Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer.

In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.

Online teaching and learning of a pharmacy curriculum designed for active learning and professional skills development - A report of students' perceptions and learning experience in two international campuses.

BACKGROUND AND PURPOSE: Pharmacy students' perception of the effectiveness of remote online learning experienced during the pandemic, and their learning expectations post-pandemic were unknown. The main purpose of this study was to examine students' perceived effectiveness of online teaching and learning activities developed for active learning and pharmacy professional skills development, and the feasibility of online assessments. EDUCATIONAL ACTIVITY AND SETTING: A cross-sectional online survey involving second-year pharmacy students of Monash Malaysia (MA) and Monash Australia (PA) campuses was conducted. The survey consisted of 15 Likert-scale multiple-choice questions and an open-ended question. Data were analysed statistically. FINDINGS: Students at both MA and PA campuses were satisfied with the remote online learning experienced during the pandemic but indicated a preference for a blended learning approach. Students at the MA campus felt that on-campus face-to-face classes were more engaging and advantageous for their learning and skills development (P < .05), and on-campus assessments allowed them to engage and perform better (P < .05) compared with students at the PA campus who felt neutral or disagreed. Both student cohorts were happy with some of the lectures being conducted online synchronously or asynchronously. SUMMARY: Differences in cultures, and learning behaviour and preference may influence learners' perceptions and expectations of online learning. This study suggests that blended learning involving both online and face-to-face interactive activities may promote engagement, satisfaction, and outcomes of culturally diverse learner populations post-pandemic.

Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study.

BACKGROUND: IMvigor130 demonstrated statistically significant investigator-assessed progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial carcinoma. Overall survival was not improved in interim analyses. Here we report the final overall analysis for group A versus group C. METHODS: In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged ≥18 years) with previously untreated locally advanced or metastatic urothelial cancer and who had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), with a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin risk factor score, and investigator's choice of platinum-based chemotherapy, to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo (ie, group A and group C) and atezolizumab monotherapy (group B) was open label. For groups A and C, all patients received gemcitabine (1000 mg/m2 intravenously; day 1 and day 8 of each 21-day cycle), plus investigator's choice of carboplatin (area under curve 4·5 mg/mL per min or 5 mg/mL per min; intravenously) or cisplatin (70 mg/m2 intravenously), plus either atezolizumab (1200 mg intravenously) or placebo on day 1 of each cycle. Co-primary endpoints of the study were investigator-assessed progression-free survival and overall survival for group A versus group C in the intention-to-treat (ITT) population (ie, all randomised patients), and overall survival for group B versus group C, tested hierarchically. Final overall survival and updated safety outcomes (safety population; all patients who received any amount of any study treatment component) for group A versus group C are reported here. The final prespecified boundary for significance of the overall survival analysis was one-sided p=0·021. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting. FINDINGS: Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 851 were assigned to group A (n=451) and group C (n=400). 338 (75%) patients in group A and 298 (75%) in group C were male, 113 (25%) in group A and 102 (25%) in group C were female, and 346 (77%) in group A and 304 (76%) in group C were White. At data cutoff (Aug 31, 2022), after a median follow up of 13·4 months (IQR 6·2-30·8), median overall survival was 16·1 months (95% CI 14·2-18·8; 336 deaths) in group A versus 13·4 months (12·0-15·3; 310 deaths) in group C (stratified hazard ratio 0·85 [95% CI 0·73-1·00]; one-sided p=0·023). The most common grade 3-4 treatment-related adverse events were anaemia (168 [37%] of 454 patients who received atezolizumab plus chemotherapy vs 133 [34%] of 389 who received placebo plus chemotherapy), neutropenia (167 [37%] vs 115 [30%]), decreased neutrophil count (98 [22%] vs 95 [24%]), thrombocytopenia (95 [21%] vs 70 [18%]), and decreased platelet count (92 [20%] vs 92 [24%]). Serious adverse events occurred in 243 (54%) patients who received atezolizumab plus chemotherapy and 196 (50%) patients who received placebo plus chemotherapy. Treatment-related deaths occurred in nine (2%; acute kidney injury, dyspnoea, hepatic failure, hepatitis, neutropenia, pneumonitis, respiratory failure, sepsis, and thrombocytopenia [n=1 each]) patients who received atezolizumab plus chemotherapy and four (1%; unexplained death, diarrhoea, febrile neutropenia, and toxic hepatitis [n=1 each]) who received placebo plus chemotherapy. INTERPRETATION: Progression-free survival benefit with first-line combination of atezolizumab plus platinum-based chemotherapy did not translate into a significant improvement in overall survival in the ITT population of IMvigor130. Further research is needed to understand which patients might benefit from first-line combination treatment. No new safety signals were observed. FUNDING: F Hoffmann-La Roche.

