Precision medicine in the era of multi-omics: can the data tsunami guide rational treatment decision?

Precision medicine for cancer is rapidly moving to an approach that integrates multiple dimensions of the biology in order to model mechanisms of cancer progression in each patient. The discovery of multiple drivers per tumor challenges medical decision that faces several treatment options. Drug sensitivity depends on the actionability of the target, its clonal or subclonal origin and coexisting genomic alterations. Sequencing has revealed a large diversity of drivers emerging at treatment failure, which are potential targets for clinical trials or drug repurposing. To effectively prioritize therapies, it is essential to rank genomic alterations based on their proven actionability. Moving beyond primary drivers, the future of precision medicine necessitates acknowledging the intricate spatial and temporal heterogeneity inherent in cancer. The advent of abundant complex biological data will make artificial intelligence algorithms indispensable for thorough analysis. Here, we will discuss the advancements brought by the use of high-throughput genomics, the advantages and limitations of precision medicine studies and future perspectives in this field.

Clinical utility of circulating tumor DNA sequencing with a large panel: a National Center for Precision Medicine (PRISM) study.

BACKGROUND: Circulating tumor DNA (ctDNA) sequencing is a promising approach for tailoring therapy in patients with cancer. We report hereby the results from a prospective study where we investigated the impact of comprehensive molecular profiling of ctDNA in patients with advanced solid tumors. PATIENTS AND METHODS: Genomic analysis was performed using the FoundationOne Liquid CDx Assay [324 genes, tumor mutational burden (TMB), microsatellite instability status]. Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were classified by ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) tier leading to molecular-based treatment suggestions wherever it was possible. RESULTS: Between December 2020 and November 2021, 1772 patients with metastatic solid tumors underwent molecular profiling. Median time to assay results was 12 days. Results were contributive for 1658 patients (94%). At least one actionable target was detected in 1059 patients (64%) with a total of 1825 actionable alterations including alteration of the DNA damage repair response pathway (n = 336, 18%), high TMB (>16 mutations/Mb; n = 243, 13%), PIK3CA mutations (n = 150, 8%), ERBB family pathway alterations (n = 127, 7%), PTEN alterations (n = 95, 5%), FGFR alterations (n = 67, 4%) and MET activations (n = 13, 0.7%). The MTB recommended a matched therapy for 597 patients (56%) with a total of 819 therapeutic orientations: clinical trials (n = 639, 78%), off-label/compassionate use (n = 81, 10%), approved drug (n = 51, 6%), and early access program (n = 48, 6%). In total, 122 patients (21%) were treated. Among the assessable patients (n = 107), 4 (4%) had complete response, 35 (33%) had partial response, 27 (25%) had stable disease, and 41 (38%) a progressive disease as best response. The median progression-free survival and median overall survival were 4.7 months (95% confidence interval 2.7-6.7 months) and 8.3 months (95% confidence interval 4.7-11.9 months) respectively. CONCLUSIONS: ctDNA sequencing with a large panel is an efficient approach to match patients with advanced cancer with targeted therapies.

Small cell lung cancer: a slightly less orphan disease after immunotherapy.

Small cell lung cancer (SCLC) is an aggressive malignancy accounting for 15% of all diagnosed cases of lung cancer. After >15 years without any clinically relevant therapeutic advances, extensive-disease SCLC has become the second thoracic malignancy for which immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm to improve overall survival. Today, atezolizumab or durvalumab in combination with platinum-etoposide chemotherapy is considered the new standard of care in the first-line setting in SCLC. However, the magnitude of benefit with this immune-chemotherapy strategy in SCLC is more modest than that observed in metastatic non-small-cell lung cancer patients. The immunosuppressive phenotype of SCLC plays an important role in hampering ICI efficacy and may explain the differences in outcomes between these two types of lung cancer. In this review, we provide a summary of recent therapeutic advances in SCLC in light of ICIs, as well as current challenges of this strategy in patients who are elderly, have poor performance status or brain metastases. We also address future perspectives of immunotherapeutic strategies currently in clinical development for these patients.

