Levels of evidence and grades of recommendation supporting European society for medical oncology clinical practice guidelines.

Background: The European Society for Medical Oncology (ESMO) guidelines are among the most comprehensive and widely used clinical practice guidelines (CPGs) globally. However, the level of scientific evidence supporting ESMO CPG recommendations has not been systematically investigated. This study assessed ESMO CPG levels of evidence (LOE) and grades of recommendations (GOR), as well as their trends over time across various cancer settings. Methods: We manually extracted every recommendation with the Infectious Diseases Society of America (IDSA) classification from each CPG. We examined the distribution of LOE and GOR in all available ESMO CPG guidelines across different topics and cancer types. Results: Among the 1,823 recommendations in the current CPG, 30% were classified as LOE I, and 43% were classified as GOR A. Overall, there was a slight decrease in LOE I (-2%) and an increase in the proportion of GOR A (+1%) in the current CPG compared to previous versions. The proportion of GOR A recommendations based on higher levels of evidence such as randomized trials (LOE I-II) shows a decrease (71% vs. 63%, p = 0.009) while recommendations based on lower levels of evidence (LOE III-V) show an increase (29% vs. 37%, p = 0.01) between previous and current version. In the current versions, the highest proportion of LOE I (42%) was found in recommendations related to pharmacotherapy, while the highest proportion of GOR A recommendations was found in the areas of pathology (50%) and diagnostic (50%) recommendations. Significant variability in LOE I and GOR A recommendations and their changes over time was observed across different cancer types. Conclusion: One-third of the current ESMO CPG recommendations are supported by the highest level of evidence. More well-designed randomized clinical trials are needed to increase the proportion of LOE I and GOR A recommendations, ultimately leading to improved outcomes for cancer patients.

Prolonged Proton Pump Inhibitor Use and Thrombohemorrhagic Risk in Essential Thrombocythemia and Polycythemia Vera Patients Treated with Long-Term Aspirin: A Pilot Study.

INTRODUCTION: Proton pump inhibitors (PPIs) are known to decrease the risk of gastrointestinal (GI) bleeding. However, concerns have been raised regarding the potential pharmacodynamic interactions of PPIs and antiplatelet drugs with respect to cardiovascular risk. Patients with BCR::ABL1-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET), and polycythemia vera (PV) often suffer from peptic ulcer disease (PUD) and frequently receive low-dose aspirin due to an intrinsically high thrombotic risk. METHOD: This retrospective multicenter study from a community setting investigated whether continuous PPI use may affect thrombohemorrhagic risk in ET and PV patients treated with long-term aspirin. RESULTS: Ninety-four aspirin-treated MPN patients (ET = 36, PV = 58) were included; median age was 69.5 years (range 21-92) and 40 (42.6%) were males. Nineteen (20.2%) patients continuously received PPIs and pantoprazole (n = 15, 78.9%) was the most frequently received PPI. PV phenotype (p = 0.085), male sex (p = 0.011), and prior thrombosis (p = 0.005) were associated with PPI use, whereas no correlations were found with respect to age, disease risk, splenomegaly, mutational status, constitutional symptoms, cardiovascular risk factors, cytoreductive treatment, or any of the blood cell counts (p > 0.050 for all analyses). The median follow-up time was 55.5 months; 19 (20.2%) thrombotic and 13 (13.8%) bleeding events occurred during this time. The use of PPIs was not associated with an increased risk of thrombosis (p = 0.158) or overall bleeding (p = 0.229) and none of the patients treated with PPIs experienced GI bleeding. CONCLUSIONS: Considering that Helicobacter pylori infection and PUD are quite frequent in ET and PV patients, these preliminary results may provide some reassurance to physicians regarding the absence of thrombohemorrhagic risk associated with prolonged PPI use in MPN patients treated with long-term aspirin. Our observations may be even more important in the light of recent evidence suggesting suboptimal platelet inhibition in ET with once-daily when compared to twice- or triple-daily aspirin which may also cause more abdominal discomfort. Limitations of this study are its retrospective design, limited number of patients included, and the lack of pharmacodynamic and pharmacokinetic assessments.

Polypharmacy, Potentially Inappropriate Medications, and Drug-to-Drug Interactions in Patients with Chronic Myeloproliferative Neoplasms.

