The TEOGIC study project: a comprehensive characterization of early onset gastrointestinal cancer in the Northern area of Spain.

BACKGROUND: Gastrointestinal cancers represent one of the most prevalent diseases worldwide. Strikingly, the incidence of Early Onset Gastrointestinal Cancer (EOGIC) has been rising during the last decades and changes in lifestyle and environmental exposure seem to play a role. EOGIC has been defined as a different entity compared to on-average gastrointestinal cancer, with distinct clinical and molecular characteristics. Inherent to the particularities of younger age, there is an unmet need for a tailored approach for the management of these patients. The TEOGIC proposes a comprehensive study to characterize EOGIC patients in the northern of Spain. METHODS: Patients with histologically confirmed new diagnosis of colorectal, gastroesophageal and pancreatic adenocarcinoma will be considered for two cohorts: EOGIC (≤ 50 years old) and non-EOGIC (60-75 years old), with a ratio of 1:2. Two hundred and forty patients will be recruited in 4 Public Hospitals from northern Spain. After receiving unified informed consent, demographic and clinical data of the patients will be collected in a REDCap database. Lifestyle related data will be obtained in questionnaires assessing diet, physical activity and the general quality of life of the patients before diagnosis. Biological samples prior to any onco-specific treatment will be obtained for the analyses of circulating inflammatory proteins, gut microbiota, and the proteome of the tumor microenvironment. Histologic characteristics and routine biomarkers will be also collected. Thereafter, data will be integrated and analyzed to assess tumor specific, pan-tumor and sex-associated differential characteristics of EOGIC. DISCUSSION: The underlying risk factors and differential characteristics of EOGIC remain poorly studied, particularly in our geographical area. Although limited by the exploratory nature and the small sample size estimated to be recruited, TEOGIC represents the first attempt to comprehensively characterize these young patients, and thus attend to their special needs. Findings derived from this study could contribute to raise awareness and preventive behaviors in the population. In parallel, molecular studies could lead to the identification of potential novel non-invasive biomarkers and therapeutic targets that would help in the development of the tailored clinical management of these patients, focusing on screening programs for early diagnosis and precision medicine.

Identification and characterization of migraine in pregnancy: A Norwegian registry-based cohort study.

BACKGROUND: Migraine is common in women of reproductive age. Migraine's episodic manifestation and acute and preventive pharmacological treatment options challenge studying drug safety for this condition during pregnancy. To improve such studies, we aimed to develop algorithms to identify and characterize migraines in electronic healthcare registries and to assess the level of care. METHODS: We linked four registries to detect pregnancies from 2009-2018 and used three algorithms for migraine identification: i) diagnostic codes, ii) triptans dispensed, and iii) a combination of both. We assessed migraine severity using dispensed drugs as proxies. ICD-10 diagnostic subcodes of migraine (G43) allowed the allocation of four subtypes: complicated and/or status migrainosus; with aura; without aura; other/unspecified. RESULTS: We included 535,089 pregnancies in 367,908 women with available one-year lookback. The prevalence of migraines identified was 2.9%-4.3% before, and 0.8%-1.5% during pregnancy, depending on algorithm used. Pregnant women with migraine were mostly managed in primary care. CONCLUSIONS: Primary care data in combination with drug dispensation records were instrumental for identification of migraine in electronic healthcare registries. Data from secondary care and drug dispensations allow better characterization of migraines. Jointly, these algorithms may contribute to improved perinatal pharmacoepidemiological studies in this population by addressing confounding by maternal migraine indication.

Parental genetically predicted liability for coronary heart disease and risk of adverse pregnancy outcomes: a cohort study.