Atezolizumab monotherapy versus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis from a randomised, controlled, phase 3 study.

BACKGROUND: The primary analysis of IMvigor130 showed a significant progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial cancer. However, this finding did not translate into significant overall survival benefit for group A versus group C at the final analysis, precluding formal statistical testing of outcomes with atezolizumab monotherapy (group B) versus group C. Here we report the final overall survival results for group B versus group C; this report is descriptive and should be considered exploratory due to the study's statistical design. METHODS: In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged ≥18 years) who had locally advanced or metastatic urothelial cancer previously untreated in the metastatic setting and Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), using a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin score, and investigator's choice of platinum-based chemotherapy, to receive either atezolizumab plus platinum-based chemotherapy (group A), atezolizumab alone (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo in group A and group C; atezolizumab monotherapy in group B was open label. For groups B and C, atezolizumab (1200 mg) or placebo was administered intravenously every 3 weeks. Chemotherapy involved 21-day cycles of gemcitabine (1000 mg/m2 body surface area on day 1 and day 8 of each cycle) plus the investigator's choice of carboplatin (area under the curve 4·5 mg/mL per min or 5 mg/mL per min) or cisplatin (70 mg/m2 body surface area), administered intravenously. Co-primary endpoints were progression-free survival and overall survival in group A versus group C, and overall survival in group B versus group C, tested hierarchically, in the intention-to-treat (ITT) population, and then the populations with high PD-L1 tumour expression (immune cell [IC] expression score of IC2/3) if the results from group A versus group C were significant. Here, we report the co-primary endpoint of overall survival for group B versus group C in the ITT and IC2/3 populations. The ITT population for this analysis comprised concurrently enrolled patients in groups B and C who were randomly assigned to treatment. For the safety analysis, all patients enrolled in group B and group C who received any study treatment were included. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting. FINDINGS: Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 362 patients were assigned to group B and 400 to group C, of whom 360 and 359, respectively, were enrolled concurrently (ITT population). 543 (76%) of 719 patients were male, 176 (24%) were female, and 534 (74%) were White. As of data cutoff (Aug 31, 2022), after a median follow-up of 13·4 months (IQR 6·2-30·8), median overall survival was 15·2 months (95% CI 13·1-17·7; 271 deaths) in group B and 13·3 months (11·9-15·6; 275 deaths) in group C (stratified hazard ratio 0·98 [95% CI 0·82-1·16]). The most common grade 3-4 treatment-related adverse events were anaemia (two [1%] in patients who received atezolizumab monotherapy vs 133 [34%] in those who received placebo plus chemotherapy), neutropenia (one [<1%] vs 115 [30%]), decreased neutrophil count (0 vs 95 [24%]), and decreased platelet count (one [<1%] vs 92 [24%]). Serious adverse events occurred in 163 (46%) patients versus 196 (50%). Treatment-related deaths occurred in three (1%; n=1 each, pneumonia, interstitial lung disease, large intestinal obstruction) patients who received atezolizumab monotherapy and four (1%; n=1 each, diarrhoea, febrile neutropenia, unexplained death, toxic hepatitis) who received placebo plus chemotherapy. INTERPRETATION: The final analysis from IMvigor130 did not show a significant improvement in overall survival with first-line atezolizumab monotherapy compared with platinum-based chemotherapy in the intention-to-treat population. The safety profile of atezolizumab monotherapy remained acceptable after extended follow-up, with no new safety signals. FUNDING: F Hoffmann-La Roche.

Effects of dietary vitamins on obesity-related metabolic parameters.

