PARC: a phase I/II study evaluating the safety and activity of pegylated recombinant human arginase BCT-100 in relapsed/refractory cancers of children and young adults.

Background: The survival for many children with relapsed/refractory cancers remains poor despite advances in therapies. Arginine metabolism plays a key role in the pathophysiology of a number of pediatric cancers. We report the first in child study of a recombinant human arginase, BCT-100, in children with relapsed/refractory hematological, solid or CNS cancers. Procedure: PARC was a single arm, Phase I/II, international, open label study. BCT-100 was given intravenously over one hour at weekly intervals. The Phase I section utilized a modified 3 + 3 design where escalation/de-escalation was based on both the safety profile and the complete depletion of arginine (defined as adequate arginine depletion; AAD <8µM arginine in the blood after 4 doses of BCT-100). The Phase II section was designed to further evaluate the clinical activity of BCT-100 at the pediatric RP2D determined in the Phase I section, by recruitment of patients with pediatric cancers into 4 individual groups. A primary evaluation of response was conducted at eight weeks with patients continuing to receive treatment until disease progression or unacceptable toxicity. Results: 49 children were recruited globally. The Phase I cohort of the trial established the Recommended Phase II Dose of 1600U/kg iv weekly in children, matching that of adults. BCT-100 was very well tolerated. No responses defined as a CR, CRi or PR were seen in any cohort within the defined 8 week primary evaluation period. However a number of these relapsed/refractory patients experienced prolonged radiological SD. Conclusion: Arginine depletion is a clinically safe and achievable strategy in children with cancer. The RP2D of BCT-100 in children with relapsed/refractory cancers is established at 1600U/kg intravenously weekly and can lead to sustained disease stability in this hard to treat population. Clinical trial registration: EudraCT, 2017-002762-44; ISRCTN, 21727048; and ClinicalTrials.gov, NCT03455140.

Subcutaneous panniculitis-like T-cell lymphoma in two unrelated individuals with BENTA disease.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous non-Hodgkin lymphoma involving CD8+ T cells, the genetic underpinnings of which remain incompletely understood. Here we report two unrelated patients with B cell Expansion with NF-κB and T cell Anergy (BENTA) disease and a novel presentation of SPTCL. Patient 1 presented early in life with recurrent infections and B cell lymphocytosis, linked to a novel gain-of-function (GOF) CARD11 mutation (p.Lys238del). He developed SPTCL-like lesions and membranoproliferative glomerulonephritis by age 2, treated successfully with cyclosporine. Patient 2 presented at 13 months with splenomegaly, lymphadenopathy, and SPTCL with evidence of hemophagocytic lymphohistiocytosis. Genetic analysis revealed two in cis germline GOF CARD11 variants (p.Glu121Asp/p.Gly126Ser). Autologous bone marrow transplant resulted in SPTCL remission despite persistent B cell lymphocytosis. These cases illuminate an unusual pathological manifestation for BENTA disease, suggesting that CARD11 GOF mutations can manifest in cutaneous CD4+and CD8+ T cell malignancies.

Why Students Cheat and How Understanding This Can Help Reduce the Frequency of Academic Misconduct in Higher Education: A Literature Review.

Academic integrity is fundamental to effective education and learning yet cheating continues to occur in diverse forms within the higher education sector. It is essential that students are educated about, and understand the importance of, good academic practice. Strict standards of academic integrity help to ensure that knowledge is acquired in an honest and ethical manner, creating fairness and equity for students, ultimately enriching the student experience at university and the wider society's trust in the value of university education. This literature review synthesizes the many varied reasons why students cheat, as presented in a large body of existing literature. We then turn our attention to what we can do as educators to help reduce the rates of academic misconduct. Factors influencing the propensity of students to cheat are diverse but relatively well understood. Whilst policing and applying appropriate punishments should be part of institutional responses to academic misconduct, it is clear that this is only part of the solution. We emphasize the need for a much broader range of proactive activities to be brought to bear. Many of these are educational in nature and should have benefits for students, staff and institutions beyond discouraging academic misconduct. Resource implication should not be a barrier to their implementation.

Pre-existing cardiovascular disease, acute kidney injury, and cardiovascular outcomes in hospitalized blacks with COVID-19 infection.

