Background and ImportancePatients with non-small-cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) exon 20 insertion mutations have poor prognosis and few therapeutic ...alternatives.Aim and ObjectivesTo develop a systematic review of platinum pre-treated NSCLC harbouring eGFR exon 20 insertions to assess efficacy of treatments and scientific quality of studies.Material and MethodsPreferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines was applied in bibliographic review. Search was conducted in PubMed® database up to 15 September 2022. Filter ‘clinical trial’ on types of articles was applied to the following review strategy: (exon 20 insertion) AND (Therapy/broadfilter). Inclusion criteria: Randomised clinical trials (RCTs) evaluating treatments in patients diagnosed with advanced or metastatic NSCLC harbouring EGFR exon 20 insertions who had previously received platinum-based chemotherapy. Efficacy endpoints considered were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Data recorded: publication date, study design, comparator arm, therapies, sample size, treatment line, efficacy data.ResultsForty search results were found in review. Twelve RCTs were included. Publication dates of studies were between April 2015 and July 2022. Design of studies: 9 (75%) phase II RCT (one was basket trial) and 3 (25%) phase I/II. None of them presented a comparator arm. Therapies assessed: poziotinib, osimertinib (high and low doses), pertuzumab-trastuzumab combination, mobocertinib, amivantamab, erlotinib-onalespib combination, luminespib, ado-trastuzumab emtansine and dacomitinib. Sample size of RCTs ranged from 10 to 114 patients. Both untreated and platinum-pretreated patients were recruited in 4 (25%) RCTs and the rest comprised exclusively platinum-pretreated population. Ado-trastuzumab emtansine showed the best numerical results according to ORR (54.5%), but the worst PFS (2.8 months; 95% CI 1.4-4.4) and OS (8.1 months; 95% CI 3.5-13.2) of all therapeutic alternatives. The highest numerical efficacy results were achieved by amivantamab PFS = 8.3 months (95% CI 6.5-10.9); OS = 22.8 months (95% CI 14.6 to not reached) and mobocertinib PFS = 7.3 months (95% CI 5.5-9.2); OS = 24.0 months (95% CI, 14.6-28.8).Conclusion and RelevanceResults of amivantamab and mobocertinib suggested a higher numerical efficacy for clinically relevant endpoints in platinum pre-treated NSCLC harbouring EGFR exon 20 insertions. However, comparative RCTs with larger sample sizes are necessary to obtain reliable data.References and/or AcknowledgementsConflict of InterestNo conflict of interest.
Background and ImportanceAppropriate optimisation of biologic agents in immune-mediated inflammatory diseases can improve treatment efficiency by decreasing number of drug administrations.Aim and ...ObjectivesTo estimate economic impact of optimising the use of etanercept and adalimumab in patients with immune-mediated dermatological and rheumatological diseases.Material and MethodsA descriptive retrospective study was conducted between November 2021 and September 2022. Patients with psoriasis, spondyloarthritis, rheumatoid arthritis and psoriatic arthritis treated with etanercept or adalimumab therapies for at least 6 months uninterruptedly were screened. Therapy optimisations were quantified. Optimised therapies were defined as treatments with extended dosing regimens or treatment discontinuations due to adequate pathology control. These therapy optimisations were applied according to a multidisciplinary protocol of clinical decisions based on biochemical tests (including serum drug levels and presence of anti-drug antibodies), pharmaceutical interviews about patients’ perception of their disease course and medical criteria. Data recorded: medical departments, drugs, biochemical tests, pharmaceutical interviews, serum drug levels and presence of anti-drug antibodies. Regarding economic impact, savings from biological therapy optimisations were estimated as the difference between costs of real doses used with optimised regimens and the hypothetical costs with doses used prior to treatment optimisations. The number of decreased drug administrations was estimated.ResultsThis study screened 256 patients: 182 of Internal Medicine Department and 74 of Dermatology. Distribution of drugs was: 171 patients received etanercept and 85 adalimumab. There were 258 biochemical test and 258 pharmaceutical interviews (2 patients required 2 biochemical tests and 2 pharmaceutical interviews). Serum drug levels were outside the optimal therapeutic ranges of drugs according to the literature in 71.6% of cases. Presence of anti-drug antibodies were found in 15 patients. Treatment optimisations were performed in 115 patients: 86 (74.8%) of Internal Medicine Department and 29 (25.2%) of Dermatology. Total economic savings associated with optimisation of biological therapies were €68804.96, €53169,58 saved in Internal Medicine Department and €15635.38 saved in Dermatology. The average monthly savings for these treatment optimisations was €6255/month. Number of drug administrations avoided was 777.Conclusion and RelevanceThe optimisation of etanercept and adalimumab regimens in our patients with immune-mediated dermatological and rheumatological diseases provided high efficiency by decreasing the number of drug administrations.References and/or AcknowledgementsNoneConflict of InterestNo conflict of interest