Polypharmacy, potentially inappropriate medications (PIMs), and drug-to-drug interactions (DDIs) are highly prevalent in the elderly and may have adverse effects on health-related outcomes. Their occurrence and clinical and prognostic associations in patients with chronic myeloproliferative neoplasms (MPN) are unknown. We retrospectively evaluated polypharmacy, PIMs, and DDIs in a cohort of 124 MPN patients (essential thrombocythemia, ET = 63, polycythemia vera, PV = 44, myelofibrosis = 9, MPN unclassifiable = 8) from a single community hematology practice. There were 761 drug prescriptions with a median of five prescribed medications per patient. Polypharmacy, at least one PIM (calculated for persons >60 years of age, n = 101), and at least one DDI were recorded in 76 (61.3%), 46 (45.5%), and 77 (62.1%) of patients, respectively. Seventy-four (59.6%) and twenty-one (16.9%) patients had at least one C or at least one D interaction, respectively. Among other associations, polypharmacy and DDIs were associated with older age, management of disease-related symptoms, osteoarthritis/osteoporosis, and different CV disorders. In multivariate analyses adjusted for clinically meaningful parameters, both polypharmacy and DDIs were significantly associated with inferior overall survival (OS) and time to thrombosis (TTT), whereas PIMs had no significant associations with neither OS nor TTT. There were no associations with bleeding or transformation risks. Polypharmacy, DDIs, and PIMs are very frequent among MPN patients and may have important clinical associations.

Evaluating ropeginterferon alfa-2b for the treatment of adults with polycythemia vera.

INTRODUCTION: Interferons (IFNs) have been used for decades to treat polycythemia vera (PV). Single-arm clinical trials assessing IFN in PV patients demonstrated high hematological and molecular response rates, indicating potential disease-modifying activity of IFN. However, discontinuation rates of IFNs have been rather high due to frequent treatment-related side-effects. AREAS COVERED: Ropeginterferon alfa-2b (ROPEG) is a monopegylated IFN consisting of a single isoform, which differentiates it from previous IFNs with respect to tolerability and dosing frequency. ROPEG has improved pharmacokinetic and pharmacodynamic properties, which allow extended dosing every 2 weeks and monthly administration during maintenance phase. This review covers ROPEG's pharmacokinetic and pharmacodynamic properties, presents results of randomized clinical trials (RCT) that evaluated ROPEG in the treatment of PV patients, and discusses contemporary findings regarding the potential disease-modifying activity of ROPEG. EXPERT OPINION: RCT have demonstrated high rates of hematological and molecular responses in PV patients treated with ROPEG, irrespective of thrombotic risk. Drug discontinuation rates were generally low. However, even though RCT captured the most important surrogate endpoints of thrombotic risk and disease progression in PV, they were not statistically powered to fully determine whether therapeutic intervention with ROPEG indeed has a direct positive effect on these important clinical outcomes.

Immune-mediated platelet transfusion refractoriness in a severely thrombocytopenic patient with myelodysplastic syndrome successfully treated with romiplostim.

Immune-mediated platelet transfusion refractoriness due to anti-human leukocyte antigen (HLA) antibodies can occur in approximately 9% of patients with myelodysplastic syndromes (MDS) and can lead to an increased risk of clinically relevant bleeds and treatment delays. These patients are typically managed with frequent platelet transfusions; however, HLA-matched platelet transfusions are usually available only in large blood centers. For this reason, alloimunized thrombocytopenic MDS patients are notoriously difficult to manage. Here, we present a case of a MDS patient with an immune-mediated platelet transfusion refractoriness, severe thrombocytopenia and spontaneous subarachnoid hemorhage who we successfully treated with romiplostim, a thrombopoietin receptor agonist.

The effect of PARP inhibitors in homologous recombination proficient ovarian cancer: meta-analysis.

