Compromise Treatment Outcomes Research Articles

Erratum. Chromosomal mosaicism in human blastocysts: the ultimate diagnostic dilemma.

BACKGROUND: Trophectoderm (TE) biopsy and next generation sequencing (NGS) are currently the preferred techniques for preimplantation genetic testing for aneuploidies (PGT-A). Although this approach delivered important improvements over previous testing strategies, increased sensitivity has also prompted a rise in diagnoses of uncertain clinical significance. This includes reports of chromosomal mosaicism, suggesting the presence of karyotypically distinct cells within a single TE biopsy. Given that PGT-A relies on the chromosomal constitution of the biopsied cells being representative of the entire embryo, the prevalence and clinical implications of blastocyst mosaicism continue to generate considerable controversy. OBJECTIVE AND RATIONALE: The objective of this review was to evaluate existing scientific evidence regarding the prevalence and impact of chromosomal mosaicism in human blastocysts. We discuss insights from a biological, technical and clinical perspective to examine the implications of this diagnostic dilemma for PGT-A. SEARCH METHODS: The PubMed and Google Scholar databases were used to search peer-reviewed publications using the following terms: 'chromosomal mosaicism', 'human', 'embryo', 'blastocyst', 'implantation', 'next generation sequencing' and 'clinical management' in combination with other keywords related to the subject area. Relevant articles in the English language, published until October 2019 were critically discussed. OUTCOMES: Chromosomal mosaicism predominately results from errors in mitosis following fertilization. Although it appears to be less pervasive at later developmental stages, establishing the true prevalence of mosaicism in human blastocysts remains exceedingly challenging. In a clinical context, blastocyst mosaicism can only be reported based on a single TE biopsy and has been ascribed to 2-13% of embryos tested using NGS. Conversely, data from NGS studies disaggregating whole embryos suggests that mosaicism may be present in up to similar to 50% of blastocysts. However, differences in testing and reporting strategies, analysis platforms and the number of cells sampled inherently overshadow current data, while added uncertainties emanate from technical artefacts. Moreover, laboratory factors and aspects of in vitro culture generate further variability. Outcome data following the transfer of blastocysts diagnosed as mosaic remain limited. Current studies suggest that the transfer of putative mosaic embryos may lead to healthy live births, but also results in significantly reduced ongoing pregnancy rates compared to the transfer of euploid blastocysts. Observations that a subset of mosaic blastocysts has the capacity to develop normally have sparked discussions regarding the ability of embryos to self-correct. However, there is currently no direct evidence to support this assumption. Nevertheless, the exclusion of mosaic blastocysts results in fewer embryos available for transfer, which may inevitably compromise treatment outcomes. WIDER IMPLICATIONS: Chromosomal mosaicism in human blastocysts remains a perpetual diagnostic and clinical dilemma in the context of PGT-A. This review offers an important scientific resource, informing about the challenges, risks and value of diagnosing mosaicism. Elucidating these uncertainties will ultimately pave the way towards improved clinical and patient management.

Chromosomal mosaicism in human blastocysts: the ultimate diagnostic dilemma

Trophectoderm (TE) biopsy and next generation sequencing (NGS) are currently the preferred techniques for preimplantation genetic testing for aneuploidies (PGT-A). Although this approach delivered important improvements over previous testing strategies, increased sensitivity has also prompted a rise in diagnoses of uncertain clinical significance. This includes reports of chromosomal mosaicism, suggesting the presence of karyotypically distinct cells within a single TE biopsy. Given that PGT-A relies on the chromosomal constitution of the biopsied cells being representative of the entire embryo, the prevalence and clinical implications of blastocyst mosaicism continue to generate considerable controversy. The objective of this review was to evaluate existing scientific evidence regarding the prevalence and impact of chromosomal mosaicism in human blastocysts. We discuss insights from a biological, technical and clinical perspective to examine the implications of this diagnostic dilemma for PGT-A. The PubMed and Google Scholar databases were used to search peer-reviewed publications using the following terms: 'chromosomal mosaicism', 'human', 'embryo', 'blastocyst', 'implantation', 'next generation sequencing' and 'clinical management' in combination with other keywords related to the subject area. Relevant articles in the English language, published until October 2019 were critically discussed. Chromosomal mosaicism predominately results from errors in mitosis following fertilization. Although it appears to be less pervasive at later developmental stages, establishing the true prevalence of mosaicism in human blastocysts remains exceedingly challenging. In a clinical context, blastocyst mosaicism can only be reported based on a single TE biopsy and has been ascribed to 2-13% of embryos tested using NGS. Conversely, data from NGS studies disaggregating whole embryos suggests that mosaicism may be present in up to ~50% of blastocysts. However, differences in testing and reporting strategies, analysis platforms and the number of cells sampled inherently overshadow current data, while added uncertainties emanate from technical artefacts. Moreover, laboratory factors and aspects of in vitro culture generate further variability. Outcome data following the transfer of blastocysts diagnosed as mosaic remain limited. Current studies suggest that the transfer of putative mosaic embryos may lead to healthy live births, but also results in significantly reduced ongoing pregnancy rates compared to the transfer of euploid blastocysts. Observations that a subset of mosaic blastocysts has the capacity to develop normally have sparked discussions regarding the ability of embryos to self-correct. However, there is currently no direct evidence to support this assumption. Nevertheless, the exclusion of mosaic blastocysts results in fewer embryos available for transfer, which may inevitably compromise treatment outcomes. Chromosomal mosaicism in human blastocysts remains a perpetual diagnostic and clinical dilemma in the context of PGT-A. This review offers an important scientific resource, informing about the challenges, risks and value of diagnosing mosaicism. Elucidating these uncertainties will ultimately pave the way towards improved clinical and patient management.

