Allelic Frequency of DPYD Genetic Variants in Patients With Cancer in Spain: The PhotoDPYD Study.

INTRODUCTION: Identifying polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene is gaining importance to be able to predict fluoropyrimidine-associated toxicity. The aim of this project was to describe the frequency of the DPYD variants DPYD*2A (rs3918290); c.1679T>G (rs55886062); c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182; HapB3) in the Spanish oncological patients. MATERIAL AND METHODS: Cross-sectional and multicentric study (PhotoDPYD study) conducted in hospitals located in Spain designed to register the frequency of the most relevant DPYD genetic variants in oncological patients. All oncological patients with DPYD genotype were recruited in the participant hospitals. The measures determined where the presence or not of the 4 DPYD previously described variants. RESULTS: Blood samples from 8054 patients with cancer from 40 different hospitals were used to determine the prevalence of the 4 variants located in the DPYD gene. The frequency of carriers of one defective DPYD variant was 4.9%. The most frequently identified variant was c.1129-5923C>G (rs75017182) (HapB3), in 2.9%, followed by c.2846A>T (rs67376798) in 1.4%, c.1905 + 1G>A (rs3918290, DPYD*2A) in 0.7% and c.1679T>G (rs55886062) in 0.2% of the patients. Only 7 patients (0.08%) were carrying the c.1129-5923C>G (rs75017182) (HapB3) variant, 3 (0.04%) the c.1905 + 1G>A (rs3918290, DPYD*2A) and one (0.01%) the DPYD c.2846A>T (rs67376798, p.D949V) variant in homozygosis. Moreover, 0.07% were compound heterozygous patients, 3 carrying the DPYD variants DPYD*2A + c.2846A>T, 2 the DPYD c.1129-5923C>G + c.2846A>T and one the DPYD*2A + c.1129-5923C>G variants. CONCLUSIONS: Our results demonstrate the relatively high frequency of DPYD genetic variants in the Spanish patient with cancer population, which highlights the relevance of their determination before initiating a fluoropirimidine-containing regimen.

Efficacy and Safety of Erenumab, Galcanezumab, and Fremanezumab in the Treatment of Drug-Resistant Chronic Migraine: Experience in Real Clinical Practice.

BACKGROUND: Due to the recent introduction of new biologic drugs for chronic migraine, a global evaluation in real clinical practice is necessary. OBJECTIVE: The objective was to evaluate the effectiveness and safety in real clinical practice of drugs targeting the calcitonin gene-related peptide receptor (CGRPr) in patients with chronic migraine. METHODS: Single-center, restrospective study (2019-2022), including patients with chronic migraine treated with erenumab, galcanezumab, or fremanezumab. Effectiveness variables were recorded, namely, number of migraine headache days per month (MHD), Migraine Disability Assessment Scale (MIDAS) score, and Headache Impact Test-6 (HIT-6) score, assessing changes at week 12, 24 from baseline. Toxicity was recorded following the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. RESULTS: In all, 104 patients were included (46.2% erenumab, 41.3% galcanezumab, 12.5% fremanezumab). A reduction in MHD, MIDAS, and HIT-6 was achieved at weeks 12 and 24 with erenumab (p75% at week 24 than those intensified; P = 0.041). There was no difference in efficacy (P = 0.154) or improvement in quality of life (P = 0.783, P = 0.150), but there was greater toxicity (P < 0.001) among nonresponders with erenumab 70 mg versus erenumab 140 mg. CONCLUSIONS: The results confirm the effectiveness and safety of anticalcitonin gene-related peptide (CGRP) drugs in real clinical practice. However, the study shows little benefit from erenumab intensification, with similar effectiveness and worse tolerability than the standard dose.

Risk factors determining adherence to tyrosine kinase inhibitors in chronic myeloid leukaemia.

OBJECTIVE: Tyrosine kinase inhibitors (TKIs) have successfully changed the natural course of chronic myeloid leukaemia (CML). Although they are highly effective drugs, their clinical benefit is conditioned by adherence. This study aims to analyse the adherence of CML patients treated with TKIs and to identify the main factors influencing their adherence to TKIs treatment. MATERIAL AND METHODS: An 8-month prospective, observational, multicentre study which included patients diagnosed with CML on treatment with TKIs attending the outpatient departments (OPD) of the Pharmacy Services of the participating hospitals. Adherence was assessed using two methods: the Simplified Medication Adherence Questionnaire (SMAQ) and the register of treatment dispensations from the OPDs. To analyse the predictors of adherence, a questionnaire was developed to report demographic and socio-economic information on the patients. RESULTS: A total of 130 patients enrolled in this study. Adherence rate was 56.9% (n = 74) among individuals, not conditioned by the type of drug used: imatinib (54.8%), nilotinib (63.6%) or dasatinib (54.3%) (p = 0.67). The patient educational level (p = 0.047) and employment status (p = 0.028) were predictors of non-adherence to treatment. CONCLUSIONS: Adherence is one of the most relevant parameters affecting the effectiveness of highly effective chronic treatments. Approximately half of our patients showed inadequate adherence to treatment with TKIs, with employment status and the individual's level of education emerging as the determining factors.

