Frailty Markers and Treatment Decisions in Patients Seen in Oncogeriatric Clinics: Results from the ASRO Pilot Study

Background

Comprehensive Geriatric Assessment (CGA) is the gold standard to help oncologists select the best cancer treatment for their older patients. Some authors have suggested that the concept of frailty could be a more useful approach in this population. We investigated whether frailty markers are associated with treatment recommendations in an oncogeriatric clinic.

Methods

This prospective study included 70 years and older patients with solid tumors and referred for an oncogeriatric assessment. The CGA included nine domains: autonomy, comorbidities, medication, cognition, nutrition, mood, neurosensory deficits, falls, and social status. Five frailty markers were assessed (nutrition, physical activity, energy, mobility, and strength). Patients were categorized as Frail (three or more frailty markers), pre-frail (one or two frailty markers), or not-frail (no frailty marker). Treatment recommendations were classified into two categories: standard treatment with and without any changes and supportive/palliative care. Multiple logistic regression models were used to analyze factors associated with treatment recommendations.

Results

217 patients, mean age 83 years (± Standard deviation (SD) 5.3), were included. In the univariate analysis, number of frailty markers, grip strength, physical activity, mobility, nutrition, energy, autonomy, depression, Eastern Cooperative Oncology Group Scale of Performance Status (ECOG-PS), and falls were significantly associated with final treatment recommendations. In the multivariate analysis, the number of frailty markers and basic Activities of Daily Living (ADL) were significantly associated with final treatment recommendations (p<0.001 and p = 0.010, respectively).

Conclusion

Frailty markers are associated with final treatment recommendations in older cancer patients. Longitudinal studies are warranted to better determine their use in a geriatric oncology setting.     

Stranding Events of Kogia Whales along the Brazilian Coast

The genus Kogia, which comprises only two extant species, Kogia sima and Kogia breviceps, represents one of the least known groups of cetaceans in the global ocean. In some coastal regions, however, stranding events of these species have been relatively common over the last decades. Stranding provides the opportunity to investigate the biology of these cetaceans and to explore the epidemiological aspects associated with the mortality of the organisms found on the beach. A number of disturbances (including pelagic fisheries, chemical pollution, boat strikes, and noise pollution) have been confirmed to pose a particular threat to the Kogia species. However, no study has yet investigated potential relationships between environmental conditions and stranding events. Here we analyse how a collection of environmental, physical, and biological variables, such as wind, sea surface temperature (SST), water depth, and chlorophyll-a, correlate to Kogia stranding events along the Brazilian coast. The results of our statistical analyses suggest that K. sima is more likely found in warm tropical waters, which provide an explanation for the high frequency of stranding in northeastern Brazilian coast. In contrast, K. breviceps appears to have a preference for temperate and productive waters. Wind speed results to be also an important factor for predicting Kogia strandings in Brazilian coast. Additionally, literature information in combination with our own data and analyses of stomach contents confirms that oceanic cephalopods constitute the primary nutritional source of both Kogia species. By using the available information as a qualitative proxy for habitat preference and feeding ecology, our study provides a novel and comprehensive assessment of Kogia stranding data in relation to environmental conditions along the Brazilian coast.     

Efficacy and Safety of Pafuramidine versus Pentamidine Maleate for Treatment of First Stage Sleeping Sickness in a Randomized,Comparator-Controlled,International Phase 3 Clinical Trial

Background

Sleeping sickness (human African trypanosomiasis [HAT]) is a neglected tropical disease with limited treatment options that currently require parenteral administration. In previous studies, orally administered pafuramidine was well tolerated in healthy patients (for up to 21 days) and stage 1 HAT patients (for up to 10 days), and demonstrated efficacy comparable to pentamidine.

Methods

This was a Phase 3, multi-center, randomized, open-label, parallel-group, active control study where 273 male and female patients with first stage Trypanosoma brucei gambiense HAT were treated at six sites: one trypanosomiasis reference center in Angola, one hospital in South Sudan, and four hospitals in the Democratic Republic of the Congo between August 2005 and September 2009 to support the registration of pafuramidine for treatment of first stage HAT in collaboration with the United States Food and Drug Administration. Patients were treated with either 100 mg of pafuramidine orally twice a day for 10 days or 4 mg/kg pentamidine intramuscularly once daily for 7 days to assess the efficacy and safety of pafuramidine versus pentamidine. Pregnant and lactating women as well as adolescents were included.The primary efficacy endpoint was the combined rate of clinical and parasitological cure at 12 months. The primary safety outcome was the frequency and severity of adverse events. The study was registered on the International Clinical Trials Registry Platform at www.clinicaltrials.gov with the number ISRCTN85534673.