Mucosal microbial load in Crohn's disease: A potential predictor of response to faecal microbiota transplantation.

BackgroundThe remission of Crohn's disease (CD) can be accomplished by faecal microbiota transplantation (FMT). However, this procedure has a low success rate, which could be attributed to mis-communication between recipient intestinal mucosa and donor microbiota.MethodsHere we used a human explant tissue model and an in vivo mouse model to examine changes in recipient intestinal mucosa upon contact with a faecal suspension (FS) obtained from a healthy donor. CD patients provided resected inflamed and non-inflamed mucosal tissues, whereas control colonic mucosa samples were collected from colorectal cancer patients. For the models, mucosal microbiome composition and tissue response were evaluated.FindingsWe show that cytokine release and tissue damage were significantly greater in inflamed compared to non-inflamed CD tissues. Moreover, mucosal samples harbouring an initial low microbial load presented a shift in composition towards that of the FS, an increase in the relative count of Faecalibacterium prausnitzii, and a higher secretion of anti-inflammatory cytokine IL-10 compared to those with a high microbial load.InterpretationOur results indicate that FMT during active inflammatory disease can compromise treatment outcome. We recommend the stratification of FMT recipients on the basis of tissue microbial load as a strategy to ensure successful colonization.FundingThis study was supported by grants from the Instituto de Salud Carlos III/FEDER (PI17/00614), the European Commission: (INCOMED-267128) and PERIS (SLT002/16). K.M. is a postdoctoral fellow and S.V. a senior clinical investigator of the Fund for Scientific Research Flanders, Belgium (FWO-Vlaanderen).

Abstract A070: A phase 1/2a, open-label, dose-escalation study of EC-18 in patients with metastatic breast cancer for the prevention of chemotherapy-induced neutropenia

Abstract Background/Aim: Chemotherapy-induced neutropenia (CIN) is the major dose-limiting toxicity of systemic cancer chemotherapy leading to dose reductions, treatment delays or treatment early termination, which may compromise treatment outcome. EC-18 is a synthetic, orally available and lipid-based small molecular compound (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol). EC-18 prevents CIN by attenuating neutrophil extravasation via down-regulation of adhesion molecules, pro-inflammatory cytokines & chemokines (Cell & Bioscience 2019;9:4). The aim of this study is to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary activity of EC-18 for CIN (NCT03104595). Methods: A standard 3+3 design was used. EC-18 (softgel capsule) was administered on Day 1 through Day 21 to patients with metastatic breast cancer receiving combined doxorubicin and cyclophosphamide (AC regimen) in four dose-escalation cohorts (500mg/day, 1,000mg/day, 1,500mg/day, 2,000mg/day, respectively) with 3 subjects per each cohort. The first cohort was treated at a starting dose (500mg/day) and the subsequent cohorts were sequentially treated at increasing doses levels. PK was assessed on Day 1 and Day 15 in the first cycle of chemotherapy. Results: EC-18 was shown to be well tolerated in all participants and none of the subjects experienced drug-related severe adverse events or adverse events leading to discontinuation of treatment. Dose-limiting toxicity (DLT) did not occur and maximum-tolerated dose (MTD) was not determined accordingly. The baseline-adjusted absolute neutrophil count (ANC) of the patients showed a tendency to improve the neutrophil decline with increasing doses of EC-18 during the course of the study. With increasing dosage amount of EC-18, the time period (day) for the recovery of neutropenia from nadir to ANC > 500/mm3 showed a tendency to become shorter proportionally; 4.0 days in 500mg/day, 3.7 days in 1,000mg/day, 3.0 days in 1,500mg/day and 2.3 days in 2,000mg/day, respectively. In the PK outcomes, the plasma exposure on 500-2000 mg was observed in a dose-dependent manner. No plasma accumulation by the repeated dosing was observed based on the PK results of Day 1 and 15. The PK analysis and simulation suggested that the higher dose than 2000 mg would reach a systemic steady-state. Conclusion: EC-18 is safe and well tolerated. Studies in patients clearly demonstrated pharmacokinetics. Preliminary results suggest EC-18 has the potential to prevent and treat chemotherapy-induced neutropenia. Further dose-expansion cohorts trial is planned to explore a maximum tolerated dose and determine an efficacious dose for phase 2 clinical trial. Citation Format: Sung-Bae Kim, Myung-Hwan Kim. A phase 1/2a, open-label, dose-escalation study of EC-18 in patients with metastatic breast cancer for the prevention of chemotherapy-induced neutropenia [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A070. doi:10.1158/1535-7163.TARG-19-A070