Imatinib plasma levels in patients with chronic myeloid leukaemia under routine clinical practice conditions.

INTRODUCTION: The addition of imatinib to the therapeutic arsenal for chronic myeloid leukaemia (CML) has changed the natural course of the disease, in such a way that it is now considered a chronic pathology. However, to achieve therapeutic success, it is necessary to reach adequate plasma concentrations to ensure efficacy and safety.In this study, we aimed to evaluate the plasma concentration of imatinib, analysing its influence on effectiveness and safety in patients with CML. METHODS: We performed a descriptive, multicentre study in which imatinib plasma levels from patients diagnosed with CML between 2019-2020 were analysed. An optimal therapeutic range of 750-1500 ng/mL was established for the stratification of patients, according to their minimum plasma concentrations measured at steady state (Cssmin). RESULTS: A total of 28 patients were included, of whom only 39.3% (n = 11) showed Cssmin within the therapeutic range. 100% of patients with Cssmin >750 ng/mL achieved an optimal molecular response, while only 50% of patients with Cssmin <750 ng/mL achieved an optimal molecular response (p = 0.0004). The toxicity rate was 36.4% for patients with Cssmin >1500 ng/mL and 5.9% for those with Cssmin <1500 ng/mL (p = 0.039). CONCLUSIONS: This study aimed to describe the correlation between the toxicity and effectiveness of imatinib according to its Cssmin in routine clinical practice conditions. Based on our findings, it would be certainly justified to monitor patient plasma concentrations of imatinib on a daily routine basis in our hospitals.

A slowdown of hepatitis C diagnosis in high-prevalence groups and with decentralized diagnostic strategies during the COVID-19 pandemic.

INTRODUCTION: the COVID-19 pandemic has had a major impact on hepatitis C virus (HCV) diagnosis by hindering the path to elimination. Albeit, in an uneven manner, depending on the risk group and diagnostic strategy. METHODS: the requests of antibodies/RNA by venipuncture at hospitals and Primary Care centers (centralized) and via venipuncture or dried blood spot tests at prison and drug treatment centers referred for central processing (integrated decentralized) were recorded for one year, before and after the onset of the COVID-19 health crisis. RESULTS: a total of 20,600 tests (51 % male, 47.9 ± 1 5.8 years) were recorded. Among them, 96.5 % of the cases came from centralized and 3.5 % from decentralized settings, with an active infection rate of 0.2 % and 2.3 % (p < 0.001), respectively. There was a 31.3 % decrease in the number of requests during the pandemic compared to the pre-pandemic period, which was more pronounced in the decentralized than centralized diagnosis setting (60 vs 30 %, p < 0.001). In addition, there was a 31.5 % decline in screening and 18.2 % decrease in the diagnosis of new cases of active infection, with a statistically significant decrease in decentralized compared to centralized diagnosis. CONCLUSIONS: during the COVID-19 pandemic, a decline in HCV diagnostic effort was observed, especially in decentralized strategies, with a higher prevalence of infection. Our results suggest a diagnostic delay that will prevent Spain from reaching the elimination target in 2023. Therefore, the reactivation of strategies, particularly targeting the priority groups, is urgently required.

Patient-reported outcomes and digital literacy of patients treated in an oncology day hospital unit.

INTRODUCTION: Patient-reported outcomes (PROs) use, via a computer registry, allows patients to report their symptoms enabling the detection of early signs of progression of the disease. For such a record, the patient needs to show certain skills in new technologies use. The present study aimed to analyse the perception and degree of digital literacy of patients undergoing oncological treatment in an Oncology Day Hospital (ODH). METHODS: A cross-sectional descriptive study was performed, where the degree of literacy of patients attending antineoplastic treatment at the ODH was examined by means of an anonymous survey. RESULTS: A total of 122 patients have been included in the study. The proportion of subjects who use the electronic mail (TM) and the Internet on a daily basis was 45.1% and 70.5%, respectively, and up to 77.9% from the subjects considered that the use of digital 2.0 strategies could help improve communication between healthcare professional and patient.The TM was determined by the age, educational level and employment status of the individual. Furthermore, the age of the patients conditioned their perception of the usefulness of the web 2.0 tools (T2.0). CONCLUSION: This study allowed us to establish a target patient profile to conduct the efficient monitoring of cancer progression by PROs. The results have shown that approximately 60% of the patients in our population could be potential candidates to receive PROs-based health care. This approach enables earlier detection of symptoms and signs of progression and consequently, improves health outcomes for cancer patients.

