First experiences of ultrasound vector flow imaging at the femoropopliteal artery in peripheral arterial disease.

Background: The femoropopliteal artery (FPA) plays a central role in diagnosing and treating peripheral arterial disease (PAD). FPA lesions are the most frequent cause of intermittent claudication, and no other artery of the lower extremities is recanalised more frequently. Generally, ultrasound is the primary imaging tool in PAD, particularly FPA. With the development of high-frame-rate ultrasound technology in addition to traditional ultrasound modes, vector flow imaging (VFI) has provided deeper haemodynamic insights when used in the carotid artery. Here, we report the use of VFI at the FPA level in routine PAD examinations. Patients and methods: In this single-centre prospective study, we evaluated consecutive patients with PAD using B-mode imaging, colour Doppler, pulsed wave Doppler (PW) and vector flow. Hemodynamic parameters at predefined locations at the carotid artery and FPA were compared. Results: Qualitatively adequate VFI at all sites was possible in 76% of the patients with PAD. With decreasing volume flow from the common carotid artery to the internal carotid artery and from the common femoral artery via the superficial femoral artery to the popliteal artery, the correlation between VFI- and PW-derived-volume flow was high at every site. Based on different techniques, the VFI-derived values were significantly lower than the PW-derived values. The mean wall shear stress was significantly lower at all femoropopliteal sites than at the carotid sites, whereas the oscillatory shear index at the femoral site was higher than that at the carotid sites rather than at the popliteal location. Conclusions: Our findings suggest that vector flow data acquisition in the FPA is feasible in most patients with PAD. Therefore, with knowledge of the method and its limitations, VFI provides haemodynamic information beyond traditional ultrasound techniques and is a promising new tool for flow analysis in PAD.

DNA Mismatch Repair Status Predicts Need for Future Colorectal Surgery for Metachronous Neoplasms in Young Individuals Undergoing Colorectal Cancer Resection.

BACKGROUND: The treatment of colorectal cancer in young patients involves both management of the incident cancer and consideration of the possibility of Lynch syndrome and the development of metachronous colorectal cancers. OBJECTIVE: This study aims to assess the prognostic role of DNA mismatch repair deficiency and extended colorectal resection for metachronous colorectal neoplasia risk in young patients with colorectal cancer. DESIGN, SETTING, AND PATIENTS: This is a retrospective review of 285 patients identified in our GI cancer registry with colorectal cancer diagnosed at 35 years or younger in the absence of polyposis. MAIN OUTCOME MEASURES: Using univariate and multivariate analysis, we assessed the prognostic role of mismatch repair deficiency and standard clinicopathologic characteristics, including the extent of resection, on the rate of developing metachronous colorectal neoplasia requiring resection. RESULTS: Mismatch repair deficiency was identified in biospecimens from 44% of patients and was significantly associated with an increased risk for metachronous colorectal neoplasia requiring resection (10-year cumulative risk, 13.5% ± 4.2%) compared with 56% of patients with mismatch repair-intact colorectal cancer (10-year cumulative risk, 5.8% ± 3.3%; p = 0.011). In multivariate analysis, mismatch repair deficiency was associated with a HR of 3.65 (95% CI, 1.44-9.21; p = 0.006) for metachronous colorectal neoplasia, whereas extended resection with ileorectal or ileosigmoid anastomosis significantly decreased the risk of metachronous colorectal neoplasia (HR, 0.21; 95% CI, 0.05-0.90; p = 0.036). LIMITATIONS: This study had a retrospective design, and, therefore, recommendations for colorectal cancer surgery and screening were not fully standardized. Quality of life after colorectal cancer surgery was not assessed. CONCLUSIONS: Young patients with colorectal cancer with molecular hallmarks of Lynch syndrome were at significantly higher risk for the development of subsequent colorectal neoplasia. This risk was significantly reduced in those who underwent extended resection compared with segmental resection.