Hepatitis C reinfection after successful antiviral treatment among people who inject drugs: A meta-analysis

HCV reinfection following successful treatment can compromise treatment outcomes. This systematic review assessed the rate of HCV reinfection following treatment among people with recent drug use and those receiving opioid agonist therapy (OAT). We searched bibliographic databases and conference abstracts for studies assessing post-treatment HCV reinfection rates among people with recent drug use (injecting or non-injecting) or those receiving OAT. Meta-analysis was used to cumulate reinfection rates and meta-regression was used to explore heterogeneity across studies. Thirty-six studies were included (6,311 person-years of follow-up). The overall rate of HCV reinfection was 5.9/100 person-years (95% CI 4.1-8.5) among people with recent drug use (injecting or non-injecting), 6.2/100 person-years (95% CI 4.3-9.0) among people recently injecting drugs, and 3.8/100 person-years (95% CI 2.5-5.8) among those receiving OAT. Reinfection rates were comparable following interferon-based (5.4/100 person-years; 95% CI 3.1-9.5) and direct-acting antiviral (3.9/100 person-years; 95% CI 2.5-5.9) therapy. In stratified analysis, reinfection rates were 1.4/100 person-years (95% CI 0.8-2.6) among people receiving OAT with no recent drug use, 5.9/100 person-years (95% CI 4.0-8.6) among people receiving OAT with recent drug use, and 6.6/100 person-years (95% CI 3.4-12.7) among people with recent drug use not receiving OAT. In meta-regression analysis, longer follow-up was associated with lower reinfection rate (adjusted rate ratio [aRR] per year increase in mean/median follow-up 0.77; 95% CI 0.69-0.86). Compared with people receiving OAT with no recent drug use, those with recent drug use receiving OAT (aRR 3.50; 95% CI 1.62-7.53), and those with recent drug use not receiving OAT (aRR 3.96; 95% CI 1.82-8.59) had higher reinfection rates. HCV reinfection risk following treatment was higher among people with recent drug use and lower among those receiving OAT. The lower rates of reinfection observed in studies with longer follow-up suggested higher reinfection risk early post-treatment. Our findings demonstrate that although reinfection by hepatitis C virus occurs following successful treatment in people with recent drug use, the rate of hepatitis C reinfection is lower than the rates of primary infection reported in the literature for this population - reinfection should not be used as a reason to withhold therapy from people with ongoing injecting drug use. The rate of hepatitis C reinfection was lowest among people receiving opioid agonist therapy with no recent drug use. These data illustrate that harm reduction services are required to reduce the reinfection risk, while regular post-treatment hepatitis C assessment is required for early detection and retreatment.

Síndrome de Mayer-Rokitansky- Küster-Hauser asociado con malformación anorectal

La agenesia vaginal es una entidad poco frecuente que puede presentarse en forma aislada o acompañada de otras anomalías congénitas. El desconocimiento de esta asociación puede retardar su diagnóstico, causar complicaciones indeseadas y comprometer el resultado del tratamiento. Se describen tres casos clínicos con agenesia vaginal y malformación anorrectal, cuyos diagnósticos no fueron realizados en el momento del nacimiento. Aunque la coexistencia de anomalías vaginales y anorectales sean poco frecuentes, los médicos responsables de su tratamiento deben ser conscientes de su existencia y practicar examen perineal cuidadoso.

