Optimal Administration Schedule Research Articles

A mathematical model to study low-dose metronomic scheduling for chemotherapy

Metronomic chemotherapy refers to the frequent administration of chemotherapeutic agents at a lower dose and presents an attractive alternative to conventional chemotherapy with encouraging response rates. However, the schedule of the therapy, including the dosage of the drug, is usually based on empiricism. The confounding effects of tumor-endothelial-immune interactions during metronomic administration of drugs have not yet been explored in detail, resulting in an incomplete assessment of drug dose and frequency evaluations. The present study aimed to gain a mechanistic understanding of different actions of metronomic chemotherapy using a mathematical model. We have established an analytical condition for determining the dosage and frequency of the drug depending on its clearance rate for complete tumor elimination. The model also brings forward the immune-mediated clearance of the tumor during the metronomic administration of the chemotherapeutic agent. The results from the global sensitivity analysis showed an increase in the sensitivity of drug and immune-mediated killing factors toward the tumor population during metronomic scheduling. Our results emphasize metronomic scheduling over the maximum tolerated dose (MTD) and define a model-based approach for approximating the optimal schedule of drug administration to eliminate tumors while minimizing harm to the immune cells and the patient’s body.

Utility and optimal management of planned drug holidays during lenvatinib treatment in patients with unresectable differentiated thyroid cancer: a real-world multi-center study.

Lenvatinib achieves favorable therapeutic outcomes for patients with radioactive iodine therapy refractory differentiated thyroid cancer (DTC); however, its use is associated with a high incidence of adverse events. To avoid severe adverse events, planned drug holidays (PDH) have been proposed. This study aimed to evaluate treatment effects, identify prognostic factors, and investigate the usefulness of PDH in patients with unresectable DTC who received lenvatinib across the multi-institutions. Fifty-one patients with unresectable DTC treated with lenvatinib were evaluated retrospectively. Overall survival (OS) and progression-free survival (PFS) were calculated, and prognostic factors were assessed. OS, PFS, and time to treatment failure (TTF) were compared between patients with and without PDH. Lenvatinib administration schedule was evaluated in PDH. The 3-year OS and PFS rate were 53.5% and 42.1%, respectively. Multivariate analysis revealed that presence of maximum size of lung metastasis ≥10 mm was independent prognostic factor for poorer OS and PFS, and histology other than papillary thyroid carcinoma was the independent prognostic factor for poorer PFS. Twenty-five patients (49%) treated with PDH. There were significant differences in OS, PFS, and TTF between patients with and without PDH. Various schedules were used in PDH. Eight (32%) patients required switch to the different administration schedule. Our results suggest that PDHs may extend OS, PFS, and TTF. In patients with PDH, various schedules used for lenvatinib administration highlight the difficulty in determining a uniform administration schedule. Therefore, it is crucial to consider the optimal lenvatinib administration schedule on a case-by-case basis.

To flare or not to flare: patients' and rheumatologists' perceptions on the on-flare retreatment strategy of rituximab in rheumatoid arthritis.

Several retreatment strategies exist for rituximab in rheumatoid arthritis (RA). In some countries, reimbursement criteria require a loss of disease control for rituximab retreatment. Understanding the patients' and rheumatologists' perceptions regarding this retreatment strategy would be informative in identifying the optimal treatment administration schedule. This study aimed to uncover patients' and rheumatologists' perceptions regarding retreatment strategies of rituximab. Qualitative study - semi-structured interviews. Patients with RA, treated with rituximab, and rheumatologists were invited to participate in a qualitative study consisting of individual, in-depth, semi-structured interviews. Interviews were analysed according to the Qualitative Analysis Guide of Leuven. A total of 16 patients and 13 rheumatologists were interviewed. Benefits (e.g. decreased risk of overtreatment, cost savings and long-lasting effectiveness of rituximab) and barriers (e.g. fluctuating disease activity, slow mode of action and increased glucocorticoid use) of on-flare retreatment were identified. To effectively treat on-flare, flares must first be identified timely. Both stakeholder groups acknowledged that patients are capable of recognizing flares. However, the patient's ability to discriminate between inflammatory and other types of pain was perceived as difficult. Furthermore, patients and rheumatologists stressed that patients must timely seek professional help in case of a flare, followed by a swift response from the rheumatologists. Remarkably, retreatment was approached in various ways among rheumatologists, and not always adhering strictly to the on-flare reimbursement criteria. This study revealed that both stakeholder groups perceived the heterogeneity in recognition of and reaction to a flare as important in influencing the effectiveness of the on-flare retreatment strategy. Moreover, this study identified the benefits and barriers of treating on-flare, which could be informative for daily practice decisions.

