Rechallenge with Anti-EGFR Treatment in RAS/BRAF wt Metastatic Colorectal Cancer (mCRC) in Real Clinical Practice: Experience of the GITuD Group.

BACKGROUND: There are few third- and fourth-line therapeutic options for metastatic colorectal cancer (mCRC). In RAS/BRAF wild-type (wt) mCRC previously treated with anti-epidermal growth factor receptor (anti-EGFR) (first-line) and relapsed after a good response, retreatment with anti-EGFR (rechallenge) emerges as a therapeutic alternative. OBJECTIVE: The aim was to show the activity and safety of anti-EGFR rechallenge in RAS/BRAF wt mCRC in real-world practice. PATIENTS AND METHODS: A multicenter, retrospective, observational study (six hospitals of the Galician Group of Research in Digestive Tumors) was conducted. Adult patients with RAS/BRAF wt mCRC, evaluated by liquid biopsy, were included. They received anti-EGFR rechallenge (cetuximab, panitumumab) as monotherapy, or combined with chemotherapy, in third- or subsequent lines. Efficacy (overall response rate [ORR], disease control rate [DCR], overall survival [OS], and progression-free survival [PFS]) and safety (incidence of adverse events [AEs]) were assessed. RESULTS: Thirty-one patients were analyzed. Rechallenge (median 6 cycles [range 1-27], mainly cetuximab [80.7%]), started at a median anti-EGFR-free time of 18.4 months (1.7-37.5 months) after two (38.7%) or more (61.3%) lines of treatment; 64.5% of patients received a full dose. Median OS and PFS were 9.8 months (95% confidence interval [CI] 8.2-11.4) and 2.6 months (95% CI 1.7-3.4), respectively. ORR was 10%, and DCR was 30%. The most common AEs were diarrhea (35.5%), anemia (29%), emesis (6.4%), and neutropenia (6.4%); < 5% grade ≥ 3; 48.4% of patients reported anti-EGFR-related skin toxicity (grade > 1). Hypomagnesemia required supplements in 29% of patients. Dose delays (≥ 3 days) and reduction (≥ 20%) were reported in 11 (35.5%) and seven patients (22.6%), respectively. CONCLUSIONS: In RAS/BRAF wt mCRC patients, an anti-EGFR rechallenge provides a feasible therapeutic option with clinical benefit (survival) and a manageable safety profile.

Sequential RAS mutations evaluation in cell-free DNA of patients with tissue RAS wild-type metastatic colorectal cancer: the PERSEIDA (Cohort 2) study.

PURPOSE: RAS (KRAS/NRAS) mutational status on a tumor biopsy is mandatory to guide the best treatment in metastatic colorectal cancer (mCRC). Determining the RAS mutational status by tumor-tissue biopsy is essential in guiding the optimal treatment decision for mCRC. RAS mutations are negative predictive factors for the use of EGFR monoclonal antibodies. Cell-free DNA (cfDNA) analysis enables minimally invasive monitoring of tumor evolution. METHODS/PATIENTS: PERSEIDA was an observational, prospective study assessing cfDNA RAS, BRAF and EGFR mutations (using Idylla™) in first-line mCRC, RAS wild-type (baseline tumor-tissue biopsy) patients (cohort 2). Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. RESULTS: 117 patients were included (103 received panitumumab + chemotherapy as first-line treatment). At baseline, 7 (6.8%) patients had RAS mutations, 4 (3.9%) BRAF mutations and no EGFR mutations were detected (cfDNA, panitumumab + chemotherapy subpopulation [panitumumab + Ch]). The baseline RAS mutational status concordance between tissue and liquid biopsies was 94.0% (93.2%, panitumumab + Ch). At 20 weeks, only one patient in the study (included in the panitumumab + Ch) had an emerging cfDNA RAS mutation. No emerging BRAF or EGFR mutations were reported. At disease progression, 6 patients had emergent mutations not present at baseline (RAS conversion rate: 13.3% [6/45]; 15.0% [6/40], panitumumab + Ch). CONCLUSIONS: The concordance rate between liquid and solid biopsies at baseline was very high, as previously reported, while our results suggest a considerable emergence of RAS mutations during disease progression. Thus, the dynamics of the genomic landscape in ctDNA may provide relevant information for the management of mCRC patients.

Advanced Lipoproteins and Lipidomic Profile in Plasma Determined by Nuclear Magnetic Resonance Before and After Bariatric Surgery.