BACKGROUND: Adverse pregnancy outcomes (APO) may unmask or exacerbate a woman's underlying risk for coronary heart disease (CHD). We estimated associations of maternal and paternal genetically predicted liability for CHD with lifelong risk of APOs. We hypothesized that associations would be found for women, but not their male partners (negative controls). METHODS: We studied up to 83,969‬ women (and up to 55,568‬ male partners) from the Norwegian Mother, Father and Child Cohort Study or the Trøndelag Health Study with genotyping data and lifetime history of any APO in their pregnancies (1967-2019) in the Medical Birth Registry of Norway (miscarriage, stillbirth, hypertensive disorders of pregnancy, gestational diabetes, small for gestational age, large for gestational age, and spontaneous preterm birth). Maternal and paternal genetic risk scores (GRS) for CHD were generated using 148 gene variants (p-value < 5 × 10-8, not in linkage disequilibrium). Associations between GRS for CHD and each APO were determined using logistic regression, adjusting for genomic principal components, in each cohort separately, and combined using fixed effects meta-analysis. RESULTS: One standard deviation higher GRS for CHD in women was related to increased risk of any hypertensive disorders of pregnancy (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.05-1.10), pre-eclampsia (OR 1.08, 95% CI 1.05-1.11), and small for gestational age (OR 1.04, 95% CI 1.01-1.06). Imprecise associations with lower odds of large for gestational age (OR 0.98, 95% CI 0.96-1.00) and higher odds of stillbirth (OR 1.04, 95% CI 0.98-1.11) were suggested. These findings remained consistent after adjusting for number of total pregnancies and the male partners' GRS and restricting analyses to stable couples. Associations for other APOs were close to the null. There was weak evidence of an association of paternal genetically predicted liability for CHD with spontaneous preterm birth in female partners (OR 1.02, 95% CI 0.99-1.05), but not with other APOs. CONCLUSIONS: Hypertensive disorders of pregnancy, small for gestational age, and stillbirth may unmask women with a genetically predicted propensity for CHD. The association of paternal genetically predicted CHD risk with spontaneous preterm birth in female partners needs further exploration.

High-Dose Methylphenidate and Carboxylesterase 1 Genetic Variability in Patients With Attention-Deficit/Hyperactivity Disorder: A Case Series.

PURPOSE/BACKGROUND: Methylphenidate (MPH) is widely used to reduce symptoms of attention-deficit/hyperactivity disorder. Methylphenidate is metabolized by the carboxylesterase 1 (CES1) enzyme. Some patients need a very high dose of MPH to reach desired clinical effects, without having adverse effects. This may be due to differences in MPH pharmacokinetics (PK), potentially caused by DNA variants in CES1 , the gene encoding the enzyme that metabolizes MPH. Here we describe 3 patients requiring high-dose MPH and investigated the CES1 gene. METHODS/PROCEDURES: The 3 patients were using short-acting MPH in a dose of 180 to 640 mg instead of the maximum advised dose of around 100 mg MPH in the Netherlands. Plasma concentrations of MPH were determined at scheduled time points (day-curve). Methylphenidate plasma concentrations were used for PK analysis using an earlier published 2-compartment PK population model of MPH. Individual data of the 3 patients were compared with simulated population data, when equivalent doses were used. In addition, CES1 was genotyped (number of gene copies and single nucleotide polymorphisms) using real-time polymerase chain reaction. FINDINGS/RESULTS: Pharmacokinetic analysis in all 3 patients showed lower plasma concentrations of MPH in comparison with the population data. The mean absorption time and volume of distribution of the central compartment were equal, but the elimination clearance was higher. However, CES1 genotyping revealed no variations that could explain a higher metabolism of MPH. IMPLICATIONS/CONCLUSIONS: In these 3 cases, we could not demonstrate a correlation between MPH clearance and known genetic variants of the CES1 gene.

Associations between endometriosis and adverse pregnancy and perinatal outcomes: a population-based cohort study.

