Baseline mutational profiles of patients with carcinoma of unknown primary origin enrolled in the CUPISCO study.

BACKGROUND: Patients with unfavorable carcinoma of unknown primary origin (CUP) have an extremely poor prognosis of ∼1 year or less, stressing the need for more tailored treatments, which are currently being tested in clinical trials. CUPISCO (NCT03498521) was a phase II randomized study of targeted therapy/cancer immunotherapy versus platinum-based chemotherapy in patients with previously untreated, unfavorable CUP, defined as per the European Society for Medical Oncology guidelines. We present a preliminary, descriptive molecular analysis of 464 patients with stringently diagnosed, unfavorable CUP enrolled in the CUPISCO study. MATERIALS AND METHODS: Genomic profiling was carried out on formalin-fixed, paraffin-embedded tissue to detect genomic alterations and assess tumor mutational burden and microsatellite instability. RESULTS: Overall, ∼32% of patients carried a potentially targetable genomic alteration, including PIK3CA, FGFR2, ERBB2, BRAFV600E, EGFR, MET, NTRK1, ROS1, and ALK. Using hierarchical clustering of co-mutational profiles, 10 clusters were identified with specific genomic alteration co-occurrences, with some mirroring defined tumor entities. CONCLUSIONS: Results reveal the molecular heterogeneity of patients with unfavorable CUP and suggest that genomic profiling may be used as part of informed decision-making to identify the potential primary tumor and targeted treatment options. Whether stringently diagnosed patients with unfavorable CUP benefit from targeted therapies in a similar manner to those with matched known primaries will be a key learning from CUPISCO.

IL-17 and TNF-α co-operation contributes to the proinflammatory response of hepatic stellate cells.

Hepatic stellate cells (HSCs) have a central role in liver inflammation and fibrosis by producing inflammatory and fibrotic mediators. Their activation is regulated through direct cell-cell interactions, but also through systemic and local effects of soluble factors such as cytokines. The effects of the proinflammatory cytokines interleukin (IL)-17 and tumor necrosis factor (TNF)-α and cell interactions with hepatocytes on HSC activation were assessed. Human HSC and HepaRG cells were exposed to IL-17 and/or TNF-α. IL-17 and TNF-α contribution from immune cells was determined in a co-culture model with phytohemagglutinin (PHA)-activated peripheral blood mononuclear cells (PBMC), HSC and/or hepatocytes. IL-17 enhanced TNF-α effects on the induction of IL-6, IL-1ß, and the chemokine IL-8, chemokine (C-C motif) ligand 20 (CCL20) and monocyte chemoattractant protein-1 (MCP-1) expression/secretion in isolated HSC cultures. HSC-hepatocyte interactions did not enhance IL-6, IL-8 and CCL20 production compared to hepatocyte alone. However, HSC-hepatocyte interactions increased C-reactive protein expression. IL-17 and/or TNF-α had no direct profibrotic effects on collagen 1 α1, tissue inhibitor of matrix metalloproteinase (TIMP) and matrix metalloproteinase (MMP) 2 gene expression, whereas mRNA levels of MMP3, an enzyme involved in matrix destruction, were up-regulated in HSCs. The use of specific inhibitors of IL-17 and TNF-α indicated their contribution to the strong increase of IL-6 and IL-8 production induced by PBMC, HSC and/or hepatocyte interactions. As chronic liver inflammation leads to liver fibrosis, IL-17 and/or TNF-α neutralization can be of interest to control liver inflammation and therefore its effects on fibrosis.

Antimicrobial Stewardship Opportunities in Patients with Bacteremia Not Identified by BioFire FilmArray.