Comparison of Functional and Morphological Estimates of Vascular Age.

BACKGROUND/AIM: Vascular age (VA) is an emerging metric in preventive cardiovascular (CV) medicine. VA can be derived from morphological parameters such as carotid intima-media thickness (CIMT), or functional parameters such as pulse wave analysis (PWA), which celebrates its 100th birthday. This study aimed to investigate whether the results of both approaches are comparable. PATIENTS AND METHODS: On the occasion of the double 100th anniversary of PWA and the Mannheim Clinic, 100 volunteers underwent a) bilateral CIMT assessment using high-resolution ultrasound and b) oscillometric PWA at the brachial forearm site. The respective VAs were calculated using previously published equations. RESULTS: Median age of the participants was 53.6 years (range=39.8-62.6 years), and 56% were female. Median CIMT was 632.5 µm (range=548.8-730.0 µm). Median PWA-derived VA was 55.3 years (36.5-70.5 years). Different values were obtained for CIMT-derived VA, depending on the reference cohort used as calculation basis, ranging from median 43.7 (26.2-59.5 years) to median 64.0 years (43.5-82.1 years). In 46% of the participants divergent VAs were found, that is, the calculated age was higher according to one method and lower according to the other. Correlation analysis revealed a strong dependence of VA (both PWA- and CIMT-derived) and chronological age, as well as an increase in CV risk factors and the detection of plaques with age. CONCLUSION: Different approaches for estimating VA are not comparable and often produce contradictory results. The current methods and their validity must be critically assessed if they are not standardized.

Adverse Cardiovascular Effects of Anti-tumor Therapies in Patients With Breast Cancer: A Single-center Cross-sectional Analysis.

BACKGROUND/AIM: Cardiotoxicity due to antitumor therapy is a dreaded complication and could thus impact the prognosis of patients with breast cancer. This study sought to analyze the occurrence of adverse cardiovascular events and to identify potential risk factors. PATIENTS AND METHODS: A total of 136 patients with breast cancer were divided into two groups based on the occurrence of treatment-related cardiovascular toxicity [event 47 (35%) vs. no event 89 (65%)]. Patients were followed over a median of 45 months (range=37-83 months). RESULTS: Most common events were thromboembolic complications (26%), followed by heart failure (15%) and acute toxic cardiomyopathy (5%), with a reduced left ventricular ejection fraction [LVEF (%), no event 59±5.0 vs. event 55±11, p=0.01 ]. Patients with leftsided breast cancer and an advanced stage disease had a higher risk of developing adverse cardiovascular events. The highest risk was found for patients with a high number of cardiovascular risk factors. In addition to LVEF, mitral annular plane systolic excursion was also significantly reduced in the event group, while there was a trend for higher global longitudinal strain. During follow-up, 26 patients (19.1%) deceased, whereof 12 had a treatment-related cardiovascular event, but without statistical difference. CONCLUSION: Treatment-related cardiovascular events are relatively common in about one third of patients with breast cancer. Women with a cardiovascular risk profile or an advanced stage disease had a higher risk for adverse events. Despite the treatment-related cardiac deterioration, no difference in mortality was observed during follow up.

Diagnostic Value of sST2, VCAM-1, and Adiponectin in Patients with Breast Cancer to Predict Anti-Tumour Treatment-Related Cardiac Events: A Pilot Study.

