Outcomes of Rituximab-abbs versus Rituximab in Patients with Diffuse Large B-Cell Lymphoma in a Noninferiority Study.

BACKGROUND: Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is one of the first line treatments for diffuse large B-cell lymphoma (DLBCL). Rituximab comprises most of the treatment cost for this regimen; therefore, biosimilars, such as rituximab-abbs are crucial to provide affordable care. Although rituximab-abbs was studied primarily in follicular lymphoma, the Food and Drug Administration (FDA) approved this drug for all indications of the reference product on the basis of extrapolation. Effectiveness and safety data surrounding the use of rituximab-abbs in DLBCL is lacking. OBJECTIVE: To evaluate the effectiveness and safety of rituximab-abbs and reference product rituximab as R-CHOP treatment for patients with DLBCL. PATIENTS AND METHODS: This noninferiority (NI) study compared the 2-year overall survival (OS), overall response rate (ORR), and incidence of adverse events (AEs) between rituximab-abbs and its reference product (RP) in R-CHOP among adult patients with newly diagnosed DLBCL. The study inclusion period was from 1 January 2019 to 31 December 2020. Analyses were performed on the basis of a noninferiority lower limit of 10% for OS and ORR, and an upper limit of 10% for serious AEs. RESULTS: There were 240 patients who received RP rituximab, while 295 patients received rituximab-abbs. The cohort had a mean age of 63.7±12.2 years and 43% were female. The 2-year OS was 81.0% and 79.6% (NI p < 0.01) while the ORR was 80.0% and 69.6% (NI p < 0.01), among the rituximab-abbs and rituximab groups, respectively. The incidence of infusion reaction AEs (NI p < 0.01) and noninfusion reaction AEs (NI p < 0.01) also met noninferiority. CONCLUSIONS: We demonstrated that rituximab-abbs was noninferior to rituximab in both effectiveness and safety among patients receiving R-CHOP for DLBCL in this study. Long-term follow-up would be needed to confirm these results.

AKT2 modulates astrocytic nicotine responses in vivo.

A better understanding of nicotine neurobiology is needed to reduce or prevent chronic addiction, ameliorate the detrimental effects of nicotine withdrawal, and increase successful cessation of use. Nicotine binds and activates two astrocyte-expressed nicotinic acetylcholine receptors (nAChRs), α4ß2 and α7. We recently found that Protein kinase B-ß (Pkb-ß or Akt2) expression is restricted to astrocytes in mice and humans. To determine if AKT2 plays a role in astrocytic nicotinic responses, we generated astrocyte-specific Akt2 conditional knockout (cKO) and full Akt2 KO mice for in vivo and in vitro experiments. For in vivo studies, we examined mice exposed to chronic nicotine for two weeks in drinking water (200 µg/mL) and following acute nicotine challenge (0.09, 0.2 mg/kg) after 24 hrs. Our in vitro studies used cultured mouse astrocytes to measure nicotine-dependent astrocytic responses. We validated our approaches using lipopolysaccharide (LPS) exposure inducing astrogliosis. Sholl analysis was used to measure glial fibrillary acidic protein responses in astrocytes. Our data show that wild-type (WT) mice exhibit increased astrocyte morphological complexity during acute nicotine exposure, with decreasing complexity during chronic nicotine use, whereas Akt2 cKO mice showed increased astrocyte morphology complexity. In culture, we found that 100µM nicotine was sufficient for morphological changes and blocking α7 or α4ß2 nAChRs prevented observed morphologic changes. Finally, we performed conditioned place preference (CPP) in Akt2 cKO mice and found that astrocytic AKT2 deficiency reduced nicotine preference compared to controls. These findings show the importance of nAChRs and Akt2 signaling in the astrocytic response to nicotine.

A national survey of children's experiences and needs when attending Canadian pediatric emergency departments.