Evaluating the appropriateness of a community pharmacy model for a colorectal cancer screening program in Catalonia (Spain).

Background The traditional model of community pharmacy has changed, with patients, caregivers and consumers having access to many cognitive services other than the traditional dispensing and supply of medicines. In December 2009, a population-based colorectal cancer screening program started in Barcelona, introducing the community pharmacist and the professional expertise of the pharmacist into the organisational model. Aim To evaluate the program implementation process in the pharmacies, identify barriers and facilitators, and know the opinion of the professionals involved in the colorectal cancer screening program in Catalonia (Spain). Methods Cross-sectional study of the pharmacies that participated in the first round of the program during the first and second trimester of 2010 in Barcelona. A validated questionnaire was used to analyse several functional aspects in the implementation process. Qualitative aspects about the opinion of the pharmacist were studied. A descriptive and bivariate analysis was performed. Results All the pharmacies involved in the program (n = 74) participated in the study. The majority of the sample population was composed of women (70.3%), mean age 44.9 years, and most of them (74%) had attended a specific training session. Pharmacists considered their participation in the program to be an added value to their professional role and a way to increase consumer's confidence on this kind of services. The average time to provide the service was estimated to be less than 10 minutes per consumer. Only three (4.1%) pharmacists considered that the program involved a lot of extra work in the daily activities of the pharmacy. The level of satisfaction of the pharmacists was very high. Conclusions Community pharmacies can be a successful alternative and great resource to implement a population cancer screening program. This functional model can improve the accessibility and participation rates on target population. The level of motivation of the community pharmacist, the specific training program and the perception to give a better care for their patients can be an enabler.

Factors influencing completion of multi-dose vaccine schedules in adolescents: a systematic review.

BACKGROUND: Completion of multiple dose vaccine schedules is crucial to ensure a protective immune response, and maximise vaccine cost-effectiveness. While barriers and facilitators to vaccine uptake have recently been reviewed, there is no comprehensive review of factors influencing subsequent adherence or completion, which is key to achieving vaccine effectiveness. This study identifies and summarises the literature on factors affecting completion of multi-dose vaccine schedules by adolescents. METHODS: Ten online databases and four websites were searched (February 2014). Studies with analysis of factors predicting completion of multi-dose vaccines were included. Study participants within 9-19 years of age were included in the review. The defined outcome was completion of the vaccine series within 1 year among those who received the first dose. RESULTS: Overall, 6159 abstracts were screened, and 502 full texts were reviewed. Sixty one studies were eligible for this review. All except two were set in high-income countries. Included studies evaluated human papillomavirus vaccine, hepatitis A, hepatitis B, and varicella vaccines. Reported vaccine completion rates, among those who initiated vaccination, ranged from 27% to over 90%. Minority racial or ethnic groups and inadequate health insurance coverage were risk factors for low completion, irrespective of initiation rates. Parental healthcare seeking behaviour was positively associated with completion. Vaccine delivery in schools was associated with higher completion than delivery in the community or health facilities. Gender, prior healthcare use and socio-economic status rarely remained significant risks or protective factors in multivariate analysis. CONCLUSIONS: Almost all studies investigating factors affecting completion have been carried out in developed countries and investigate a limited range of variables. Increased understanding of barriers to completion in adolescents will be invaluable to future new vaccine introductions and the further development of an adolescent health platform. PROSPERO reg# CRD42014006765.

Comparison of haematopoietic stem cell engraftment through the retro-orbital venous sinus and the lateral vein: alternative routes for bone marrow transplantation in mice.