Findings/Conclusions

The overall cure rate at 12 months was 89% in the pafuramidine group and 95% in the pentamidine group; pafuramidine was non-inferior to pentamidine as the upper bound of the 95% confidence interval did not exceed 15%. The safety profile of pafuramidine was superior to pentamidine; however, 3 patients in the pafuramidine group had glomerulonephritis or nephropathy approximately 8 weeks post-treatment. Two of these events were judged as possibly related to pafuramidine. Despite good tolerability observed in preceding studies, the development program for pafuramidine was discontinued due to delayed post-treatment toxicity.     

Evaluation of a glycoengineered monoclonal antibody via LC-MS analysis in combination with multiple enzymatic digestion

Glycosylation affects the efficacy, safety and pharmacokinetics/pharmacodynamics properties of therapeutic monoclonal antibodies (mAbs), and glycoengineering is now being used to produce mAbs with improved efficacy. In this work, a glycoengineered version of rituximab was produced by chemoenzymatic modification to generate human-like N-glycosylation with α 2,6 linked sialic acid. This modified rituximab was comprehensively characterized by liquid chromatography-mass spectrometry and compared to commercially available rituximab. As anticipated, the majority of N-glycans were converted to α 2,6 linked sialic acid, in contrast to CHO-produced rituximab, which only contains α 2,3 linked sialic acid. Typical posttranslational modifications, such as pyro-glutamic acid formation at the N-terminus, oxidation at methionine, deamidation at asparagine, and disulfide linkages were also characterized in both the commercial and glycoengineered mAbs using multiple enzymatic digestion and mass spectrometric analysis. The comparative study reveals that the glycoengineering approach does not cause any additional posttranslational modifications in the antibody except the specific transformation of the glycoforms, demonstrating the mildness and efficiency of the chemoenzymatic approach for glycoengineering of therapeutic antibodies.     

Skeletal Muscle Insulin Resistance and Absence of Inflammation Characterize Insulin-Resistant Grade I Obese Women

ContextObesity is associated with insulin-resistance (IR), the key feature of type 2 diabetes. Although chronic low-grade inflammation has been identified as a central effector of IR development, it has never been investigated simultaneously at systemic level and locally in skeletal muscle and adipose tissue in obese humans characterized for their insulin sensitivity.ObjectivesWe compared metabolic parameters and inflammation at systemic and tissue levels in normal-weight and obese subjects with different insulin sensitivity to better understand the mechanisms involved in IR development.Methods30 post-menopausal women were classified as normal-weight insulin-sensitive (controls, CT) and obese (grade I) insulin-sensitive (OIS) or insulin-resistant (OIR) according to their body mass index and homeostasis model assessment of IR index. They underwent a hyperinsulinemic-euglycemic clamp, blood sampling, skeletal muscle and subcutaneous adipose tissue biopsies, an activity questionnaire and a self-administrated dietary recall. We analyzed insulin sensitivity, inflammation and IR-related parameters at the systemic level. In tissues, insulin response was assessed by P-Akt/Akt expression and inflammation by macrophage infiltration as well as cytokines and IκBα expression.ResultsSystemic levels of lipids, adipokines, inflammatory cytokines, and lipopolysaccharides were equivalent between OIS and OIR subjects. In subcutaneous adipose tissue, the number of anti-inflammatory macrophages was higher in OIR than in CT and OIS and was associated with higher IL-6 level. Insulin induced Akt phosphorylation to the same extent in CT, OIS and OIR. In skeletal muscle, we could not detect any inflammation even though IκBα expression was lower in OIR compared to CT. However, while P-Akt/Akt level increased following insulin stimulation in CT and OIS, it remained unchanged in OIR.ConclusionOur results show that systemic IR occurs without any change in systemic and tissues inflammation. We identified a muscle defect in insulin response as an early mechanism of IR development in grade I obese post-menopausal women.     