BACKGROUND: Optimizing a child's emergency department (ED) experience positively impacts their memories and future healthcare interactions. Our objectives were to describe children's perspectives of their needs and experiences during their ED visit and relate this to their understanding of their condition. METHODS: 514 children, aged 7-17 years, and their caregivers presenting to 10 Canadian pediatric EDs completed a descriptive cross-sectional survey from 2018-2020. RESULTS: Median child age was 12.0 years (IQR 9.0-14.0); 56.5% (290/513) were female. 78.8% (398/505) reported adequate privacy during healthcare conversations and 78.3% (395/504) during examination. 69.5% (348/501) understood their diagnosis, 89.4% (355/397) the rationale for performed tests, and 67.2% (338/503) their treatment plan. Children felt well taken care of by nurses (90.9%, 457/503) and doctors (90.8%, 444/489). Overall, 94.8% (475/501) of children were happy with their ED visit. Predictors of a child better understanding their diagnosis included doctors talking directly to them (OR 2.21 [1.15, 4.28]), having someone answer questions and worries (OR 2.51 [1.26, 5.01]), and older age (OR 1.08 [1.01, 1.16]). Direct communication with a doctor (OR 2.08 [1.09, 3.99]) was associated with children better understanding their treatment, while greater fear/ 'being scared' at baseline (OR 0.59 [0.39, 0.89]) or at discharge (OR 0.46 [0.22, 0.96]) had the opposite effect. INTERPRETATION: While almost all children felt well taken care of and were happy with their visit, close to 1/3 did not understand their diagnosis or its management. Children's reported satisfaction in the ED should not be equated with understanding of their medical condition. Further, caution should be employed in using caregiver satisfaction as a proxy for children's satisfaction with their ED visit, as caregiver satisfaction is highly linked to having their own needs being met.

Contact X-ray brachytherapy (CXB) as a salvage treatment for rectal cancer patients who developed local tumor re-growth after watch-and-wait approach.

Purpose: A watch-and-wait approach is an alternative to surgery for rectal cancer patients who have achieved a clinical complete response (cCR) following neoadjuvant (chemo)radiotherapy. However, approximately 25-38% of patients experience subsequent local tumor re-growth that requires salvage surgery. We evaluated the effectiveness of contact X-ray brachytherapy (CXB) as an alternative method of salvage therapy for those patients who were either unfit for or refused surgery. Oncological outcomes, tolerability, and feasibility of subsequent surgery for local treatment failure following CXB were reported. Material and methods: From 2009-2021, all patients treated with CXB as salvage therapy for local rectal cancer re-growth after watch-and-wait approach at our center were analyzed. Results: Contact X-ray brachytherapy as a salvage treatment (range, 90-110 Gy) was offered to 56 patients who experienced tumor re-growth following (chemo)radiation and watch-and-wait protocol. Median age was 76 (IQR = 66-83) years. Most patients (82%) had early-stage re-growth (ycT1/ycT2, ycN0), and 18% had more advanced stages (ycT3/ycT4, ycN0). After a median of 37-month follow-up (IQR = 19-53), 48% of patients who had early-stage re-growth achieved a sustained complete remission after CXB compared with 20% of those who had more advanced tumor stages. Disease-free and overall survivals for the whole cohort were 69% and 100% at 1-year, 51% and 82% at 3-year, and 51% and 65% at 5-years. CXB effectively controlled local re-growth-related symptoms. Mild post-CXB side effects occurred in 18% of cases. All (100%) eight patients who developed further local relapse, and 29% of those who had residual disease post-CXB salvage were successfully managed with subsequent surgery. Conclusions: Contact X-ray brachytherapy offers a new treatment option for patients in this situation whose other therapy options are not suitable for or refused initial surgery. Early local tumor re-growth responded best with minimal treatment-related toxicity and excellent symptom control. Disease-free and overall survival rates were acceptable, and delaying surgical salvage for local re-growth did not compromise patients' eventual long-term outcomes.

Intracranial Efficacy of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel in Real-World Patients with Non-Small-Cell Lung Cancer and EGFR or ALK Alterations.