Bone marrow transplantation in mice is performed by intravenous administration of haematopoietic repopulating cells, usually via the lateral tail vein. This technique can be technically challenging to carry out and may cause distress to the mice. The retro-orbital sinus is a large area where there is a confluence of several vessels that provides an alternative route for intravenous access. Retro-orbital injection, although aesthetically unpleasant, can be performed rapidly without requiring mechanical restriction or heat-induced vasodilation. In addition, this technique can be easily learned by novice manipulators. This route of administration has been reported for use in bone marrow transplantation but there is no comparison of retro-orbital and tail vein injections reported for this specific purpose, although both routes have been compared for many other applications. Here, we provide for the first time a comprehensive comparison between tail vein and retro-orbital injections for two different bone marrow transplant scenarios in P3B and B6D2F1 mice. In both cases, no significant differences regarding donor engraftment were observed between mice transplanted using each of the techniques. Haematological counts and leukocyte subpopulation distribution were practically identical between both animal groups. Moreover, donor engraftment levels were less homogenous when cells were transplanted by tail vein injection, probably due to a higher risk of failure associated with this technique. All these data suggest that retro-orbital injection is a compelling alternative to conventional tail vein injection for bone marrow transplant in mice, providing similar and more homogenous haematopoietic reconstitution.

Glioblastoma stem cells: a new target for metformin and arsenic trioxide.

The high malignancy of glioblastoma has been recently attributed to the presence, within the tumor, of glioblastoma stem cells (GSC) poorly responsive to chemo- and radiotherapy. Here, the potential employment of metformin and arsenic trioxide (ATO) in glioblastoma therapy is discussed focusing on their effects on GSC. Metformin exerts anticancer effects by primarily blocking the pivotal LKB1/AMPK/mTOR/S6K1 pathway-dependent cell growth, induces selective lethal effects on GSC by impairing the GSC-initiating spherogenesis and inhibits the proliferation of CD133+ cells, while having a low or null effect on differentiated glioblastoma cells and normal human stem cells. Metformin and ATO induce autophagy and apoptosis in glioma cells by inhibiting and stimulating the PI3K/Akt and the mitogen-activated protein kinase pathways, respectively. Both drugs promote differentiation of GSC into non-tumorigenic cells. In this regard, metformin acts via activation of the AMPK-FOXO3 axis, whereas ATO blocks the interleukin 6-induced promotion of STAT3 phosphorylation. Blood-brain barrier, easily crossed by metformin but not by ATO, undergoes important glioblastoma-induced alterations that increase its permeability, thus allowing ATO to distribute more into the glioblastoma bulk than in the normal brain parenchyma. A prompt clinical assessment of metformin and ATO in glioblastoma patients would represent a valid attempt to improve their survival.

Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers.

Recent findings in colon cancer cells indicate that inhibition of the mitochondrial H(+)-adenosine triphosphate (ATP) synthase by the ATPase inhibitory factor 1 (IF1) promotes aerobic glycolysis and a reactive oxygen species (ROS)-mediated signal that enhances proliferation and cell survival. Herein, we have studied the expression, biological relevance, mechanism of regulation and potential clinical impact of IF1 in some prevalent human carcinomas. We show that IF1 is highly overexpressed in most (>90%) of the colon (n=64), lung (n=30), breast (n=129) and ovarian (n=10) carcinomas studied as assessed by different approaches in independent cohorts of cancer patients. The expression of IF1 in the corresponding normal tissues is negligible. By contrast, the endometrium, stomach and kidney show high expression of IF1 in the normal tissue revealing subtle differences by carcinogenesis. The overexpression of IF1 also promotes the activation of aerobic glycolysis and a concurrent ROS signal in mitochondria of the lung, breast and ovarian cancer cells mimicking the activity of oligomycin. IF1-mediated ROS signaling activates cell-type specific adaptive responses aimed at preventing death in these cell lines. Remarkably, regulation of IF1 expression in the colon, lung, breast and ovarian carcinomas is exerted at post-transcriptional levels. We demonstrate that IF1 is a short-lived protein (t1/2 ∼100 min) strongly implicating translation and/or protein stabilization as main drivers of metabolic reprogramming and cell survival in these human cancers. Analysis of tumor expression of IF1 in cohorts of breast and colon cancer patients revealed its relevance as a predictive marker for clinical outcome, emphasizing the high potential of IF1 as therapeutic target.

Phosphate-activated cyclin-dependent kinase stabilizes G1 cyclin to trigger cell cycle entry.