Promotion of tumor angiogenesis and growth induced by low-dose antineoplastic agents via bone-marrow-derived cells in tumor tissues.

More research is needed to solidify the basis for reasonable metronomic chemotherapy regimens due to the inconsistent clinical outcomes from studies on metronomic chemotherapy with antineoplastic agents, along with signs of a nonlinear dose-response relationship at low doses. The present study therefore explored the dose-response relationships of representative antineoplastic agents in low dose ranges and their underlying mechanisms. Cyclophosphamide (CPA) and 5-fluorouracil (5-Fu) were employed to observe the effects of the frequent administration of low-dose antineoplastic agents on tumor growth, tumor angiogenesis, and bone-marrow-derived cell (BMDC) mobilization in mouse models. The effects of antineoplastic agents on tumor and endothelial cell functions with or without BMDCs were analyzed in vitro. Tumor growth and metastasis were significantly promoted after the administration of CPA or 5-Fu at certain low dose ranges, and were accompanied by enhanced tumor angiogenesis and proangiogenic factor expression in tumor tissues, increased proangiogenic BMDC release in the circulating blood, and augmented proangiogenic BMDC retention in tumor tissues. Low concentrations of CPA or 5-Fu were found to significantly promote tumor cell migration and invasion, and enhance BMDC adhesion to endothelial cells in vitro. These results suggest that there are risks in empirical metronomic chemotherapy using low-dose antineoplastic agents and the optimal dosage and administration schedule of antineoplastic agents need to be determined through further research.

Comparison of the Effectiveness of Prolonged Infusion and Intermittent Infusion of Meropenem in Patients With Sepsis: A Meta-Analysis.

The aim of this study was to compare the clinical effectiveness of prolonged infusion and intermittent infusion of meropenem in patients with sepsis.This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines.PubMed, Web of Science, Scopus, and the Cochrane Library were searched without any language or time restrictions, up to September 25, 2023.The primary outcomes assessed in this meta-analysis included clinical success and all-cause mortality. Other outcomes assessed in this study encompassedthe mean length of ICU stay. Total eight studies met the eligibility criteria and were included in this meta-analysis. Pooled analysis showed that the clinical success rate was significantly higher in patients receiving prolonged infusion of meropenem compared to intermittent infusion (RR: 1.49, 95% CI: 1.30 to 1.70). All-cause mortality was 24% significantly lower in patients receiving prolonged infusion of meropenem compared to intermittent infusion (RR: 0.76, 95% CI: 0.60 to 0.96).The results suggest that prolonged infusion of meropenem could be a more effective and efficient treatment for sepsis patients. However, more randomized controlled trials are needed to confirm these findings and to establish the optimal dosing and administration schedule for prolonged infusion of meropenem.

High Potency Vasoactive Intestinal Peptide Receptor Antagonists Induce Durable Antileukemia/Tumor T Cell Memory in Mice with Once Daily Dosing