Hepatitis C virus infection screening reduces mortality and is cost-effective independently of the intervention test.

INTRODUCTION: Chronic infection due to hepatitis C virus (HCV) is frequently asymptomatic even in advanced stages of liver disease. Implementation of a screening program based on different HCV tests may enable an earlier diagnosis of HCV liver disease and subsequent application of highly effective treatment. PATIENTS AND METHODS: A Markov model which compares three different screening strategies for hepatitis C versus no screening in low-risk prevalence (general population) and high-risk prevalence population (people who inject drugs or prison population) was designed, taking into account age at the start of screening and participation. The three strategies were: 1) serological detection of antibodies against the HCV, 2) dried blood spot test (DBS) to detect antibodies against HCV and 3) detection of RNA from HCV. Quality-adjusted life-years (QALY) were taken as a measurement of effectiveness. The incremental cost-effectiveness ratio (ICER) was calculated and a deterministic and probabilistic sensitivity analysis was performed. RESULTS: All three screening strategies were found to be cost-effective with an ICER of €13,633, €12,015 and €12,328/QALY for AntiHCV, DBS-AntiHCV and DBS-RNA HCV, respectively. There was a decrease in mortality due to liver disease in comparison to no screening for AntiHCV (40.7% and 52%), DBS-AntiHCV (45% and 80%) and DBS-RNA HCV (45.2% and 80%) for low-prevalence and high-prevalence populations, respectively. CONCLUSION: All test interventions for HCV screening are cost-effective for the early detection of HCV infection, also achieving a reduction in mortality. Thus, implementation of screening programs for HCV should not be halted by decisions on monetary policy.

Adherence to subcutaneous biologic treatment for inflammatory bowel disease.

BACKGROUND: Nonadherence to medication is common in patients with inflammatory bowel disease (IBD) and can result in disease complications, therapy escalation, and the need for corticosteroids. The aim of this study was to assess the adherence to self-administered subcutaneous biologic medications prescribed for IBD and to identify the risk factors for nonadherence. METHODS: A retrospective cohort study on IBD patients initiated on subcutaneous biologic therapy between January 2016 and July 2019 was performed. Medical records were retrospectively reviewed for collection of demographic and IBD data. Medication possession ratios (mMPRs) during the first 12 months of treatment and at the end of the follow-up period (global, 42 months) were calculated. Nonadherence was defined as an mMPR of <90%. Multiple regression analysis was performed to assess the risk factors for nonadherence to therapy. RESULTS: A total of 154 patients (84 male and 70 female; mean age at biologic treatment initiation, 36±14 years; Crohn's disease, n=118; ulcerative colitis, n=31; indeterminate colitis, n=5) were included; 121 received adalimumab (ADA) and 33 received ustekinumab (UST); 63% were naive to anti-TNF therapy, while 16.9% previously received more than two biologic treatments. Mean time from IBD diagnosis to subcutaneous biological agent use was 16±10 months. Mean duration of subcutaneous agent use was 17.6 (SD, 11.0) and 17.08 (SD, 6.8) months for ADA and UST, respectively. Global nonadherence (mMPR≤90%) rate was 6.6% for all patients receiving subcutaneous treatment, 6.3% for ADA, and 6.5% for UST. Nonadherence during the first 12 months of treatment (n=98) was 6.1% for all patients, 2.7% for ADA, and 16% for UST. In the multivariate analysis, UST use was independently associated with higher nonadherence only within the first 12 months (OR, 6.7; 95% CI, 1.1-39.5). CONCLUSIONS: High global adherence to self-administered subcutaneous biologic treatment was shown in our study, with higher rates of adherence to ADA than to UST within the first 12 months.

Extended enzymatic stability of reconstituted lyophilized PEG-asparaginase in vials.