AIM: The present exploratory study investigated the diagnostic value of inflammatory markers in patients with breast cancer to predict anti-tumour treatment-related cardiac events. METHODS: Twenty-one patients with breast cancer were enrolled in this prospective observational study and followed over 6 months. Transthoracic echocardiography and measurement of cardiac (N-terminal prohormone of brain natriuretic peptide (NT-proBNP), troponin I (TnI)) and inflammatory biomarkers (vascular adhesion molecule 1 (VCAM-1), soluble suppression of tumorigenesis-2 (sST2), adiponectin) was performed at 3-month intervals (baseline, follow-up, final visit). Cardiac events were defined as decrease in left ventricular ejection fraction (LVEF, decrease by 10% or <50%) or increase in global longitudinal strain (GLS, increase by 15% or > -16%), as a more sensitive marker of LV function. RESULTS: Cardiac deterioration was observed in 9 out of 21 patients (event group). While LVEF did not differ significantly between the two groups (event vs. no event) at any visit, GLS was significantly higher during follow-up (follow-up: event -16 ± 3.3% vs. no event -18 ± 1.6%, p = 0.04; final visit: event -16 ± 2.1% vs. no event -19 ± 1.9%, p = 0.003). NT-proBNP was numerically higher in patients with a cardiac event during all visits, with NT-proBNP negatively correlated with LVEF and MAPSE (both r = -0.33, p = 0.02), whereas GLS (r = 0.40, p = 0.006), TnI (r = 0.44, p = 0.001), and VCAM-1 (r = 0.48, p = 0.003) showed a positive association with NT-proBNP. In comparison, higher VCAM-1 and sST2 concentrations were detected in the event group at both baseline and the final visit, with a significant difference for baseline (VCAM-1: p = 0.02; sST2: p = 0.03). Adiponectin was also lower in patients with a treatment-related event. Thresholds for VCAM-1 >762 ng/mL and sST2 >18.7 ng/mL, as detected by ROC analysis, correlated best with the primary endpoint. CONCLUSION: Cardiac events during anti-tumour treatment in patients with breast cancer are relatively common. Inflammatory markers such as VCAM-1 or sST2 were associated with an increased likelihood for occurrence of a treatment-related event, which may therefore hold the promise to better identify patients at high risk.

The regional distribution of resident immune cells shapes distinct immunological environments along the murine epididymis.

The epididymis functions as transition zone for post-testicular sperm maturation and storage and faces contrasting immunological challenges, i.e. tolerance towards spermatozoa vs. reactivity against pathogens. Thus, normal organ function and integrity relies heavily on a tightly controlled immune balance. Previous studies described inflammation-associated tissue damage solely in the distal regions (corpus, cauda), but not in the proximal regions (initial segment, caput). To understand the observed region-specific immunity along the epididymal duct, we have used an acute bacterial epididymitis mouse model and analyzed the disease progression. Whole transcriptome analysis using RNAseq 10 days post infection showed a pro-inflammatory environment within the cauda, while the caput exhibited only minor transcriptional changes. High-dimensional flow cytometry analyses revealed drastic changes in the immune cell composition upon infection with uropathogenic Escherichia coli. A massive influx of neutrophils and monocytes was observed exclusively in distal regions and was associated with bacterial appearance and tissue alterations. In order to clarify the reasons for the region-specific differences in the intensity of immune responses, we investigated the heterogeneity of resident immune cell populations under physiological conditions by scRNASeq analysis of extravascular CD45+ cells. Twelve distinct immune cell subsets were identified, displaying substantial differences in distribution along the epididymis as further assessed by flow cytometry and immunofluorescence staining. Macrophages constituted the majority of resident immune cells and were further separated in distinct subgroups based on their transcriptional profile, tissue location and monocyte-dependence. Crucially, the proximal and distal regions showed striking differences in their immunological landscapes. These findings indicate that resident immune cells are strategically positioned along the epididymal duct, potentially providing different immunological environments required for addressing the contrasting immunological challenges and thus, preserving tissue integrity and organ function.

A Pluralistic Perspective on Research in Psychotherapy: Harnessing Passion, Difference and Dialogue to Promote Justice and Relevance.