Type 2 diabetes mellitus (T2DM) is one of the leading causes of death worldwide. Genetic factors, some underlying medical conditions, and obesity are risk factors of T2DM. Unlike other risk factors which are non-modifiable, obesity is preventable and usually treatable, and is largely contributed by lifestyle factors. Management of these lifestyle factors may curb the development of T2DM and reduces T2DM prevalence. Dietary vitamins have been recommended as a lifestyle modification intervention to support obesity treatment. Vitamins correlate negatively with body weight, body mass index and body composition. Some of the vitamins may also have anti-adipogenic, anti-inflammatory and antioxidant effects. However, results from pre-clinical and clinical studies of the effects of vitamins on obesity are inconsistent. A clear understanding of the effects of vitamins on obesity will help determine dietary intervention that is truly effective in preventing and treating obesity as well as obesity-related complications including T2DM. This article reviews existing evidences of the effects of vitamin supplementation on obesity and obesity-related metabolic status.

Improved systemic half-life of glucagon-like peptide-1-loaded carbonate apatite nanoparticles in rats.

BACKGROUND: Glucagon-like peptide-1 (GLP1) is an endogenous peptide that regulates blood glucose level. But its susceptibility to rapid metabolic degradation limits its therapeutic use. AIM: To prepare GLP1-encapsulated nanosize particle with controlled release property to improve the systemic half-life of GLP1. METHODS: GLP1 nanoparticles were prepared by complexation of GLP1 with carbonate apatite nanoparticles (CA NPs). The physicochemical properties of the CA NPs, the effects of GLP1-loaded CA NPs on cell viability, and the systemic bioavailability of GLP1 after CA NPs administration were determined. RESULTS: The GLP1-loaded CA NPs was within 200 nm in size and stable in fetal bovine serum. The formulation did not affect the viability of human cell lines suggesting that the accumulation of CA NPs in target tissues is safe. In Sprague Dawley rats, the plasma GLP1 Levels as measured from the GLP1-loaded CA NPs-treated rats, were significantly higher than that of the control rats and free GLP1-treated rats at 1 h post-treatment (P < 0.05), and the level remained higher than the other two groups for at least 4 h. CONCLUSION: The GLP1-loaded CA NPs improved the plasma half-life of GLP1. The systemic bioavailability of GLP1 is longer than other GLP1 nanoparticles reported to date.

Implementing a collaborative medicine and pharmacy educational activity in two countries.

BACKGROUND: To promote better collaboration for patient care, interprofessional education (IPE) is required in many health professions courses. However, successful IPE implementation at scale can be challenging because of complicated logistics and competing priorities. Implementing across multiple geographies adds further complexity. OBJECTIVE: This paper describes the implementation of a full cohort IPE activity for medical and pharmacy students delivered at both the Australian and Malaysian campuses of Monash University. DESIGN: We designed a 150-minute, blended learning activity centred around asthma care for second-year medical and pharmacy students. Student perceptions were measured with a pre- and post-activity survey using the validated ten-item, three-factor, SPICE-R2 instrument. Analysis focused on differences between professions and countries. RESULTS: All second-year medicine (N = 301 in Australia and N = 107 in Malaysia) and pharmacy students (N = 168 in Australia and N = 117 in Malaysia) participated in the learning activity. A total of 326/693 (47%) students participated in the associated research by completing both the pre- and post-activity surveys. The pre-activity survey showed significant differences in four items between medicine and pharmacy students in Australia and two items in Malaysia. Post-activity, we observed significant changes in 8/10 items when the two professions were combined. Specifically, we noted changes across the countries in perceptions of roles and responsibilities for collaborative practice and patient outcomes from collaborative practice. CONCLUSIONS: IPE across different professions and countries is feasible. Positive outcomes in role understanding and perceived patient outcomes are achievable through a context-sensitive, locally driven approach to implementation. Longitudinal experiences may be required to influence perceptions of teamwork and team-based care.

The Gut-Brain-Axis on the Manifestation of Depressive Symptoms in Epilepsy: An Evidence-Driven Hypothesis.