Contrary to Pemetrexed-containing chemo-immunotherapy studies, Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel (ABCP) treatment has consistently shown clinical benefit in prospective studies in patients with lung cancer and actionable mutations, where intracranial metastases are common. Here, we aimed to describe the real-life population of patients fit to receive ABCP after targeted therapy and quantify its clinical effect in patients with brain metastases. Patients treated in Cheshire and Merseyside between 2019 and 2022 were identified. Data were collected retrospectively. A total of 34 patients with actionable EGFR or ALK alterations had treatment with a median age of 59 years (range 32-77). The disease control rate was 100% in patients with PDL1 ≥ 1% (n = 10). In total, 19 patients (56%) had brain metastases before starting ABCP, 17 (50%) had untreated CNS disease, and 4 (22%) had PDL1 ≥ 1%. The median time to symptom improvement was 12.5 days (range 4-21 days), with 74% intracranial disease control rates and 89.5% synchronous intracranial (IC) and extracranial (EC) responses. IC median Progression Free Survival (mPFS) was 6.48 months, EC mPFS was 10.75 months, and median Overall Survival 11.47 months. ABCP in real-life patients with brain metastases (treated or untreated) was feasible and showed similar efficacy to that described in patients without actionable mutations treated with upfront chemo-immunotherapy.

Analytical and Functional Similarity of Aflibercept Biosimilar ABP 938 with Aflibercept Reference Product.

INTRODUCTION: ABP 938 is being developed as a biosimilar candidate to aflibercept reference product (RP), a biologic used for certain angiogenic eye disorders. This study was designed to provide a comparative analytical assessment of the structural and functional attributes of ABP 938 and aflibercept RP sourced from the United States (US) and the European Union (EU). METHODS: Structural and functional characterization studies were performed using state-of-the-art analytical techniques that were appropriate to assess relevant quality attributes and capable of detecting qualitative and quantitative differences in primary structure, higher-order structure and biophysical properties, product-related substances and impurities, general properties, and biological activities. RESULTS: ABP 938 had the same amino acid sequence and exhibited similar secondary and tertiary structures, and biological activity as aflibercept RP. There were minor differences in a small number of biochemical attributes which are not expected to impact clinical performance. In addition, aflibercept RP sourced from the US and EU were analytically similar. CONCLUSIONS: ABP 938 was structurally and functionally similar to aflibercept RP. Since aflibercept RP sourced from the US and EU were analytically similar, this allows for the development of a scientific bridge such that a single-source RP can be used in nonclinical and clinical studies.

Eylea^® (aflibercept) is a biologic medication approved for the treatment of patients with certain eye diseases that can result in low vision or blindness. Biosimilars are biologic medications that are highly similar to an existing approved biologic medication, often called a reference product. Biosimilars have the potential to reduce medication costs despite having no clinically significant differences in quality, efficacy, and safety from their reference products. ABP 938 is currently being developed as a biosimilar to aflibercept reference product. We have conducted similarity studies to compare multiple batches of ABP 938 and aflibercept reference product sourced from both the United States and the European Union, using state-of-the-art analytical methods. The results demonstrated that ABP 938 had the same amino acid sequence and similar structural and biological activities as aflibercept reference product. Before biosimilars can be used as medicines, studies such as this one are required by the Food and Drug Administration and other regulatory authorities to ensure that biosimilars are as safe and effective as their reference products.

Family caregivers' emotional and communication needs in Canadian pediatric emergency departments.