G1 cyclins, in association with a cyclin-dependent kinase (CDK), are universal activators of the transcriptional G1-S machinery during entry into the cell cycle. Regulation of cyclin degradation is crucial for coordinating progression through the cell cycle, but the mechanisms that modulate cyclin stability to control cell cycle entry are still unknown. Here, we show that a lack of phosphate downregulates Cln3 cyclin and leads to G1 arrest in Saccharomyces cerevisiae. The stability of Cln3 protein is diminished in strains with low activity of Pho85, a phosphate-sensing CDK. Cln3 is an in vitro substrate of Pho85, and both proteins interact in vivo. More interestingly, cells that carry a CLN3 allele encoding aspartic acid substitutions at the sites of Pho85 phosphorylation maintain high levels of Cln3 independently of Pho85 activity. Moreover, these cells do not properly arrest in G1 in the absence of phosphate and they die prematurely. Finally, the activity of Pho85 is essential for accumulating Cln3 and for reentering the cell cycle after phosphate refeeding. Taken together, our data indicate that Cln3 is a molecular target of the Pho85 kinase that is required to modulate cell cycle entry in response to environmental changes in nutrient availability.

The use of GlideScope for biopsies of the tongue base.

OBJECTIVE: To report a case where GlideScope is used for the biopsy of the tongue base. BACKGROUND: GlideScopes are used by anaesthetists for difficult intubations. CASE REPORT: This paper reports a case where a GlideScope was used for biopsy of the tongue base. A review of the literature indicated that this was the first time a GlideScope had been utilised for this purpose. CONCLUSION: It is suggested that this is a safe and ideal technique for biopsy of the tongue base, and GlideScopes could be used more frequently for this purpose in the future.

Metformin plus PIAF combination chemotherapy for hepatocellular carcinoma.

OBJECTIVES: Metformin, the most used oral antidiabetic drug for the treatment of type 2 diabetus mellitus, has proved encouraging results when used in the treatment of various types of cancer such as triple-negative breast cancer. Despite compelling evidence of a role of metformin as an anticancer drug, the mechanisms by which metformin exerts its oncostatic actions are not fully understood yet. Therefore, we tried to bring new insights by analyzing the anti-neoplastic effect of metformin for hepatocellular carcinoma-derived stem-like cells treated with conventional combination chemotherapy. METHODS: Cancer stem-like cells previusly isolated from a hepatocellular carcinoma biopsy were treated with metformin, PIAF chemotherapy regimen and the combination of these two protocols. Measurements of lipid peroxidation, reduced glutathione, fluorescein diacetate and proliferation rates were determined, apart from the autophagy assay and apoptosis determination by chip flow cytometry. RESULTS: Metformin alone and especially metformin in association with PIAF increases oxidative stress within the cells by increasing the levels of lipid peroxids as well as decreasing the levels of reduced glutathione. The MTT cell proliferation assay showed decreased prolife-ration rates for the arm treated with metformin and with the combination of drugs in comparison with the control arm, proving high correlation with the oxidative stress results. The autophagy assay and determination of apoptosis by chip flow cytometry confirmed the results obtained in the previous assays. CONCLUSION: Metformin could be used in chemotherapy treatments to induce reactive oxygen species and increase the cytostatics effects within the tumor cell. Still, further experiments must be carried out on murine models before we can move on and use this drugs in the adjuvant setting for unresectable primary liver cancer.

Caracterización molecular de cepas de Staphylococcus aureus resistentes a meticilina ST398 en pacientes con infecciones cutáneas y sus familiares / Molecular characterisation of methicillin resistant Staphylococcus aureus strains ST398 in patients with skin infections and their relatives