Background and ImportancePharmaceutical proposals (PPs) in a multidisciplinary programme (MP) for immune-mediated inflammatory diseases could improve drug effectiveness and efficiency of clinical ...decision-making.Aim and ObjectivesTo evaluate the impact of PPs in a MP for the management of immune-mediated inflammatory dermatological and rheumatological diseases.Material and MethodsPatients with rheumatoid arthritis (RA), spondyloarthritis, psoriasis and psoriatic arthritis (PA) receiving etanercept or adalimumab for at least 6 months continuously were screened in MP during May 2021 to September 2022. Internists, dermatologists, pharmacologists and pharmacists composed the MP. Bibliographic search on optimal therapeutic ranges (OTRs) of drugs was developed and PP protocol based on biochemical and clinical criteria was designed. Biochemical tests on serum drug levels and anti-drug antibodies were provided by pharmacists. Pharmaceutical interviews (PIs) about disease evolution were conducted before PPs. PPs were treatment optimisation (TO) based on extended dosing regimens or treatment discontinuations, drug switching (DS) due to loss of effectiveness, or unchanged therapy (UT). Patients with accepted TO had telematic PIs after 1 and 3 months (answers: ‘good course’/’mild disease’/’poor course’). Recorded data: drugs, multidisciplinary meetings, biochemical test and PIs, drugs levels and anti-drug antibodies, type of accepted PPs and telematic PI answers.ResultsMP included 645 patients. Drugs distribution: 51.8% etanercept and 48.2% adalimumab. There were 25 multidisciplinary meetings. Up to study cut-off time, 408 biochemical tests and PIs were performed. Results of bibliographic search presented adalimumab OTRs of 5-8 μg/mL for RA and PA, 3.2-7 μg/mL for psoriasis and 4.6-12 μg/mL for spondyloarthritis. Etanercept OTRs: 2-3 μg/mL for RA and spondyloarthritis, and 2-7 μg/mL for PA and psoriasis. Serum drug levels were outside the OTR in 72.9% of patients. Anti-drug antibodies were found in 18 patients. PPs accepted were 305: 183 (60%) TO, 52 (17%) DS and 70 (23%) UT. Telematic PIs answers 1 month after TO were: 81.8% ‘good course’, 3.6% ‘mild disease’ and 14.6% ‘poor course’. At 3 months were: 69.8% ‘good course’, 5.7% ‘mild disease’ and 24.5% ‘poor course’.Conclusion and RelevanceMost of accepted PPs in our MP (DS and TO) can improve effectiveness and efficiency of treatments for immune-mediated inflammatory diseases in clinical decision-making. Almost three quarters of patients with TO presented good disease evolution.References and/or AcknowledgementsNoneConflict of InterestNo conflict of interest
A nanocomposite obtained by a thiol DAB-dendrimer (generation 5), coated with fluorescent ZnSe quantum dots, was successfully synthesized for the selective recognition of C-reactive protein. The ...procedure presented was carried out by a novel, cheap and non-toxic bottom up synthesis. The nanocomposite showed an excitation at 180nm, with two emission bands at 411 and 465nm, with a full-width at half-maximum of 336nm. The Stokes shift was influenced by the presence of coating molecules and the intensity was dependent on pH due to the presence of a charge transfer process. The transmission electron microscopy images demonstrated that the spherical nanoparticles obtained displayed a regular shape of 30nm size. The fluorescence intensity was markedly quenched by the presence of C-reactive protein, with a dynamic Stern–Volmer constant of 0.036M−1. The quenching profile shows that about 51% of the ZnSe QDs are located in the external layer of the thiol dendrimer accessible to the quencher. The precision of the method obtained as relative standard deviation was 3.76% (4mgL−1, n=3). This water soluble fluorescent nanocomposite showed a set of favorable properties to be used as a sensor for the C-reactive protein in serum samples, at concentrations of risk levels.
► Fluorescence chemical sensor for the C-RP recognition in thiol DAB-dendrimer generation 5. ► Capped by fluorescent ZnSe quantum dots assembly to O-phosphorylethanolamine. ► The fluorescence of S-DAB–ZnSe–PEA QDs was explained due to the quenching of the C-RP. ► The precision of the method obtained (as RSD) for 4mgL−1 (n=3) was 3.76%. ► Application to human serum.
PATIENTS with rheumatoid arthritis (RA) are at increased risk of developing comorbid conditions.
To evaluate the prevalence of comorbidities and compare their management in RA patients from different ...countries worldwide.
international, cross-sectional.
consecutive RA patients.
demographics, disease characteristics (activity, severity, treatment), comorbidities (cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and psychiatric disorders).
