Five versus seven days of nitrofurantoin for urinary tract infections in women with diabetes: a retrospective cohort study

Objective: To compare the effectiveness of 5 versus 7 days of nitrofurantoin treatment for urinary tract infection (UTI) in women with diabetes. Methods: Data were collected retrospectively from Dutch general practitioners between 2013 and 2020. Nitrofurantoin prescriptions with a duration of 5 days (5DN) or 7 days (7DN) in women with diabetes were included. Inverse propensity weighting was performed to calculate adjusted risk differences (RD) for treatment failure within 28 days. Secondary outcomes were 14-day treatment failure, severe treatment failure and 28-day treatment failure in defined risk groups. Results: Nitrofurantoin was prescribed in 6866 episodes, 3247 (47.3%) episodes with 5DN and 3619 (52.7%) episodes with 7DN. Patients in the 7DN group had more co-morbidities, more diabetes-related complications and were more insulin-dependent. There were 517/3247 (15.9%) failures in the 5DN group versus 520/3619 (14.4%) in the 7DN group. The adjusted RD for failure within 28 days was 1.4% (95% CI –0.6 to 3.4). Conclusion: We found no clinically significant difference in treatment failure in women with diabetes with UTI treated with either 5DN or 7DN within 28 days. A 5-day treatment should be considered to reduce cumulative nitrofurantoin exposure in DM patients

A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer

Background: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. Objective: We aimed to develop alternative dosing regimens to reduce drug expenses. Methods: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. Results: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. Conclusions: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.</p

Radioimmunotherapy Improves Survival of Rats with Microscopic Liver Metastases of Colorectal Origin

BACKGROUND: Half of the patients with colorectal cancer develop liver metastases during the course of their disease. The aim of the present study was to assess the efficacy of radioimmunotherapy (RIT) with a radiolabeled monoclonal antibody (mAb) to treat experimental colorectal liver metastases. METHODS: Male Wag/Rij rats underwent a minilaparotomy with intraportal injection of 1 x 10(6) CC531 tumor cells. The biodistribution of (111)In-labeled MG1, 1 day after intravenous administration, was determined in vivo and compared with that of an isotype-matched control antibody (UPC-10). The maximal tolerated dose (MTD) of (177)Lu-labeled MG1 was determined and the therapeutic efficacy of (177)Lu-MG1 at MTD was compared with that of (177)Lu-UPC-10 and saline only. RIT was administered either at the day of tumor inoculation or 14 days after tumor inoculation. Primary endpoint was survival. RESULTS: (111)In-MG1 preferentially accumulated in CC531 liver tumors (9.2 +/- 3.7%ID/g), whereas (111)In-UPC-10 did not (0.8 +/- 0.1%ID/g). The MTD of (177)Lu-MG1 was 400 MBq/kg body weight. Both the administration of (177)Lu-MG1 and (177)Lu-UPC-10 had no side-effects except a transient decrease in body weight. The survival curves of the group that received (177)Lu-UPC-10 and the group that received saline only did not differ (P = 0.407). Administration of (177)Lu-MG1 RIT immediately after surgery improved survival significantly compared with administration of (177)Lu-UPC-10 (P = 0.009) whereas delayed treatment did not (P = 0.940). CONCLUSION: This study provides proof of principle that RIT can be an effective treatment modality for microscopic liver metastases, whereas RIT is not effective in larger tumors

Study Protocol PROMETHEUS:Prospective Multicenter Study to Evaluate the Correlation Between Safety Margin and Local Recurrence After Thermal Ablation Using Image Co-registration in Patients with Hepatocellular Carcinoma

Purpose: The primary objective is to determine the minimal ablation margin required to achieve a local recurrence rate of 18 years with Barcelona Clinic Liver Cancer stage 0/A hepatocellular carcinoma (or B with a maximum of two lesions < 5 cm each) are eligible. Patients will undergo dual-phase contrast-enhanced computed tomography directly before and after ablation. Ablation margins will be quantitatively assessed using co-registration software, blinding assessors (i.e. two experienced radiologists) for outcome. Presence and location of recurrence are evaluated independently on follow-up scans by two other experienced radiologists, blinded for the quantitative margin analysis. A sample size of 189 tumors (~ 145 patients) is required to show with 80% power that the risk of local recurrence is confidently below 10%. A two-sided binomial z-test will be used to test the null hypothesis that the local recurrence rate is ≥ 10% for patients with a minimal ablation margin ≥ 2 mm. Logistic regression will be used to find the relationship between minimal ablation margins and local recurrence. Kaplan–Meier estimates are used to assess local and overall recurrence, disease-free and overall survival. Discussion: It is expected that this study will result in a clear understanding of the correlation between ablation margins and local recurrence. Using co-registration software in future patients undergoing ablation for hepatocellular carcinoma may improve intraprocedural evaluation of technical success. Trial registration The Netherlands Trial Register (NL9713), https://www.trialregister.nl/trial/9713

Repair of Parastomal Hernias with Biologic Grafts: A Systematic Review

Contains fulltext : 98303.pdf (publisher's version ) (Open Access)BACKGROUND: Biologic grafts are increasingly used instead of synthetic mesh for parastomal hernia repair due to concerns of synthetic mesh-related complications. This systematic review was designed to evaluate the use of these collagen-based scaffolds for the repair of parastomal hernias. METHODS: Studies were retrieved after searching the electronic databases MEDLINE, EMBASE and Cochrane CENTRAL. The search terms 'paracolostomy', 'paraileostomy', 'parastomal', 'colostomy', 'ileostomy', 'hernia', 'defect', 'closure', 'repair' and 'reconstruction' were used. Selection of studies and assessment of methodological quality were performed with a modified MINORS index. All reports on repair of parastomal hernias using a collagen-based biologic scaffold to reinforce or bridge the defect were included. Outcomes were recurrence rate, mortality and morbidity. RESULTS: Four retrospective studies with a combined enrolment of 57 patients were included. Recurrence occurred in 15.7% (95% confidence interval [CI] 7.8-25.9) of patients and wound-related complications in 26.2% (95% CI 14.7-39.5). No mortality or graft infections were reported. CONCLUSIONS: The use of reinforcing or bridging biologic grafts during parastomal hernia repair results in acceptable rates of recurrence and complications. However, given the similar rates of recurrence and complications achieved using synthetic mesh in this scenario, the evidence does not support use of biologic grafts

Repositioning of the global epicentre of non-optimal cholesterol

High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world