BACKGROUND: The Corona Virus 19 (COVID-19) infection is associated with worse outcomes in blacks, although the mechanisms are unclear. We sought to determine the significance of black race, pre-existing cardiovascular disease (pCVD), and acute kidney injury (AKI) on cardiopulmonary outcomes and in-hospital mortality of COVID-19 patients. METHODS: We conducted a retrospective cohort study of blacks with/without pCVD and with/without in-hospital AKI, hospitalized within Grady Memorial Hospital in Georgia between February and July 2020, who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on qualitative polymerase-chain-reaction assay. The primary outcome was a composite of in-hospital cardiac events. RESULTS: Of the 293 patients hospitalized with COVID-19 in this study, 71 were excluded from the primary analysis (for race/ethnicity other than black non-Hispanic). Of the 222 hospitalized COVID-19 patients included in our analyses, 41.4% were female, 78.8% had pCVD, and 30.6% developed AKI during the admission. In multivariable analyses, pCVD (OR 4.7, 95% CI 1.5-14.8, P=0.008) and AKI (OR 2.7, 95% CI 1.3-5.5, P=0.006) were associated with increased odds of in-hospital cardiac events. AKI was associated with increased odds of in-hospital mortality (OR 8.9, 95% CI 3.3-23.9, P<0.0001). The presence of AKI was associated with increased odds of ICU stay, mechanical ventilation, and acute respiratory distress syndrome (ARDS). CONCLUSION: pCVD and AKI were associated with higher risk of in-hospital cardiac events, and AKI was associated with a higher risk of in-hospital mortality in blacks.

Growth hormone and targeted oncological agents: Are we stopping children with brain tumours from reaching their true height potential?

Children with low-grade gliomas have excellent long-term survival outcomes. The development of therapies targeted to the driver mutations along the Mitogen Activated Protein (MAP) kinase signalling pathway are providing long-term stability for many patients with these tumours. Given the frequency of these tumours residing within or near the suprasellar region, our patients commonly suffer from hormone deficiencies. In Australia, the Pharmaceutical Benefits Scheme currently restricts growth hormone therapy to patients who are not being actively treated for cancer, including those receiving targeted therapies. This viewpoint hopes to facilitate an important discussion amongst our colleagues as to whether this should be changed to allow growth hormone to become available to children on chronic tumour suppressive therapy.

Distribution of semen examination results 2020 - A follow up of data collated for the WHO semen analysis manual 2010.

BACKGROUND: It is now 11 years since publication of the WHO 2010 guidelines for semen assessment values, and it is critical to determine whether they are still valid and/or whether they should be modified. OBJECTIVES: To utilise data published since 2010 and combine these with data used in the 2010 assessment to provide an updated and more comprehensive representation of the fertile man. This may be utilised to present an updated distribution of values for use by WHO in 2021. MATERIALS AND METHODS: Two specific analyses were performed namely, (1) Analysis 1: Examination of published data following publication of WHO 2010 [termed 2010-2020 data]. (2) Analysis 2: Examination of the data used to help formulate the 2010 distribution of values combined with the data from Analysis (1) [termed WHO 2020]. RESULTS: In total, data from more than 3500 subjects, from twelve countries and five continents were analysed. The 5th centile values for concentration, motility and morphology are: 16 × 106 /ml, 30% progressive motility [42% total motility] and 4% normal forms. DISCUSSION: This study presents substantial additional information to establish more comprehensive and globally applicable lower reference values for semen parameters for fertile men although they do not represent distinct limits between fertile and subfertile men. There are still data missing from many countries and, some geographical regions are not represented. Moreover, the number of subjects although significant is still relatively low (<4000). CONCLUSION: These distributions of values now include semen analysis providing a more global representation of the fertile man. Increasing the number of subjects provides robust information that is also more geographically representative.

Sex-based differences in procedural complications associated with atrial fibrillation catheter ablation: A systematic review and meta-analysis.