Introduction: Allogeneic bone marrow transplantation (allo-BMT) is curative for patients with myeloid leukemia (AML) through the activity of cytotoxic effector donor T cells, but high morbidity and mortality of allo-BMT limits the use of this therapy. A long-standing goal is the development of strategies that induce an autologous immune response to leukemic blasts by the patient's T cells. Vasoactive intestinal peptide (VIP) is a neuropeptide with pleiotropic functions, including modulation of immune and inflammatory responses. Previous studies demonstrated that VIP hybrid (VIPhyb), a peptide antagonist of VIP-signaling, induced T cell-dependent anti-leukemic activity in murine allotransplant models and promoted activation of mouse and human T cells (Li et al., 2016, Cancer Res). We developed a series of novel peptide VIP antagonists (VIP-ANT) based upon predicted binding affinity in silico to human VIP receptors VPAC1 and VPAC2. We tested the anti-cancer potential of these new VIP-ANT peptides in murine models of myeloid leukemia and mastocytoma, investigating the optimal dose and schedule of administration, and explored mechanisms underlying anti-tumor memory induced by VIP-ANT peptides. Methods: B6 (CD45.1, or albino) mice were injected intravenously with 1 x 106 C1498 cells (AML), and DBA/2j mice were injected subcutaneously with 5 x 104 P815 cells (myeloid mastocytoma). Leukemia-bearing mice were treated with subcutaneous injections of VIP-ANT or control scrambled peptides. Treatment started six days after injection of cells when C1498 leukemia cells were detectable in the blood, and luciferase+ P815 cells as tumors were palpable. A range of VIP-ANT doses was administered s.c. at 10, 30, or 100 μg. Treatment schedules tested included twice daily for 14 doses, once daily, once every other day, once every three days, and once weekly for 7 doses. Some mice received a single dose at day +6 following leukemia cell injection. Lymphocyte kinetics and leukemia cell burden were analyzed weekly through submandibular peripheral blood collections. Mice without evidence of AML/mastocytoma >60 days post-inoculation received a second injection of a two-fold higher dose of C1498 (2 × 106 cells) or P815 (1 × 105 cells). Results: We tested over 13 new VIP-ANT peptides. Daily or every other day (qod) administration of the novel VIP-ANT peptides to leukemia/tumor-bearing mice led to clearance of C1498 cells from blood or complete regression of P815 in 40 % of mice, leading to significantly improved survival over 60 days. Daily administration of 10 μg of novel VIP-ANT peptides for 7 days to leukemic mice prolonged survival(p<0.0001 VIP-ANT vs scramble, Fig 1A), with the fraction of mice that remained leukemia-free proportional to the predicted binding affinity of the VIP-ANT to human VPAC1 and VPAC2. With increased dose intensity and dose-density of ANT308, the most potent peptide, 40%-80% of mice survived to 70 days (median survival days (MSD) of 60 days) after ANT308 treatment compared with the survival of <20% in mice receiving scrambled peptide (MSD 36 days). Increasing the dose and schedule of ANT308 administration to 100 μg twice-daily led to 65% survival (MSD not reached) versus 40% with daily dosing, 30% with every-other-day dosing, and 0% survival with scrambled-sequence control peptide (MSD 33 days) (p<0.001, Fig 1B). Notably, the affinity of different VIP-ANT peptides to VPAC1 and VPAC2 VIP receptors significantly correlated with the survival of C1498-leukemic mice following prior treatment with the corresponding peptide. Prior treatment of leukemic mice with VIP-ANT induced protective immunological memory, rendering mice resistant to re-challenge with C1498 acute myeloid leukemia (80% survival) and P815 mastocytoma (60% survival) cells, compared with 0% survival (MSD 21 days) among immunologically naïve mice. Conclusion: Blocking VIP-signaling with high-affinity VIP-R peptide antagonists represents a novel pharmacological approach to enhance adaptive T cell responses to leukemia/myeloid sarcoma-associated antigens in murine leukemia/tumor models. We are continuing PK and toxicology studies with the lead VIP-ANT peptides to support the development of phase 1 clinical trials for patients with relapsed AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Bimodal antibody-titer decline following BNT162b2 mRNA anti-SARS-CoV-2 vaccination in healthcare workers of the INT – IRCCS “Fondazione Pascale” Cancer Center (Naples, Italy)