OBJECTIVES: To describe the extent to which caregivers' emotional and communication needs were met during pediatric emergency department (PED) visits. Secondary objectives included describing the association of caregiver emotional needs, satisfaction with care, and comfort in caring for their child's illness at the time of discharge with demographic characteristics, caregiver experiences, and ED visit details. STUDY DESIGN: Electronic surveys with medical record review were deployed at ten Canadian PEDs from October 2018 -March 2020. A convenience sample of families with children <18 years presenting to a PED were enrolled, for one week every three months, for one year per site. Caregivers completed one in-PED survey and a follow-up survey, up to seven days post-visit. RESULTS: This study recruited 2005 caregivers who self-identified as mothers (74.3%, 1462/1969); mean age was 37.8 years (SD 7.7). 71.7% (1081/1507) of caregivers felt their emotional needs were met. 86.4% (1293/1496) identified communication with the doctor as good/very good and 83.4% (1249/1498) with their child's nurse. Caregiver involvement in their child's care was reported as good/very good 85.6% (1271/1485) of the time. 81.8% (1074/1313) of caregivers felt comfortable in caring for their child at home at the time of discharge. Lower caregiver anxiety scores, caregiver involvement in their child's care, satisfactory updates, and having questions adequately addressed positively impacted caregiver emotional needs and increased caregiver comfort in caring for their child's illness at home. CONCLUSION: Approximately 30% of caregivers presenting to PEDs have unmet emotional needs, over 15% had unmet communication needs, and 15% felt inadequately involved in their child's care. Family caregiver involvement in care and good communication from PED staff are key elements in improving overall patient experience and satisfaction.

Implementing Electronic Discharge Communication Tools in Pediatric Emergency Departments: Multicountry, Cross-Sectional Readiness Survey of Nurses and Physicians.

BACKGROUND: Pediatric emergency departments (ED) in many countries are implementing electronic tools such as kiosks, mobile apps, and electronic patient portals, to improve the effectiveness of discharge communication. OBJECTIVE: This study aimed to survey nurse and physician readiness to adopt these tools. METHODS: An electronic, cross-sectional survey was distributed to a convenience sample of currently practicing ED nurses and physicians affiliated with national pediatric research organizations in Canada, Australia, and New Zealand. Survey development was informed by the nonadoption, abandonment, scale-up, spread, sustainability framework. Measures of central tendency, and parametric and nonparametric tests were used to describe and compare nurse and physician responses. RESULTS: Out of the 270 participants, the majority were physicians (61%, 164/270), female (65%, 176/270), and had 5 or more years of ED experience (76%, 205/270). There were high levels of consensus related to the value proposition of electronic discharge communication tools (EDCTs) with 82% (221/270) of them agreeing that they help parents and patients with comprehension and recall. Lower levels of consensus were observed for organizational factors with only 37% (100/270) agreeing that their staff is equipped to handle challenges with communication technologies. Nurses and physicians showed significant differences on 3 out of 21 readiness factors. Compared to physicians, nurses were significantly more likely to report that EDs have a responsibility to integrate EDCTs as part of a modern system (P<.001) and that policies are in place to guide safe and secure electronic communication (P=.02). Physicians were more likely to agree that using an EDCT would change their routine tasks (P=.04). One third (33%, 89/270) of participants indicated that they use or have used EDCT. CONCLUSIONS: Despite low levels of uptake, both nurses and physicians in multiple countries view EDCTs as a valuable support to families visiting pediatric ED. Leadership for technology change, unclear impact on workflow, and disparities in digital literacy skills require focused research effort.

Effectiveness of face masks for reducing transmission of SARS-CoV-2: a rapid systematic review.

This rapid systematic review of evidence asks whether (i) wearing a face mask, (ii) one type of mask over another and (iii) mandatory mask policies can reduce the transmission of SARS-CoV-2 infection, either in community-based or healthcare settings. A search of studies published 1 January 2020-27 January 2023 yielded 5185 unique records. Due to a paucity of randomized controlled trials (RCTs), observational studies were included in the analysis. We analysed 35 studies in community settings (three RCTs and 32 observational) and 40 in healthcare settings (one RCT and 39 observational). Ninety-five per cent of studies included were conducted before highly transmissible Omicron variants emerged. Ninety-one per cent of observational studies were at 'critical' risk of bias (ROB) in at least one domain, often failing to separate the effects of masks from concurrent interventions. More studies found that masks (n = 39/47; 83%) and mask mandates (n = 16/18; 89%) reduced infection than found no effect (n = 8/65; 12%) or favoured controls (n = 1/65; 2%). Seven observational studies found that respirators were more protective than surgical masks, while five found no statistically significant difference between the two mask types. Despite the ROB, and allowing for uncertain and variable efficacy, we conclude that wearing masks, wearing higher quality masks (respirators), and mask mandates generally reduced SARS-CoV-2 transmission in these study populations. This article is part of the theme issue 'The effectiveness of non-pharmaceutical interventions on the COVID-19 pandemic: the evidence'.