Epilepsy is a severe neurological disorder involving 70 million people around the globe. Epilepsy-related neuropsychiatric comorbidities such as depression, which is the most common, is an additional factor that negatively impacts the living quality of epilepsy patients. There are many theories and complexities associated with both epilepsy and associated comorbidities, one of which is the gut-brain-axis influence. The gut microbiome is hypothesized to be linked with many neurological disorders; however, little conclusive evidence is available in this area. Thus, highlighting the role will create interest in researchers to conduct detailed research in comprehending the influence of gut-brain-axis in the manifestation of depressive symptoms in epilepsy. The hypothesis which is explored in this review is that the gut-brain-axis do play an important role in the genesis of epilepsy and associated depression. The correction of this dysbiosis might be beneficial in treating both epilepsy and related depression. This hypothesis is illustrated through extensive literature discussion, proposed experimental models, and its applicability in the field. There is indirect evidence which revealed some specific bacterial strains that might cause depression in epilepsy.

Current strategies in extending half-lives of therapeutic proteins.

Macromolecular protein and peptide therapeutics have been proven to be effective in treating critical human diseases precisely. Thanks to biotechnological advancement, a huge number of proteins and peptide therapeutics were made their way to pharmaceutical market in past few decades. However, one of the biggest challenges to be addressed for protein therapeutics during clinical application is their fast degradation in serum and quick elimination owing to enzymatic degradation, renal clearance, liver metabolism and immunogenicity, attributing to the short half-lives. Size and hydrophobicity of protein molecules make them prone to kidney filtration and liver metabolism. On the other hand, proteasomes responsible for protein destruction possess the capability of specifically recognizing almost all kinds of foreign proteins while avoiding any unwanted destruction of cellular components. At present almost all protein-based drug formulations available in market are administered intravenously (IV) or subcutaneously (SC) with high dosing at frequent interval, eventually creating dose-fluctuation-related complications and reducing patient compliance vastly. Therefore, artificially increasing the therapeutic half-life of a protein by attaching to it a molecule that increases the overall size (eg, PEG) or helps with receptor mediated recycling (eg, albumin), or manipulating amino acid chain in a way that makes it more prone towards aggregate formation, are some of the revolutionary approaches to avoid the fast degradation in vivo. Half-life extension technologies that are capable of dramatically enhancing half-lives of proteins in circulation (2-100 folds) and thus improving their overall pharmacokinetic (PK) parameters have been successfully applied on a wide range of protein therapeutics from hormones and enzymes, growth factor, clotting factor to interferon. The focus of the review is to assess the technological advancements made so far in enhancing circulatory half-lives and improving therapeutic potency of proteins.

Lipopolysaccharide reduces gonadotrophin-releasing hormone (GnRH) gene expression: role of RFamide-related peptide-3 and kisspeptin.

RFamide-related peptide (RFRP)-3 reduces luteinising hormone (LH) secretion in rodents. Stress has been shown to upregulate the expression of the RFRP gene (Rfrp) with a concomitant reduction in LH secretion, but an effect on expression of the gonadotrophin-releasing hormone (GnRH) gene (Gnrh1) has not been shown. We hypothesised that lipopolysaccharide (LPS)-induced stress affects expression of Rfrp, the gene for kisspeptin (Kiss1) and/or Gnrh1, leading to suppression of LH levels in rats. Intracerebroventricular injections of RFRP-3 (0.1, 1, 5 nmol) or i.v. LPS (15µgkg-1) reduced LH levels. Doses of 1 and 5 nmol RFRP-3 were then administered to analyse gene expression by in situ hybridisation. RFRP-3 (5 nmol) had no effect on Gnrh1 or Kiss1 expression. LPS stress reduced GnRH and Kiss1 expression, without affecting Rfrp1 expression. These data indicate that LPS stress directly or indirectly reduces Gnrh1 expression, but this is unlikely to be due to a change in Rfrp1 expression.

A phase Ib trial of continuous once-daily oral afatinib plus sirolimus in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer and/or disease progression following prior erlotinib or gefitinib.