BackgroundBoth SARS-CoV-2 mRNA-based vaccines [BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)] have shown high efficacy, with very modest side effects in limiting transmission of SARS-CoV-2 and in preventing the severe COVID-19 disease, characterized by a worrying high occupation of intensive care units (ICU), high frequency of intubation and ultimately high mortality rate. At the INT, in Naples, only the BNT162b2/Pfizer vaccine has been administered to cancer patients and healthcare professionals aged 16 and over. In the present study, the antibody response levels and their decline were monitored in an interval of 6–9 months after vaccine administration in the two different cohorts of workers of the INT – IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy): the group of individuals previously infected with SARS-CoV-2 and vaccinated with a single dose; and that of individuals negative for previous exposure to SARS-CoV-2 vaccinated with two doses 21 days apart.MethodsSpecific anti-RBD (receptor-binding domain) titers against trimeric spike glycoprotein (S) of SARS-CoV-2 by Roche Elecsys Anti-SARS-CoV-2 S ECLIA immunoassay were determined in serum samples of 27 healthcare workers with a previously documented history of SARS-CoV-2 infection and 123 healthcare workers without, during antibody titers’ monitoring. Moreover, geometric mean titers (GMT) and relative fold changes (FC) were calculated.ResultsBimodal titer decline was observed in both previously infected and uninfected SARS-CoV-2 subjects. A first rapid decline was followed by a progressive slow decline in the 6/9 month-period before the further vaccine boost. The trend was explained by 2 different mathematical models, exponential and power function, the latter revealing as predictive of antibody titer decline either in infected or in not previously infected ones. The value of the prolonged lower vaccine titer was about 1 log below in the 6/9-month interval after the single dose for previously infected individuals with SARS-CoV-2 and the two doses for those not previously infected. The titer change, after the boost dose administration, on the other hand, was ≥ 1.5 FC higher than the titers at the 6/9-month time-points in both cohorts. A similar quantitative immune titer was observed in both cohorts 8 days after the last boost dose. The subsequent immunoresponse trend remains to be verified.DiscussionThe results show that a very rapid first decline, from the highest antibody peak, was followed by a very slow decline which ensured immune protection lasting more than 6 months. The apparent absence of adverse effects of the rapid decline on the vaccine's immune protective role has been related to a large majority of low avidity antibodies induced by current vaccines. High avidity antibodies with prolonged anti-transmission efficacy show a longer half-life and are lost over a longer interval period. The cellular immunity, capable of preventing severe clinical diseases, lasts much longer. The unbalanced dual activity (cellular vs humoral) while effective in limiting ICU pressure and overall mortality, does not protect against transmission of SARS-CoV-2, resulting in high circulation of the virus among unvaccinated subjects, including the younger population, and the continuous production of variants characterized by changes in transmissibility and pathogenicity. The high mutation rate, peculiar to the RNA virus, can however lead to a dual opposite results: selection of defective and less efficient viruses up to extinction; risk of more efficiently transmitted variants as the current omicron pandemic.ConclusionsIn conclusion the current bimodal antibody-titer decline, following BNT162b2 mRNA anti-SARS-CoV-2 vaccination, needs a further extended analysis to verify the protective borderline levels of immunity and the optimal administration schedule of vaccine boosters. Our current results can contribute to such goal, besides a direct comparison of other FDA-approved and candidate vaccines.

Subcutaneous IL-6 Inhibitor Sarilumab vs. Standard Care in Hospitalized Patients With Moderate-To-Severe COVID-19: An Open Label Randomized Clinical Trial

