Measurement of adherence to BCR-ABL inhibitor therapy in chronic myeloid leukemia: current situation and future challenges

BCR-ABL inhibitors for treating chronic myeloid leukemia in chronic phase have transformed a previously incurable malignancy into a manageable condition. However, suboptimal medication adherence has been observed with these agents affecting clinical outcomes and healthcare costs. In order to raise awareness of the problem of adherence, and before developing pragmatic strategies to enhance medication adherence, a deep understanding of the best approaches for measuring adherence in chronic myeloid leukemia patients and identifying non-adherence is required. A systematic literature review on the prevalence, measurement methods, consequences and risk factors for non-adherence to BCR-ABL inhibitors and adherence-enhancing interventions was performed and critically appraised. Of the 19 included articles, 9 were retrospective. Average adherence varied from 19% to almost 100% of the proportion of prescribed drug taken, but it was measured through various different methods and within different study groups. Suboptimal adherence was associated with a negative impact on both clinical and economic outcomes. There is a lack of supportive evidence demonstrating a difference in adherence across BCR-ABL inhibitors and even contradictory results between the 2^nd generation inhibitors. Drug-related adverse events and forgetfulness were common reasons for intentional and unintentional non-adherence, respectively, but further research is required to identify additional reasons behind non-adherence or patients at risk of non-adherence. Non-adherence in chronic myeloid leukemia patients treated with BCR-ABL inhibitors is common and associated with critical outcomes. However, this review highlights important existing gaps, reveals inconsistent definitions, and a lack of standardized methods for measuring adherence in chronic myeloid leukemia. All require further investigation.     

Clinicopathologic and molecular features of intracranial desmoplastic small round cell tumors

Desmoplastic small round cell tumors (DSRCTs) are highly aggressive sarcomas that most commonly occur intra‐abdominally, and are defined by EWSR1‐WT1 gene fusion. Intracranial DSRCTs are exceptionally rare with only seven previously reported fusion‐positive cases. Herein, we evaluate the clinical, morphologic, immunohistochemical and molecular features of five additional examples. All patients were male (age range 6–25 years; median 11 years), with four tumors located supratentorially and one within the posterior fossa. The histologic features were highly variable including small cell, embryonal, clear cell, rhabdoid, anaplastic and glioma‐like appearances. A prominent desmoplastic stroma was seen in only two cases. The mitotic index ranged from <1 to 12/10 HPF (median 5). While all tumors showed strong desmin positivity, epithelial markers such as EMA, CAM 5.2 and other keratins were strongly positive in only one, focally positive in two and negative in two cases. EWSR1‐WT1 gene fusion was present in all cases, with accompanying mutations in the TERT promoter or STAG2 gene in individual cases. Given the significant histologic diversity, in the absence of genetic evaluation these cases could easily be misinterpreted as other entities. Desmin immunostaining is a useful initial screening method for consideration of a DSRCT diagnosis, prompting confirmatory molecular testing. Demonstrating the presence of an EWSR1‐WT1 fusion provides a definitive diagnosis of DSRCT. Genome‐wide methylation profiles of intracranial DSRCTs matched those of extracranial DSRCTs. Thus, despite the occasionally unusual histologic features and immunoprofile, intracranial DSRCTs likely represent a similar, if not the same, entity as their soft tissue counterpart based on the shared fusion and methylation profiles.     

In vivo biocompatibility of porous silicon biomaterials for drug delivery to the heart

Myocardial infarction (MI), commonly known as a heart attack, is the irreversible necrosis of heart muscle secondary to prolonged ischemia, which is an increasing problem in terms of morbidity, mortality and healthcare costs worldwide. Along with the idea to develop nanocarriers that efficiently deliver therapeutic agents to target the heart, in this study, we aimed to test the in vivo biocompatibility of different sizes of thermally hydrocarbonized porous silicon (THCPSi) microparticles and thermally oxidized porous silicon (TOPSi) micro and nanoparticles in the heart tissue. Despite the absence or low cytotoxicity, both particle types showed good in vivo biocompatibility, with no influence on hematological parameters and no considerable changes in cardiac function before and after MI. The local injection of THCPSi microparticles into the myocardium led to significant higher activation of inflammatory cytokine and fibrosis promoting genes compared to TOPSi micro and nanoparticles; however, both particles showed no significant effect on myocardial fibrosis at one week post-injection. Our results suggest that THCPSi and TOPSi micro and nanoparticles could be applied for cardiac delivery of therapeutic agents in the future, and the PSi biomaterials might serve as a promising platform for the specific treatment of heart diseases.     

NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes

Alzheimer's disease (AD) is a common dementia affecting a vast number of individuals and significantly impairing quality of life. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for AD. Astrocytes, the most common cell type of the central nervous system, have been shown to play a role in the major AD pathologies, including accumulation of amyloid plaques, neuroinflammation, and oxidative stress. Here, we show that inflammatory stimulation leads to metabolic activation of human astrocytes and reduces amyloid secretion. On the other hand, the activation of oxidative metabolism leads to increased reactive oxygen species production especially in AD astrocytes. While healthy astrocytes increase glutathione (GSH) release to protect the cells, Presenilin-1-mutated AD patient astrocytes do not. Thus, chronic inflammation is likely to induce oxidative damage in AD astrocytes. Activation of NRF2, the major regulator of cellular antioxidant defenses, encoded by the NFE2L2 gene, poses several beneficial effects on AD astrocytes. We report here that the activation of NRF2 pathway reduces amyloid secretion, normalizes cytokine release, and increases GSH secretion in AD astrocytes. NRF2 induction also activates the metabolism of astrocytes and increases the utilization of glycolysis. Taken together, targeting NRF2 in astrocytes could be a potent therapeutic strategy in AD.     

SLEEVEPASS: A randomized prospective multicenter study comparing laparoscopic sleeve gastrectomy and gastric bypass in the treatment of morbid obesity: preliminary results

Background

The long-term efficacy of laparoscopic Roux-en-Y gastric bypass (RYGB) in the treatment of morbid obesity has been demonstrated. Laparoscopic sleeve gastrectomy (SG) as a single procedure has shown promising short-term results, but the long-term efficacy of SG has not yet been demonstrated. The aim of this study was to determine the preliminary 30-day morbidity and mortality of RYGB and SG in a prospective multicenter randomized setting.

Methods

A total of 240 morbidly obese (BMI?=?35–66?kg/m2) patients evaluated by a multidisciplinary team were randomized to undergo either RYGB or SG. There were 117 patients in the RYGB group and 121 in the SG group; two patients had to be excluded after randomization. Both study groups were comparable regarding age, gender, BMI, and comorbidities.

Results

There was no 30-day mortality. The median operating time was significantly shorter in the SG group (66?min vs. 94?min, p?p?=?0.292). Nine (7.4 %) SG patients and 20 (17.1 %) RYGB patients had minor complications (p?=?0.023). The overall morbidity was 13.2 % after SG and 26.5 % after RYGB (p?=?0.010). There were three (2.5 %) early reoperations after SG and four (3.3 %) after RYGB (p?=?0.719).

Conclusions

At 30-day analysis SG is associated with a shorter operating time and fewer early minor complications compared to RYGB. There were no significant differences in major complications or early reoperations. Long-term follow-up is required to determine the effect on weight loss, resolution of obesity-related comorbidities, and improvement of quality of life.     

Health and social service use among old people in the last 2 years of life

This study focuses on differences in health and social service use in the last 2 years of life among Finnish people aged 70–79, 80–89, and 90 or older and on the variation in service use in the various municipalities. The data set, derived from multiple national registers, consists of 75,578 people who died in 1998–2001. The services included hospitals and long-term-care facilities, use of regular home care, and prescribed medicines. General hospital and public long-term care were the services most commonly used: general hospitals for younger age groups and public long-term care for older groups. The number of inpatient days in hospital was lower with increasing age, but older age groups used long-term care more frequently. Men had more hospital inpatient days than women, but women used more long-term care. The number of hospital inpatient days increased rapidly in the last months of life, almost doubling in the final month. Days in public long-term care increased regularly in the last 2 years of life. Variation in both hospital and long-term care by municipality was remarkable. The results indicate that, among people aged 70 years and older, age is a major determinant of care in the last 2 years of life. The variation in the use of care by municipality and the differences between men and women deserve more detailed analysis in future.     

The usefulness of nutrition and health videos displayed on mobile phones in rural Uganda: Experiences of community health workers and mothers

Improvements in community health workers'' (CHWs) knowledge and practices in low‐income countries increasingly involve mobile phones and videos. However, little data exists on CHWs’ and mothers’ experiences of using such phones and videos. In this study, educational videos on nutrition, health and hygiene were downloaded onto mobile phones, which were given to 12 CHWs in rural Uganda. In 2018, these CHWs used the videos for a period of 3 months to support their work during their visits with families. We subsequently conducted individual interviews with eight CHWs and held four focus group discussions with 16 mothers. From the inductively analysed data, we identified four key themes: impact, competence, meaningfulness and choice, which are also dimensions of the Intrinsic Task Motivation Model. The model describes the motivation of workers and has previously been used in connection with CHWs. In our study, CHWs and mothers considered that the videos had more strongly impacted their learning than traditional teaching methods, and they felt the videos improved the child feeding and caring competence of both CHWs and mothers. Furthermore, the CHWs found that the videos enhanced the meaningfulness of their work, as they felt more greatly appreciated and necessary. In addition, they experienced more freedom of choice in their ability to influence their working routines. This study shows that educational videos are well received among CHWs and mothers. Educational videos are a promising method to maintain and improve the motivation of voluntary CHWs and influence correct child feeding and hygiene practices in Uganda.