BACKGROUND: Obesity is related to cardiovascular risk factors (CVRF) such as dyslipidemia, diabetes, and hypertension, which increase mortality. Basic lipid determinations could underestimate the true atherogenic risk of patients and the impact of bariatric surgery. The objective of the study is to demonstrate the change in the advanced molecular profile of lipoproteins determined by nuclear magnetic resonance spectroscopy in plasma after bariatric surgery, thus reducing the risk of cardiovascular disease. MATERIAL AND METHODS: Descriptive, observational, and prospective study in obese patients undergoing bariatric surgery. Advanced lipid profile was analyzed in plasma from the immediate preoperative period and at the 18th postoperative month by sending samples and performing plasma magnetic resonance spectroscopy in the BiosferTreslab® laboratory. RESULTS: Fifty-two patients were included. Average age of 46.3 years; 63.46% were women, 36.54% men. The average BMI was 43.57; the abdominal perimeter 133.50 cm; 32.6% were diabetics under medical treatment, 44.23% hypertensive, and 19.23% smokers; 86.53% of the patients presented alterations in at least one of the analytical parameters in the lipid study. Twenty-nine (55.7%) underwent banded gastric bypass (PGB), 19.23% underwent GBP, and 17.31% vertical gastrectomy. The rest were revision surgeries, two BPG-A and two biliopancreatic diversions after GV. All patients presented some improvement in advanced molecular profile of lipoproteins. Twenty percent of the patients normalized all the parameters. CONCLUSIONS: Bariatric surgery improves advanced molecular profile of lipoproteins, decreasing CVRF. Analysis of the characteristics of lipoprotein particles by NMR spectrometry is optimal for studying lipoprotein metabolism in patients undergoing bariatric surgery.

Strategies for Drug Delivery into the Brain: A Review on Adenosine Receptors Modulation for Central Nervous System Diseases Therapy.

The blood-brain barrier (BBB) is a biological barrier that protects the central nervous system (CNS) by ensuring an appropriate microenvironment. Brain microvascular endothelial cells (ECs) control the passage of molecules from blood to brain tissue and regulate their concentration-versus-time profiles to guarantee proper neuronal activity, angiogenesis and neurogenesis, as well as to prevent the entry of immune cells into the brain. However, the BBB also restricts the penetration of drugs, thus presenting a challenge in the development of therapeutics for CNS diseases. On the other hand, adenosine, an endogenous purine-based nucleoside that is expressed in most body tissues, regulates different body functions by acting through its G-protein-coupled receptors (A1, A2A, A2B and A3). Adenosine receptors (ARs) are thus considered potential drug targets for treating different metabolic, inflammatory and neurological diseases. In the CNS, A1 and A2A are expressed by astrocytes, oligodendrocytes, neurons, immune cells and ECs. Moreover, adenosine, by acting locally through its receptors A1 and/or A2A, may modulate BBB permeability, and this effect is potentiated when both receptors are simultaneously activated. This review showcases in vivo and in vitro evidence supporting AR signaling as a candidate for modifying endothelial barrier permeability in the treatment of CNS disorders.

Post-Chemoradiation Metastatic, Persistent and Resistant Nodes in Locally Advanced Rectal Cancer: Metrics and Their Impact on Long-Term Outcome.

BACKGROUND: The purpose of this study was to evaluate the long-term oncological progression pattern of locally advanced rectal cancer patients with post-neoadjuvant nodal metastatic disease (ypN+) and correlate potential prognostic features associated with proven radiochemoresistant nodal biology. METHODS: Individual patient data (100 variables) from a 20-year consecutive single-institution multidisciplinary experience (1995-2015), delivering multimodal therapy to rectal cancer patient candidates for radical treatment, including a neoadjuvant component and surgical resection with or without intraoperative radiotherapy followed by optional adjuvant chemotherapy. The ypN+ disease data was registered in the context of initial staging categories post-neoadjuvant T status (ypT). RESULTS: Data on 487 patients showed histologically confirmed diagnoses of metastatic nodal disease in 108 specimens (ypN+, 22.1). There was a significant age difference (p = 0.009) between the ypN groups: age ≥ 65 was 57.6% in pN0 and 43.5% in ypN+ and patients aged < 65 constituted 42.4% of pN0 and 56.5% of ypN+. According to the clinical stage there were statistically significant differences (p = 0.001) in the categories' distribution: ypN+ patients 10.8% were stage II and 89.2% were stage III. Univariant analysis on outcome variables showed statistically significant differences in overall survival at 7 years (63.8% vs. 55.7%, p = 0.016) disease-free survival (DFS) (78% vs. 53.8%, p = 0.000) and local recurrence-free survival (LRFS) (93.6% vs. 84%, p = 0.002). CONCLUSIONS: The presence of nodal metastases (ypN+) after neoadjuvant therapy containing long-course pelvic irradiation severely impacts the long-term outcome for patients with locally advanced rectal cancer and correlates with multiple clinical and therapeutic variable metrics. Implementation of local and systemic therapies should be adapted and intensified in relation to the finding of ypN+ category in surgical specimens.