Baseline Features and Reasons for Nonparticipation in the Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) Study, a Colorectal Cancer Screening Trial.

Importance: The Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) randomized clinical trial sought to recruit 50 000 adults into a study comparing colorectal cancer (CRC) mortality outcomes after randomization to either an annual fecal immunochemical test (FIT) or colonoscopy. Objective: To (1) describe study participant characteristics and (2) examine who declined participation because of a preference for colonoscopy or stool testing (ie, fecal occult blood test [FOBT]/FIT) and assess that preference's association with geographic and temporal factors. Design, Setting, and Participants: This cross-sectional study within CONFIRM, which completed enrollment through 46 Department of Veterans Affairs medical centers between May 22, 2012, and December 1, 2017, with follow-up planned through 2028, comprised veterans aged 50 to 75 years with an average CRC risk and due for screening. Data were analyzed between March 7 and December 5, 2022. Exposure: Case report forms were used to capture enrolled participant data and reasons for declining participation among otherwise eligible individuals. Main Outcomes and Measures: Descriptive statistics were used to characterize the cohort overall and by intervention. Among individuals declining participation, logistic regression was used to compare preference for FOBT/FIT or colonoscopy by recruitment region and year. Results: A total of 50 126 participants were recruited (mean [SD] age, 59.1 [6.9] years; 46 618 [93.0%] male and 3508 [7.0%] female). The cohort was racially and ethnically diverse, with 748 (1.5%) identifying as Asian, 12 021 (24.0%) as Black, 415 (0.8%) as Native American or Alaska Native, 34 629 (69.1%) as White, and 1877 (3.7%) as other race, including multiracial; and 5734 (11.4%) as having Hispanic ethnicity. Of the 11 109 eligible individuals who declined participation (18.0%), 4824 (43.4%) declined due to a stated preference for a specific screening test, with FOBT/FIT being the most preferred method (2820 [58.5%]) vs colonoscopy (1958 [40.6%]; P < .001) or other screening tests (46 [1.0%] P < .001). Preference for FOBT/FIT was strongest in the West (963 of 1472 [65.4%]) and modest elsewhere, ranging from 199 of 371 (53.6%) in the Northeast to 884 of 1543 (57.3%) in the Midwest (P = .001). Adjusting for region, the preference for FOBT/FIT increased by 19% per recruitment year (odds ratio, 1.19; 95% CI, 1.14-1.25). Conclusions and Relevance: In this cross-sectional analysis of veterans choosing nonenrollment in the CONFIRM study, those who declined participation more often preferred FOBT or FIT over colonoscopy. This preference increased over time and was strongest in the western US and may provide insight into trends in CRC screening preferences.

Clinical Outcomes of Tivozanib Monotherapy as First-Line Treatment for Metastatic Renal Cell Carcinoma: A Multicentric UK Real-World Analysis.