Asparaginase (ASNase) use as a tumour-inhibitor drug has changed completely the natural course of paediatric acute lymphoblastic leukaemia (ALL) in such a way that it represents a paradigm shift in ALL management. ASNase treatment emergence has significantly improved pathologic responses and increased survival rates of ALL patients. Although different ASNase forms are currently available, only the pegylated form (PEG-ASNase) is recommended by relevant clinic guides. PEG-ASNase form shows longer elimination half-life, reducing the number of administrations, along with an enhanced safety profile. In spite of all of these advantages, PEG-ASNase elevated cost limits enormously its use. PEG-ASNase is commercialised as a lyophilised powder which according to the manufacturer it is stable for 24 hours once reconstituted, as a result, the leftover is usually discarded. In this study we analysed the enzymatic stability of reconstituted PEG-ASNase after conservation in three different temperature conditions for 5 and 14 days, aiming to take advantage of the remaining leftover for the subsequent administration. Our results have shown that PEG-ASNase is stable at 4°C, -20°C and -80°C for at least 14 days, retaining the 95% from the initial enzymatic activity in all three storage temperatures. According to our results, it is feasible to reuse the remaining content of PEG-ASNase vial after reconstitution, which means a 50% reduction of its cost for paediatric patient treatment and, consequently, removes the main barrier to use this drug in a wider population.

Pharmacokinetics of Trastuzumab After Subcutaneous and Intravenous Administration in Obese Patients.

Background: Subcutaneous trastuzumab (T-SC) administration does not allow the historical target concentration of 20 µg/mL for efficacy to be reached, from the start of treatment in patients with a body mass index (BMI) >30 kg/m2. Objectives: To analyze the influence of the strategy of dosification (fixed vs adjusted patient's body weight dose) on the initial minimum plasma concentration (Cmin) of trastuzumab in obese patients. Methods: This was an observational, prospective study, which included patients with HER2-positive nonmetastatic breast cancer treated with trastuzumab. The determination of the Cmin of trastuzumab was performed on day +21 of the first cycle using the ELISA technique. Patients were stratified according to the strategy of dosification and BMI. Results: A total of 50 patients were included; 16 patients received the drug intravenously and 34 in a fixed dosage subcutaneous (T-SC) regimen. The proportion of patients who achieved an adequate plasma concentration since the beginning of treatment was significantly higher when the drug was administered intravenously (93.8% vs 67.6%, P = 0.042). These differences are especially greater in T-SC patients with BMI >30 kg/m2, with only 20% of patients exceeding the pharmacokinetic target. Conclusion and Relevance: Our study suggests that trastuzumab SC fixed dose of 600 mg is not equivalent to IV administration, especially in obese patients. An adequate trastuzumab exposure in this population needs patient weight-adjusted IV dosage in the first administration. The clinical relevance of these findings remains to be elucidated, and further research, including larger controlled trials, is warranted.

Influence of Anthropometric Characteristics in Patients With Her2-Positive Breast Cancer on Initial Plasma Concentrations of Trastuzumab.

BACKGROUND: Plasma concentrations of trastuzumab <20 µg/mL in patients with gastric cancer are associated with reduced progression-free and overall survival. In breast cancer treatment, this relationship has not yet been studied, but a suboptimal pharmacodynamic exposure to trastuzumab could be a reason for therapeutic failure of treatment of HER2-positive breast cancer. OBJECTIVE: The objective of the present study was to determine the proportion of nonmetastatic HER2-positive breast cancers that do not reach a minimum plasma concentration ( Cmin) of 20 µg/mL after first drug administration, established as therapeutically effective in clinical trials. The secondary objective was to identify the physiological and anthropometric characteristics that determine interindividual pharmacokinetic variability. METHODS: Serum concentrations of trastuzumab were assessed by ELISA on day 1 of the second cycle before administration of the second dose ( Cmin). RESULTS: Of 19 patients included, 9 (47.4%) had a mean Cmin of 19.0 µg/mL (±12.1) after the first administration. Body mass index (BMI) and weight was the main variable that determined the achievement of therapeutic levels after the first administration. Thus, the proportion of patients reaching the target concentration was 89% when BMI was ≤30 kg/m2 but only 11% when BMI was >30 kg/m2 ( P < 0.01). CONCLUSIONS: The standard dose of 600 mg subcutaneous trastuzumab did not ensure adequate pharmacodynamic exposure from the first administration in 52% of patients, with weight and BMI being related to the plasma levels obtained.

5-fluorouracil toxicity in the treatment of colon cancer associated with the genetic polymorphism 2846 A>G (rs67376798).

Colorectal cancer is the second most common cancer in Europe. Most antineoplastic regimens in first-line treatment involve 5-fluorouracil or oral prodrug capecitabine, combined with other antineoplastic agents such as oxaliplatin or irinotecan. It is well known that 5-fluorouracil and capecitabine are agents that can be toxic in cases of decreased dihydropyrimidine dehydrogenase activity because this enzyme is the main limiting factor in the metabolism of both agents. In this paper, we describe the case of a patient who developed severe toxicity to 5-fluouracil and who had a mutation in the gene encoding the enzyme dihydropyrimidine dehydrogenase.

Long-term effectiveness and safety of tolvaptan in autosomal dominant polycystic kidney disease.