BackgroundThe use of IL-6 blockers in COVID-19 hospitalized patients has been associated with a reduction in mortality compared to standard care. However, many uncertainties remain pertaining to optimal intervention time, administration schedule, and predictors of response. To date, data on the use of subcutaneous sarilumab is limited and no randomized trial results are available.MethodsOpen label randomized controlled trial at a single center in Spain. We included adult patients admitted with microbiology documented COVID-19 infection, imaging confirmed pneumonia, fever and/or laboratory evidence of inflammatory phenotype, and no need for invasive ventilation. Participants were randomly assigned to receive sarilumab, a single 400 mg dose in two 200 mg subcutaneous injections, added to standard care or standard care, in a 2:1 proportion. Primary endpoints included 30-day mortality, mean change in clinical status at day 7 scored in a 7-category ordinal scale ranging from death (category 1) to discharge (category 7), and duration of hospitalization. The primary efficacy analysis was conducted on the intention-to-treat population.ResultsA total of 30 patients underwent randomization: 20 to sarilumab and 10 to standard care. Most patients were male (20/30, 67%) with a median (interquartile range) age of 61.5 years (56–72). At day 30, 2/20 (10%) patients died in the sarilumab arm vs. none (0/10) in standard care (Log HR 15.11, SE 22.64; p = 0.54). At day 7, no significant differences were observed in the median change in clinical status (2 [0–3]) vs. 3 [0–3], p = 0.32). Median time to discharge (days) was similar (7 [6–11] vs. 6 [4–12]; HR 0.65, SE 0.26; p = 0.27). No significant differences were detected in the rate of progression to invasive and noninvasive mechanical ventilation.Conclusions and RelevanceOur pragmatic pilot study has failed to demonstrate the benefit of adding subcutaneous sarilumab to standard care for mortality by 30 days, functional status at day 7, or hospital stay. Findings herein do not exclude a potential effect of sarilumab in severe COVID-19 but adequately powered blinded randomized phase III trials are warranted to assess the impact of the subcutaneous route and a more selected target population.Trial Registrationwww.ClinicalTrials.gov, Identifier: NCT04357808.

Survival outcomes of alternate dosing schedule of pemetrexed as maintenance therapy in NSCLC: Single institution experience

BackgroundMaintenance therapy with pemetrexed has shown survival benefit in patients with advanced stage non-small cell lung cancer (NSCLC). The recommended dose schedule is 500 mg/m 2 in 21-day cycles. Prolonged treatment with maintenance pemetrexed can result in cumulative toxicities. We sought to compare treatment outcomes in patients receiving an alternate maintenance schedule in realworld practice. MethodsThis single-center, retrospective study investigated patients with advanced stage (IIIB and IV) NSCLC receiving at least two doses of maintenance pemetrexed from May 1, 2011 to June 30, 2016. The objective was to compare time on treatment with maintenance pemetrexed therapy initiated at a standard schedule (q3 weeks) versus an alternate schedule (q4 weeks or longer). Also evaluated were progressionfree survival (PFS) and overall survival (OS) differences between the two groups. Results129 patients were included, of whom 40 started the alternate schedule no later than cycle 3 of treatment (29 of 40 patients initiated maintenance treatment on the alternate schedule). Average time on maintenance treatment for patients appeared to be longer in the patients who received the alternate schedule regimen (195 vs 263 days, p =0.008). OS trended towards better survival among patients receiving the alternate schedule regimen (11.9 vs 18.1 months, p =0.3). Limiting the analysis to ALK wildtype, the patients showed a similar trend, with median PFS (7.6 vs 11.5 months, p =0.46) and OS (11.9 vs 17.6 months, p =0.38), still favoring the alternate schedule. ConclusionsThe alternate dosing schedule of maintenance pemetrexed (q4 weeks or longer) is feasible and not detrimental to OS. Future investigations evaluating the optimal administration schedule of maintenance pemetrexed is warranted.

Blocking the orexin system following therapeutic exposure promoted between session habituation, but not PTSD symptom reduction

There is a need to identify strategies to increase the effectiveness of treatments for posttraumatic stress disorder (PTSD). Sleep is often disturbed in PTSD and has been implicated in learning processes that underlie recovery from PTSD, including extinction of conditioned fear. Our prior study suggested that diminished arousal during sleep may enhance benefits of therapeutic exposure for PTSD. The orexin system regulates arousal, and blocking the system diminishes arousal and promotes sleep. We, therefore, examined whether a dual orexin receptor antagonist, suvorexant, administered following evening exposure sessions, would enhance their therapeutic effectiveness for PTSD. In this randomized double-blind placebo-controlled trial, adults with PTSD completed four written narrative exposure (WNE) sessions, two of which took place in the evening, and two the next morning. Participants received either suvorexant or placebo after each evening WNE. We found that suvorexant increased N3 sleep and decreased N2 sleep and rapid-eye-movement latency measured by polysomnography. Between session habituation indexed by subjective distress ratings was greater with suvorexant, but there was no group difference in the reduction of PTSD severity from baseline to 1-week follow-up. No safety concerns emerged. The present findings provide preliminary support for enhancement of an effect of therapeutic exposure for PTSD by suvorexant. Further studies with larger samples are needed to translate the present findings into clinical applications, including studies to develop optimal suvorexant administration and exposure session schedules to achieve persistent benefits to sleep and possibly greater treatment augmentation.