BACKGROUND: Tivozanib is a licensed as first-line treatment for metastatic renal cell carcinoma (mRCC). OBJECTIVE: To evaluate the outcomes from tivozanib in a real-world mRCC population. PATIENTS AND METHODS: Patients with mRCC commencing first-line tivozanib between March 2017 and May 2019 were identified across four specialist cancer centres in the UK. Data relating to response, overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were collected retrospectively with censoring on 31 December 2020. RESULTS: A total of 113 patients were identified: median age was 69 years; 78% had ECOG PS 0-1; 82% had clear cell histology; 66% had previous nephrectomy; International Metastatic RCC Database Consortium (IMDC) score was 22% favourable (F), 52% intermediate (I) and 26% poor (P). Twenty-six per cent were switched from another tyrosine kinase inhibitor (TKI) to tivozanib due to toxicity. Median follow-up was 26.6 months with 18% remaining on treatment at data censoring. Median PFS was 8.75 months. Median PFS by IMDC risk group was: F = 23.0 months; I = 10.0 months; P = 3.0 months, p value < 0.0001. Median OS was 25.0 months (F = not reached (NR) with 72% alive at data cut-off; I = 26.0 months; P = 7.0 months, p value < 0.0001). Seventy-seven per cent had an AE of any grade, and 13% had a grade ≥ 3 AE. Eighteen per cent of patients discontinued treatment due to toxicity. No patients who discontinued a prior TKI due to AEs stopped tivozanib due to AEs. CONCLUSIONS: These data suggest comparable activity of tivozanib with the pivotal trial data and other TKIs in a real-world population. Its tolerability positions tivozanib as an attractive first-line option for those unsuitable for combination therapies or unable to tolerate other TKIs.

A tile model of circuit topology for self-entangled biopolymers.

Building on the theory of circuit topology for intra-chain contacts in entangled proteins, we introduce tiles as a way to rigorously model local entanglements which are held in place by molecular forces. We develop operations that combine tiles so that entangled chains can be represented by algebraic expressions. Then we use our model to show that the only knot types that such entangled chains can have are [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] and connected sums of these knots. This includes all proteins knots that have thus far been identified.

Cat Eye Syndrome with a Unique Liver and Dermatological Presentation.

Cat eye syndrome (CES), also known as Schmid-Fraccaro syndrome, is a complex genetic syndrome with a highly variable phenotype that includes ocular coloboma, anal atresia, preauricular skin tags and pits, heart defects, kidney malformations, dysmorphic facial features, and mild to moderate intellectual disability. We describe a case of a 23-year-old male with a past medical history of CES with short stature, mild learning disability, and some dysmorphic facial features who presented with recurrent pruritus and rashes and had mild liver dysfunction. Furthermore, the patient did not have the classic presentation of CES but a clinically milder expression of the phenotypes. Abnormalities in the abdominal ultrasound prompted an ultrasound-guided liver biopsy, which showed bile ductular proliferation with mild portal inflammation composed of lymphocytes and plasma cells, and bridging fibrosis. The patient's labs showed elevated immunoglobulins with the highest increase observed in IgG, along with negative antinuclear antibodies (ANA), negative anti-mitochondrial antibody, and negative hepatitis A/B/C but a weak positive anti-smooth muscle antibody (ASMA). These findings indicated that the patient most likely had autoimmune hepatitis (AIH) or an overlap syndrome with primary sclerosing cholangitis (PSC). The patient was initially treated with steroids and antihistamines for pruritus, which led to some clinical improvement. After dermatological evaluation, the patient was diagnosed with atopic dermatitis and was recently started on a dupilumab 600 mg loading dose and would continue with biweekly dupilumab 300 mg injections. This dermatological finding may require additional examination and can be a unique presentation in patients with CES. This case illustrates that even patients with milder CES expression can experience intense dermatological complications if not effectively managed. CES is a multifactorial disease that requires intervention from multiple specialists. Therefore, primary care physicians must be aware of the potential complications of CES and make adequate referrals to closely monitor patients' symptoms.

The Delivery of Palliative and End-of-Life Care to Adolescents and Young Adults Living with Cancer: A Scoping Review.