BACKGROUND: Women undergoing atrial fibrillation catheter ablation (AFCA) have higher rates of vascular complications and major bleeding. However, most studies have been underpowered to detect differences in rarer complications such as stroke/transient ischemic attack (TIA) and procedural mortality. METHODS: We performed a systematic review of databases (PubMed, World of Science, and Embase) to identify studies published since 2010 reporting AFCA complications by sex. Six complications of interest were (1) vascular/groin complications; (2) pericardial effusion/tamponade; (3) stroke/TIA; (4) permanent phrenic nerve injury; (5) major bleeding; and (6) procedural mortality. For meta-analysis, random effects models were used when heterogeneity between studies was ≥50% (vascular complications and major bleeding) and fixed effects models for other endpoints. RESULTS: Of 5716 citations, 19 studies met inclusion criteria, comprising 244,353 patients undergoing AFCA, of whom 33% were women. Women were older (65.3 ± 11.2 vs. 60.4 ± 13.2 years), more likely hypertensive (60.6% vs. 55.5%) and diabetic (18.3% vs. 16.5%), and had higher CHA2 DS2 -VASc scores (3.0 ± 1.8 vs. 1.4 ± 1.4) (p < .0001 for all comparisons). The rates of all six complications were significantly higher in women. However, despite statistically significant differences, the overall incidences of major complications were very low in both sexes: stroke/TIA (women 0.51% vs. men 0.39%) and procedural mortality (women 0.25% vs. men 0.19%). CONCLUSION: Women experience significantly higher rates of AFCA complications. However, the incidence of major procedural complications is very low in both sexes. The higher rate of complications in women may be partially attributable to older age and a higher prevalence of comorbidities at the time of ablation. More detailed studies are needed to better define the mechanisms of increased risk in women and to identify strategies for closing the sex gap.

Wilms Tumor Associated With the 9q22.3 Microdeletion Syndrome: 2 New Case Reports and a Review of The Literature.

BACKGROUND: The 9q22.3 syndrome is an autosomal dominant microdeletion syndrome with similarities to Gorlin syndrome (GS). It encompasses the PTCH1 gene locus that harbors mutations for GS. Although the 9q22.3 syndrome is associated with Wilms tumor (WT), WT is not a GS-associated tumor, implying a different mechanism involving PTCH1, or a different locus in the 9q22.3 region. The goal of this study is to report the association between WT and 9q22.3 syndrome and review the outcome of treatment. OBSERVATIONS: We report 2 new cases of WT with 9q22.3 deletion and review the literature. Among the 44 described patients with 9q22.3 deletion, 7 developed WT (16%) at a mean age of 45 months (range, 4 to 84 mo). All patients had dysmorphic features, macrocephaly, and developmental delay, and there was an association with overgrowth (4/7). One patient had bilateral WT, another had a synchronous rhabdomyosarcoma. The outcome was excellent with all cases reported to be in complete remission. CONCLUSIONS: The 9q22.3 microdeletion syndrome should be considered at diagnosis of WT in children with dysmorphic features. Conversely, patients with a known 9q22.3 deletion syndrome should be considered for a WT predisposition surveillance program, especially those with overgrowth. The management should be individualized and given the excellent prognosis, and the unknown future risk of metachronous disease or other malignancy, the surgical approach should be carefully considered.

Practice educators' attitudes and perspectives of interprofessional collaboration and interprofessional practice learning for students: A mixed-methods case study.

Interprofessional collaboration (IPC) is important for the delivery of effective integrated health and social care systems. Interprofessional practice learning (IPPL) enables students to learn to work together within a relevant context and prepare for future IPC. While there is some evidence that negative attitudes impact on IPC and interprofessional education, there is a dearth of research on health and social work professionals' attitudes and perspectives of IPC and IPPL opportunities for students. A mixed-methods case study was used to investigate practice educators' attitudes and perspectives of IPC and IPPL for their students. Results showed that attitudes were positive and that mainly meso- and macro-level factors, as opposed to the micro level, impacted on the implementation of IPC and IPPL for students' learning in practice settings. IPC was perceived to be best enabled by effective communication, established teams, IPPL for staff, and shared processes and policies. Close working proximity to other professionals encouraged informal communication and positive interprofessional relationships. Motivation and resources were perceived as enablers of IPPL, but there were often missed opportunities for IPPL. These findings suggest that further work is required to identify systems for improving IPC and to enhance IPPL opportunities for students learning within practice settings.

Addressing the Absence of Black Men in Medicine.