BACKGROUND AND OBJECTIVES: Evidence on the long-term use of tolvaptan in autosomal dominant polycystic kidney disease (ADPKD) is limited. The aim was to evaluate the tolvaptan effectiveness and safety in real clinical setting. MATERIAL AND METHODS: A single-center observational study (2016-2022) involving ADPKD patients treated with tolvaptan was conducted. Annual change in serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) before and after treatment initiation were evaluated. Change in total kidney volume (TKV), blood pressure (BP) and urinary albuminuria at 12, 24 and 36 months after initiation were also determined. Adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 were analyzed. RESULTS: A total of 22 patients were included. No significant differences pre- vs post tolvaptan treatment in annual rate of change in eGFR (-3.52ml/min/1.73m2 [-4.98%] vs -3.98ml/min/1.73m2 [-8.48%], p=0.121) and sCr (+0.06mg/dL [4.22%] vs +0.15mg/dL [7.77%], p=0.429) were observed. Tolvaptan improved urinary osmolality at 12 (p=0.019) and 24 months (p=0.008), but not at 36 months (p=0.11). There were no changes in TKV, BP control and urinary albuminuria at 12, 24 or 36 months. A worse response was shown in patients with rapid kidney function decline (p=0.042). A 36.4% of the patients developed grade III/IV AEs. A 22.7% discontinued treatment due to unacceptable toxicity. CONCLUSIONS: This study shows a modest benefit of tolvaptan in ADPKD patients, as well as safety concerns.

Definition of a therapeutic range for predicting long-term infliximab response in patients with inflammatory bowel disease.

INTRODUCTION: Monitoring plasma levels of Infliximab plays an important role in optimising treatment in patients with inflammatory bowel disease (IBD). The aim of the following study has been to determine the predictive potential of monitoring infliximab plasma levels for sustained clinical response and evaluate its usefulness to improve treatment efficacy and symptom control, in patients with IBD. METHODS: This single-centre retrospective study (2017-2019) included patients diagnosed with IBD treated with infliximab. Serum levels and the occurrence of drug-associated immunogenicity were analysed at Week 8 post-induction and 6, 12 and 24 months. Clinical parameters and inflammatory markers were recorded such as subjective global assessment (SGA), C-reactive protein (CRP) and faecal calprotectin (FC). Factors associated with early discontinuation and dose intensification of infliximab were determined. RESULTS: Multivariate analysis determined that IFX concentrations>7µg/mL at week 8, and at 6 months, are associated with inflammatory remission (p=0.046, 0.045). IFX>7µg/mL at 12 months predicted remission at 18 months of treatment (p=0.006). IFX values>3µg/mL at 12 months are associated with stable SGA at 18 months (p=0.001). Such values at 18 months are associated with stable SGA at 24 months (p=0.044). CONCLUSIONS AND RELEVANCE: The predictive potential of monitoring IFX plasma levels as a strategy to evaluate sustained long-term clinical response was confirmed. Our results highlight the importance of its introduction into routine clinical practice to enable early identification of non-responders, treatment optimisation, relapse prevention and improve long-term therapy maintenance.

Effect of Concomitant Use of Proton Pump Inhibitors on Immunotherapy Clinical Response in Advanced Cancer Patients: Real-Life Setting.

The alteration of the gut microbiota mediated by proton pump inhibitor (PPI) drugs could be involved in the clinical response associated with immunotherapy [immunocheckpoint inhibitors (ICIs)] in cancer patients. Due to the current controversy in the scientific evidence, it has been proposed to evaluate the correlation between the concomitant use of PPIs and the effectiveness of immunotherapy in a real clinical practice setting. Single-center retrospective cohort study that included patients treated with anti-PD-1 or anti-CTLA4, including nivolumab, pembrolizumab, atezolizumab, or the combination ipilimumab-nivolumab in metastatic neoplastic disease. The clinical effectiveness of ICI, measured in progression-free survival (PFS) and overall survival (OS), was compared between the PPI-use versus PPI-no-use group. PPI-use group was associated with lower PFS [hazard ratio (HR):1.89 (1.38-2.59), P<0.001] and OS [HR: 2.02 (1.45-2.82), P<0.001] versus PPI-no-use group. However, this difference was not observed for pembrolizumab PFS [HR: 1.38 (0.93-2.39), P=0.160] and OS [HR: 1.41 (0.81-2.44), P=0.187]. The study showed significantly lower PFS and OS in the chronic PPI-use group (P<0.001), recent PPI-use group (P<0.001) and concomitant PPI-use group (P=0.001, 0.007) versus PPI-no-use group. However, late PPI use >30 days after the onset of ICI has no significant effect on the efficacy of treatment [HR: 0.92 (0.49-1.70), P=0.791; HR: 1.10 (0.59-2.05), P=0.756]. The concomitant use of PPIs in immunotherapy is associated with worse clinical outcomes compared with the group without PPI use. In addition, the study shows how the late use of PPIs does not have a significant effect on clinical benefit.