A subset of bacteremia cases are caused by organisms not detected by a rapid-diagnostics platform, BioFire blood culture identification (BCID), with unknown clinical characteristics and outcomes. Patients with ≥1 positive blood culture over a 15-month period were grouped by negative (NB-PC) versus positive (PB-PC) BioFire BCID results and compared with respect to demographics, infection characteristics, antibiotic therapy, and outcomes (length of hospital stay [LOS] and in-hospital mortality). Six percent of 1,044 positive blood cultures were NB-PC. The overall mean age was 65 ± 22 years, 54% of the patients were male, and most were admitted from home; fewer NB-PC had diabetes (19% versus 31%, P = 0.0469), although the intensive care unit admission data were similar. Anaerobes were identified in 57% of the bacteremia cases from the NB-PC group by conventional methods: Bacteroides spp. (30%), Clostridium (11%), and Fusobacterium spp. (8%). Final identification of the NB-PC pathogen was delayed by 2 days (P < 0.01) versus the PB-PC group. The sources of bacteremia were more frequently unknown for the NB-PC group (32% versus 11%, P < 0.01) and of pelvic origin (5% versus 0.1%, P < 0.01) compared to urine (31% versus 9%, P < 0.01) for the PB-PC patients. Fewer NB-PC patients received effective treatment before (68% versus 84%, P = 0.017) and after BCID results (82% versus 96%, P = 0.0048). The median LOS was similar (7 days), but more NB-PC patients died from infection (26% versus 8%, P < 0.01). Our findings affirm the need for the inclusion of anaerobes in BioFire BCID or other rapid diagnostic platforms to facilitate the prompt initiation of effective therapy for bacteremia.

Synergistic effect of interleukin-17 and tumour necrosis factor-α on inflammatory response in hepatocytes through interleukin-6-dependent and independent pathways.

The proinflammatory cytokines interleukin (IL)-17 and tumour necrosis factor (TNF)-α are targets for treatment in many chronic inflammatory diseases. Here, we examined their role in liver inflammatory response compared to that of IL-6. Human hepatoma cells (HepaRG, Huh7.5 and HepG2 cells) and primary human hepatocytes (PHH) were cultured with IL-6, IL-17 and/or TNF-α. To determine the contribution of the IL-6 pathway in the IL-17/TNF-α-mediated effect, an anti-IL-6 receptor antibody was used. IL-17 and TNF-α increased in synergy IL-6 secretion by HepaRG cells and PHH but not by Huh7.5 and HepG2 cells. This IL-17/TNF-α synergistic cooperation enhanced the levels of C-reactive protein (CRP) and aspartate aminotransferase (ASAT) in HepaRG cell and PHH cultures through the induction of IL-6. IL-17/TNF-α also up-regulated IL-8, monocyte chemoattractant protein (MCP)-1 and chemokine (C-C motif) ligand 20 (CCL20) chemokines in synergy through an IL-6-independent pathway. Interestingly, first exposure to IL-17, but not to TNF-α, was crucial for the initiation of the IL-17/TNF-α synergistic effect on IL-6 and IL-8 production. In HepaRG cells, IL-17 enhanced IL-6 mRNA stability resulting in increased IL-6 protein levels. The IL-17A/TNF-α synergistic effect on IL-6 and IL-8 induction was mediated through the activation of extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase, nuclear factor-κB and/or protein kinase B (Akt)-phosphatidylinositol 3-kinase signalling pathways. Therefore, the IL-17/TNF-α synergistic interaction mediates systemic inflammation and cell damage in hepatocytes mainly through IL-6 for CRP and ASAT induction. Independently of IL-6, the IL-17A/TNF-α combination may also induce immune cell recruitment by chemokine up-regulation. IL-17 and/or TNF-α neutralization can be a promising therapeutic strategy to control both systemic inflammation and liver cell attraction.

Emergency Department Urinary Antibiograms Differ by Specific Patient Group.

Patients presenting to the emergency department (ED) represent a heterogeneous population comprised of all ages, various backgrounds, such as from the community and skilled-nursing facilities (SNFs), and at various risks for resistant pathogens. The aim of this study was to compare patient group-specific urinary antibiograms in the ED. Adults presented to the ED with an ICD 9/10 code urinary tract infection (UTI) diagnosis during July 2015 to June 2016 were randomly selected (n = 500) to extract relevant demographic, laboratory, and clinical data from the medical record. Urinary Escherichia coli antibiograms were compared between institutional versus ED and among ED patients (male versus female; age of 18 to 64 years versus ≥65 years; female aged 18 to 50 years versus >50 years; home versus SNF; and admitted versus discharged). E. coli grew from 56% (145/259) of the positive urine cultures. Overall ciprofloxacin (CIP), trimethoprim-sulfamethoxazole (SXT), and cefazolin (CFZ) susceptibilities were <71%. Differences in antibiograms were the following: lower CFZ and SXT susceptibilities in ED versus institutional (CFZ, 67% versus 86% [P = 0.001]; SXT, 66% versus 74% [P = 0.02]), lower ampicillin and gentamicin susceptibilities in females aged 18 to 50 years versus >50 years (32% versus 52% [P = 0.04]; 78% versus 93% [P = 0.02]), lower CIP susceptibilities in the elderly (64% versus 81%; P = 0.03), SNF versus home (35% versus 77%; P < 0.001), admitted versus discharged (63% versus 78%; P = 0.04), and lower SXT susceptibilities in patients aged <65 years versus the elderly (58% versus 71%; P = 0.01). Nitrofurantoin showed >80% susceptibility in all groups. Patient group-specific urinary antibiograms revealed distinct differences in E. coli susceptibility and should be developed to better inform empirical UTI therapy selection in the ED.