There is a profound absence of Black men in medicine. Addressing this issue requires a concerted and holistic effort that includes learning from the current generation of medical students. This article summarizes three medical student perspectives presented as posters at the National Academies of Science, Engineering, and Medicine inaugural workshop on the growing absence of Black men in medicine. These posters present perspectives from men of color each from one of the three historically Black medical colleges in the country. The authors provide narratives on the importance of early access to resources and adequate inter-generational mentorship in preparing Black men for a career in medicine. Popular culture is also discussed as a means of facilitating further engagement of premedical Black students. Black men interested in medicine face unique challenges in the United States, and initiatives to improve the declining matriculation rate into medical schools need to be well-designed, relevant, and facilitating of early mentorship.

ALK-positive histiocytosis: an expanded clinicopathologic spectrum and frequent presence of KIF5B-ALK fusion.

In 2008, we presented three cases of ALK-positive histiocytosis as a novel systemic histiocytic proliferation of early infancy with hepatosplenomegaly and dramatic hematological disturbances. This series of 10 cases (including the original three cases) describes an expanded clinicopathological spectrum and the molecular findings of this histiocytic proliferation. Six patients had disseminated disease: five presented in early infancy with eventual disease resolution, and the sixth presented at 2 years of age and died of intestinal, bone marrow, and brain involvement. The other four patients had localized disease involving nasal skin, foot, breast, and intracranial cavernous sinus - the first three had no recurrence after surgical resection, while the cavernous sinus lesion showed complete resolution with crizotinib therapy. The lesional histiocytes were very large, with irregularly folded nuclei, fine chromatin, and abundant eosinophilic cytoplasm, sometimes with emperipolesis. There could be an increase in foamy histiocytes and Touton giant cells with time, resembling juvenile xanthogranuloma. Immunostaining showed that the histiocytes were positive for ALK, histiocytic markers (CD68, CD163) and variably S100, while being negative for CD1a, CD207, and BRAF-V600E. Next-generation sequencing-based anchored multiplex PCR (Archer® FusionPlex®) performed in six cases identified KIF5B-ALK gene fusion in five and COL1A2-ALK fusion in one. There was no correlation of gene fusion type with disease localization or dissemination. The clinicopathological spectrum of ALK-positive histiocytosis is broader than originally described, and this entity is characterized by frequent presence of KIF5B-ALK gene fusion. We recommend that every unusual histiocytic proliferative disorder, especially disseminated lesions, be tested for ALK expression because of the potential efficacy of ALK inhibitor therapy in unresectable or disseminated disease.

Use of bevacizumab as a single agent or in adjunct with traditional chemotherapy regimens in children with unresectable or progressive low-grade glioma.

In pediatric low-grade gliomas not amenable to complete resection, various chemotherapy regimens are the mainstream of treatment. An excellent overall survival of these patients makes justification of the intensification of chemotherapy difficult and calls for the development of new strategies. Bevacizumab, a humanized monoclonal antibody directed against Vascular endothelial growth factor (VEGF), has been successfully used in combination with irinotecan in a number of adult and pediatric studies and reports. Fifteen patients at median age of 7 years old (range 3 months to 15 years) were treated with bevacizumab in combination with conventional low-toxicity chemotherapy. The majority had chiasmatic/hypothalamic and midline tumors, seven had confirmed BRAF pathway alterations including neurofibromatosis type 1 (2). Fourteen patients had more than one progression and three had radiotherapy. No deaths were documented, PFS at 11 and 15 months was 71.5% ± 13.9% and 44.7% ± 17.6% respectively. At the end of follow-up 40% of patients has radiologically stable disease, three patients progressed shortly after completion of bevacizumab and two showed mixed response with progression of cystic component. Rapid visual improvement was seen in 6/8 patients, resolution of endocrine symptoms in 2/4 and motor function improvement in 4/6. No relation between histology or BRAF status and treatment response was observed. Treatment-limiting toxicities included grade 4 proteinuria (2) and hypertension (2) managed with cessation (1) and pausing of therapy plus antihypertensives (1). In conclusion, bevacizumab is well tolerated and appears most effective for rapid tumor control to preserve vision and improve morbidity.

Laparoscopic nephrectomy for Wilms' tumor: Can we expand on the current SIOP criteria?