Dynamics of Acquired Resistance to Nivolumab Therapies Varies From Administration Strategies

PurposeThe identification of optimal drug administration schedules to overcome the emergence of resistance that causes treatment failure is a major challenge in cancer research. We report the outcomes of a computational strategy to assess the dynamics of tumor progression as a function of time under different treatment regimens. MethodsWe developed an evolutionary game theory model that combined Lotka-Volterra equations and pharmacokinetic properties with 2 competing cancer species: nivolumab-response cells and Janus kinase (JAK1/2) mutation cells. We selected 3 therapeutic schemes that have been tested in the clinical trials: 3 mg/kg Q2w, 10 mg/kg Q2w, and 480 mg Q4w. The simulation was performed under the intervals of 75, 125, and 175 days, respectively, for each regimen. The data sources of the pharmacokinetic parameters used in this study were collected from previous published clinical trials. Other parameters in the evolutionary model come from the existing references. FindingsPredictions under various dose schedules indicated a strong selection for nivolumab-independent cells. Under the 3 mg/kg dose strategy, the reproduction rate of JAK mutation cells was highest, with strongest tumor elimination ability at a 75-day interval between treatments. Prolonged drug intervals to 125 or 175 days delayed tumor evolution but accelerated tumor recurrence. Although 10 mg/kg Q2w had an obvious clinical effect in a short time, it further promotes the progress of resistant population compared with the 3 mg/kg dose. Our model suggests that 480 mg Q4w would be more valuable in terms of clinical efficacy, but complete resistant occurs earlier regardless the interval. ImplicationsThe results of this study emphasize that increasing the dose or shortening the interval between doses accelerates the evolution of heterogeneous populations, although the short-term effect is significant. In practice, the therapeutic regimen should be balanced according to the evolutionary principle.

Experimental Validation of a Mathematical Model to Describe the Drug Cytotoxicity of Leukemic Cells

Chlorambucil (Chl), Melphalan (Mel), and Cytarabine (Cyt) are recognized drugs used in the chemotherapy of patients with advanced Chronic Lymphocytic Leukemia (CLL). The optimal treatment schedule and timing of Chl, Mel, and Cyt administration remains unknown and has traditionally been decided empirically and independently of preclinical in vitro efficacy studies. As a first step toward mathematical prediction of in vivo drug efficacy from in vitro cytotoxicity studies, we used murine A20 leukemic cells as a test case of CLL. We first found that logistic growth best described the proliferation of the cells in vitro. Then, we tested in vitro the cytotoxic efficacy of Chl, Mel, and Cyt against A20 cells. On the basis of these experimental data, we found the parameters for cancer cell death rates that were dependent on the concentration of the respective drugs and developed a mathematical model involving nonlinear ordinary differential equations. For the proposed mathematical model, three equilibrium states were analyzed using the general method of Lyapunov, with only one equilibrium being stable. We obtained a very good symmetry between the experimental results and numerical simulations of the model. Our novel model can be used as a general tool to study the cytotoxic activity of various drugs with different doses and modes of action by appropriate adjustment of the values for the selected parameters.