A Pilot Study of One-Session Treatment for Specific Phobias in Children with ASD Traits

Objectives: One-Session Treatment (OST), a three-hour treatment which includes psychoeducation, exposure, participant modeling, cognitive challenges, and positive reinforcement, has been shown to be effective for the treatment of childhood phobias. Several comorbid anxiety conditions such as Generalized Anxiety Disorder and Social Anxiety Disorder have been shown to have little or no negative effects on treatment outcomes for OST whereas others such as Attention-Deficit Hyperactivity Disorder have been shown to compromise treatment outcomes. This study sought to examine the initial efficacy of OST for children with a behavioral profile demonstrating specific traits of Autism Spectrum Disorder (ASD). We undertook this exploratory study to determine the feasibility and potential efficacy of this brief treatment with these youth. Methods: Two variations of the treatment were trialed. In the OST condition, the child alone received treatment with minimal parental involvement. In the Augmented OST condition, two clinicians were assigned to each family: one clinician worked with the child and the other with the parent. Families in both treatments returned for follow-up assessments one-week, 6-months, and 1-year later. Results: A repeated-measures ANOVA revealed significant reductions in phobia severity as well as increases in overall functioning for both forms of treatment. Conclusions: These results suggest that OST may be an effective intervention for children with ASD traits who evince SPs. Future controlled studies will need to examine the efficacy of this brief intervention with carefully diagnosed youth with ASD as well as explore specific components that make it effective for these children.

Preventing Radiation-Induced Injury by Topical Application of an Amifostine Metabolite-Loaded Thermogel

Despite the development of high-precision radiation therapy, ionizing radiation inevitably damages healthy tissues. Radiodermatitis and radioinduced oral mucositis are frequent and significant side effects among patients with breast and head and neck cancer, respectively. These radiation-related injuries negatively affect patient quality of life and can lead to unplanned therapeutic breaks and compromise treatment outcomes. Currently, no preventive or mitigating agent has emerged to address these issues. Although amifostine, a well-known free radical scavenger, has proven efficacy against specific radio- and chemo-induced toxicities, severe adverse side effects (reversible hypotension, nausea, emesis, etc) combined with logistical hurdles are associated with its recommended intravenous route of administration, limiting its use. We developed a thermogel containing the active thiol metabolite of amifostine (CPh-1014) that polymerizes at body temperature and serves as a matrix for topical application onto the skin or mucosa. Applied before irradiation, CPh-1014 greatly reduced the severity of oral mucositis and dermatitis induced byeither a single dose or fractionated irradiation regimens in invivo mouse models. The cytoprotective effect of CPh-1014 was confirmed by the decrease in DNA double-strand breaks in the irradiated epithelium. Noticeably, CPh-1014 did not affect radiation therapy efficacy against tumors grafted at submucosal and subcutaneous sites. Incontrast to the intravenous administration of amifostine, CPh-1014 oral application did not induce hypotension indogs. CPh-1014 confers radioprotective effects in healthy tissues with reduced systemic side effects without compromising radiation therapy efficacy. We propose CPh-1014 as an easy-to-implement therapeutic approach to alleviate radiation therapy toxicity in patients with breast and head and neck cancer.

Targeting the Spleen as an Alternative Site for Hematopoiesis.

Bone marrow is the main site for hematopoiesis in adults. It acts as a niche for hematopoietic stem cells (HSCs) and contains non-hematopoietic cells that contribute to stem cell dormancy, quiescence, self-renewal, and differentiation. HSC also exist in resting spleen of several species, although their contribution to hematopoiesis under steady-state conditions is unknown. The spleen can however undergo extramedullary hematopoiesis (EMH) triggered by physiological stress or disease. With the loss of bone marrow niches in aging and disease, the spleen as an alternative tissue site for hematopoiesis is an important consideration for future therapy, particularly during HSC transplantation. In terms of harnessing the spleen as a site for hematopoiesis, here the remarkable regenerative capacity of the spleen is considered with a view to forming additional or ectopic spleen tissue through cell engraftment. Studies in mice indicate the potential for such grafts to support the influx of hematopoietic cells leading to the development of normal spleen architecture. An important goal will be the formation of functional ectopic spleen tissue as an aid to hematopoietic recovery following clinical treatments that impact bone marrow. For example, expansion or replacement of niches could be considered where myeloablation ahead of HSC transplantation compromises treatment outcomes.