Was there a plan? End-of-life care for children with life-limiting conditions: a review of multi-service healthcare records.

BACKGROUND: Planning for care at the end of life (EoL) is an essential component of support and care for families of children with life-limiting conditions. The purpose of this review was to compare documented EoL planning with published children's palliative care standards, across a range of children's healthcare services and to assess the impact on practice of written guidelines to support EoL care planning. METHOD: A manual retrospective review of healthcare records using a purpose-built form. Inclusion criteria were the records of children with a diagnosed life-limiting or life-threatening condition, who had died before the age of 18 years, between October 2008 and March 2010, within a defined geographical area served by one or more of the participating services. The sample was 114 sets of notes relating to a cohort of 48 children: 24 girls and 24 boys, the majority of whose deaths were cancer related. RESULTS: Examples of good practice were found in the records of individual services. Services had each developed their own systems and documents to support EoL care planning rather than using a unified documentation system. Where documented practice fell short, this was related to a lack of evidence that choice in location of death had been offered, delays in sharing of information between services, and information being buried in the narrative of the notes, making it difficult to find. CONCLUSIONS: Current documented EoL planning varies between services. Those who are infrequently involved in the provision of EoL care may benefit from support by those for whom this is part of their daily working life. These professionals can help prepare staff to engage families in these difficult but important conversations - and encourage them to document them in a way that can be easily and readily accessed and shared.

The experience of mothers caring for a child with a brain tumour.

BACKGROUND: Brain tumours are the second most common form of childhood cancer, accounting for over 20% of all cases in European children. Understanding the impact of diagnosis and treatment of a brain tumour on the family is an essential pre-requisite to identifying ways to provide effective support. AIM: (1) To explore the impact of having a child with a brain tumour on the main caregiver in the family; (2) to describe mothers' experiences of coping with their child's illness, including personal barriers and strengths; and (3) to identify causes of stress and sources of support to inform improvements in care delivery. METHOD: Participants were drawn from a group of caregivers enrolled in a longitudinal study of outcome following diagnosis of a childhood brain tumour. Six caregivers took part, two from each of the high-, medium- and low-impact groups based on their Impact on Families Scale scores. Semi-structured interviews were used, with questions covering: (1) impact of the diagnosis on main caregiver and family; (2) personal barriers and strengths; and (3) causes of stress and sources of support. Interviews were transcribed verbatim and coded manually into five themes, which comprised 19 subthemes. FINDINGS: Coping methods and provision of help and support were major preoccupations for main caregivers from all impact groups. Caregivers in the high-impact group reported less conflict. High- and medium-impact group caregivers had experienced less 'hindrance and heartache', than those with low impact scores, suggesting that the stress associated with diagnosis and treatment of the tumour may have increased cohesion and acceptance within these families. CONCLUSION: Families of children diagnosed with a brain tumour experience considerable negative impact and may perceive themselves as struggling to cope. Provision of help and support, within and outside the extended family, including from health, education and other services, is perceived as helpful.

Comparison of type III secretion system virulence among fluoroquinolone-susceptible and -resistant clinical isolates of Pseudomonas aeruginosa.