PURPOSE: To examine the association between endometriosis and adverse pregnancy and perinatal outcomes (preeclampsia, placenta previa, and preterm birth). METHODS: A population-based retrospective cohort study was conducted among 468,778 eligible women who contributed 912,747 singleton livebirths between 1980 and 2015 in Western Australia (WA). We used probabilistically linked perinatal and hospital separation data from the WA data linkage system's Midwives Notification System and Hospital Morbidity Data Collection databases. We used a doubly robust estimator by combining the inverse probability weighting with the outcome regression model to estimate adjusted risk ratios (RR) and 95% confidence intervals (CIs). RESULTS: There were 19,476 singleton livebirths among 8874 women diagnosed with endometriosis. Using a doubly robust estimator, we found pregnancies in women with endometriosis to be associated with an increased risk of preeclampsia with RR of 1.18, 95% CI 1.11-1.26, placenta previa (RR 1.59, 95% CI 1.42-1.79) and preterm birth (RR 1.45, 95% CI 1.37-1.54). The observed association persisted after stratified by the use of Medically Assisted Reproduction, with a slightly elevated risk among pregnancies conceived spontaneously. CONCLUSIONS: In this large population-based cohort, endometriosis is associated with an increased risk of preeclampsia, placenta previa, and preterm birth, independent of the use of Medically Assisted Reproduction. This may help to enhance future obstetric care among this population.

Tailored Prevention of Functional Decline through a Multicomponent Exercise Program in Hospitalized Oncogeriatric Patients: Study Protocol for a Randomized Clinical Trial.

BACKGROUND: Cancer mostly affects older adults, causing a wide variety of diagnostic and therapeutic dilemmas. One of the most important moments in cancer patients is the hospitalization period, in which older patients usually remain bedridden for many hours and this may lead to the appearance of sarcopenia and disability. METHODS: We present the research protocol for a randomized controlled trial that will analyze whether an intervention applied to older patients (≥ 65 years) who are hospitalized for acute medical conditions in an Oncology Department improves function. A total of 240 hospitalized older patients will be recruited in the Hospital Universitario de Navarra, Pamplona, Spain, and they will be randomized. The intervention consists of a multicomponent exercise training program that will take place for 4 consecutive days (2 sessions/day). The control group will receive usual hospital care, which will include physical rehabilitation when needed. The primary end point will be the change in functional capacity from baseline to hospital discharge, assessed with the Short Physical Performance Battery (SPPB). Secondary end points will be changes in cognitive and mood status, quality of life, fatigue, strength (dynamic and handgrip), pain, nutrition, length of stay, falls, readmission rate and mortality at 3 months after discharge. RESULTS: Basal data of the patients included in the RCT are described. The foreseen recruitment will not be achieved due to the context of the Covid pandemic and the significantly different responses observed during the clinical trial in oncogeriatric patients compared to our previous experience in older adults hospitalized for medical reasons. DISCUSSION: If our hypothesis is correct and shows that a multicomponent, individualized and progressive exercise program is an effective therapy for improving the capacity of acutely hospitalized older patients compared to usual care, a change in the current system of hospitalization may be justified in oncogeriatric patients.

Effect of Alirocumab Added to High-Intensity Statin on Platelet Reactivity and Noncoding RNAs in Patients with AMI: A Substudy of the PACMAN-AMI Trial.

OBJECTIVE: The effect of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor alirocumab on platelet aggregation among patients with acute myocardial infarction (AMI) remains unknown. We aimed to explore the effect of alirocumab added to high-intensity statin therapy on P2Y12 reaction unit (PRU) among AMI patients receiving dual antiplatelet therapy (DAPT) with a potent P2Y12 inhibitor (ticagrelor or prasugrel). In addition, we assessed circulating platelet-derived noncoding RNAs (microRNAs and YRNAs). METHODS: This was a prespecified, powered, pharmacodynamic substudy of the PACMAN trial, a randomized, double-blind trial comparing biweekly alirocumab (150 mg) versus placebo in AMI patients undergoing percutaneous coronary intervention. Patients recruited at Bern University Hospital, receiving DAPT with a potent P2Y12 inhibitor, and adherent to the study drug (alirocumab or placebo) were analyzed for the current study. The primary endpoint was PRU at 4 weeks after study drug initiation as assessed by VerifyNow P2Y12 point-of-care assays. RESULTS: Among 139 randomized patients, the majority of patients received ticagrelor DAPT at 4 weeks (57 [86.4%] in the alirocumab group vs. 69 [94.5%] in the placebo group, p = 0.14). There were no significant differences in the primary endpoint PRU at 4 weeks between groups (12.5 [interquartile range, IQR: 27.0] vs. 19.0 [IQR: 30.0], p = 0.26). Consistent results were observed in 126 patients treated with ticagrelor (13.0 [IQR: 20.0] vs. 18.0 [IQR: 27.0], p = 0.28). Similarly, platelet-derived noncoding RNAs did not significantly differ between groups. CONCLUSION: Among AMI patients receiving DAPT with a potent P2Y12 inhibitor, alirocumab had no significant effect on platelet reactivity as assessed by PRU and platelet-derived noncoding RNAs.