INTRODUCTION: Wilms' tumor now has a good overall prognosis with open radical nephrectomy having been the mainstay of surgical treatment. Recently laparoscopic nephrectomy (LN) has been growing in popularity. The aim of our study was to review our indications and outcomes for laparoscopic resections for Wilms' tumor and compare indications with International Society of Paediatric Oncology (SIOP) criteria for LN. MATERIAL AND METHODS: Patient demographics, preoperative management, surgical data, respect of SIOP criteria, complications, disease outcome, and follow-up were recorded on consecutive children who underwent nephrectomy for Wilms' tumor. RESULTS AND DISCUSSION: Fifty-four consecutive children with Wilms' tumor underwent a nephrectomy; 20 had a LN (Table). Nine of 20 (45%) patients who had LN did not meet SIOP criteria for LN. No patients had an intraoperative tumor rupture and one patient had positive margins because of preoperative rupture. There were two conversions: one caused by difficulty accessing the renal hilum and the other caused by difficulty maintaining oxygen saturations. There was one local recurrence. CONCLUSION: SIOP criteria are conservative and safe. Indications can be extended for teams experienced in surgical oncology and laparoscopy after agreement at a multidisciplinary meeting (MDM).

More than Grapes and Bleeding: An Updated Look at Pelvic Rhabdomyosarcoma in Young Women.

STUDY OBJECTIVE: To review our local experience with urogenital rhabdomyosarcoma (RMS) to determine the most common clinical presentation(s). DESIGN: Retrospective case series of all female patients with urogenital RMS who presented to a tertiary pediatric hospital between 1996 and 2016. All institutional electronic pathology reports were screened for RMS and those that were pelvic in origin and occurred in female patients were included for further analysis. Seventeen cases of urogenital RMS in female patients were identified and reviewed. SETTING: This study was conducted at The Royal Children's Hospital in Melbourne, Australia. This is a tertiary referral center for the state of Victoria and surrounding areas, which services more than 1.5 million pediatric patients. PARTICIPANTS: Female pediatric patients (ages 0-18 years) who presented to The Royal Children's Hospital with eventual pathologic tissue diagnosis of urogenital RMS. MAIN OUTCOME MEASURES: The cases were reviewed for clinical presentation, duration of symptoms before initial presentation, time to tissue diagnosis, and outcomes of treatment. RESULTS: Of the 17 cases reviewed, 5 (29%) presented with perineal mass, 4 (24%) presented with each of abdominal mass and grape-like lesions/hemorrhagic mass at the introitus, 3 (18%) with nonspecific symptoms only, and 1 (6%) with vulvar inflammation. CONCLUSION: The clinical presentation of urogenital RMS in women is heterogeneous, and the classically described presentation of grape-like lesions at the introitus and vaginal bleeding represents only a small proportion of clinical presentations. Awareness of other presentations, which appear to be more common than previously recognized, needs to be increased to ensure timely diagnosis and treatment.

Information-sharing with respite care services for older adults: a qualitative exploration of carers' experiences.

Respite services play an important role in supporting older adults and their carers. When an older person is unable to fully represent themselves, provision of respite care relies on effective information-sharing between carers and respite staff. This study aimed to explore, from carers' perspectives, the scope, quality and fit of information-sharing between carers, older people and respite services. An explorative, cross-sectional qualitative study involving a purposive sample of 24 carers, recruited via carer support groups and community groups in voluntary organisations, was undertaken in North East Scotland. Data were collected from August 2013 to September 2014, with participants taking part in a focus group or individual interview. Data were analysed systematically using the Framework Approach. The multiple accounts elicited from carers identified how barriers and facilitators to information-sharing with respite services changed over time across three temporal phases: 'Reaching a point', 'Trying it out' and 'Settled in'. Proactive information-sharing about accessibility and eligibility for respite care, and assessment of carers' needs in their own right, were initially important; as carers and older people moved on to try services out, time and space to develop mutual understandings and negotiate care arrangements came to the fore; then, once shared expectations had been established, carers' chief concerns were around continuity of care and maintaining good interpersonal relationships. The three temporal phases also impacted on which modes of information-sharing were available to, and worked best for, carers as well as on carers' perceptions of how information and communication technologies should be utilised. This study highlights the need for respite staff to take proactive, flexible approaches to working with carers and to make ongoing efforts to engage with carers, and older people, throughout the months and years of them utilising respite services. Information and communication technologies have potential to enhance information-sharing but traditional approaches will remain important.