The primary purpose of this scoping review was to provide an overview of the existing evidence on the delivery of palliative and end-of-life care to adolescents and young adults (AYAs) living with cancer, by identifying knowledge gaps and discussing the key characteristics and types of evidence in this field. This study employed a JBI scoping review design. CINAHL (EBSCO), Embase (Elsevier), MEDLINE (Ovid), APA PsycINFO (EBSCO), and Web of Science (Science Citation Index Expanded and Social Sciences Citation Index; Clarivate Analytics) databases were searched along with grey literature sources to February 2022 for related studies on the delivery of palliative and end-of-life care to AYAs. No search restrictions were applied. Two independent reviewers screened titles, abstracts, and full-text articles for eligibility, and they extracted data from studies that met the inclusion criteria. A total of 29,394 records were identified through our search strategy and 51 studies met the inclusion criteria of the study. The studies were published between 2004 and 2022, with the majority from North America (65%). The included studies involved patient, healthcare provider, caregiver, and public stakeholders. Their primary foci were often on end-of-life outcomes (41%) and/or advance care planning/end-of-life priorities and decision-making (35%). This review identified several evidence gaps within the field, including a focus primarily on patients who have died. Findings highlight the need for more collaborative research with AYAs on their experiences with palliative and end-of-life care, as well as their involvement as patient partners in research.

Palliative care clinical nurse specialists leading enhanced supportive care in hepatopancreatobiliary cancer.

BACKGROUND: Integration of care between palliative care and oncology can improve patient outcomes and is increasingly recommended. Enhanced supportive care (ESC), led and delivered by palliative care clinical nurse specialists, is a potential model to achieve this but evidence about it is lacking. AIM: This research aimed to evaluate a nurse-led integrated ESC model within hepatopancreatobiliary cancer care. METHOD: Some 101 patients with hepatopancreatobiliary cancer were supported by integrated ESC delivered in a co-located clinic. Data on symptoms and quality of life were collected prospectively. Survival data and chemotherapy use were retrospectively analysed following minimum follow-up, using a matched control technique. RESULTS: Patients receiving ESC exhibited less severe symptoms and better mood over time. They also had less aggressive treatment towards the end of life, receiving 31% less chemotherapy than controls with comparable survival. CONCLUSION: An integrated, nurse-led ESC model can be effective in improving outcomes for patients with hepatopancreatobiliary cancer.

An Unusual Case of Primary Gastric Balloon Cell Melanoma.

Most cases of melanoma found in the gastrointestinal tract are the result of metastasis. Although uncommon and only described in isolated case reports, primary gastric melanoma should be considered when patients present with vague gastrointestinal symptoms and a mass is identified on esophagogastroduodenoscopy or imaging. We describe a case of primary gastric balloon cell melanoma in a 73-year-old man who presented with melena. Given the high morbidity and mortality of gastric mucosal melanoma, early diagnosis and initiation of treatment can lead to improved outcomes and survival.

Children, young people and parent engagement in health intervention design and implementation: A scoping review.

INTRODUCTION: Engaging children and young people (CYP) with and without their parents in health research has the potential to improve the development and implementation of health interventions. However, to our knowledge, the scope of engagement activities used with this population and barriers to their engagement is unknown. The objective of this review was to identify and describe CYP engagement with and without their parents in the development and/or implementation of health interventions. METHODS: This scoping review included any primary research studies reporting on engaging CYP, with or without parents, in the design and/or implementation of health interventions. Healthcare professionals had to be involved over the course of the study and the study had to take place in either community, primary or tertiary care settings. The following databases were searched in May 2017, May 2020 and June 2021: Medline (OVID), CINAHL (EBSCO) and Embase (Elsevier). Two independent reviewers screened titles, abstracts and full-text articles and used a previously piloted extraction form to extract and summarize information from the included articles. RESULTS: Twenty-eight articles discussing twenty-four studies were included. CYP engagement throughout the research cycle was limited. There were no observed differences in the reported presence of engagement, types of interventions or outcomes of engagement between studies engaging CYP or CYP and parents. Studies engaging CYP and parents contained limited information on how these relationships affected outcomes of engagement. Engagement was enabled primarily by the maintenance of resources and relationships among stakeholders. CONCLUSIONS: Although CYP engagement often influenced health intervention and implementation design, they are inconsistently engaged across the research cycle. It is unclear whether parental involvement enhances CYP engagement. Future research should consider reporting guidelines to clarify the level of CYP and/or parent engagement, and enhance CYP engagement by fostering synergistic and sustainable partnerships with key stakeholders. PATIENT OR PUBLIC CONTRIBUTION: A parent partner with codesign experience contributed to the creation of the research questions, screened titles, abstracts and full texts, helped with data extraction and provided feedback on the manuscript.