BRCA1/2 mutations and homologous recombination deficiency (HRD) predispose to increased sensitivity to poly(ADP-ribose)polymerase (PARP) inhibitor treatment. Our aim was to evaluate the PARP inhibitors effect on progression free survival (PFS) in a subpopulation with homologous recombination proficient status (HRD-BRCA-). A systematic literature search was performed for all studies reporting on the effect of PARP inhibitors regarding PFS in the HRD-BRCA- subpopulation, in patients with epithelial ovarian, tubal or primary peritoneal cancers (EOC). Five studies were included, enrolling a population of 3413 patients, with 1070 of them being HRD-BRCA-. PARP inhibitors were effective in the treatment of EOC, regardless of HRD and BRCA status or line of therapy. The estimated pooled effect hazard ratio (HR), assessing PFS for PARP inhibitors compared with control, was 0.76 (95% CI: 0.65-0.88, I2 = 46%) in the HRD-BRCA- subpopulation. Comparing both subpopulations with HRD positive status (HRD+ BRCA+, HRD+ BRCA-) versus the HRD-BRCA-subpopulation, we have found statistically significant differences in the effect on PFS (P < 0.05 for every interaction test) favouring HRD positive subpopulations (HRD+ BRCA+, HRD+ BRCA-). In the HRD-BRCA- subpopulation of patients, PARP inhibitors used as the second- or later-line of therapy showed more pronounced effect then when given as first line treatment (P = 0.04). Treatment of EOC with PARP inhibitors showed a significant effect regarding PFS in the HRD-BRCA- subpopulation, although a much higher benefit was evident for patients with HRD+ status (HRD+ BRCA+ and HRD+ BRCA-). In the HRD- subpopulation second line PARP inhibitor treatment showed greater benefit compared to first line PARP inhibitor treatment.

Scurvy.

Dear Editor, Scurvy is a nutritional disorder which can develop after prolonged (>1-3 months) severe vitamin C deficiency. Vitamin C is a cofactor in several enzyme reactions involved in collagen synthesis. The defect in collagen causes blood vessel fragility, poor wound healing, mucocutaneous bleedings, hair abnormalities, bone pains, and joint contractures due to periosteal and intraarticular bleeding (1,2). Risk factors for scurvy development are undernutrition, low socioeconomic status, older age, male sex, alcoholism, tobacco smoking, and severe psychiatric illnesses (1-3). The required daily intake for vitamin C is ~60 mg, and this amount of vitamin C can be found in only one medium-sized orange. For this reason, the disease is rarely encountered in developed countries and is often underrecognized by healthcare personnel. Herein, we present an illustrative case of scurvy in order to raise the awareness of this disorder. A 61-year-old Caucasian man was admitted to hospital due to fatigue, hypotension (80/50 mmHg), severe normocytic anemia (hemoglobin 76 g/L), kidney failure (estimated glomerular filtration rate of 6 mL/min/1.73m2) and mild elevation in C-reactive protein (30.9 mg/L). Prior medical history included radical cystoprostatectomy with an ileal conduit performed eight years ago due to a bladder tumor and moderate chronic kidney disease with recurrent urinary tract infections. The patient was also an alcoholic and tobacco smoker, with a very low-income and a poor diet. He did not use any medications. Heteroanamnestically, the current clinical state had developed slowly over several weeks. At admission, the patient was afebrile, lethargic, malnourished, and immobile due to generalized weakness, bone pains, and hip and knee contractures. He had generalized edema, mostly related to kidney failure, as well as severe hypoalbuminemia (serum albumin 19 g/L). There were multiple ecchymoses (Figure 1, a) and perifollicular bleedings (Figure 1, b) in the skin. The teeth were defective, and the patient's facial hair had a "corkscrew" appearance (Figure 1, c). The platelet count was normal, as was the serum fibrinogen level and the prothrombin- and activated partial thromboplastin times. Vancomycin-resistant Enterococcus faecium and multi-drug-resistant Acinetobacter baumanii were isolated from the urine. Therefore, hemodialysis, linezolid, and colistin were started. However, the patient continued to be lethargic, immobile, and with prominent skin bleeding. Medical workup excluded the possibility of an underlying malignancy or an autoimmune disorder. Finally, scurvy was suspected and 500 mg daily of oral vitamin C was introduced into therapy. In the following two weeks, the general condition of the patient significantly improved and he was discharged from the hospital in good condition - mobile and with complete resolution of skin lesions (Figure 1, d and e). Three months later, the patient was still under maintenance hemodialysis and had mild anemia (hemoglobin 123 g/L). Interestingly, scurvy was the first disease in the history of medicine for which a randomized trial found a cure (4). The differential diagnosis of scurvy includes skin infections, hematologic disorders, collagen vascular disorders, and anticoagulant/antiplatelet side-effects (1). Pathognomonic skin findings which may help raise suspicion of scurvy are perifollicular bleedings and "corkscrew" hair. Notably, laboratory testing for vitamin C concentration is not necessary to confirm scurvy as it tends to reflect recent dietary intake of vitamin C (2). Nevertheless, it may be useful to identify less typical cases (2). In our case, rapid clinical improvement with the resolution of skin lesions and joint contractures after the introduction of vitamin C confirmed the clinical diagnosis of scurvy. Additionally, vitamin C deficiency could be, at least partly (besides kidney failure and acute infection), responsible for severe anemia at disease presentation (5). This case serves to remind clinicians not to forget scurvy when treating patients at risk for vitamin C deficiency who present with fatigue, anemia, bone pains, and unexplained mucocutaneous bleedings. In suspected cases, vitamin C should be administered without hesitation.