Of 4586 patients recruited in 17 participating countries, 3920 were analysed (age, 56±13 years; disease duration, 10±9 years (mean±SD); female gender, 82%; DAS28 (Disease Activity Score using 28 joints)-erythrocyte sedimentation rate, 3.7±1.6 (mean±SD); Health Assessment Questionnaire, 1.0±0.7 (mean±SD); past or current methotrexate use, 89%; past or current use of biological agents, 39%. The most frequently associated diseases (past or current) were: depression, 15%; asthma, 6.6%; cardiovascular events (myocardial infarction, stroke), 6%; solid malignancies (excluding basal cell carcinoma), 4.5%; chronic obstructive pulmonary disease, 3.5%. High intercountry variability was observed for both the prevalence of comorbidities and the proportion of subjects complying with recommendations for preventing and managing comorbidities. The systematic evaluation of comorbidities in this study detected abnormalities in vital signs, such as elevated blood pressure in 11.2%, and identified conditions that manifest as laboratory test abnormalities, such as hyperglycaemia in 3.3% and hyperlipidaemia in 8.3%.
Among RA patients, there is a high prevalence of comorbidities and their risk factors. In this multinational sample, variability among countries was wide, not only in prevalence but also in compliance with recommendations for preventing and managing these comorbidities. Systematic measurement of vital signs and laboratory testing detects otherwise unrecognised comorbid conditions.
Background and ImportanceRibociclib and abemaciclib are cyclin-dependent kinase 4/6 inhibitors (CDK4/6-i) used as treatment for patients with negative epidermal growth factor receptor 2 (HER2-) and ...positive hormone receptor (HR+) metastatic breast cancer (MBC). MONALEESA-2 and MONARCH-3 trials evaluated the efficacy of this drugs as first line treatment in post-menopausal women.Aim and ObjectivesTo assess effectiveness of ribociclib and abemaciclib in HER2- and HR+ MBC in clinical practice, comparing results with reference bibliography.Material and MethodsDescriptive retrospective study included post-menopausal women with HER2- and HR+ MBC receiving CDK4/6-i as first line of treatment between August-2017 and September-2022. Data were recorded from electronic clinical history and prescription program Prisma®: gender, age, ECOG, CDK4/6-i and combined endocrine therapy, dosage and treatment duration. Effectiveness was assessed by progression free survival (PFS), overall survival (OS) and PFS rate at 12 months, using Kaplan-Meyer statistical analysis with SPSS V.21.0. Results were compared with those described in pivotal clinical trials.ResultsA total of 63 women were included. Mean age was 63 (range 50–84) years. At baseline, ECOG=0/1 was observed in 93.7% cases and ECOG=2/3 in 6.3%. Abemaciclib was used in 50.8% patients and 49.2% ribociclib. CDK4/6-i were combined with letrozole in 58.7% patients and fulvestrant in 41.3%. Dose reduction occurred in 48.4% patients with ribociclib and 34.4% with abemaciclib. For ribociclib, median treatment duration was 16 (2–54) months and 11 (2–32) months for abemaciclib. Estimated PFS median for ribociclib was 28.0 (95% Confidence Interval: 6.6–49.3) months and was not reached for abemaciclib. Ribociclib and abemaciclib estimated OS median were not reached at data cut-off. PFS rate at 12 months was 67.3% (95% CI: 58.8–75.8) for ribociclib, and 60.7% (95% CI: 51.4–70.0) for abemaciclib. For ribociclib, MONALEESA-2 trial presented a PFS median of 25.3 months, OS median of 63.9 months and 12-month PFS rate of 72.8%. For abemaciclib, MONARCH-3 showed a PFS median of 28.2 months, OS median was not reached and 12-month PFS rate was not described.Conclusion and RelevanceReal-life effectiveness results confirmed a substantial benefit of ribociclib and abemaciclib. These data appeared to be slightly superior than those described in the literature. Larger sample size and longer follow-up time are necessary to extract more conclusive information.References and/or AcknowledgementsConflict of InterestNo conflict of interest
A novel single degree of freedom method is proposed to identify the modal mass or mode shape scaling of an isolated vibration mode from output-only data, using the response of the system coupled with ...an oscillator which can be very small in comparison. The expedient is considerably simpler than some alternatives requiring controlled input, and no prior assumption is required concerning the unknown parameter, but the frequency of the mode must be known in advance. Two proof-of-concept algorithms were developed for testing the method: a frequency domain peak picking algorithm for lightly damped systems and a time domain one that can take heavy damping into account. Tests were performed on a laboratory set-up and on a real lively footbridge (with and oscillator mass around 1% of the modal mass), assessing the viability of the method and its suitability for real applications.