Health-related quality of life before and during the COVID-19 pandemic in Switzerland: a cross-sectional study.

INTRODUCTION: The COVID-19 pandemic forced people to give up their daily routines and adjust to new circumstances. This might have affected health-related quality of life (HRQOL). We aimed to compare HRQOL during the first COVID-19 wave in 2020 to HRQOL before the pandemic and to identify determinants of HRQOL during the pandemic in Switzerland. METHODS: We conducted a cross-sectional online survey during the pandemic (between May and July 2020; CoWELL sample; convenience sample). Before the pandemic (2015-2016), we had conducted a cross-sectional paper-based survey among a representative random sample of the Swiss general population (SGP sample). In both samples, we assessed physical and mental HRQOL (Short Form-36) and socio-demographic characteristics. In the CoWELL sample, we additionally assessed health- and COVID-19-related characteristics. Data were analysed using linear regressions. RESULTS: The CoWELL sample included 1581 participants (76% women; mean age = 43 years, SD = 14 years) and the SGP sample 1209 participants (58% women, mean age = 49 years, SD = 15 years). Adjusted for sex, age, and education, the CoWELL sample reported higher physical HRQOL (PCS, +5.8 (95% CI: 5.1, 6.6), p < 0.001) and lower mental HRQOL (MCS, -6.9 (-7.8, -6.0), p < 0.001) than the SGP sample. In the CoWELL sample, especially persons with lower health literacy, who had no support network or who have had COVID-19, reported lower HRQOL. DISCUSSION: Aspects unique to the COVID-19 pandemic affected HRQOL. Vulnerable persons such as those having had COVID-19, less support opportunities, and with lower health literacy are especially prone to impaired HRQOL during the COVID-19 pandemic.

Non-bacterial Thrombotic Endocarditis as a Rare Manifestation of Early Stage Gastric Cancer.

Endocarditis is an inflammation of the endocardium and is characterized by the presence of vegetation, which may occur in the context of infectious or non-infectious diseases. Despite the higher rate of infective endocarditis diagnosis, it may also surge in other non-infectious conditions such as cancer or chronic inflammatory syndromes. Cancer defines a hypercoagulable state, and cancer-associated thrombophilia can have a diverse clinical presentation, most commonly venous thromboembolism and rarely non-bacterial thrombotic endocarditis (NBTE). The diagnosis of NBTE is difficult and requires a high level of suspicion. The treatment relies on anticoagulant therapy, control of underlying disease, and valve replacement when applied. Independently of the etiology, without treatment, endocarditis may lead to valve dysfunction and to the worst prognosis. In this paper, we describe a case of a patient with persistent fever and NBTE of the tricuspid valve, disclosing a rare presentation of gastric cancer.

Clinical landscape of LAG-3-targeted therapy.

Lymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed.

Anti-Inflammatory and Analgesic Evaluation of a Phytochemical Intercalated into Layered Double Hydroxide.