Intra-individual variability in the neuroprotective and promyelinating properties of conditioned culture medium obtained from human adipose mesenchymal stromal cells.

BACKGROUND: Greater knowledge of mesenchymal stromal cell (MSC)-based therapies is driving the research into their secretome, identified as the main element responsible for their therapeutic effects. The aim of this study is to characterize the individual variability of the secretome of adipose tissue-derived MSCs (adMSCs) with regard to potential therapeutical applications in neurology. METHODS: adMSCs were isolated from the intact adipose tissue of ten subjects undergoing abdominal plastic surgery or reduction mammoplasty. Two commercial lines were also included. We analyzed the expansion rate, production, and secretion of growth factors of interest for neurological applications (VEGF-A, BDNF, PDGF-AA and AA/BB, HGF, NGF, FGF-21, GDNF, IGF-I, IGF-II, EGF and FGF-2). To correlate these characteristics with the biological effects on the cellular targets, we used individual media conditioned with adMSCs from the various donors on primary cultures of neurons/astrocytes and oligodendrocyte precursor cells (OPCs) exposed to noxious stimuli (oxygen-glucose deprivation, OGD) to evaluate their protective and promyelinating properties, using MSC medium as a control group. RESULTS: The MSC secretome showed significant individual variability within the considered population with regard to PDGF-AA, PDGF-AB/BB, VEGF-A and BDNF. None of the MSC-derived supernatants affected neuron viability in normoxia, while substantial protection by high BDNF-containing conditioned MSC medium was observed in neuronal cultures exposed to OGD conditions. In OPC cultures, the MSC-derived supernatants protected cells from OGD-induced cell death, also increasing the differentiation in mature oligodendrocytes. Neuroprotection showed a positive correlation with VEGF-A, BDNF and PDGF-AA concentrations in the culture supernatants, and an inverse correlation with HGF, while OPC differentiation following OGD was positively correlated to PDGF-AA concentration. CONCLUSIONS: Despite the limited number of adMSC donors, this study showed significant individual variability in the biological properties of interest for neurological applications for adMSC secretome, an under-researched aspect which may represent an important step in the translation of MSC-derived acellular products to clinical practice. We also showed the potential protection capability of MSC conditioned medium on neuronal and oligodendroglial lineages exposed to oxygen-glucose deprivation. These effects are directly correlated to the concentration of specific growth factors, and indicate that the remyelination should be included as a primary target in MSC-based therapies.

Incidence, risk factors, and evolution of venous thromboembolic events in patients diagnosed with pancreatic carcinoma and treated with chemotherapy on an outpatient basis.

BACKGROUND: Pancreatic carcinoma is one of the tumors associated with a higher risk for thromboembolic events, with incidence rates ranging from 5% to 41% in previous retrospective series. PATIENTS AND METHODS: We conducted a retrospective study in eleven Spanish hospitals that included 666 patients diagnosed with pancreatic carcinoma (any stage) between 2008 and 2011 and treated with chemotherapy. The main objective was to evaluate the incidence of venous thromboembolic events (VTE) in this population, as well as potential risk factors for thrombosis. The impact of VTE on mortality was also assessed. RESULTS: With a median follow-up of 9.3 months, the incidence of VTE was 22.1%; 52% were diagnosed incidentally. Our study was unable to confirm the ability of the Khorana score to discriminate between patients in the intermediate or high risk category for thrombosis. The presence of VTE proved to be an independent prognostic factor associated with increased risk of death (HR 2.39, 95% CI 1.96-2.92). Symptomatic events correlated with higher mortality than asymptomatic events (HR 1.72; 95% CI, 1.21-2.45; p = 0.002), but incidental VTE, including visceral vein thrombosis (VVT), negatively affected survival compared to patients without VTE. Subjects who developed VTE within the first 3 months of diagnosis of pancreatic carcinoma had lower survival rates than those with VTE after 3 months (HR 1.92, 95% CI 1.30-2.84; p<0.001). CONCLUSIONS: Pancreatic carcinoma is associated with a high incidence of VTE, which, when present, correlates with worse survival, even when thrombosis is incidental. Early onset VTE has a particularly negative impact.

Efficacy and safety of FOLFIRI/aflibercept (FA) in an elderly population with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin-based regimen.