The adoption of a pluralistic perspective on research design, processes of data collection and analysis and dissemination of findings, has the potential to enable psychotherapy research to make a more effective contribution to building a just society. A review of the key features of the concept of pluralism is followed by a historical analysis of the ways in which research in counselling, psychotherapy and related disciplines has moved in the direction of a pluralistic position around knowledge creation. Core principles of a pluralistic approach to research are identified and explored in the context of a critical case study of contemporary research into psychotherapy for depression, examples of pluralistically oriented research practices, and analysis of a pluralistic conceptualisation of the nature of evidence. Implications of a pluralistic perspective for research training and practice are discussed. Pluralistic inquiry that emphasises dialogue, collaboration, epistemic justice and the co-existence of multiple truths, creates opportunities for individuals, families and communities from a wide range of backgrounds to co-produce knowledge in ways that support their capacities for active citizenship and involvement in open democratic decision-making. To fulfil these possibilities, it is necessary for psychotherapy research to be oriented towards social goals that are sufficiently relevant to both researchers and co-participants to harness their passion and work together for a common good.

'Like a human being, I was an equal, I wasn't just a patient': Service users' perspectives on their experiences of relationships with staff in mental health services.

OBJECTIVES: The quality of therapeutic relationships in psychiatric services has a significant impact upon the therapeutic outcomes for people diagnosed with a severe mental illness. As previous work has not explicitly explored service users' in-depth views about the emotional impact of these relationships, the objective of this work was to bring this perspective to the fore and to gain a greater understanding about which relational components can lead to psychological change. DESIGN: The project was conducted alongside a service user organization. An interview design was used to qualitatively explore service users' experiences and perceptions of their relationships with mental health practitioners. METHODS: Eight individuals who had experience of the mental health system in the United Kingdom were interviewed. Interpretative phenomenological analysis was used to analyse the data. FINDINGS: Three superordinate themes emerged from the analysis. These were (1) Trying to survive: am I a person or just an object in the system?; (2) Traumatic experiences within relationships; and (3) Helpful and transformative relationships. Further, the key transformative components of these relationships were power, safety, and identity. CONCLUSIONS: Mental health services should be more focused upon care, rather than control. The Power Safety Identity (PSI) model, a reflexive model based upon key relational components highlighted by participants, is proposed for services and professionals to consider their work. The components of this model are managed by mental health practitioners and can determine whether these relationships maintain, increase, or alleviate psychological distress. PRACTITIONER POINTS: Awareness of the relational components of power, safety, and identity has the potential to help practitioners reflect upon the tensions they experience in their relationships with service users. Mental health services and professionals that are sensitive to issues related to power, safety, and identity when responding to the needs of the service users can improve how individuals perceive the quality of care provided by them. Relationships between service users and mental health practitioners can encourage recovery if they are consistent, safe, trusting, provide protective power, and mirror a positive sense of self.

Supporting emotional well-being in schools in the context of austerity: An ecologically informed humanistic perspective.

BACKGROUND: Schools are commonly asked to take on roles that support the emotional well-being of students. These practices are in line with humanistic education theory and can be difficult to fulfil by schools. Broader ecological pressures, such as periods of austerity, are likely to add to the difficulty in meeting students' needs. AIMS: To explore whether professionals in schools believe that their work supporting pupils' emotional well-being has changed as a consequence of the current period of austerity. SAMPLE: This project reports the views of staff from three secondary schools in the North West of England. A purposive sample of 29 individuals, including members of the senior leadership team and newly qualified teachers, were involved. METHODS: All participants were interviewed about their perceptions of the impact of a sustained period of austerity upon their work. The transcripts of these interviews were analysed using thematic analysis. FINDINGS: Educational professionals associated wider socio-political factors with a perceived increase in the need for emotional support of pupils. They reported taking on new roles and responsibilities to accommodate this and noted they are doing so with fewer resources and limited governmental support. CONCLUSIONS: This paper concludes that considering humanistic education theory alongside ecological theory helps to conceptualize how socio-political factors can impact upon the emotional well-being in schools. An ecologically informed humanistic framework is depicted based upon the findings of this project as a means of understanding how these two theories complement one another and interact.