Efficacy and safety of high doses of irinotecan in patients with metastatic colorectal cancer treated with the FOLFIRI regimen based on the UGT1A1 genotype: A systematic review.

OBJECTIVE: The purpose of this systematic review is to analyze the published data on the efficacy and safety of doses higher than 180 mg/m2 of irinotecan recommended in the drug's summary of product characteristics in  metastatic colorectal cancer patients with genotypes UGT1A1*1/*1 or *1/*28  who are treated with the FOLFIRI regimen. METHOD: A systematic review of the literature was carried out in Medline and  Embase searching for articles published up to December 2021. The methods  used were based on the recommendations of the Preferred Reporting Items for  Systematic Reviews and Meta-Analyses (PRISMA) statement. The criteria  for the inclusion of studies were previously defined based on the two secondary goals addressed in this review: 1) To analyze the magnitude of the differences  in clinical responses and 2) To study the magnitude of the differences in  adverse effects of irinotecan at high doses, as compared to the doses  described in the summary of product characteristics corresponding to the  FOLFIRI regimen in patients with metastatic colorectal cancer with genotypes  UGT1A1*1/* 1 or *1/*28. RESULTS: The search yielded a total of 985 references, of which 13 were selected for analysis. Seven evaluated both efficacy and safety and six  only safety. With regard to the studies that evaluated both efficacy and safety,  six out of seven (85.7%) were in favor of increasing irinotecan dose according  to the objective response rate and progression-free survival. Two of them even  recommended dose increases based on overall survival. Irinotecan safety  studies suggest that doses higher than 180 mg/m2 are tolerated by  most UGT1A1*1/*1 and *1/*28 patients. CONCLUSIONS: The present systematic review shows the advisability of considering adjusting the dose of irinotecan when used as part of the FOLFIRI regimen based on the polymorphisms of the UGT1A1 gene as this may increase the likelihood of an adequate clinical response.

OBJETIVO: El objetivo de la presente revisión sistemática es analizar los datos  publicados sobre la eficacia y seguridad de las dosis superiores a los 180  mg/m2 de irinotecán recomendadas en la ficha técnica en pacientes con cáncer  colorrectal metastásico tratados con el esquema FOLFIRI y con  genotipo UGT1A1*1/*1 y *1/*28.Método: Se realizó una revisión sistemática mediante una búsqueda bibliográfica en Medline y Embase de los artículos publicados hasta diciembre de 2021. Los métodos utilizados se basaron en los  recomendados según Preferred Reporting Items for Systematic Reviews and  Meta-Analyses (PRISMA). Los criterios para la inclusión de los estudios se  definieron previamente en base a los dos objetivos secundarios que aborda  esta revisión: 1) Analizar la magnitud de la diferencia de la respuesta clínica y 2) estudiar la magnitud de la diferencia de los efectos  dversos a irinotecán a dosis altas, en comparación con las dosis descritas en la ficha técnica para el esquema FOLFIRI en pacientes con cáncer colorrectal metastásico con el genotipo UGT1A1*1/*1 o *1/*28. RESULTADOS: La estrategia de búsqueda reportó un total de 98 referencias, de  las que 13 fueron seleccionadas para el análisis, 7 (53,8%)  evaluando tanto  eficacia como seguridad y 6 (46,2%) únicamente seguridad. En relación con  los estudios que evaluaron eficacia y seguridad, 6 (85,7%) se mostraron  favorables al aumento de dosis en términos de tasa de respuesta objetiva y  supervivencia libre de progresión e, incluso, en 2 de ellos en supervivencia  global. Los estudios que evaluaron seguridad apuntan a que dosis de irinotecán  superiores a 180 mg/m2 son toleradas por la mayor parte de los  pacientes UGT1A1*1/*1 y *1/*28. CONCLUSIONES: La presente revisión sistemática muestra la conveniencia de  valorar el ajuste de dosis de irinotecán dentro del esquema FOLFIRI en función  de los polimorfismos del gen UGT1A1, con un potencial aumento de  las probabilidades de una adecuada respuesta clínica.

Biomarkers for characterization and therapeutic orientation in castration-resistant prostate cancer. / Biomarcadores para la caracterización y orientación terapéutica en Cáncer de Próstata Resistente a la Castración (CPRC).

