to their poor functionality. However, feasible mixtures of normal breast fillets with those affected by WB myopathy at relatively low proportions could be considered by processors as an alternative in commercial chicken patty formulations.

Detection of woody breast condition in commercial broiler carcasses using image analysis.

Image analysis could be an objective and rapid method to identify woody breast (WB) myopathy and benefit the global poultry industry. The objective of this study was to determine if there are conformational changes that can be used to detect WB characteristics in commercial broiler carcasses across strains, gender, and ages using image analysis. A total of 900 images of male and female broiler carcasses from commercial standard and high breast-yielding strains and 5 ages (6 through 10 wk) were captured before evisceration. These images were processed and analyzed using ImageJ software. Conformational measurements were M0: breast length; M1: breast width in the cranial region; M2: vertical line from the tip of keel to 1/5th of breast length; M3: breast width at the end of M2; M4: angle formed at the tip of keel and extending to outer points of M3; M5: area of the triangle formed by M3 and lines generated by M4; M6: area of the breast above M3; M7: M6 minus M5. Ratios of these measurements were also considered. Intact breast fillets were scored for WB severity based on tactile evaluation. Regardless of strain, sex, and age, M11 (M1/M0), M9 (M3/M2), and M4 had the highest correlation to WB score (rs ≥ 0.65; P < 0.01). Overall, the best validated model (Gen. R2 = 0.61) to predict WB included M1, M2, and M3. Using this model, 91% of broiler carcasses were properly classified as normal or WB along with a sensitivity of 71% to detect affected carcasses. Although the predictive performance of models for detecting the WB condition using these measurements was associated with the broiler strain, sex, and age or live weight, these data also support the feasibility of using image analysis to predict WB defect in broiler carcasses. The possible integration of these image measurements into commercial noncontact, nondestructive, and fast in-line vision grading systems would allow processors to identify broilers with WB and potentially sort, provide large-scale information downstream to further processing operations and upstream to live production.

Use of image analysis to identify woody breast characteristics in 8-week-old broiler carcasses.

Woody breast (WB) condition causes significant economic losses to the global poultry industry, and the lack of an objective and fast tool to identify this myopathy is a contributing factor. The aim of this study was to determine if there are broiler carcass conformation changes that can be used to identify WB characteristics using image analysis. Images of 8-wk-old male broiler carcasses (n = 544) of high breast-yielding strains were captured before evisceration, which were processed and analyzed using ImageJ software. Measurements were as follows: M0, breast length; M1, breast width in the cranial region; M2, one-fifth of the breast length starting at the tip of keel; M3, breast width at the end of M2; M4, angle formed at the tip of keel and extending to outer points of M3; M5, area of the triangle formed by M3 and lines generated by M4; M6, area of the breast above M3; and M7, M6 minus M5. Ratios of these measurements were also considered. Whole breast fillets were scored for WB severity based on tactile assessment and compression analysis to correlate them. Spearman's correlation coefficient (rs) between WB scores and compression force was highly significant (rs = 0.83, P < 0.01). Measurements M4 and M3 as well as ratios M9 (M3/M2) and M11 (M1/M0) had the highest correlation to the WB score (rs ≥ 0.70; P < 0.01) and compression force (rs ≥ 0.64; P < 0.01). The best validated model (generalized [Gen.] R2 = 0.60) to predict WB included M1, M2, and M3. Using this model, 84% of broiler carcasses were correctly classified as WB or normal with a sensitivity of 82% to detect affected samples. Alternatively, M4 and M6 as well as ratios M9 and M11 could be considered as predictors in different models (Gen. R2 ≥ 0.56). The same predictors were significant to estimate compression force (Gen. R2 ≥ 0.49). These data support the use of image analysis to predict WB condition in broiler carcasses. The potential integration of these image measurements into commercial in-line vision grading systems would allow processors to sort broiler carcasses by WB severity.

An olaparib window-of-opportunity trial in patients with early-stage endometrial carcinoma: POLEN study.