Pre-hydration in cisplatin-based CCRT: Effects on tumour concentrations and treatment outcome

AimsPre-hydration is routinely applied to reduce nephrotoxicity in concurrent cisplatin-based chemo-radiotherapy (CCRT). However, pre-hydration may also have systemic effects, potentially leading to lower tumour cisplatin concentrations. We investigated the impact of pre-hydration on tumour cisplatin concentrations in mice, and on treatment outcomes in a clinical cohort study. Materials and methodsFour groups of 20 mice received either no pre-hydration prior to full-dose (6 mg/kg) or half-dose cisplatin, overnight dehydration prior to full-dose cisplatin (dehydration), or NaCl intraperitoneally prior to full-dose cisplatin (pre-hydration). Kidney function and tumour platinum concentration were measured. In patients, a retrospective study compared 2 historical NSCLC cohorts which received CCRT with daily cisplatin, with and without standard pre-hydration. Overall survival (OS) and progression free survival (PFS) were compared using Kaplan–Meier and cox-regression. ResultsPre-hydration significantly decreased cisplatin tumour concentrations in mice, comparable to mice receiving half the dose. In 419 patients (211 without and 208 with pre-hydration) with median follow-up 22 months, there were no significant differences in PFS (18 vs. 15 months) or OS (23 vs. 23 months). ConclusionPre-hydration reduces cisplatin tumour concentrations in mice, but it does not compromise treatment outcomes in NSCLC patients treated with daily cisplatin and radiotherapy.

Negative Affect, Type D Personality, Quality of Life, and Dysfunctional Outcomes of Total Knee Arthroplasty.

Background Type D personality (TDP) is a sign of tapered stress and compromises treatment outcomes including those of hip arthroplasty. The common dissatisfaction with total knee arthroplasty (TKA) is predicted by fear avoidance, pain catastrophizing and emotional lability, with poor quality of life (QoL) reflecting these strains. This study is the first to investigate the influence of TDP on TKA assuming (1) negative affect (NA) to be linked to fear avoidance and to increased dissatisfaction with TKA and (2) the expression of NA and social inhibition (SI) to not be stable over time. Method We studied 79 participants using the brief symptom inventory-18, the pain-catastrophizing scale, the Tampa scale of kinesiophobia, the SF-36, and the WOMAC preoperatively and 12 months postoperatively. T-test and regression were used to compare the variables of interest between groups built based upon outcome severity. Result NA at follow-up predicted knee pain (p=0.02) and knee function (p < 0.01) at follow-up. Contrarily, increased expressions of NA/SI at follow-up were predicted by NA (p=0.04) and rumination (p=0.05) at the baseline. Conclusion The present results suggest the postoperative increase of NA to be linked to dysfunctional outcomes of TKA due to an interaction with pain catastrophizing. Baseline self-rated physical health did not connect to the dissatisfaction with TKA 1-year postoperatively.

The Effectiveness of Micro-osteoperforations during Canine Retraction: A Three-dimensional Randomized Clinical Trial.

Aim:A major challenge in orthodontics is decreasing treatment time without compromising treatment outcome. The purpose of this split-mouth trial was to evaluate micro-osteoperforations (MOPs) in accelerating orthodontic tooth movement.Materials and Methods:Eight patients of both genders were selected, age ranging between 15 and 40 years, with Class II Division 1 malocclusion. The participants in this trial with MOPs were randomly allocated to either the right or the left side, distal to the maxillary canine. First maxillary premolars were extracted as part of the treatment plan on both sides and then canine retraction was applied. Miniscrews were used to support anchorage. MOP side received (three small perforations) placed on the buccal bone, distal to the maxillary canine, on randomly selected side using an automated mini-implant driver and the other side was the control side. Blinding was used at the data collection and analysis stages. The primary outcome was the rate of canine retraction measured with a three-dimensional (3D) digital model from the baseline to the first 2 weeks superimposed at the rugae area from the baseline to the first, second, and third months. The following secondary outcomes were examined: anchorage loss, canine tipping, canine rotation, root resorption, plaque index, and gingival index. Pain level, pain interference with the patients’ daily life, patients’ satisfaction with the procedure and degree of ease, willingness to repeat the procedure, and recommendation to others were also evaluated.Results:No statistically significant difference was observed in the rates of tooth movement between the MOP and the control sides at all-time points (first month: P = 0.77; mean difference, 0.2 mm; 95% CI, −0.13, 0.18 mm; second month: P = 0.50; mean difference, −0.08 mm; 95% CI, −0.33, 0.16 mm; third month: P = 0.76; mean difference, −0.05 mm; 95% CI, −0.40, 0.29 mm). There were also no differences in anchorage loss, rotation, tipping, root resorption, plaque index, periodontal index, and pain perception between the MOP and control sides at any time point (P > 0.05). MOPs had no effect on the patients’ daily life except for a feeling of swelling on the first day (P = 0.05). Level of satisfaction and degree of easiness of the procedure were high.Conclusion:According to our clinical trial, MOPs cannot help in speeding up a canine retraction.