Long-term outcome after combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) for vertebral tumors.

INTRODUCTION: The spine represents the site which is most frequently affected by bone metastases in patients with systemic cancer. Of all local treatment options, combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provides both, instantaneous stabilization and immediate pain relief. We here report on the long-term outcomes of the largest cohort treated with Kypho-IORT to date. METHODS: Between 2009 and 2019 a total of 104 patients underwent Kypho-IORT to vertebral tumors in the thoracic, lumbar, or sacral spine with transpedicular kyphoplasty and intraoperative irradiation with a needle-shaped electronic brachytherapy source at our center. Patients were treated either on trial, within the prospective Kypho-IORT studies (NCT01280032 and NCT02773966), or, after completion of the study, off trial but compliant with the study protocol. Follow-up and imaging with computed tomography (CT) or magnetic resonance imaging was scheduled after 3 and 6 months and then bi-annually. RESULTS: A total of 143 vertebrae (89 thoracic spine, 53 lumbar spine, and 1 sacral spine) were treated in 104 patients. The median follow-up was 14.5 months (range 0.4-109). Local progression occurred in 10 patients (10 vertebrae) after a median time of 22.3 months (range 1.5-73) resulting in local control rates of 97.1, 95.9, and 94.2% at 6, 12, and 24 months, respectively. Overall survival was 74.6, 61.7, and 50.3% at 6, 12, and 24 months, respectively. A single serious adverse event was reported. CONCLUSION: In addition to immediate pain reduction and stabilization, Kypho-IORT shows excellent long-term local control with minimal side effects.

Pegfilgrastim for prevention of chemotherapy-associated neutropenia in pediatric patients with solid tumors.

BACKGROUND: Pegfilgrastim has similar efficacy to filgrastim in adults, but studies in pediatrics are limited. We report our institutional experience with pegfilgrastim following dose intensive chemotherapy for solid tumors. PROCEDURE: We evaluated the initial four courses of myelosuppressive chemotherapy for 47 patients (total 176 courses) diagnosed between 1/1/07 and 2/6/08 who received chemotherapy with pegfilgrastim support (100 mcg/kg; 6 mg maximum dose) in this retrospective review. We collected demographic data, treatment characteristics, frequency of severe neutropenia (absolute neutrophil count (ANC) <200/mm(3)), duration of neutropenia, and frequency of neutropenic fever. RESULTS: The median age of treated patients was 13 years (range 0.17-23 years) and the median weight was 50.8 kg (range 4-107 kg), including 16 (34%) <20 kg, and 22 (47%) <45 kg. Primary diagnoses included osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, soft tissue sarcoma, neuroblastoma, Hodgkin disease, and other solid tumors. No significant adverse events secondary to pegfilgrastim were noted. Severe neutropenia occurred in 57% of courses. The median duration of severe neutropenia was 1 day (range 0-11 days). Febrile neutropenia occurred in 28% of courses. Eight patients were treated with interval-compressed (every 14 days) sarcoma chemotherapy. Of the 30-interval compressed courses, the median duration per course was 14 days (range 14-18 days). CONCLUSIONS: Pegfilgrastim following dose intensive chemotherapy for solid tumors is feasible in children, including those <45 kg. The frequency and duration of severe neutropenia, as well as incidence of febrile neutropenia, were similar to filgrastim historic data.

Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children's Oncology Group trial AAML0531.