OBJECTIVES: Dysregulation of the downstream PI3K/AKT/mTOR signaling pathway is a proposed mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We investigated safety and antitumor activity of afatinib plus sirolimus as a potential combination to reverse acquired resistance to EGFR-TKIs in a phase IB trial in patients with EGFR mutation-positive non-small-cell lung cancer (EGFR mut NSCLC) and/or disease progression following prior erlotinib/gefitinib. MATERIALS AND METHODS: Patients with EGFR mut NSCLC and/or disease progression following at least prior erlotinib/gefitinib were included in the trial. The primary endpoint was incidence of dose-limiting toxicities (DLT) to determine the maximum tolerated dose (MTD). Four initial dose cohorts were proposed to evaluate DLTs. Other endpoints included tumor response, safety, progression-free survival (PFS) and pharmacokinetics. RESULTS: Thirty-nine patients received afatinib and sirolimus. Additional dose cohorts were added since the second cohort (afatinib 40mg/day and sirolimus 5mg/day) was considered to have excessive toxicity. All patients experienced adverse events (AE) [grade 3: 66.7%; serious AE: 56.4%]. The most frequent AEs were diarrhea (94.9%), mucosal inflammation (64.1%), asthenia (53.8%) and rash (53.8%). Discontinuations and dose reduction due to AEs occurred in 23.1% and 25.6% of patients. MTD was determined as afatinib 30mg and sirolimus 1mg. Responses were observed in 5 patients (12.8%) [2 (5.1%) with confirmed partial response (PR); 3 (7.7%) with unconfirmed PR], and stable disease in 18 patients (46.2%). Four of the 5 responses were at doses above MTD. PFS at 6 months was estimated in 33.3% (median PFS 3.4 months). Pharmacokinetic parameters of afatinib and sirolimus were similar after single administration or in combination. CONCLUSION: The combination of afatinib and sirolimus showed lower responses than expected. Together with increased AEs and poor tolerability, this precludes clinical use and further clinical development of this combination. No pharmacokinetic interactions were observed. CLINICALTRIALS. GOV IDENTIFIER: NCT00993499.

Multidetector CT improving surgical outcomes in breast cancer (MISO-BC): A randomised controlled trial.

BACKGROUND: Early diagnosis of malignant axillary nodes in breast cancer guides the extent of axillary surgery: patients with known axillary malignancy receive a more extensive single operation at the same time as surgery to their breast. A multicentre randomised controlled trial assessed whether a Computed Tomography (CT) scan of the axilla could more accurately diagnose malignant axillary lymph node involvement in patients with newly diagnosed breast cancer when compared to usual care. METHODS: Patients with newly diagnosed breast cancer (identified via screening and symptomatic pathways) at two NHS Trusts in the North East of England were recruited and randomised in equal numbers. Both groups received routine diagnostic and surgical care. In addition, one group received a CT scan of their axilla on the same side as the breast cancer. The primary endpoint was the need to undergo a second axillary surgical procedure. FINDINGS: The trial recruited 297 patients of whom 291 contributed to findings. The proportion of patients undergoing a second operation was similar (CT vs UC: 19.4% vs. 19.7%; CT-UC: -0.3%, 95%CI: = -9.5% to 8.9%, χ2 [1]: p = 1.00). Patients in the two groups were similar before treatment, had similar types and grade of cancer, experienced similar patterns of post-operative complications and reported similar experiences of care. INTERPRETATION: CT scan-guided care did not result in a change in the number of patients requiring a second operation; similar numbers of patients needed further axillary surgery in both groups. New diagnostic imaging technologies regularly enter NHS centres. It is important these are evaluated rigorously before becoming routine care.

Strategies of temozolomide in future glioblastoma treatment.

Glioblastoma multiforme (GBM) may be one of the most challenging brain tumors to treat, as patients generally do not live more than 2 years. This review aimed to give a timely review of potential future treatments for GBM by looking at the latest strategies, involving mainly the use of temozolomide (TMZ). Although these studies were carried out either in vitro or in rodents, the findings collectively suggested that we are moving toward developing a more efficacious therapy for GBM patients. Nanoparticles preparation was, by far, the most extensively studied strategy for targeted brain delivery. Therefore, the first section of this review presents a treatment strategy using TMZ-loaded nanocarriers, which encompassed nanoparticles, nanoliposomes, and nanosponges. Besides nanocarriers, new complexes that were formed between TMZ and another chemical agent or molecule have shown increased cytotoxicity and antitumor activity. Another approach was by reducing GBM cell resistance to TMZ, and this was achieved either through the suppression of metabolic change occurring in the cells, inhibition of the DNA repair protein, or up-regulation of the protein that mediates autophagy. Finally, the review collates a list of substances that have demonstrated the ability to suppress tumor cell growth.