High discordance in blood and genital tract HIV-1 drug resistance in Indian women failing first-line therapy.

Examine HIV-1 plasma viral load (PVL) and genital tract (GT) viral load (GVL) and drug resistance in India. At the YRG Centre for AIDS Research and Education, Chennai, we tested: PVL in women on first-line ART for ≥6 months; GVL when PVL >2000 copies/mL; and plasma, genital and proviral reverse transcriptase drug resistance when GVL >2000 copies/mL. Wilcoxon rank-sum and Fisher's exact tests were used to identify failure and resistance associations. Pearson correlations were calculated to evaluate PVL-GVL associations. Inter-compartmental resistance discordance was evaluated using generalized estimating equations. Of 200 women, 37% had detectable (>400 copies/mL) PVL and 31% had PVL >1000 copies/mL. Of women with detectable PVL, 74% had PVL >2000 copies/mL, of which 74% had detectable GVL. Higher PVL was associated with higher GVL. Paired plasma and genital sequences were available for 21 women; mean age of 34 years, median ART duration of 33 months, median CD4 count of 217 cells/mm3, median PVL of 5.4 log10 copies/mL and median GVL of 4.6 log10 copies/mL. Drug resistance was detected in 81%-91% of samples and 67%-76% of samples had dual-class resistance. Complete three-compartment concordance was seen in only 10% of women. GT-proviral discordance was significantly larger than plasma-proviral discordance. GT or proviral mutations discordant from plasma led to clinically relevant resistance in 24% and 30%, respectively. We identified high resistance and high inter-compartmental resistance discordance in Indian women, which might lead to unrecognized resistance transmission and re-emergence compromising treatment outcomes, particularly relevant to countries like India, where sexual HIV transmission is predominant.

Emergency department presentations in early stage breast cancer patients receiving adjuvant and neoadjuvant chemotherapy.

(Neo)adjuvant chemotherapy for early stage breast cancer is associated with side-effects, resulting in increased emergency department (ED) presentations. Treatment-related toxicity can affect quality of life, compromise chemotherapy delivery and treatment outcomes, and increase healthcare use. We performed a retrospective study of ED presentations in patients receiving curative chemotherapy for early breast cancer to identify factors contributing to ED presentations. Of 102 patients, 39 (38%) presented to ED within 30 days of chemotherapy, resulting in 63 ED presentations in total. Most common reasons were non-neutropenic fever (17 presentations/27%), neutropenic fever (15/24%), pain (9/14%), drug reaction (6/10%) and infection (4/6%). Factors significantly associated with ED presentation were adjuvant chemotherapy timing compared to neoadjuvant timing (P = 0.031), prophylactic antibiotics (P = 0.045) and docetaxel-containing regimen (P = 0.018).

The effectiveness of treatment for Severe Acute Malnutrition (SAM) delivered by community health workers compared to a traditional facility based model

BackgroundIn most health systems, Community Health Workers (CHWs) identify and screen for severe acute malnutrition (SAM) in the community. This study aimed to investigate the potential of integrating SAM identification and treatment delivered by CHWs, in order to improve the coverage of SAM treatment services.MethodsThis multicentre, randomised intervention study was conducted in Kita, Southwest Mali between February 2015 and February 2016. Treatment for uncomplicated SAM was provided in health facilities in the control area, and by Community Health Workers and health facilities in the intervention area. Clinical outcomes (cure, death and defaulter ratios), treatment coverage and quality of care were examined in both the control and intervention group.ResultsSix hundred ninety nine children were admitted to the intervention group and 235 children to the control group. The intervention group reported cure ratios of 94.2% compared to 88.6% in the control group (risk ratio 1.07 [95% CI 1.01; 1.13]). Defaulter ratios were twice as high in the control group compared to the intervention group (10.8% vs 4.5%; RR 0.42 [95% CI 0.25; 0.71]). Differences in mortality ratios were not statistically significant (0.9% in the intervention group compared to 0.8% in the control group). Coverage rates in December 2015 were 86.7% in intervention group compared to 41.6% in the control (p < 0.0001).ConclusionsWith minimal training, CHWs are able to appropriately treat SAM in the community. Allowing CHWs to treat SAM reduces defaulter ratios without compromising treatment outcomes and can lead to improved access to treatment.Trial registrationRetrospectively registered in ISRCTN Register with ISRCTN33578874 on March 7th 2018.