Whole exome sequencing studies haverevealed the molecular landscape of metastatic CastrateResistant Prostate Cancer (mCRPC) providingnew information about prognostic and predictive factorsof response to therapies. These studies highlightedpotentially actionable targets leading to the beginingof the biomarker-driven era in prostate cancer.Alterations in androgen receptor (AR), DNA repair genes,PI3K-AKT-MTOR pathway or in genes involved incell cycle are frequently observed in mCRPC patientsand may be relevant in the resistance induced mechanismto approve therapy in this setting. Poly(ADP-ribose)polymerase (PARP) inhibitor in BRCA mutatedpatients, pembrolizumab (inmune checkpoint inhibitors)in mCRPC patients with mismatch repair genedefects and microsatellite instability and ipatasertib(AKT inhibitor) in patients with loss of function inPTEN are examples on how molecular information canbe useful to improve treatment selection. Nonethelessthe heterogeneity of advanced PC, the lack of consensusregarding the optimal biological source of analysisand the optimal time and technique for the analisysare still challenges that need to be defined in the nextfuture. The aim is to review the current literature concerningprognostic and predictive marker of responseto therapies in the mCRPC setting.

Estudios de secuenciación completa delexoma han revelado el perfil molecular del pacientecon Cáncer de Próstata Resistente a la Castración metastásico(CPRCm) proporcionando nueva informaciónsobre factores pronósticos y predictivos de respuestaa las distintas alternativas terapéuticas. Muchos deestos estudios han resaltado numerosas dianas molecularesaccionables desde un punto de vista farmacológico,conduciéndonos al comienzo de la medicina deprecisión en el Cáncer de Próstata (CP). Alteracionesen el Receptor de Andrógenos (RA), en genes reparadoresde DNA, en la vía de PI3K-AKT-MTOR o en genesimplicados en el ciclo celular son frecuentementeobservadas en CPRCm y pueden ser relevantes en la selección terapéutica y en la comprensión de los mecanismosde resistencia.Los inhibidores de la poli (ADP-ribosa) polimerasaen pacientes con mutaciones en BRCA, pembrolizumab(inhibidor de los puntos de control inmunológico)en pacientes CPRCm con alteraciones en genesimplicados en el "mismatch repair" o inestabilidad demicrosatélites e ipatasertib (inhibidor de AKT) en pacientescon pérdida de función de PTEN son ejemplosde cómo la información molecular puede ser útil paraoptimizar la selección terapéutica en este escenario.No obstante, la heterogeneidad del CP avanzado, lafalta de consenso sobre la fuente biológica óptima parael análisis, el momento y la técnica de análisis continúansiendo desafíos a definir en un fututo próximo.El objetivo es revisar la literatura actual sobre marcadorespronósticos y predictivos de respuesta a tratamientoen el entorno del CPRCm.

Assessment of exposure-response relationship for cetuximab in patients with metastatic colorectal cancer and head and neck cancer.

OBJECTIVE: There is limited scientific evidence on the cetuximab exposure-response relationship and no concentration threshold has been associated with optimal disease control. The aims were to assess, in a real-life setting, the  relationship between steady state cetuximab concentrations (Ctrough, SS) and  disease control. METHOD: A prospective observational study in patients with metastatic colorectal cancer or head and neck cancer treated with cetuximab.  Steady state trough concentrations were compared with the results of  radiological assessment of response (progression or clinical benefit).  Generalized estimating equations analysis was performed. To test the  association between steady state concentrations and overall survival and  progression-free survival, Cox proportional hazard models were developed. An  optimal cut-off point was searched using the area under the receiver operating  characteristic curve. RESULTS: A total of 30 steady state cetuximab concentrations from 16 patients  were analysed. Median Ctrough, SS was 26.86 mg/L and there was marked  inter- and intraindividual variability (standard deviation 32.4 mg/L and 16.9 mg/L, respectively). A positive association was found between cetuximab  Ctrough, SS and clinical benefit (odds ratio 1.24, 95% confidence interval:  0.95-1.63, p = 0.113), although without reaching statistical significance. The  area under the receiver operating characteristic curve (n = 30) had moderate  discrimination power (0.71; 95% confidence interval 0.49­0.93), and the  empirical optimal cutoff point was 19.12 mg/L. However, no association was  observed between cetuximab Ctrough, SS and survival in metastatic colorectal  cancer or neck cancer patients. CONCLUSIONS: We cannot confirm a relationship between cetuximab Ctrough,  SS and disease control despite a positive association. This study was  conducted with a small sample, which reduces the power analysis. Further  controlled randomised studies with a sufficient number of patients are needed.