Preparation of Temozolomide-Loaded Nanoparticles for Glioblastoma Multiforme Targeting-Ideal Versus Reality.

Temozolomide (TMZ) is one of the most effective chemotherapeutic agents for glioblastoma multiforme, but the required high administration dose is accompanied by side effects. To overcome this problem and to further improve TMZ's efficacy, targeted delivery of TMZ by using polymeric nanoparticles has been explored. We synthesised the PLGA-PEG-FOL copolymer and attempted encapsulation of TMZ into PLGA-PEG-FOL nanoparticles using the emulsion solvent evaporation method and the nanoprecipitation method. Conjugation of PEG and FOL to PLGA has been reported to be able to increase the delivery of TMZ to the brain as well as targeting the glioma cells. However, despite making numerous modifications to these methods, the loading of TMZ in the nanoparticles only ranged between 0.2% and 2%, and the nanoparticles were between 400 nm and 600 nm in size after freeze-drying. We proceed with determining the release profile of TMZ in phosphate buffered saline (PBS). Our initial data indicated that TMZ was slowly released from the nanoparticles. The metabolite of TMZ rather than the parent compound was detected in PBS. Our study suggests that while PLGA-PEG-FOL can be used as a polymeric or encapsulation material for central delivery of TMZ, a practical and cost effective formulation method is still far from reach.

A phase I study of BI 811283, an Aurora B kinase inhibitor, in patients with advanced solid tumors.

PURPOSE: This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and antitumor activity of the Aurora B kinase inhibitor BI 811283 in patients with advanced solid tumors. METHODS: BI 811283 was administered via 24-h infusion on Days 1 and 15 of a 4-week cycle (schedule A) or Day 1 of a 3-week cycle (schedule B) in a modified 3 + 3 dose-escalation design. Pharmacodynamic assessments included immunohistochemistry for phosphorylated histone H3 (pHH3) on skin biopsies to determine Aurora B kinase inhibition and plasma concentrations of caspase-cleaved CK-18 (apoptosis marker). RESULTS: A total of 121 patients were treated. The MTDs of BI 811283 were 125 mg (schedule A) and 230 mg (schedule B). Dose-limiting toxicities were primarily hematological (febrile neutropenia and grade 4 neutropenia); the most common drug-related adverse effects included neutropenia, fatigue, leukopenia, nausea, alopecia, diarrhea, and decreased appetite. A trend toward a decrease in pHH3 was observed, with increasing BI 811283 doses, indicating target engagement; there was no consistent trend regarding caspase-cleaved CK-18 levels. No objective response was observed although 19 patients in each schedule achieved clinical benefit (stable disease). CONCLUSIONS: BI 811283 demonstrated a generally manageable safety profile and disease stabilization in some patients. TRIAL REGISTRATION: EudraCT No: 2007-000191-17, ClinicalTrials.gov Identifier: NCT00701324.

A phase I study of two dosing schedules of oral BI 847325 in patients with advanced solid tumors.

PURPOSE: This study determined the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary efficacy of BI 847325, an oral dual MEK and Aurora kinase inhibitor, in patients with refractory solid tumors. METHODS: This trial recruited patients with an advanced non-resectable and/or metastatic solid tumor following failure of conventional treatment (NCT01324830; 1287.1). BI 847325 was administered orally, once daily (starting at 6 mg in the first cohort) using two dosing schedules: Schedule A (2 weeks on, 1 week off) and Schedule B (three periods of 5 days on, 2 days off). The primary objective was to identify the MTD of BI 847325 for both dosing schedules. RESULTS: Sixty-nine patients (Schedule A, n = 47; Schedule B, n = 22) were treated. The MTD was 120 mg per day for Schedule A (cumulative dose of 1680 mg per 3-week cycle) and 150 mg per day for Schedule B (cumulative dose of 2250 mg per 3-week cycle). Reversible hematologic and gastrointestinal toxicities were the most common dose-limiting toxicities. One patient with esophageal cancer (receiving 160 mg BI 847325, Schedule A) experienced a partial response for 67 days, and 21 patients (n = 11 [23.4%], Schedule A; n = 10 [45.5%], Schedule B) had stable disease. Pharmacokinetic analyses showed at least bi-exponential disposition, with high inter-subject variability. There was no obvious relationship between markers of MEK or Aurora kinase inhibition and exposure to BI 847325 (exploratory analysis). CONCLUSIONS: This first-in-human trial suggests that BI 847325 has an acceptable safety profile. However, due to insufficient drug exposure at the MTD to achieve relevant MEK inhibition, a decision was taken to halt the development of BI 847325.