Fluoroquinolone resistance and type III secretion system (TTSS) virulence are independently associated in Pseudomonas aeruginosa infections with poor patient outcomes. In the present study, the virulence of fluoroquinolone-susceptible and -resistant isolates of P. aeruginosa was compared, focusing on TTSS virulence. Clinical isolates (n = 45) exhibiting a broad range of susceptibilities to fluoroquinolones, with differing mechanisms of resistance and associated with varying disease sites, were selected for the study. PCR, Southern blot and western immunoblot analyses were performed to determine the presence of TTSS-encoding genes and secretion of gene products. The cytotoxicity of the clinical isolates towards human lung epithelial cells was also determined. Clinical isolates encoding only the exoS cytotoxin gene occurred more frequently than those encoding only exoU (62% vs. 27%; p 0.0007). Compared with exoS(+) isolates, exoU(+) isolates were more likely to be fluoroquinolone-resistant (92% vs. 61%, p 0.05) and to exhibit both a gyrA mutation and the efflux pump over-expressed (EPO) phenotype (91% vs. 59%; p 0.06). Almost all exoU(+) strains secreted ExoU and exhibited increased cytotoxicity compared with ExoS-secreting strains (7% vs. 92.5%, relative to a PA103 reference strain control). These data suggest that exoU(+) and fluoroquinolone resistance may be co-selected traits that result in highly virulent and resistant strains. Adverse outcomes associated with infections caused by fluoroquinolone-resistant strains may, in part, be attributable to this co-association, which warrants further clinical investigation.

Providing a children's palliative care service in the community through fixed-term grants: the staff perspective.

BACKGROUND: Children's palliative care services have recently been awarded fixed-term grants, aimed at improving the provision of care for children with life-limiting conditions in the community. We report findings of a qualitative study to investigate the experience of a cohort of community children's nurses from teams involved in setting up or extending community-based children's palliative care services. The purpose of the study was to identify factors that affect service delivery, from the staff perspective, and to suggest ways of promoting their sustainable development. METHODS: Semi-structured telephone interviews were conducted with 21 nurses from 12 different teams providing palliative care for children at home and in hospices. Participants were questioned about the services they provided and their own roles in that provision. NVIVO qualitative data analysis software was used to explore themes arising from the transcribed recorded interviews. FINDINGS: Key findings were the importance of physical location in facilitating multidisciplinary communication, the importance of defining role boundaries between existing and new providers of children's palliative care, and the potentially detrimental impact of insecure funding on referral patterns and recruitment to posts. Staff named the opportunity to offer direct 'hands-on' care to families, access to work-based support and networking opportunities as important factors in helping them cope with the stresses involved in managing finite resources and the emotional challenges of their work. CONCLUSIONS: The maintenance of a mixed caseload with a significant proportion of direct care, provision of ongoing support and clearly defined roles are recommended as means of bolstering the ability of staff to develop their services. The deliberate locating of services to enhance communication between staff and guidance on the preparation of funding applications may further contribute to the sustainability of these services.

Implementing a program for switching from i.v. to oral antimicrobial therapy.

Management Case Studies describe approaches to real-life management problems in health systems. Each installment is a brief description of a problem and how it was dealt with. The cases are intended to help readers deal with similar experiences in their own work sites. Problem solving, not hypothesis testing, is emphasized. Successful resolution of the management issue is not a criterion for publication--important lessons can be learned from failures, too.

Therapeutic challenges associated with extended-spectrum, beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae.

The emergence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, particularly Escherichia coli and Klebsiella pneumoniae, presents significant diagnostic and therapeutic challenges to the management of infections due to these organisms. Detection of resistant isolates is difficult based on routine susceptibility testing performed by a clinical microbiology laboratory. In addition, the utility of penicillins, cephalosporins, and aztreonam in treating serious infections due to these organisms is uncertain due to reports of treatment failure despite apparent in vitro susceptibility. A critical evaluation of the English literature was performed on treatment outcomes associated with ESBL-producing Enterobacteriaceae. Imipenem and extended-spectrum cephalosporins were commonly administered. Discordant outcomes in relation to in vitro susceptibility of the agent did not occur exclusively with cephalosporins but with all drugs including imipenem. Until more outcome data are available, drug selection must take into consideration whether or not an outbreak is occurring and whether therapy is empirical or definitive.

Fluconazole-induced agranulocytosis with eosinophilia.