A Pilot Study on the Utility of Serum Metabolomics in Neuroblastoma Patients and Xenograft Models.

BACKGROUND: Improved prediction of neuroblastoma (NB) behavior is needed to detect treatment-refractory disease and may allow further reduction in therapy for some patients. In this regard, serum metabolomic analysis has proven utility in several cancer types. We hypothesize that serum metabolomic analysis will correlate with risk-group classification for patients with NB, and sensitively detect NB in murine xenograft models. PROCEDURE: A pilot study was done on Children's Oncology Group (COG) tumor bank sera from 10 patients (five high-, five low-risk). An institutional pilot study was carried out on five patients comparing sera obtained during active versus minimal disease (complete response/very good partial response; CR/VGPR). XENOGRAFT: Flank tumors were established in Nu/Nu mice by injection of NB cell lines (IMR-32, SH-EP, SK-N-AS). Serum for comparison was drawn pre-injection, at 1 week after injection when there was no visible tumor, and again once tumors were grossly visible. Comparisons were also made between tumor bearing mouse serum and supernatants from NB cell lines. METABOLOMIC ANALYSIS: Samples were analyzed by nuclear magnetic resonance and/or gas chromatography-mass spectrometry. Multivariate data analysis was conducted using SIMCA-P (Umetrics). RESULTS: Serum metabolomic analysis differentiated high- and low-risk patients as well as active disease from CR/VGPR. Differences were in nitrogen, amino acid, and carbohydrate metabolism, as well as ketosis. The serum metabolomic signature in murine xenograft models sensitively detected NB cells and correlated with disease burden. Similar metabolic changes attributable to NB were noted in both human and murine serum. CONCLUSIONS: Serum metabolomic analysis can distinguish several characteristics of NB. A larger analysis of COG banked sera is warranted.

Health and social care professionals' attitudes to interprofessional working and interprofessional education: A literature review.

The healthcare setting is a rich learning environment for students to experience interprofessional working (IPW) and interprofessional education (IPE). However, opportunities for IPE are limited, and student experiences of effective IPW are varied. This raises the question of how IPW and IPE are valued by health or social care professionals. A search of the literature was carried out to identify studies of health and social care staff attitudes to IPW and IPE. This review provides a summary of the main factors found to influence attitudes and the strengths and limitations of these studies. Professional background and prior IPE experience were identified as the influencing factors for which there is most evidence. The main limitations of the studies accessed included a focus on the value of IPE for staff, as opposed to students, and a limited number of studies considering the relationship between attitudes to IPW and the value placed on IPE. It is important that health and social care professionals lead by example by working collaboratively and providing students with opportunities for IPE. Identifying the variables influencing attitudes to IPW and IPE may assist in improving IPW and experiences of IPE for students learning in the healthcare setting.

Changing day services: do you agree?

Models of day services for people with intellectual disabilities in Scotland are changing, with the purpose, content and availability being reviewed. There has been concern that a move to more flexible 'alternative day opportunities' is driven more by reduced budgets than a policy of modernising day services in response to individual needs. During a day services review, a questionnaire was used to rate and to collect views on existing services from 60 carers, service users and staff. This included evaluating day activities available, care plans, opening times, transport and the most valued aspects of existing day services. Respondents indicated general satisfaction with existing day services, although half believed that day services should be reviewed. The most valued parts of day services were forming and building friendships, and a safe place to go. Day services are highly valued by families and service users. Recommendations are made for a robust and transparent review process.

Workforce development and challenging behaviour: training staff to treat, to manage or to cope?

Staff working directly with adults' challenging behaviours in learning disability services need to be very good at what they do. They also need to want to do the job. A theory-practice gap exists, however, between what is known about effective, evidence-based approaches and whether and how these are used in person-centred community services. Many frontline staff working with people with the most serious challenging behaviours do not have the skills to implement programmes to change behaviour. This discussion article reviews workforce development in the context of clinical and service guidelines and asks whether the legitimate purview of frontline staff is treating challenging behaviour, managing it or simply coping with it on a daily basis, whilst maintaining the best quality of life possible for service users.