Junior doctor dementia champions in a district general hospital (innovative practice).

Dementia is a common condition in the UK with around 25% of patients in acute hospitals having dementia. In the UK, there is national guidance on the assessment of cognitive impairment in acute hospitals. This article is a qualitative study of junior doctors' experiences as part of a dementia and delirium team involved in changing the care of patients with dementia in a hospital in the UK. It draws on data from a focus group and follow-up questionnaire in two hospital trusts. We examine what drives doctors to become involved in such projects and the effects of this experience upon them. We suggest a typology for getting junior doctors involved in projects generating change when working with patients with dementia. Being more actively involved in caring for and developing services for patients with dementia may represent the crossing of an educational threshold for these junior doctors.

Glucagon-Like Peptide-1 Formulation--the Present and Future Development in Diabetes Treatment.

Type 2 diabetes mellitus is a chronic metabolic disorder that has become the fourth leading cause of death in the developed countries. The disorder is characterized by pancreatic ß-cells dysfunction, which causes hyperglycaemia leading to several other complications. Treatment by far, which focuses on insulin administration and glycaemic control, has not been satisfactory. Glucagon-like peptide-1 (GLP1) is an endogenous peptide that stimulates post-prandial insulin secretion. Despite being able to mimic the effect of insulin, GLP1 has not been the target drug in diabetes treatment due to the peptide's metabolic instability. After a decade-long effort to improve the pharmacokinetics of GLP1, a number of GLP1 analogues are currently available on the market. The current Minireview does not discuss these drugs but presents strategies that were undertaken to address the weaknesses of the native GLP1, particularly drug delivery techniques used in developing GLP1 nanoparticles and modified GLP1 molecule. The article highlights how each of the selected preparations has improved the efficacy of GLP1, and more importantly, through an overview of these studies, it will provide an insight into strategies that may be adopted in the future in the development of a more effective oral GLP1 formulation.

Phase I study of nintedanib incorporating dynamic contrast-enhanced magnetic resonance imaging in patients with advanced solid tumors.

BACKGROUND: This open-label phase I dose-escalation study investigated the safety, efficacy, pharmacokinetics (PK), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) effects of the oral angiokinase inhibitor nintedanib in patients with advanced solid tumors. METHODS: Nintedanib was administered once daily continuously, starting at 100 mg and later amended to allow evaluation of 250 mg b.i.d. The primary endpoint was maximum tolerated dose (MTD). DCE-MRI studies were performed at baseline and on days 2 and 28. RESULTS: Fifty-one patients received nintedanib 100-450 mg once daily (n = 40) or 250 mg b.i.d. (n = 11). Asymptomatic reversible liver enzyme elevations (grade 3) were dose limiting in 2 of 5 patients at 450 mg once daily. At 250 mg b.i.d., 2 of 11 patients experienced dose-limiting toxicity (grade 3 liver enzyme elevation and gastrointestinal symptoms). Common toxicities included fatigue, diarrhea, nausea, vomiting, and abdominal pain (mainly grade ≤2). Among 45 patients, 22 (49%) achieved stable disease; 7 remained on treatment for >6 months. DCE-MRI of target lesions revealed effects in some patients at 200 and ≥400 mg once daily. CONCLUSION: Nintedanib is well tolerated by patients with advanced solid malignancies, with MTD defined as 250 mg b.i.d., and can induce changes in DCE-MRI. Disease stabilization >6 months was observed in 7 of 51 patients.