Comparison of media and academic attention of recently published positive and neutral or negative randomized cardiovascular clinical trials.

BACKGROUND: Citations are used to assess the importance of authors, articles and journals in the scientific community, but do not examine how they affect general public journal readership. The Altmetric Attention Score (AAS) is a new metric for measuring media attention of the published paper. METHODS: We examined cardiovascular (CV) randomized clinical trials (RCTs), published in the 3 highest Web of Science Impact Factor journals (Journal Citation Reports 2019: category "Medicine, General & Internal") and in the 3 highest Web of Science Impact Factor CV journals (Journal Citation Reports 2019: category "Cardiac & Cardiovascular Systems"), through the calendar year of 2017, 2018 and 2019. The primary outcomes were the assessment of the difference between number of citations and AAS among positive and negative CV RCTs. RESULTS: Among the included 262 RCTs, more positive CV RCTs were published (p = 0.002). There was no significant statistical difference between the positive and negative trials, considering the number of citations (p = 0.61). Interestingly, positive trials had a tendency towards a higher AAS (p = 0.058). The correlation between the AAS and the number of citations was moderate positively correlated (ρ = 0.47, p < 0.001). CONCLUSION: We did not find any differences between CV RCTs with positive vs CV RCTs with negative results considering the number of their citations. A tendency towards a higher AAS among positive CV RCTs could indicate higher activity on social media regarding CV trials with positive results. A higher number of published positive CV RCTs among all published CV RCTs could indicate the presence of publication bias but further investigation of unpublished RCTs in trial registries (e.g., clinicaltrials.gov) is needed.

The economic impact of a clinical pharmacist's involvement in the hospital medicines policy in a rural area.

AIM: The evidence of the value of pharmaceutical care continues to grow, however, data on its effect in rural areas are still scarce. The aim of this article was to evaluate the economic impact of a clinical pharmacist's involvement in the hospital medicines policy design in a rural area, through the drug and therapeutics committee (DTC) and public procurement for medicines. METHODS: An economic evaluation was conducted in the General Hospital Bjelovar which covers the Bjelovarsko-Bilogorska County in Croatia. It included costs from denial and approval decisions of the drug and therapeutics committee, during a 1-year period between June 1, 2019 and June 1, 2020, and costs for medicines in 2018 and 2019 that were intended for public procurement. The cost-benefit analysis and cost-minimisation analyses for the DTC and public procurement data have been conducted for the evaluation of the economic impact of a clinical pharmacist. RESULTS: The involvement of a clinical pharmacist in the hospital medicines policy design through the DTC and public procurement for medicines provides an economic benefit. This resulted in a cost-benefit ratio of 14.18:1 and 18.31% and 17.58% savings through the DTC and public procurement process, respectively. To put in a different perspective, around 14 yearly gross salaries can be paid out from savings achieved by the clinical pharmacist through a 1-year period. CONCLUSION: The involvement of a clinical pharmacist in the hospital medicines policy in a rural area hospital results with an optimisation of investment in medicines and leads to substantial cost savings for the healthcare system.