BACKGROUND: The VELOUR study showed the benefit of FOLFIRI-Aflibercept (FA) versus FOLFIRI in patients with metastatic colorectal cancer (mCRC) in second-line treatment. However, only 36% of the included patients were ≥65 years. Thus, we seek to evaluate the efficacy and safety of FA in the elderly population in the context of routine practice. MATERIALS AND METHODS: We conducted an observational, retrospective, multicenter, observational study of patients ≥70 years with mCRC treated with FA after progression to oxaliplatin chemotherapy in routine clinical practice in 9 hospitals of the GITuD group. RESULTS: Of 388 patients treated with FA between June 2013 and November 2018, 75 patients ≥70 years were included. The median number of cycles was 10 and the objective response (ORR) and disease control rates (DCR) were 33.8% and 72.0%, respectively. With a median follow-up of 27.1 months, median Progression-free survival (PFS) was 6.6 months and median Overall Survival (OS) was 15.1 months. One third fewer metastasectomies were performed in the ≥75 years' subgroup (24 vs. 52%, p = 0.024) and more initial FOLFIRI dose reductions (68 vs. 36%, p = 0.014). ORR (23.8% vs. 38.3%), DCR (42.8% vs. 85.1%), and PFS (4 vs. 7.8 months; p = 0.017) were significantly less, without difference in OS (9.9 vs. 17.1 months; p = 0.129). The presence of prior hypertension (HT) (PFS 7.9 vs. 5.7 months, p = 0.049) and HT ≥ grade 3 during treatment (PFS 7.6 vs. 6.6 months, p = 0.024) were associated with longer PFS. The most frequent grade 3/4 adverse events were: asthenia (21.3%), neutropenia (14.7%), and diarrhea (14.7%). 57.3% required FOLFIRI dose reduction; 34.7% of aflibercept, including discontinuation (5.3% and 18.7%, respectively). CONCLUSIONS: FA combination is effective in patients ≥70 years. The occurrence of HT is predictive of efficacy. Close monitoring of toxicity and initial dose adjustment is recommended.

Immune translational control by CPEB4 regulates intestinal inflammation resolution and colorectal cancer development.

Upon tissue injury, cytokine expression reprogramming transiently remodels the inflammatory immune microenvironment to activate repair processes and subsequently return to homeostasis. However, chronic inflammation induces permanent changes in cytokine production which exacerbate tissue damage and may even favor tumor development. Here, we address the contribution of post-transcriptional regulation, by the RNA-binding protein CPEB4, to intestinal immune homeostasis and its role in inflammatory bowel diseases (IBD) and colorectal cancer (CRC) development. We found that intestinal damage induces CPEB4 expression in adaptive and innate immune cells, which is required for the translation of cytokine mRNA(s) such as the one encoding interleukin-22. Accordingly, CPEB4 is required for the development of gut-associated lymphoid tissues and to maintain intestinal immune homeostasis, mediating repair and remodeling after acute inflammatory tissue damage and promoting the resolution of intestinal inflammation. CPEB4 is chronically overexpressed in inflammatory cells in patients with IBD and in CRC, favoring tumor development.

Retrospective Analysis of Patients with Gynaecological Uterine Sarcomas in a Tertiary Hospital.

Uterine sarcomas are rare and heterogeneous malignancies accounting for 1% to 3% of all gynaecological tumours. There are many histological subtypes recognised, including leiomyosarcomas, endometrial stromal sarcoma, and uterine carcinosarcoma, although the latest has been recently discarded in this group. Despite its low incidence, these types of cancer currently entail multiple challenges, either in diagnostics or clinical management, with a poor prognosis associated. The present work aimed to complete a comparative analysis of the different histological subtypes based on the clinicopathological characteristics of our population, the therapeutic characteristics, and associated prognosis in 161 patients treated in our centre during the period between 1985 and 2020. Moreover, a systematic review grouped a total of 2211 patients with a diagnosis of uterine sarcoma from 19 articles published in 16 countries from 2002 to 2021 was performed, all with retrospective analyses. Our results showed that apart from uterine carcinosarcoma, leiomyosarcoma is the most frequent subtype of uterine sarcoma, with unique clinical, demographic, and survival parameters. To our knowledge, this is the first systematic review conducted in this field and, thus, it shows the difficulties of collecting a significant number of patients per year, a valid reason why multicentre or national registries are recommended to allow a more exhaustive analysis of this pathology.

Ductular reaction promotes intrahepatic angiogenesis through Slit2-Roundabout 1 signaling.