Fluconazole is a commonly prescribed antifungal agent with a favorable safety profile. A patient experienced agranulocytosis and eosinophilia associated with the drug. Similar bone marrow-suppressive effect due to the azoles is rarely described in the English-language literature.

Lipid formulations of amphotericin B: clinical efficacy and toxicities.

Commercially available lipid formulations of amphotericin B (Abelcet, Amphotec, and AmBisome) represent a significant advance in drug delivery technology. Differences in biochemical, pharmacokinetic, and pharmacodynamic properties among the lipid products have been shown in in vitro and in vivo models. Clinical experience with these products has been primarily in patients either refractory to or intolerant of conventional amphotericin B deoxycholate (AmBd). None of the lipid-based products demonstrates superior efficacy when prospectively compared with AmBd in the treatment of documented infections. When used for the empirical treatment of febrile neutropenia, AmBisome significantly reduced the incidence of proven emergent fungal infections but did not improve short-term survival rates, in comparison with AmBd. Acute infusion-related adverse events vary, whereas nephrotoxicity is reduced with all three lipid formulations. Until superior efficacy is clearly shown (for documented infections) or pharmacoeconomic analyses document the value of these drugs, use of such expensive agents should be highly restricted to those who are intolerant of or refractory to AmBd.

Crystalluria: a clinically useful investigation in children with primary hyperoxaluria post-transplantation.

Primary hyperoxaluria type I (PH I) is a congenital error of metabolism that can be manifested by an increased oxalate production, and ultimately result in kidney failure. After a combined liver/kidney transplantation, children with PH I have persistent excretion of oxalate that causes crystal formation in the urinary tract, and could result in systemic oxalosis and eventual graft failure. We speculated that crystalluria may be predictive of this nephrolithogenic tendency and thus investigated the effect of an intensive therapeutic strategy to prevent crystal formation in 13 children at our hospital. Oxalate crystal volume (OCV) measurements were performed at regular intervals for 36 months, and compared with urine supersaturation measurements. We found that crystalluria with the OCV measurement is non-invasive, easily performed, and gives feedback on the efficacy of PH I therapy within one hour. Further study is needed to determine whether this method is a better predictor of nephrocalcinosis than is supersaturation alone.

Predictive performance of a vancomycin-aminoglycoside population model.

OBJECTIVE: To evaluate the Wragge-Cooper method of predicting vancomycin serum concentrations utilizing knowledge of aminoglycoside pharmacokinetic parameters in general medicine and intensive care unit populations, and to develop a revised model if necessary. DESIGN: This study consists of two phases evaluating 50 adults receiving concurrent vancomycin and aminoglycoside therapy. Patients were identified by a retrospective review of medical records. Bayesian analysis of measured serum aminoglycoside and vancomycin concentrations was performed to determine the individualized pharmacokinetic parameters. Phase I of the study tested the predictive performance of a published model incorporating aminoglycoside elimination (Wragge-Cooper) in 25 patients (group 1), and a revised model was developed. Phase II determined the predictive performance of the revised model (revised) and its performance relative to the Wragge-Cooper model and a traditional model incorporating estimated creatinine clearance (traditional) in an additional 25 patients (group 2). SETTING: Two tertiary care university teaching hospitals. MAIN OUTCOME MEASURES: The predictive performance of the models was determined by comparing predicted with measured vancomycin serum concentrations. Bias and precision were evaluated by calculating the mean prediction error (ME) and mean absolute error (MAE), respectively. Linear regression was performed to determine relationships between parameters. RESULTS: The Wragge-Cooper model consistently underpredicts vancomycin serum concentrations in general medicine and intensive care unit populations (ME = -5.18, MAE = 6.63). Relative predictive performance analysis indicates no significant difference in bias or precision between the traditional and Wragge-Cooper models (delta ME 1.17, delta MAE -0.80). Regression analysis of individualized aminoglycoside and vancomycin elimination derived from patients in group 1 reveals the following relationship: vancomycin k10 (1/h) = 0.081 + 1.037ke,amg, r = 0.73. The revised model is significantly less biased and more precise compared with the traditional model (delta ME -4.48; delta MAE 1.22), and is significantly less biased (delta ME 4.29) but no more precise than the Wragge-Cooper model (delta MAE -0.58), using patients from group 2. CONCLUSIONS: The revised model is an accurate method of predicting vancomycin serum concentrations in both general medicine and intensive care unit populations. Use of this model enables individualization of vancomycin dosage in patients receiving concurrent aminoglycoside therapy and minimizes vancomycin serum concentration monitoring.