Introducción Staphylococcus aureus resistente a meticilina (SARM) ST398 es una línea genética asociada con ganado que puede causar infecciones en humanos. Métodos Se presentan 4 casos de lesiones cutáneas por SARM ST398 en 3 pacientes, dos de ellos trabajadores de granja de cerdos. Asimismo, se estudió el estado de portador nasal de los pacientes y sus familiares convivientes. Las cepas SARM fueron tipadas (SCCmec, spa, agr y MLST) y se determinó su fenotipo y genotipo de resistencia a antimicrobianos y la presencia de los genes de virulencia. Resultados Se aislaron 20 cepas SARM ST398 de lesiones de 3 pacientes y de muestras nasales de 2 pacientes y 5 familiares. Los aislados se tiparon: spa-tipo t011 o t108; agr-tipo I y SCCmec IVa o V. Las cepas fueron todas resistentes a tetraciclina y 15 de ellas presentaron un fenotipo de multirresistencia, pero no genes de virulencia. Conclusiones SARM ST398 está emergiendo en nuestro medio, frecuentemente asociado a infección de piel y partes blandas en individuos con relación profesional con granjas de cerdos. La resistencia a tetraciclina es un marcador importante para la detección de estas cepas(AU)

Introduction Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) of sequence type ST398 is a genetic lineage also described in human infections. Methods Cutaneous infections related with MRSA ST398 are described in 3 patients, two of them pig farmers. The MRSA nasal carriage by patients and their relatives was also studied. MRSA ST398 strains were typed (SCCmec, spa, agr and MLST) and the antimicrobial resistance pattern and virulence genes were determined. Results Twenty MRSA ST398 isolates were recovered in lesions of three patients, and in nasal samples of two patients and five relatives. Isolates were typed: spa-type t011 or t108; agr-type I and SCCmec IVa or V. MRSA strains were tetracycline-resistant and 15 of them showed a phenotype and genotype of multi-resistance, but they were free of tested virulence genes. Conclusions LA-MRSA ST398 is an emergent problem in our country, mainly associated with skin and soft tissue infections in people with professional relationships with pig farms. Tetracycline resistance is an important marker for MRSA ST398 detection(AU)

[Molecular characterisation of methicillin resistant Staphylococcus aureus strains ST398 in patients with skin infections and their relatives]. / Caracterización molecular de cepas de Staphylococcus aureus resistentes a meticilina ST398 en pacientes con infecciones cutáneas y sus familiares.

INTRODUCTION: Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) of sequence type ST398 is a genetic lineage also described in human infections. METHODS: Cutaneous infections related with MRSA ST398 are described in 3 patients, two of them pig farmers. The MRSA nasal carriage by patients and their relatives was also studied. MRSA ST398 strains were typed (SCCmec, spa, agr and MLST) and the antimicrobial resistance pattern and virulence genes were determined. RESULTS: Twenty MRSA ST398 isolates were recovered in lesions of three patients, and in nasal samples of two patients and five relatives. Isolates were typed: spa-type t011 or t108; agr-type I and SCCmec IVa or V. MRSA strains were tetracycline-resistant and 15 of them showed a phenotype and genotype of multi-resistance, but they were free of tested virulence genes. CONCLUSIONS: LA-MRSA ST398 is an emergent problem in our country, mainly associated with skin and soft tissue infections in people with professional relationships with pig farms. Tetracycline resistance is an important marker for MRSA ST398 detection.

Detection and characterization of a ST6 clone of vanB2-Enterococcus faecalis from three different hospitals in Spain.

Thirteen vancomycin-resistant and teicoplanin-susceptible Enterococcus faecalis isolates were recovered from unrelated patients in three Spanish hospitals from November 2009 to December 2010. All isolates carried the vanB2 gene, showed indistinguishable or closely-related PFGE patterns and were ascribed to the sequence type ST6 (included into the high-risk clonal-complex CC2). They showed a multiresistance phenotype (erythromycin, tetracycline, ciprofloxacin and high-level-resistance to streptomycin, gentamicin and kanamycin) and harboured the aac(6')-aph(2"), ant(6)-Ia, and tet(M)+/-tet(L) genes. All isolates produced gelatinase and harboured the gelE gene, but not the esp or hyl genes. The inclusion of the vanB2 gene into the Tn5382 transposon was demonstrated in one isolate. Clonal dissemination of vanB2-containing the E. faecalis strain is demonstrated.