A Canadian Survey of the Management of Radiation-Induced Skin Reactions

IntroductionRadiation therapy skin reactions are one of the most common side effects and can cause patient distress. In some cases, a severe radiation-induced skin reaction may limit delivered dose and potentially compromise treatment outcomes. There are some established best practices, but approaches and patient advice appear to have changed little over the years and are often based on tradition, not evidence. Canadian radiation therapy departments use different skin care products and approaches, and there has been little previous work to examine national practice patterns. Materials and MethodsThis study used a 42-item electronic survey based on a questionnaire designed by the UK Society and College of Radiographers. Practice data were collected related to assessment and prophylactics, interventions for prevention and management, and use of tools and guidelines. The final survey version was distributed to an identified radiation therapist-registered nurse dyad at each radiation therapy department in Canada (n = 44). ResultsThirty-three departments responded (75% response rate). Results suggest a variation in national management. A number of departments continue to advise patients not to wash or use deodorant/antiperspirant despite having evidence to the contrary. There are also unnecessary restrictions on the use and timing of application of lotions as well as conflicting postradiotherapy skin care instructions regarding sun exposure. ConclusionThe study demonstrated variation in practice across Canadian radiation therapy departments. National interprofessional guidelines could improve uptake of best practices. Where there is little evidence, a stress-reduction approach with more collaborative decision-making should be used to minimize patient disruption.

A qualitative analysis of the impact of Carboplatin AUC 10 on physical, work functioning, and bone marrow toxicity, in patients with metastatic seminoma: A single centre experience.

558 Background: We studied the efficacy, safety and tolerability of dose dense Carboplatin AUC10 chemotherapy and explored the HRQoL (health-related quality of life) in metastatic seminoma patients receiving this regimen. Methods: 46 patients with metastatic seminoma treated with Carboplatin AUC10 were identified in our centre. Carboplatin dosing at AUC 10 was used and calculated based on Calvert formula and EDTA clearance. Treatment was administered as a single dose every 21 days for 3 or 4 cycles. Response to treatment was determined by radiological imaging and serum tumour markers. Toxicities were evaluated using the CTCAE Version 4.0. Quality of life (QOL) and long-term treatment related toxicities were assessed post treatment using a self-designed telephonic questionnaire consisting of 4 questions about toxicity, which included- hair loss, hearing impairment, days absence from work and neuropathy. Results: Clinical characteristics are as follows: median age 44 (range 26-77), 34 patients had stage II and 12 stage III seminoma; average dose of carboplatin administered was 1240mg per cycle. 4.3% patients received 2, 87% 3 and 8.7.% 4 cycles of chemotherapy. 93% of patients achieved a complete remission (CR), 4 (all stage IIC) patients required a fourth cycle of chemotherapy, 2 undergoing RPLND and 2 watchful waiting. There was no disease relapse at median follow-up of 27.5 (range 4-84) months. 13 patients (28%) had grade 3 and 2 (4%) grade 4 neutropenia, thirteen (28%) grade 3/4 thrombocytopenia, Nine (19.5%) patients required prophylactic filgrastim. Commonest non-heamatological toxicities were fatigue in 28 (50%) and nausea 14(28%) patients. QOL data was available for 35/46 (76%) of patients. 40/46 (87%) patients had no residual tinnitus, one had residual grade 1 peripheral neuropathy. Eight patients continued to work throughout treatment, 16(45%) took &lt; 5 days off work during chemotherapy, 4 took 5 to 21 days, 13 &gt; 21 days, two were retired. Conclusions: Carbo AUC10 is a safe and effective treatment. Our results suggest the lack of negative impact of Carbo AUC10 on short and intermediate QOL without compromising treatment outcomes.

Increasing lean muscle mass in mice via nanoparticle-mediated hepatic delivery of follistatin mRNA

Muscle atrophy occurs during chronic diseases, resulting in diminished quality of life and compromised treatment outcomes. There is a high demand for therapeutics that increase muscle mass while abrogating the need for special dietary and exercise requirements. Therefore, we developed an efficient nanomedicine approach capable of increasing muscle mass.Methods: The therapy is based on nanoparticle-mediated delivery of follistatin messenger RNA (mRNA) to the liver after subcutaneous administration. The delivered mRNA directs hepatic cellular machinery to produce follistatin, a glycoprotein that increases lean mass through inhibition of negative regulators of muscle mass (myostatin and activin A). These factors are elevated in numerous disease states, thereby providing a target for therapeutic intervention.Results: Animal studies validated that mRNA-loaded nanoparticles enter systemic circulation following subcutaneous injection, accumulate and internalize in the liver, where the mRNA is translated into follistatin. Follistatin serum levels were elevated for 72 h post injection and efficiently reduced activin A and myostatin serum concentrations. After eight weeks of repeated injections, the lean mass of mice in the treatment group was ~10% higher when compared to that of the controls.Conclusion: Based on the obtained results demonstrating an increased muscle mass as well as restricted fat accumulation, this nanoplatform might be a milestone in the development of mRNA technologies and the treatment of muscle wasting disorders.