Coumaric acid (CouH), an antioxidant molecule assimilated by food consumption, was intercalated into layered double hydroxide (LDH) nanocarrier, having zinc and aluminium ions in the layers (LDH-Cou), to evaluate its pharmacological activity through in vitro and in vivo assays in mice. Therefore, the following tests were performed: coumarate delivery in saline solution, fibroblasts' cell viability using neutral red, peritonitis induced by carrageenan, formalin test, acetic-acid-induced writhing, and tail-flick assay, for the non-intercalated CouH and the intercalated LDH-Cou system. Furthermore, different pharmacological pathways were also investigated to evaluate their possible anti-inflammatory and antinociceptive mechanisms of action, in comparison to traditionally used agents (morphine, naloxone, caffeine, and indomethacin). The LDH-Cou drug delivery system showed more pronounced anti-inflammatory effect than CouH but not more than that evoked by the classic non-steroidal anti-inflammatory drug (NSAID) indomethacin. For the analgesic effect, according to the tail-flick test, the treatment with LDH-Cou expressively increased the analgesia duration (p < 0.001) by approximately 1.7−1.8 times compared to CouH or indomethacin. Thus, the results pointed out that the LDH-Cou system induced in vivo analgesic and anti-inflammatory activities and possibly uses similar mechanisms to that observed for classic NSAIDs, such as indomethacin.

Potential mechanisms underlying lithium treatment for Alzheimer's disease and COVID-19.

Disruption of intracellular Ca2+ homeostasis plays an important role as an upstream pathology in Alzheimer's disease (AD), and correction of Ca2+ dysregulation has been increasingly proposed as a target of future effective disease-modified drugs for treating AD. Calcium dysregulation is also an upstream pathology for the COVID-19 virus SARS-CoV-2 infection and replication, leading to host cell damage. Clinically available drugs that can inhibit the disturbed intracellular Ca2+ homeostasis have been repurposed to treat COVID-19 patients. This narrative review aims at exploring the underlying mechanism by which lithium, a first line drug for the treatment of bipolar disorder, inhibits Ca2+ dysregulation and associated downstream pathology in both AD and COVID-19. It is suggested that lithium can be repurposed to treat AD patients, especially those afflicted with COVID-19.

Folic acid and sodium folate salts: Thermal behavior and spectroscopic (IR, Raman, and solid-state 13C NMR) characterization.

Folic acid (FA; vitamin B9) and its associated sodium salts, strongly relevant for many scientific and technological applications - from nutrition to pharmacology and nanomedicine, suffer from a lack of characterization combining experimental and theoretical. In this work, a spectroscopic investigation of FA and its synthesized sodium salts in the form of dianion (Na2HFol) or trianion (Na3Fol) was scrutinized in their solid state. The spectroscopic (infrared, Raman, and solid state 13C-nuclear magnetic resonance) data interpretation was supported by theoretical calculations using the Density Functional Theory (DFT). Additionally, the compounds were characterized by UV-VIS diffuse-reflectance spectroscopy, combined thermal analysis (TG/DTG-DSC) coupled to mass spectrometry, and X-ray diffractometry. The main signatures of each species were identified, as well as the influence of the protonation level on their physicochemical properties. These distinct properties for the three compounds are mainly based on signals assigned to glutamic acid (glutamate) and pterin (neutral or anionic) moieties. This work should help developing new products based on FA or its anionic forms, such as theragnostic/drug delivery systems, supramolecular structures, nanocarbons, or metal complexes.

Future care for long-term cancer survivors: towards a new model

PurposeThe increase in the prevalence "long-term cancer survivor” (LCS) patients is expected to increase the cost of LCS care. The aim of this study was to obtain information that would allow to optimise the current model of health management in Spain to adapt it to one of efficient LCS patient care.MethodsThis qualitative study was carried out using Delphi methodology. An advisory committee defined the criteria for participation, select the panel of experts, prepare the questionnaire, interpret the results and draft the final report.Results232 people took part in the study (48 oncologists). Absolute consensus was reached in three of the proposed sections: oncological epidemiology, training of health professionals and ICT functions.ConclusionThe role of primary care in the clinical management of LCS patients needs to be upgraded, coordination with the oncologist and hospital care is essential. The funding model needs to be adapted to determine the funding conditions for new drugs and technologies.