Intravenous albumin for spontaneous bacterial peritonitis and renal dysfunction in patients with cirrhosis-short review

Current clinical guidelines for albumin use in decompensated cirrhosis recommend the use of intravenous albumin infusions for management of ascites-related symptoms and paracentesis (removal of ascitic fluid) and for the management of spontaneous bacterial peritonitis (SBP), renal dysfunction and variceal bleeding. Routine albumin use is not recommended for the management of non-SBP infections. The aim of this review is to improve our understanding of the effects of albumin use in cirrhosis by reviewing the currently available and quantifying the effectiveness of intravenous albumin therapy to prevent specific cirrhosis complications, spontaneous bacterial peritonitis (SBP) and renal dysfunction. Long-term albumin administration to patients with decompensated cirrhosis improves survival, prevents complications, eases the management of ascites and reduces hospitalizations, thus being cost-effective. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.

TAK-573, an Anti-CD38/Attenuated Ifnα Fusion Protein, Has Clinical Activity and Modulates the Ifnα Receptor (IFNAR) Pathway in Patients with Relapsed/Refractory Multiple Myeloma

TAK-573, an Anti-CD38/Attenuated Ifnα Fusion Protein, Has Clinical Activity and Modulates the Ifnα Receptor (IFNAR) Pathway in Patients with Relapsed/Refractory Multiple Myeloma

News for usage of albumin in patients with liver disease

The recommended indications for short-term use of human albumin in patients with decompensated cirrhosis are the following: prevention of paracenteses induced circulatory dysfunction, treatment of hypovolemia, prevention of hepatorenal syndrome in high-risk patients with spontaneous bacterial peritonitis, as well as treatment of hepatorenal syndrome. Liver cirrhosis is associated with systemic inflammation, which is further increased in decompensated cirrhosis and acute-on-chronic liver failure. Besides its function as plasma expander, albumin is known to have pleiotropic non-oncotic properties. It serves as antioxidant, scavenging and provides immune-modulating and endothelium protective functions. Albumin treatment may be beneficial to prevent further decompensation and acute-on-chronic liver failure. Recent studies suggest, that long-term albumin administration in patients with cirrhosis and ascites improves survival, prevents complications, facilitates the management of ascites and reduces hospitalizations. Moreover, during infections albumin may prevent development of acute-on-chronic liver failure. Still, further studies are needed to confirm these disease-modifying effects of albumin, define its optimal dosage and administration schedule and detect patients who benefit most from albumin administration in different scenarios.

The benefits of voluntary physical exercise after traumatic brain injury on rat's object recognition memory: A comparison of different temporal schedules

Physical exercise can reduce the cognitive decline associated with traumatic brain injury, yet little is known about the optimal administration schedules. Here, different protocols of voluntary wheel running were evaluated for their effects on object recognition memory (ORM), neuroprotection (NeuN+ cells), microglial reactivity (Iba1 staining) and neurogenesis (DCX+ cells) after controlled cortical impact injury (CCI). CCI-lesioned rats were divided into a sedentary group and three exercise groups: early discontinued exercise (3 weeks of exercise initiated 4 days post-injury, followed by 4 weeks in a sedentary state); delayed exercise (3 weeks of exercise initiated 4 weeks post-injury), and early continuous exercise (7 weeks of exercise starting 4 days post-injury). The deficits induced by CCI in a 24 h ORM test were reversed in the delayed exercise group and reduced in the early discontinued and early continuous groups. The early discontinued protocol also reduced the loss of NeuN+ cells in the hilus, while attenuated microglial reactivity was found in the dorsal hippocampus of both the early exercising groups. Running at the end of the experiment increased the number of DCX+ cells in the early continuous and delayed groups, and an inverted U-shaped relationship was found between the mean daily exercise time and the amount of neurogenesis. Thus, exercise had benefits on memory both when it was commenced soon and later after injury, although the neural mechanisms implicated differed. Accordingly, the effects of exercise on memory and neurogenesis appear to not only depend on the specific temporal schedule but also, they may be influenced by the amount of daily exercise.

What Are Optimal P2Y12 Inhibitor and Schedule of Administration in Patients With Acute Coronary Syndrome?