Do Moderate Surgical Treatment Delays Influence Survival in Colon Cancer?

Studies examining treatment delay and survival after surgical treatment of colon cancer have varied in quality and outcome, with little evidence available regarding the safety of longer surgical treatment wait times. Our study examined the effect of surgical treatment wait times on survival for patients with stage I to III colon cancer. A subset cohort analysis was performed using data from a prospectively maintained database. The study was conducted at a tertiary referral center. Data on all of the patients undergoing elective surgery for stage I to III colon cancer from 2006 to 2015 were collected from a prospectively maintained clinical and administrative database. We examined the impact of prolonged wait time to surgery on disease-free and overall survival. Patients were divided into 2 groups based on a treatment wait time of ≤30 or >30 days and were compared using a Cox proportional hazards model. A subgroup analysis was performed using alternative treatment delay cutoffs of 60 and 90 days. There were 908 patients with stage I to III colon cancer treated over the study period, with a median treatment wait time of 38 days (interquartile range, 21-61 days); 368 patients were treated within 30 days, and 540 were treated beyond 30 days from diagnosis. In adjusted multivariate analysis, a treatment delay of >30 days was not associated with decreased disease-free survival (HR = 0.89 (95% CI, 0.61-1.3); p = 0.52) or overall survival (HR = 0.82 (95% CI, 0.63-1.1); p = 0.16). Likewise, subgroup analysis using alternative treatment delay cutoffs of 60 and 90 days did not demonstrate an adverse effect on survival. This study was limited by retrospective analysis. Despite longer median treatment wait times from diagnosis to surgery, with the majority of patients exceeding 30 days and many experiencing delays of 2 to 3 months, no adverse impact on survival was observed. Patients who require additional consultations or investigations preoperatively may safely have their surgery moderately delayed to minimize their perioperative risk without any evidence that this will compromise treatment outcomes. See Video Abstract at http://links.lww.com/DCR/A397.

Attenuation of doxorubicin-induced cardiotoxicity and genotoxicity by an indole-based natural compound 3,3′-diindolylmethane (DIM) through activation of Nrf2/ARE signaling pathways and inhibiting apoptosis

The most crucial complication related to doxorubicin (DOX) therapy is nonspecific cytotoxic effect on healthy normal cells. The clinical use of this broad-spectrum chemotherapeutic agent is restricted due to development of severe form of cardiotoxicity, myelosuppression, and genotoxicity which interfere with therapeutic schedule, compromise treatment outcome and may lead to secondary malignancy. 3,3′-diindolylmethane (DIM) is a naturally occurring plant alkaloid formed by the hydrolysis of indolylmethyl glucosinolate (glucobrassicin). Therefore, the present study was undertaken to investigate the protective role of DIM against DOX-induced toxicity in mice. DOX was administered (5 mg/kg b.w., i.p.) and DIM was administered (25 mg/kg b.w., p.o.) in concomitant and 15 days pretreatment schedule. Results showed that DIM significantly attenuated DOX-induced oxidative stress in the cardiac tissues by reducing the levels of free radicals and lipid peroxidation, and by enhancing the level of glutathione (reduced) and the activity of antioxidant enzymes. The chemoprotective potential of DIM was confirmed by histopathological evaluation of heart and bone marrow niche. Moreover, DIM considerably mitigated DOX-induced clastogenicity, DNA damage, apoptosis, and myeloid hyperplasia in bone marrow niche. In addition, oral administration of DIM significantly (p < .05) stimulated the Nrf2-mediated activation of antioxidant response element (ARE) pathway and promoted expression of ARE-driven cytoprotective proteins, HO-1, NQO1, and glutathione-S-transferase (GST). In connection with that, DIM significantly attenuated DOX-induced apoptosis by upregulation of Bcl-2 expression and downregulation of Bax and caspase-3 expression. Thus, this study suggests that DIM has promising chemoprotective efficacy against DOX-induced toxicity and indicates its future use as an adjuvant in chemotherapy.