OBJECTIVE: Olaparib is a potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1, 2, and 3 with potential activity in endometrial cancer (EC). METHODS: In this window-of-opportunity trial, women with operable type 1 EC received olaparib oral tablets (300mg) twice daily for 28days before surgery. The primary objective was to evaluate the effects of olaparib on EC in tissue samples taken at baseline and at treatment completion. Signal of activity was defined as significant changes in the expression of the cell cycle-related proteins cyclin D1, Ki67, and cleaved caspase-3. RESULTS: A total of 31 patients were included in the biomarker analysis. The median time of olaparib exposure was 24 days (1-39). Significant inhibition was found for cyclin D1 (p < 0.01), but not for Ki67 and active caspase 3 immunostaining. PARP-1 levels positively correlated with cyclin D1 levels (rho = 0.661, p = 0.0001). Both PARP-1 and cyclin D1 levels were significantly lower (p = 0.022 and p = 0.004, respectively) in patients with ARID1A[-] tumors than ARID1A[+] tumors. A significant relationship between plasma olaparib concentrations and decreased GLUT1 activity was observed (r = -0.5885; p < 0.05). Drug-related toxicity consisted mostly of gastrointestinal and grade 1 or 2 adverse events. CONCLUSIONS: Olaparib reduced expression of cyclin D1, which positively correlated with PARP-1 levels. This effect was more evident in ARID1A-deficient tumors. Olaparib further induced inhibition of GLUT1 plasma activity. Our findings could have noteworthy implications in predicting which patients with EC would benefit from olaparib-based strategies.

A review on the woody breast condition, detection methods, and product utilization in the contemporary poultry industry.

In recent years, the global poultry industry has been facing increasing and challenging myopathies such as the woody breast (WB) condition that has caused significant economic losses. Even though the etiological causes of WB myopathy are still unknown or partially understood, the intensive genetic selection for rapid-growth rates and high yields in broilers may be the main factor associated with the development of this abnormality. The severity of this anomaly and its incidence rates are associated with fast-growing and heavier broilers, especially with those from high breast yielding strains. Such WB myopathy is primarily characterized by a notorious hardness in broiler breast muscles, which exhibit morphometric and histopathological alterations coupled with physicochemical abnormalities that result in undesired sensory, nutritional, and technological properties. In this negative context, although scientists are trying to solve or reduce the prevalence of this meat quality problem, the poultry industry needs noncontact and rapid in-line methods for WB detection at the fillet and/or carcass level that could help to establish automated objective grading or sorting systems according to its severity. Another need is the development and selection of profitable alternatives for the utilization of WB meat once poultry carcasses or deboned fillets affected by this abnormality are objectively detected and sorted. Indeed, there is a need for studies to expand the industrial applications of WB meat in further processed products, optimizing the incorporation of this affected chicken meat based on sensorial, technological, and nutritional profile evaluations. Even though a better understanding of the contribution of genetic and nongenetic factors to the development of growth-related myopathies can be the main strategy to mitigate their negative effects, the poultry industry could benefit from meeting the aforementioned needs.

Analysis of a Real-World Cohort of Metastatic Breast Cancer Patients Shows Circulating Tumor Cell Clusters (CTC-clusters) as Predictors of Patient Outcomes.

Circulating tumor cell (CTC) enumeration has emerged as a powerful biomarker for the assessment of prognosis and the response to treatment in metastatic breast cancer (MBC). Moreover, clinical evidences show that CTC-cluster counts add prognostic information to CTC enumeration, however, their significance is not well understood, and more clinical evidences are needed. We aim to evaluate the prognostic value of longitudinally collected single CTCs and CTC-clusters in a heterogeneous real-world cohort of 54 MBC patients. Blood samples were longitudinally collected at baseline and follow up. CTC and CTC-cluster enumeration was performed using the CellSearch® system. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using Cox proportional hazards modelling. Elevated CTC counts and CTC-clusters at baseline were significantly associated with a shorter survival time. In joint analysis, patients with high CTC counts and CTC-cluster at baseline were at a higher risk of progression and death, and longitudinal analysis showed that patients with CTC-clusters had significantly shorter survival compared to patients without clusters. Moreover, patients with CTC-cluster of a larger size were at a higher risk of death. A longitudinal analysis of a real-world cohort of MBC patients indicates that CTC-clusters analysis provides additional prognostic value to single CTC enumeration, and that CTC-cluster size correlates with patient outcome.