A strategic reflection for the management and implementation of CAR-T therapy in Spain: an expert consensus paper.

CAR-T cell therapy represents a therapeutic revolution in the prognosis and treatment of patients with certain types of hematological cancer. However, they also pose new challenges in the healthcare, regulatory and financial fields. The aim of the RET-A project was to undertake a strategic reflection on the management of CAR-T therapies within the Spanish National Health System, to agree on recommendations that will help to better deal with the new context introduced by these cell therapies in the present and in the future. This think tank involved 40 key agents and opinion leaders. The experts identified three great challenges for implementing advanced therapies in Spain: therapeutic individualisation, with a multidisciplinary approach; acceleration of access times, by minimizing bureaucracy; and increase in the number of centers qualified to manage the CAR-T therapies in the NHS. The experts agreed on the ideal criteria for designating those qualified centers. They also agreed on a comprehensive CAR-T care pathway with the timings and roles which would ideally be involved in each part of the process.

Clinical nutrition as part of the treatment pathway of pancreatic cancer patients: an expert consensus

PurposeMalnutrition is a common problem among pancreatic cancer (PC) patients that negatively impacts on their quality of life (QoL) and clinical outcomes. The main objective of this consensus is to address the role of Medical Nutrition Therapy (MNT) into the comprehensive therapeutic management of PC patients.MethodsA Spanish multidisciplinary group of specialists from the areas of Medical Oncology; Radiation Oncology; Endocrinology and Nutrition; and General Surgery agreed to assess the role of MNT as part of the best therapeutic management of PC patients.ResultsThe panel established different recommendations focused on nutritional screening and nutritional screening tools, MNT strategies according to PC status, and MNT in palliative treatment.ConclusionsThere is an unmet need to integrate nutritional therapy as a crucial part of the multimodal care process in PC patients. Health authorities, health care professionals, cancer patients, and their families should be aware of the relevance of nutritional status and MNT on clinical outcomes and QoL of PC patients.

Clinical nutrition as part of the treatment pathway of pancreatic cancer patients: an expert consensus.

PURPOSE: Malnutrition is a common problem among pancreatic cancer (PC) patients that negatively impacts on their quality of life (QoL) and clinical outcomes. The main objective of this consensus is to address the role of Medical Nutrition Therapy (MNT) into the comprehensive therapeutic management of PC patients. METHODS: A Spanish multidisciplinary group of specialists from the areas of Medical Oncology; Radiation Oncology; Endocrinology and Nutrition; and General Surgery agreed to assess the role of MNT as part of the best therapeutic management of PC patients. RESULTS: The panel established different recommendations focused on nutritional screening and nutritional screening tools, MNT strategies according to PC status, and MNT in palliative treatment. CONCLUSIONS: There is an unmet need to integrate nutritional therapy as a crucial part of the multimodal care process in PC patients. Health authorities, health care professionals, cancer patients, and their families should be aware of the relevance of nutritional status and MNT on clinical outcomes and QoL of PC patients.

Future care for long-term cancer survivors: towards a new model.

PURPOSE: The increase in the prevalence "long-term cancer survivor" (LCS) patients is expected to increase the cost of LCS care. The aim of this study was to obtain information that would allow to optimise the current model of health management in Spain to adapt it to one of efficient LCS patient care. METHODS: This qualitative study was carried out using Delphi methodology. An advisory committee defined the criteria for participation, select the panel of experts, prepare the questionnaire, interpret the results and draft the final report. RESULTS: 232 people took part in the study (48 oncologists). Absolute consensus was reached in three of the proposed sections: oncological epidemiology, training of health professionals and ICT functions. CONCLUSION: The role of primary care in the clinical management of LCS patients needs to be upgraded, coordination with the oncologist and hospital care is essential. The funding model needs to be adapted to determine the funding conditions for new drugs and technologies.