► The mass or scale of a vibration mode is found by attaching an oscillating mass. ► Two algorithms are proposed to extract this information from free response. ► Tests were performed on a laboratory set-up and a footbridge.
Background and ImportanceVandetanib is a tyrosine kinase inhibitor used for the treatment of metastatic medullary thyroid cancer (MMTC). This drug has been associated with phototoxicity, but rarely ...severe.Aim and ObjectivesTo report a case of severe phototoxicity reaction associated with vandetanib.Material and MethodsThe clinical management of a case with rare phototoxicity adverse reaction was described. Electronic medical records were used to collect patient data: baseline clinical context, adverse events, treatment, and clinical evolution. Naranjo algorithm was used by hospital pharmacist to stablish the causality of phototoxicity.ResultsAn 82-year-old man newly diagnosed with MMTC started treatment with vandetanib. After 12 days, he presented slight rash in dorsal region. The patient received one radiotherapy session. Seventeen days after starting vandetanib, he visited Emergency department for generalised erythema (on face, neck, upper and lower limbs), flushing and pruritus, related to brief sun exposure. The patient was treated with single dose intramuscular methylprednisolone and oral dexchlorpheniramine. Vandetanib and radiotherapy were discontinued. Five days later, the patient presented severe deterioration, progression of erythema and intense oedema in hands, feet and face. Deflazacort was prescribed. After diagnosis by Dermatology department of acute phototoxic eruption, treatment was started with prednisone 45 mg/day for 7 days with progressive decrease, emollients and topical methylprednisolone. Between days 26-40, gradual improvement of oedema and erythema was observed without appearance of new toxicity. Prednisone dose was reduced. Progressively, desquamation and scabs were observed on both hands, with improvement of leg and foot ulcers. Poor pain control required tapentadol 25 mg/12 hours. On day 62, there was a worsening with increased erythema since oral prednisone was reduced. Treatment with Polypodium leucotomos, vitamin D, C and E was initiated. On day 68, there was a significant improvement with no itchiness. Three months after symptom onset, itching and erythema had almost disappeared. Remaining hyperpigmentation of the skin was observed. Naranjo's algorithm determined a probable relationship (score 5) and reintroduction of vandetanib was discouraged.Conclusion and RelevanceHospital pharmacist determined a probable relationship between vandetanib and severe phototoxicity reaction in a patient with MMTC. The role of hospital pharmacists is essential in pharmacovigilance and in informing patients about possible adverse events of drugs.References and/or AcknowledgementsConflict of InterestNo conflict of interest
Abstract Background Induction therapy for simultaneous pancreas-kidney (SPK) transplantation. Both thymoglobulin (ATG) and basiliximab are the most-used types of induction antibodies therapies in ...clinical practice. The aim of our report was to analyze our experience comparing 2 induction therapies, for SPK transplantation in terms of pancreas and patient survival, as well as rejection rate. Methods We reviewed retrospectively a total of 97 SPK transplantations in our institution. The cases were divided according to induction therapy in 2 groups, basiliximab (n = 38) and ATG (n = 59). Rejection, patient and graft survival, and postoperative complications were analyzed. Results Survival in the ATG group was better without statistical difference at 1-, 3-, and 5-year follow-up (97%, 95%, and 95% versus 92%, 90%, and 87%, respectively). No difference was detected in pancreas graft survival after 1-, 3-, and 5-year follow-up (basiliximab 85%, 80%, and 77% versus ATG 84%, 84%, and 81%, respectively; log-rank, 0.847). Overall cellular rejection and early rejection were more common in the basiliximab group (30 versus 14%, and 21% versus 6%). In the multivariate analysis considering human leukocyte antigen (HLA) mismatches, the ATG group was a protective factor for cellular rejection. Major complications (Grade III-IV) and median length of the hospital stay were higher in the basiliximab group (55% versus 34%, P = .057, and 21 versus 16 days, P = .056). Conclusions The pancreas graft survival was not affected by induction therapy. ATG induction therapy compared with basiliximab is associated with lower overall and early rejection rate. Over time this difference disappears.
Second homes - the cottage, the summer house, the bach - are an important part of the tourism and leisure lifestyles of many people in the developed world. Second homes are therefore an integral ...component of tourism experiences in rural and peripheral areas. Yet, despite their significance not only for tourism but also for rural communities and the rural economy, relatively little research has been undertaken on the topic until recent times. This volume represents the first major international analysis and review of second homes for over 25 years. It will provide a significant resource for those interested in changing patterns of tourism and leisure behaviour as well as the use of the countryside and peripheral areas. The book describes the economic, social and environmental impacts of second homes as well as their planning implications and places such discussions within the context of contemporary human mobility. The volume represents essential reading for those interested in rural regional development processes and the development of new rural leisure landscapes.
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