Economic aspects of antibacterial adverse effects.

The economic impact of adverse effects is often understated. Increased hospitalisations attributed to adverse drug reactions alone account for billions of dollars each year within the US healthcare system. Although most classes of antibacterials are well tolerated, severe reactions do occur and can add significantly to the cost of care. Among hospitalised patients, antibacterial adverse effects account for nearly 25% of adverse drug reactions. Published pharmacoeconomic data on direct and indirect costs of antibacterial adverse effects are lacking. The importance of determining the most cost-effective treatment regimen is becoming more apparent due to limited resources available within the healthcare system. When considering the cost of new antibacterials, a simple comparison of acquisition costs may not accurately reflect the true costs of treatment. A drug with a lower acquisition cost may be more toxic and/or less effective, resulting in higher complication rates and/or treatment failures, thus leading to a higher overall treatment cost. In addition, nephrotoxic agents such as aminoglycosides and vancomycin often require close monitoring of serum drug concentrations and creatinine levels, which also contributes to the total cost of therapy. Indirect costs as a result of reduced quality of life or loss of productivity are certainly not reflected in the acquisition costs of antimicrobials. Institutions must evaluate a drug's potential for causing and adverse event, among various other factors, when considering drugs for inclusion on their formularies. Drugs with good safety profiles may minimise hospitalisation or facilitate early discharge. Thus, the adverse effect profile of an antimicrobial agent can contribute significantly to its overall direct costs, primarily as a result of higher monitoring costs and additional days of hospitalisation. For example, in the US, the cost associated with adverse effects, such as nephrotoxicity, observed with aminoglycosides and vancomycin, may add approximately $US2500 per patient with nephrotoxicity (1990 values). Indirect costs can also be substantial as a result of reduced productivity. Many adverse effects of antibacterial agents are predictable and may be minimised with appropriate monitoring and care. This article reviews the pharmacoeconomic aspects of adverse effects associated with some of the more important antibacterial classes such as the beta-lactams, aminoglycosides, vancomycin, macrolides and fluoroquinolones.

Successful bronchotracheal reconstruction in esophageal bronchus: two case reports.

Esophageal bronchus is the most common congenital bronchopulmonary foregut malformation. Current surgical treatment is resection of anomalous pulmonary tissue, which is often hypoplastic and destroyed by infection. The authors report two cases of bronchotracheal reconstruction. The diagnosis was early, before 15 days of age. The anomalous pulmonary tissue had a pulmonary arterial supply and venous drainage as assessed by angiography and a good functional capacity on selective ventilation. Bronchotracheal anastomosis was successful in both cases: a right main bronchus at 25 days of age and a left main bronchus at 13 days of age. One child underwent reoperation 1 year later for bronchomalacia of the reimplanted bronchus. Both children are well with normal growth 3 and 7 years after surgery. Chest roentgenograms showed normal and symmetrical lung aeration. Tracheal reimplantation may be preferred to pulmonary resection when the anomalous pulmonary tissue is not destroyed. The pulmonary functional capacity is increased and the complications of pneumonectomy avoided.

Safety and efficacy of Intralipid emulsions of amphotericin B.

To evaluate the clinical role of amphotericin/20% Intralipid emulsions (ILA), we conducted a Medline search of the English literature to locate the relevant case reports and clinical studies involving the use of this formulation. Due to differences in study design and definitions, we applied a set of treatment outcome definitions to determine the clinical efficacy of this treatment modality. Only 37 patients received ILA for the treatment of documented fungal infections. Using our definitions, four were considered successfully treated, one improved, two failed, and 30 were unevaluable. While infusion-related adverse events and nephrotoxicity were reportedly reduced with ILA, use of adjunctive therapies and concomitant nephrotoxic agents, and comparisons with high infusion concentrations complicate evaluation. Furthermore, incomplete and conflicting data exist regarding the physiochemical stability of ILA. The currently available data do not support recommendations for the use of this formulation for the treatment of systemic fungal infections.