BACKGROUND AND AIMS: Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in the wound-healing response of the liver, promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis. In the current study we investigated the potential contribution of DR cells to hepatic vascular remodeling during chronic liver disease. APPROACH AND RESULTS: In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis-related genes, the expression of Slit2 and its receptor Roundabout 1 (Robo1) was localized in DR cells and neoangiogenic vessels, respectively. The angiogenic role of the Slit2-Robo1 pathway in chronic liver disease was confirmed in ROBO1/2-/+ mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which displayed reduced intrahepatic neovascular density compared to wild-type mice. However, ROBO1/2 deficiency did not affect angiogenesis in partial hepatectomy. In patients with advanced alcohol-associated disease, angiogenesis was associated with DR, and up-regulation of SLIT2-ROBO1 correlated with DR and disease severity. In vitro, human liver-derived organoids produced SLIT2 and induced tube formation of endothelial cells. CONCLUSIONS: Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2-Robo1 pathway and recognize DR cells as key players in the liver wound-healing response.

Translational Control in Liver Disease.

Chronic liver disease is one of the biggest threats to public health worldwide. Worryingly, the incidence of liver disease is dramatically rising due to the aging of the population and the global epidemics of obesity. Both are major risk factors for chronic liver disease and adverse prognostic factors, causing an increase in mortality rate. It is of great concern that 80-95% of obese people have non-alcoholic fatty liver disease, the major precursor for liver failure and a global health challenge. Currently, the only curative treatment for advanced chronic liver disease is liver transplantation, which is, however, hampered by high treatment costs and the scarcity of donor organs. New strategies are therefore urgently needed to prevent and reverse chronic liver disease. And for that it is essential to understand better the molecular mechanisms underlying human disease. This review focuses on the abnormalities in the regulation of translation by RNA-binding proteins during chronic liver disease and their pathological impact on portal hypertension, fibrosis, steatosis, neovascularization, and cancer development.

Grafos de conocimiento para gestionar información epidemiológica sobre COVID-19 / Knowledge graphs to manage epidemiological information about COVID-19

El control de la propagación de las enfermedades infecciosas requiere investigaciones epidemiológicas exhaustivas, lo que ha quedado validado con el desempeño del Ministerio de Salud Pública a lo largo de varias décadas en el combate a numerosas enfermedades como el dengue, el cólera y varios tipos de influenza, entre otras. Sin embargo, la pandemia COVID-19 está poniendo a prueba los más rigurosos protocolos epidemiológicos de Cuba y del mundo por su elevada capacidad de contagio y propagación. Ante este contexto, el presente artículo se propuso emplear los grafos de conocimiento para el apoyo a los estudios epidemiológicos de la COVID-19, haciendo mayor énfasis en los factores de exposición y rastreo de los contactos. Para alcanzar este objetivo se realizó un estudio relacionado con el estado del arte sobre grafos de conocimiento y su empleo en el sector de la salud, particularmente en la lucha contra el nuevo coronavirus SARS-CoV-2. La investigación tuvo como soporte un enfoque metodológico de creación y uso de grafos de conocimiento adaptado al campo de estudio. Los resultados se simulan en el escenario del brote producido a mediados del mes de julio del año 2020 en el municipio de Bauta de la provincia de Artemisa, empleando para esto datos de la realidad, extraídos de la Web, combinados con otros datos simulados(AU)

Control of the spread of infectious diseases requires exhaustive epidemiological research, as has been validated by the performance of the Ministry of Public Health during several decades of combat against numerous diseases, such as dengue, cholera and various types of influenza, among others. However, the COVID-19 pandemic is testing the limits of the most rigorous epidemiological protocols in Cuba and worldwide, due to its high transmissibility and fast spread. In this context, the present study had the purpose of using knowledge graphs to support epidemiological research about COVID-19, with greater emphasis on exposure factors and contact tracing. To achieve this end, a study was conducted about the state of the art of knowledge graphs and their use in the health care sector, particularly in the combat against the novel coronavirus SARS-CoV-2. The research applied a methodological approach based on the development and use of knowledge graphs adjusted to the study field. Results are simulated in the context of the outbreak occurring in mid July 2020 in the municipality of Bauta, Artemisa province, using real data obtained from the Internet and combined with other simulated data(AU)

Dynamic perspective of the neutrophil-to-lymphocyte ratio in metastatic gastric cancer.