Guidelines recommend treatment with a P2Y12 platelet adenosine diphosphate receptor inhibitor in patients undergoing elective or urgent percutaneous coronary intervention (PCI), but the optimal agent or timing of administration is still not clearly specified. The P2Y12 inhibitor was initially used for its platelet anti-aggregatory action to block thrombosis of the recanalized coronary artery or deployed stent. It is now recognized that these agents also offer potent cardioprotection against a reperfusion injury that occurs in the first minutes of reperfusion if platelet aggregation is blocked at the time of reperfusion. But this is difficult to achieve with oral agents which are slowly absorbed and often require time-consuming metabolic activation. Patients with ST-segment elevation myocardial infarction who usually have a large mass of myocardium at risk of infarction seldom have sufficient time for upstream-administered oral agents to achieve a therapeutic P2Y12 level of inhibition by the time of balloon inflation. However, optimal treatment could be assured by initiating an IV cangrelor infusion shortly prior to stenting followed by subsequent post-PCI transition to an oral agent, that is, ticagrelor, once success of the recanalization and absence of need for surgical intervention are confirmed. Not only should this sequence provide optimal protection against infarction, it should also negate bleeding if coronary artery bypass grafting should be required since stopping the cangrelor infusion at any time will quickly restore platelet reactivity. It is anticipated that cangrelor-induced myocardial salvage will help preserve myocardial function and significantly diminish postinfarction heart failure.

Efficacy and safety of early administration of pegfilgrastim for esophageal cancer treated with DCF: A phase 2 study

Abstract Background It has been reported that docetaxel, cisplatin and 5-fluorouracil (DCF) regimen was effective for advanced esophageal cancer. However, the DCF regimen is associated with a high risk of severe neutropenia or febrile neutropenia (FN). In our retrospective study evaluating the efficacy of pegfilgrastim administration on day 7 (D7) in DCF regimen, the neutrophil count nadir was observed from D7. Thus, the timing of its administration could be too late. In this study, we assess the efficacy and safety of early administration (D3) of pegfilgrastim in DCF therapy for advanced esophageal cancer. Methods In this single-arm phase 2 study, patients with advanced esophageal cancer were recruited. They were treated with DCF therapy (DTX: 70mg/m2 on D1, CDDP: 70mg/m2 on D1, and 5-FU: 750mg/m2 on D1-5), and were administrated pegfilgrastim on D3. The primary endpoint was grade4 neutropenia. The secondary endpoints were the rate of FN and the incidence of other adverse events. This study was registered in UMIN system (UMI23393). Results Between July 2016 and Dec. 2018, we enrolled 23 patients (median age 62y ). The incidence of grade4 neutropenia was 8.7% (95%CI:4.7 - 22.1). The rate of FN was 0%. The rate of grade3 neutropenia was 17.4% (95%CI: 1.7 - 33.1), but no other serious adverse events related to pegfilgrastim were observed. Conclusion Primary prophylaxis with pegfilgrastim is recommended for the prevention of FN in patients receiving high-risk chemotherapy regimens such as DCF. According to the guidelines, G-CSF should be administered 24 h after the completion of chemotherapy. The optimal administration schedule remains unclear in regimens including IV continuous 5-FU administration like DCF. These results have shown that early administration (D3) of pegfilgrastim was safe and seemed to be more effective than D7 in DCF therapy. Further clinical studies with a larger sample size should be conducted to confirm our results.

Intravesical bacillus Calmette-Guérin for bladder cancer: are all the strains equal?

Intravesical immunotherapy with bacillus Calmette-Guérin (BCG) is the standard of care for high-risk and intermediate-risk non-muscle-invasive bladder cancer (NMIBC). Several BCG strains are available. Despite originating all from subcultures of the same Mycobacterium, strains are genetically different which may lead to differences in treatment efficacy and adverse events. Identification of a more efficient strain and assessing its optimal administration schedule may improve oncological outcomes in NMIBC, specifically because of the worldwide shortage in BCG availability. This review focused on the antitumor effect of different BCG strains with a particular emphasis on the evidence underlying BCG dose and treatment schedules.

MS25.05 Targeting the Micro-RNA: A New Therapeutic Venture

MS25.05 Targeting the Micro-RNA: A New Therapeutic Venture