Paradoxical Sensitivity to an Integrated Stress Response Blocking Mutation in Vanishing White Matter Cells

The eukaryotic translation initiation factor eIF2B promotes mRNA translation as a guanine nucleotide exchange factor (GEF) for translation initiation factor 2 (eIF2). Endoplasmic reticulum (ER) stress-mediated activation of the kinase PERK and the resultant phosphorylation of eIF2’s alpha subunit (eIF2α) attenuates eIF2B GEF activity thereby inducing an integrated stress response (ISR) that defends against protein misfolding in the ER. Mutations in all five subunits of human eIF2B cause an inherited leukoencephalopathy with vanishing white matter (VWM), but the role of the ISR in its pathogenesis remains unclear. Using CRISPR-Cas9 genome editing we introduced the most severe known VWM mutation, EIF2B4^A391D, into CHO cells. Compared to isogenic wildtype cells, GEF activity of cells with the VWM mutation was impaired and the mutant cells experienced modest enhancement of the ISR. However, despite their enhanced ISR, imposed by the intrinsic defect in eIF2B, disrupting the inhibitory effect of phosphorylated eIF2α on GEF by a contravening EIF2S1/eIF2α^S51A mutation that functions upstream of eIF2B, selectively enfeebled both EIF2B4^A391D and the related severe VWM EIF2B4^R483W cells. The basis for paradoxical dependence of cells with the VWM mutations on an intact eIF2α genotype remains unclear, as both translation rates and survival from stressors that normally activate the ISR were not reproducibly affected by the VWM mutations. Nonetheless, our findings support an additional layer of complexity in the development of VWM, beyond a hyperactive ISR.     

How Effective Is Help on the Doorstep? A Longitudinal Evaluation of Community-Based Organisation Support

Community-based responses have a lengthy history. The ravages of HIV on family functioning has included a widespread community response. Although much funding has been invested in front line community-based organisations (CBO), there was no equal investment in evaluations. This study was set up to compare children aged 9–13 years old, randomly sampled from two South African provinces, who had not received CBO support over time (YC) with a group of similarly aged children who were CBO attenders (CCC). YC baseline refusal rate was 2.5% and retention rate was 97%. CCC baseline refusal rate was 0.7% and retention rate was 86.5%. 1848 children were included—446 CBO attenders compared to 1402 9–13 year olds drawn from a random sample of high-HIV prevalence areas. Data were gathered at baseline and 12–15 months follow-up. Standardised measures recorded demographics, violence and abuse, mental health, social and educational factors. Multivariate regression analyses revealed that children attending CBOs had lower odds of experiencing weekly domestic conflict between adults in their home (OR 0.17; 95% CI 0.09, 0.32), domestic violence (OR 0.22; 95% CI 0.08, 0.62), or abuse (OR 0.11; 95% CI 0.05, 0.25) at follow-up compared to participants without CBO contact. CBO attenders had lower odds of suicidal ideation (OR 0.41; 95% CI 0.18, 0.91), fewer depressive symptoms (B = -0.40; 95% CI -0.62, -0.17), less perceived stigma (B = -0.37; 95% CI -0.57, -0.18), fewer peer problems (B = -1.08; 95% CI -1.29, -0.86) and fewer conduct problems (B = -0.77; 95% CI -0.95, -0.60) at follow-up. In addition, CBO contact was associated with more prosocial behaviours at follow-up (B = 1.40; 95% CI 1.13, 1.67). No associations were observed between CBO contact and parental praise or post-traumatic symptoms. These results suggest that CBO exposure is associated with behavioural and mental health benefits for children over time. More severe psychopathology was not affected by attendance and may need more specialised input.     