PURPOSE: The neutrophil-to-lymphocyte ratio (NLR) is an accessible marker from a routine blood test. This study explored the prognostic and predictive value of a change in NLR (c-NLR) after chemotherapy, baseline NLR (bNLR) and chemotherapy response, in metastatic gastric cancer (mGC) patients. METHODS: A total of 116 mGC patients treated between 2009 to 2019 at seven hospitals from Galician Research Group on Digestive Tumors (GITuD) were reviewed in a multicentre, ambispective and observational study. NLR was calculated and the optimal cut-off was defined as NLR=3.96 based on ROC method. NLR was determined at baseline and after two chemotherapy cycles in first line treatment. Change NLR was calculated as NLR after two chemotherapy cycles minus bNLR. The relation of bNLR and c-NLR to overall survival (OS) was evaluated by Kaplan-Meier method and compared by log-rank test. Dynamic Score (DScore) based on c-NLR and baseline NLR were correlated with OS and radiological response. Univariate, multivariate and chi-square analyses were performed. RESULTS: Median patient age was 68.7 years, and 66% were male. Univariate analysis showed OS correlation for bNLR ≥3.96 (5.97 vs 10.87 months, p=0.001), c-NLR increase (6.63 vs 10.34 months, p=0.021) and DScore (12.74 vs 7.68 vs 2.43 months, p<0.001). High DScore was associated with radiological progression after two cycles (x2=10.26, p=0.006). Multivariate analysis: bNLR ≥3.96 (HR=2.16, p=0.003) and c-NLR increase (HR= 2.36, p=0.003) were prognostic factors of poor OS. CONCLUSION: High bNLR and increased NLR after chemotherapy were associated with worse outcome. Dynamic measurement of NLR provides information for stratifying patients to guide optimal treatment.

Motixafortide and Pembrolizumab Combined to Nanoliposomal Irinotecan, Fluorouracil, and Folinic Acid in Metastatic Pancreatic Cancer: The COMBAT/KEYNOTE-202 Trial.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC. PATIENTS AND METHODS: Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1-5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability. RESULTS: A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen. CONCLUSIONS: Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.

Do Clinical Trials Meet Current Care Needs? Views of Digestive Oncology Specialists in Galicia (Spain) Using the Delphi Method.

Background: In recent years, abundant scientific evidence has been generated based on clinical trials (CT) in the field of oncology. The general objective of this paper is to find out the extent to which decision making is based on knowledge of the most recent CT. Its specific objectives are to pinpoint difficulties with decision making based on the CT performed and find out the motivations patients and clinicians have when taking part in a CT. Methodology: Combined, prospective study, based on the Delphi method. A lack of correspondence between the people who take part in CT and patients who come for consultation has been identified. A need for training in analysing and interpreting CT has also been identified and a lack of trust in the results of CT financed by the pharmaceutical industry itself has been perceived. Conclusions: There is a difficulty in selecting oncological treatment due to the lack of correspondence between the patients included in the CT and patients seen in consultation. In this process, real world data studies may be highly useful, as they may provide this group with greater training in interpreting CT and their results.

Microencapsulación mediante secado por atomización a partir de un extracto de los cálices de Hibiscus sabdariffa L / Microencapsulation by spray drying from an extract of the calyces of Hibiscus sabdariffa L / Microencapsulação por secagem por pulverização a partir de um extrato dos cálices de Hibiscus sabdariffa L

Resumen La investigación tuvo como objetivo definir las mejores condiciones de extracción asistida por ultrasonido de los cálices de H. sabdariffa L. y la obtención de polvos microencapsulados, mediante secado por aspersión. Los extractos fueron analizados, considerando como variables: disolvente (agua y agua/etanol) y la relación temperatura/tiempo de extracción (25 °C/60 min y 60 °C/30 min). Para el secado se evaluaron las variables temperatura de entrada (150 °C; 190 °C) y la mezcla de encapsulantes goma arábiga (G) y maltodextrina (MD) (G40/ MD60; G60/MD40). Los parámetros utilizados para el análisis fueron: rendimiento, pH, °Bx, composición química (fenoles y antocianinas totales, CLAE-EM) y capacidad antioxidante (DPPH). La mejor condición para la extracción de polifenoles resultó ser con agua:etanol (80:20), a 60 °C y durante 30 min. Se identificó la presencia de ácidos fenólicos, glicósidos de flavonoles y las antocianinas (delfinidina-3-sambubiósido y cianidina-3-sambubiósido), como las señales de mayor intensidad. Con el secado por atomización a 150°Cy con G60/MD40, se logró el mayor contenido de fenoles totales y antocianinas, sin embargo, la capacidad antioxidante se favoreció a 150 °C y con G40/MD60. Las micropartículas obtenidas podrían valorarse como materia prima para la elaboración de fitofármacos o alimentos funcionales, considerando su fácil manipulación, posible estabilidad y su valor antioxidante.