OBJETIVO: Evaluar, en condiciones de vida real, la relación entre las concentraciones valle en estado estacionario de cetuximab y el control de  la enfermedad, así como buscar la relación entre estas concentraciones y la supervivencia. Además, estudiar si existe una concentración límite que se  pueda asociar con la probabilidad de beneficio clínico.Método: Estudio observacional prospectivo llevado a cabo en pacientes con  cáncer colorrectal metastásico o cáncer de cabeza y cuello en tratamiento con  cetuximab. Se realizó un análisis de regresión de ecuaciones de estimación  generalizadas para evaluar la asociación entre la concentración valle en estado  estacionario de cetuximab y la respuesta al tratamiento (progresión o beneficio  clínico). Mediante modelos de riesgos proporcionales de Cox, se  evaluó la asociación entre la mediana de concentraciones valle en estado  estacionario de cetuximab en cada paciente o la última medida con la  supervivencia global y la supervivencia libre de progresión, en cada una de las  patologías. Asimismo, se buscó un punto de corte óptimo a través del área  bajo la curva de características operativas del receptor. RESULTADOS: Se analizaron 30 muestras de 16 pacientes. La concentración valle en estado estacionario mediana fue 26,86 mg/l y se  encontró una gran variabilidad inter e intraindividual (desviación estándar de  32,4 y 16,9 mg/l, respectivamente). Se observó una asociación positiva entre  la concentración valle en estado estacionario y el beneficio clínico (odds ratio  1,24; intervalo de confianza del 95%: 0,95-1,63; p = 0,113), aunque no alcanzó significación estadística debido a la baja potencia. El área bajo la  curva de características operativas del receptor de las concentraciones (n =  30) tuvo una moderada capacidad discriminatoria (área bajo la curva de  características operativas del receptor 0,710; intervalo de confianza del 95%:  0,49-0,93) y el punto de corte estimado fue de 19,12 mg/l. Sin embargo, no  se observó relación entre la supervivencia y las concentraciones valle en  estado estacionario en ninguna de las patologías. CONCLUSIONES: No se ha podido confirmar una relación entre exposición a  cetuximab y eficacia, a pesar de encontrar una tendencia positiva en el control  de la enfermedad con el aumento de la concentración valle en estado  estacionario. El nivel de evidencia se vio reducido por la pequeña muestra de  pacientes en cada grupo, por lo que se necesitan estudios aleatorizados y  controlados, con un número suficiente de pacientes, para evaluar  adecuadamente esta relación.

Assessment of exposure-response relationship for bevacizumab in patients with metastatic colorectal cancer.

Limited literature is available for bevacizumab exposure-response relationship and there is not a concentration threshold associated with an optimal disease control. This prospective observational study in patients with metastatic colorectal cancer (mCRC) aims to evaluate, in a real-life setting, the relationship between bevacizumab through concentrations at steady state (Ctrough, SS) and disease control. Ctrough, SS were drawn, coinciding with the radiological evaluation of the response (progression or clinical benefit). Generalized estimating equations (GEE) analysis was performed. To test the association between Ctrough, SS in each patient with overall survival (OS) or progression-free survival (PFS), Cox proportional hazard models were developed. Data included 50 bevacizumab Ctrough, SS from 27 patients. The GEE model did not suggest any positive association between bevacizumab Ctrough, SS and clinical benefit (OR 0.99, 95% CI: 0.98-1.02, p = 0.863). The Cox regression showed association between higher median Ctrough, SS with better OS (HR 0.86, 95% CI: 0.73-1.01, p = 0.060), but not with PFS. We cannot confirm a relationship between bevacizumab Ctrough, SS and clinical benefit but this is the first real-world study trying to show a relationship between bevacizumab Ctrough, SS and disease control in mCRC. It was conducted in a small sample size which reduces the level of evidence. Further controlled randomized studies with a sufficient number of patients are required.

Extended Stability of Reconstituted Lyophilized Erwinia L-asparaginase in Vials.

BACKGROUND/AIM: L-Asparaginase (L-ASNase) is used as a tumor-inhibitory drug on paediatric acute lymphoblastic leukemia (ALL). ERW-ASNase is commercialised as a lyophilized powder stable only for 8 hours once reconstituted and, consequently, the leftover is usually discarded. The aim of this study will be to analyse the stability of the reconstituted lyophilised ERW-ASNase. MATERIALS AND METHODS: In the present study, we analysed the enzymatic stability of reconstituted ERW-ASNase after conservation in three different temperature conditions for 2 and 5 days. RESULTS: Our results show that ERW-ASNase is stable at 4°C, -20°C and -80°C for up to 5 days, retaining 95% of the initial enzymatic activity in all three storage temperatures tested. CONCLUSION: It is feasible to reuse the remaining content of ERW-ASNase vial after reconstitution, which allows the optimization of the content of ERW-ASNase vials use and reduces the cost of this formulation usage, making it more accessible.