Characterization of the Variability of Epstein-Barr Virus Genes in Nasopharyngeal Biopsies: Potential Predictors for Carcinoma Progression

Epstein-Barr virus (EBV) infection is a significant factor in the pathogenesis of nasopharyngeal carcinoma, especially in the undifferentiated carcinoma of nasopharyngeal type (UCNT, World Health Organization type III), which is the dominant histopathological type in high-risk areas. The major EBV oncogene is latent membrane protein 1 (LMP1). LMP1 gene shows variability with different tumorigenic and immunogenic potentials. EBV nuclear antigen 1 (EBNA1) regulates progression of EBV-related tumors; however, the influence of EBNA1 sequence variability on tumor pathogenesis is controversial. The aims of this study were to characterize polymorphisms of EBV genes in non-endemic nasopharyngeal carcinoma biopsies and to investigate potential sequence patterns that correlate with the clinical presentation of nasopharyngeal carcinoma. In total, 116 tumor biopsies of undifferentiated carcinoma of nasopharyngeal type (UCNT), collected from 2008 to 2014, were evaluated in this study. The genes EBNA2, LMP1, and EBNA1 were amplified using nested-PCR. EBNA2 genotyping was performed by visualization of PCR products using gel electrophoresis. Investigation of LMP1 and EBNA1 included sequence, phylogenetic, and statistical analyses. The presence of EBV DNA was significantly distributed between TNM stages. LMP1 variability showed six variants, with the detection of the first China1 and North Carolina variants in European nasopharyngeal carcinoma biopsies. Newly discovered variants Srb1 and Srb2 were UCNT-specific LMP1 polymorphisms. The B95-8 and North Carolina variants are possible predictors for favorable TNM stages. In contrast, deletions in LMP1 are possible risk factors for the most disfavorable TNM stage, independent of EBNA2 or EBNA1 variability. A newly discovered EBNA1 subvariant, P-thr-sv-5, could be a potential diagnostic marker, as it represented a UCNT-specific EBNA1 subvariant. A particular combination of EBNA2, LMP1, and EBNA1 polymorphisms, type 1/Med/P-thr was identified as a possible risk factor for TNM stage IVB or progression to the N3 stage.     

Computational Modeling of Open-Irrigated Electrodes for Radiofrequency Cardiac Ablation Including Blood Motion-Saline Flow Interaction

Radiofrequency catheter ablation (RFCA) is a routine treatment for cardiac arrhythmias. During RFCA, the electrode-tissue interface temperature should be kept below 80°C to avoid thrombus formation. Open-irrigated electrodes facilitate power delivery while keeping low temperatures around the catheter. No computational model of an open-irrigated electrode in endocardial RFCA accounting for both the saline irrigation flow and the blood motion in the cardiac chamber has been proposed yet. We present the first computational model including both effects at once. The model has been validated against existing experimental results. Computational results showed that the surface lesion width and blood temperature are affected by both the electrode design and the irrigation flow rate. Smaller surface lesion widths and blood temperatures are obtained with higher irrigation flow rate, while the lesion depth is not affected by changing the irrigation flow rate. Larger lesions are obtained with increasing power and the electrode-tissue contact. Also, larger lesions are obtained when electrode is placed horizontally. Overall, the computational findings are in close agreement with previous experimental results providing an excellent tool for future catheter research.     

Homogeneous Canine Chest Phantom Construction: A Tool for Image Quality Optimization

Digital radiographic imaging is increasing in veterinary practice. The use of radiation demands responsibility to maintain high image quality. Low doses are necessary because workers are requested to restrain the animal. Optimizing digital systems is necessary to avoid unnecessary exposure, causing the phenomenon known as dose creep. Homogeneous phantoms are widely used to optimize image quality and dose. We developed an automatic computational methodology to classify and quantify tissues (i.e., lung tissue, adipose tissue, muscle tissue, and bone) in canine chest computed tomography exams. The thickness of each tissue was converted to simulator materials (i.e., Lucite, aluminum, and air). Dogs were separated into groups of 20 animals each according to weight. Mean weights were 6.5 ± 2.0 kg, 15.0 ± 5.0 kg, 32.0 ± 5.5 kg, and 50.0 ± 12.0 kg, for the small, medium, large, and giant groups, respectively. The one-way analysis of variance revealed significant differences in all simulator material thicknesses (p < 0.05) quantified between groups. As a result, four phantoms were constructed for dorsoventral and lateral views. In conclusion, the present methodology allows the development of phantoms of the canine chest and possibly other body regions and/or animals. The proposed phantom is a practical tool that may be employed in future work to optimize veterinary X-ray procedures.