Abstract The objective of the research was to define the best conditions for ultrasound-assisted extraction of H. sabdariffa L. calyces, and to obtain microencapsulated powders, by spray drying. The extracts were analyzed, considering as variables: extracting solvent (water and water/ethanol) and the temperature /extraction time ratio (25 °C/ 60 min and 60 °C/30 min). Inlet air temperature (150 °C; 190 °C) and the mixture of gum arabic (G) and maltodextrin (MD) as encapsulating agents (G40/MD60; G60/MD40) were the variables studied. The parameters used for the analysis were: yield, pH, °Bx, chemical composition (phenols and total anthocyanins, HPLC-MS), and antioxidant capacity (DPPH). The best polyphenols extraction conditions were water:ethanol (80:20), at 60 °C for 30 min. The presence of phenolic acids, flavonol glycosides, and anthocyanins (delphinidin-3-sambubioside and cyanidin-3-sambubioside) were identified as the signals of highest intensity. Inlet air temperature at 150 °C and G60/MD40 allowed the highest total phenols and anthocyanins content. However, the antioxidant capacity was better at 150 °C and G40/MD60. The microparticle obtained could be used as an ingredient for the preparation of phytopharmaceuticals or functional foods, considering their easy handling, and antioxidant capacity.

Resumo O objetivo da pesquisa foi definir as melhores condições para a extração assistida por ultrassom de H. sabdariffa L. calyces e obter pós microencapsulados, por meio de secagem por pulverização. Os extratos foram analisados considerando-se variáveis: menstruação (água e água/etanol) e a razão temperatura/tempo de extração (25 °C/60 min e 60°C/30 min). Para a secagem, os variais foram avaliados: temperatura de entrada (150 °C; 190 °C) e mistura dos encapsulantes goma arábica (G) e maltodextrina (MD) (G40/ MD60; G60/MD40). Os parâmetros utilizados para a análise foram: rendimento, pH, °Bx, composição química (fenóis e antocianinas totais, HPLC-MS) e capacidade antioxidante (DPPH). A melhor condição de extração acabou com a água: etanol (80:20), a 60 °C e por 30 min. A presença de ácidos fenólicos, flavonol glicosídeos e antocianinas (delfinidin-3-sambubiosídeo e cianidin-3-sambubiosídeo) foram identificados como sinais de maior intensidade. Com a secagem por pulverização a 150°Ce com G60/MD40, foi atingido o maior teor de fenóis e antocianinas totais, no entanto, a capacidade antioxidante foi favorecida a 150 °C e com G40/MD60. As microcápsulas obtidas podem ser utilizadas como matéria-prima na preparação de fitofarmacêuticos ou alimentos funcionais, considerando seu fácil manuseio, possível estabilidade e seu valor antioxidante.

Effect of antiangiogenic-based treatment and systemic inflammatory factors on outcomes in patients with BRAF v600-mutated metastatic colorectal cancer: a real-world study in Spain.

BACKGROUND: Outcomes are poorer in metastatic colorectal cancer (mCRC) patients with BRAF V600E mutations than those without it, but the effect of these mutations on treatment response is unclear. This real-world study assessed the effects of antiangiogenic-based treatment and systemic inflammatory factors on outcomes in patients with BRAF V600-mutated mCRC. METHODS: This real-world, multicenter, retrospective, observational study included patients with BRAF V600-mutated mCRC treated in eight hospitals in Spain. The primary endpoints were overall survival (OS) and progression-free survival (PFS); overall response rate (ORR) and disease control rate (DCR) were also assessed. The effect of first- and second-line treatment type on OS, PFS, ORR, and DCR were evaluated, plus the impact of systemic inflammatory markers on these outcomes. A systemic inflammation score (SIS) of 1-3 was assigned based on one point each for platelet-lymphocyte ratio (PLR) ≥200, neutrophil-lymphocyte ratio (NLR) ≥3, and serum albumin < 3.6 g/dL. RESULTS: Of 72 patients, data from 64 were analyzed. After a median of 69.1 months, median OS was 11.9 months and median first-line PFS was 4.4 months. First-line treatment was triplet chemotherapy-antiangiogenic (12.5%), doublet chemotherapy-antiangiogenic (47.2%), doublet chemotherapy-anti-EGFR (11.1%), or doublet chemotherapy (18.1%). Although first-line treatment showed no significant effect on OS, antiangiogenic-based regimens were associated with prolonged median PFS versus non-antiangiogenic regimens. Negative predictors of survival with antiangiogenic-based treatment were NLR, serum albumin, and SIS 1-3, but not PLR. Patients with SIS 1-3 showed significantly prolonged PFS with antiangiogenic-based treatment versus non-antiangiogenic-based treatment, while those with SIS=0 showed no PFS benefit. CONCLUSIONS: Antiangiogenic-based regimens, SIS, NLR, and albumin were predictors of survival in patients with mCRC, while SIS, NLR and serum albumin may predict response to antiangiogenic-based chemotherapy. TRIAL REGISTRATION: GIT-BRAF-2017-01.

FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab for patients with metastatic colorectal cancer and ≥3 circulating tumour cells: the randomised phase III VISNÚ-1 trial.

PURPOSE: 5-Fluorouracil/leucovorin, oxaliplatin, irinotecan (FOLFOXIRI) plus bevacizumab is more effective than doublets plus bevacizumab as first-line therapy for metastatic colorectal cancer, but is not widely used because of concerns about toxicity and lack of predictive biomarkers. This study was designed to explore the role of circulating tumour cell (CTC) count as a biomarker to select patients for therapy with FOLFOXIRI-bevacizumab. PATIENTS AND METHODS: VISNÚ-1 was a multicentre, open-label, randomised, phase III study in patients with previously untreated, unresectable, metastatic colorectal carcinoma and ≥3 CTC/7.5 mL blood. Patients received bevacizumab 5 mg/kg plus FOLFOXIRI (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and 5-fluorouracil 3200 mg/m2) or FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 then 2400 mg/m2) by intravenous administration every 2 weeks. The primary outcome was progression-free survival (PFS). RESULTS: The intention-to-treat population comprised 349 patients (FOLFOXIRI-bevacizumab, n=172; FOLFOX-bevacizumab, n=177). Median PFS was 12.4 months (95% CI 11.2 to 14.0) with FOLFOXIRI bevacizumab and 9.3 months (95% CI 8.5 to 10.7) with FOLFOX-bevacizumab (stratified HR, 0.64; 95% CI 0.49 to 0.82; p=0.0006). Grade≥3 adverse events were more common with FOLFOXIRI-bevacizumab 85.3% vs 75.1% with FOLFOX-bevacizumab (p=0.0178). Treatment-related deaths occurred in 8 (4.7%) and 6 (3.4%) patients, respectively. CONCLUSIONS: First-line FOLFOXIRI-bevacizumab significantly improved PFS compared with FOLFOX-bevacizumab in patients with metastatic colorectal cancer and ≥3 CTCs at baseline, which indicate a poor prognosis. CTC count may be a useful non-invasive biomarker to assist with the selection of patients for intensive first-line therapy.

First-line panitumumab plus capecitabine for the treatment of older patients with wild-type RAS metastatic colorectal cancer. The phase II, PANEL study.

BACKGROUND: Despite the high morbidity and mortality of metastatic colorectal cancer (mCRC) in older patients, they have been underrepresented in clinical trials and their optimal treatment is yet to be determined. This open-label phase II study evaluated the benefits of panitumumab and capecitabine as a first-line chemotherapy regimen in older patients with wild-type [WT] RAS mCRC. PATIENTS AND METHODS: Patients (≥70 years; ECOG≤2) received 3-week cycles of panitumumab (9 mg/kg on day 1) plus capecitabine (850 mg/m2 twice daily on days 1-14) until disease progression or unacceptable toxicity. Response was evaluated every 9 weeks according to RECIST_1.1. Outcome measures were: objective response rate (ORR), duration of response (DoR), time to response (TTR), progression (TTP) and treatment failure (TTF), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Twenty-seven patients (11 women; median age: 78 years; ECOG: 0 [26%], 1 [67%], 2 [7%]) were evaluated. Median follow-up was 17.7 months. Confirmed ORR (95%CI) was 44.4% (25.7-63.2), with 25.9% of patients achieving at least stable disease. Median (95%CI) DoR was 8.7 (5.5-10.4) months, and median TTR was 2.2 (1.9-2.8) months. Median TTP was 9.6 (4.8-11.5) months, with a median TTF of 5.2 (2.8-7.2) months. The median PFS was 7.5 (4.4-10.4) months, and the median OS was 23.7 (7.4-27.5) months. Seventeen (63%) patients reported panitumumab and/or capecitabine-related adverse events grade 3-4, with skin toxicity (18.5%) being the most common. Two (7.4%) deaths were treatment-related. CONCLUSION: This study suggests that panitumumab plus capecitabine is a safe and effective regimen in older patients with WT RAS mCRC.