PURPOSE: To improve survival rates in children with acute myeloid leukemia (AML), we evaluated gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification. PATIENTS AND METHODS: Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children's Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three). RESULTS: There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v. 46.9%; hazard ratio [HzR], 0.83; 95% CI, 0.70 to 0.99; P.04) but not OS (3 years: 69.4% v. 65.4%; HzR, 0.91; 95% CI, 0.74 to 1.13; P = .39). Although remission was not improved (88% v. 85%; P = .15), posthoc analyses found relapse risk (RR) was significantly reduced among GO recipients overall (3 years: 32.8% v. 41.3%; HzR, 0.73; 95% CI, 0.58 to 0.91; P = .006). Despite an increased postremission toxic mortality (3 years: 6.6% v. 4.1%; HzR, 1.69; 95% CI, 0.93 to 3.08; P = .09), disease-free survival was better among GO recipients (3 years: 60.6% v. 54.7%; HzR, 0.82; 95% CI, 0.67 to 1.02; P = .07). CONCLUSION: GO added to chemotherapy improved EFS through a reduction in RR for children and adolescents with AML.

Variation in prescribing patterns and therapeutic drug monitoring of intravenous busulfan in pediatric hematopoietic cell transplant recipients.

Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8-fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4-fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors- group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children.

Multiplex mutation screening by mass spectrometry evaluation of 820 cases from a personalized cancer medicine registry.

There is an immediate and critical need for a rapid, broad-based genotyping method that can evaluate multiple mutations simultaneously in clinical cancer specimens and identify patients most likely to benefit from targeted agents now in use or in late-stage clinical development. We have implemented a prospective genotyping approach to characterize the frequency and spectrum of mutations amenable to drug targeting present in urothelial, colorectal, endometrioid, and thyroid carcinomas and in melanoma. Cancer patients were enrolled in a Personalized Cancer Medicine Registry that houses both clinical information and genotyping data, and mutation screening was performed using a multiplexed assay panel with mass spectrometry-based analysis to detect 390 mutations across 30 cancer genes. Formalin fixed, paraffin-embedded specimens were evaluated from 820 Registry patients. The genes most frequently mutated across multiple cancer types were BRAF, PIK3CA, KRAS, and NRAS. Less common mutations were also observed in AKT1, CTNNB1, FGFR2, FGFR3, GNAQ, HRAS, and MAP2K1. Notably, 48 of 77 PIK3CA-mutant cases (62%) harbored at least one additional mutation in another gene, most often KRAS. Among melanomas, only 54 of 73 BRAF mutations (74%) were the V600E substitution. These findings demonstrate the diversity and complexity of mutations in druggable targets among the different cancer types and underscore the need for a broad-spectrum, prospective genotyping approach to personalized cancer medicine.

Oral outpatient chemotherapy medication errors in children with acute lymphoblastic leukemia.

BACKGROUND: Although medication errors are 1 of the most common types of medical errors, their frequency in pediatric patients receiving oral outpatient chemotherapeutic agents is unknown. The prescribing, dispensing, and parental administration of these medications to children receiving treatment for acute lymphoblastic leukemia (ALL) were systematically reviewed to determine the rate and types of medication errors occurring in these patients. METHODS: During a 2-month study period, parents of children with ALL were contacted and asked to participate in the study before a regularly scheduled clinic appointment. At the visit, the parent demonstrated how each medication was administered. A pediatric oncologist reviewed the medical record to determine the correct treatment regimen for study patients. After comparing the correct treatment regimen with what was administered, a classification of "no medication error," "medication error," or "cannot determine" due to insufficient information was made for each indicated drug. Identified medication errors were subclassified as prescribing, dispensing, or administration errors. RESULTS: Data on 172 chemotherapeutic medications for 69 patients were analyzed. One or more errors occurred with 17 of the 172 (9.9%) medications; a classification of "cannot determine" was made for 12 (7.0%) medications. Among the 17 medication errors there were 12 (7.0%) administration errors and 5 (2.9%) prescribing errors. There were no pharmacy dispensing errors. All errors were due to incorrect dosing or failure to administer an indicated medication. At least 1 medication error occurred in 13 of the 69 (18.8%) study patients. CONCLUSIONS: Prescribing and administration medication errors occurred with nearly 10% of chemotherapeutic drugs administered to outpatient children with ALL. Systematic changes, including computerized physician order entry and simplification of treatment protocols, should be considered.