Neoadjuvant Trastuzumab and Pertuzumab for Early HER2-Positive Breast Cancer: A Real World Experience.

Background: Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete response (pCR) rates of 39 to 61%. This study aimed to determine the real-world efficacy and toxicity of NA trastuzumab and pertuzumab combined with chemotherapy in a UK tertiary referral cancer centre. Methods: HER2-positive early BC patients given neoadjuvant chemotherapy with trastuzumab and pertuzumab between October 2016 and February 2018 at our tertiary referral cancer centre were identified via pharmacy records. Clinico-pathological information, treatment regimens, treatment-emergent toxicities, operative details, and pathological responses and outcomes were recorded. Results: 78 female patients were identified; 2 had bilateral diseases and 48 of 78 (62%) were node positive at presentation. 55 of 80 (71%) tumours were ER-positive. PCR occurred in 37 of 78 (46.3%; 95% CI: 35.3-57.2%) patients. 14 of 23 (60.8%) patients with ER-negative tumours achieved pCR; 23 of 55 (41.8%) were ER-positive and 6 of 19 (31.6%) were ER-positive and PgR-positive. No cardiac toxicity was documented. Diarrhoea occurred in 53 of 72 (74%) patients. Grade 3-4 toxicity occurred in ≥2% patients. These were diarrhoea, fatigue, and infection. The Median follow up period was 45.2 months (95% CI 43.8-46.3) with 71 of 78 (91.0%) remaining disease-free and 72 of 78 (92.3%) alive. Estimated OS at 2 years 86% (95% CI: 75-99%). Conclusion: This data confirms the efficacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy. While no cardiac toxicity was observed, diarrhoea occurred frequently. The low pCR rate observed in ER and PgR-positive BCs warrants further investigation and consideration of strategies to increase the pCR rate.

Strategies to adapt and implement health system guidelines and recommendations: a scoping review.

BACKGROUND: Evidence-based health system guidelines are pivotal tools to help outline the important financial, policy and service components recommended to achieve a sustainable and resilient health system. However, not all guidelines are readily translatable into practice and/or policy without effective and tailored implementation and adaptation techniques. This scoping review mapped the evidence related to the adaptation and implementation of health system guidelines in low- and middle-income countries. METHODS: We conducted a scoping review following the Joanna Briggs Institute methodology for scoping reviews. A search strategy was implemented in MEDLINE (Ovid), Embase, CINAHL, LILACS (VHL Regional Portal), and Web of Science databases in late August 2020. We also searched sources of grey literature and reference lists of potentially relevant reviews. All findings were reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. RESULTS: A total of 41 studies were included in the final set of papers. Common strategies were identified for adapting and implementing health system guidelines, related barriers and enablers, and indicators of success. The most common types of implementation strategies included education, clinical supervision, training and the formation of advisory groups. A paucity of reported information was also identified related to adaptation initiatives. Barriers to and enablers of implementation and adaptation were reported across studies, including the need for financial sustainability. Common approaches to evaluation were identified and included outcomes of interest at both the patient and health system level. CONCLUSIONS: The findings from this review suggest several themes in the literature and identify a need for future research to strengthen the evidence base for improving the implementation and adaptation of health system guidelines in low- and middle-income countries. The findings can serve as a future resource for researchers seeking to evaluate implementation and adaptation of health system guidelines. Our findings also suggest that more effort may be required across research, policy and practice sectors to support the adaptation and implementation of health system guidelines to local contexts and health system arrangements in low- and middle-income countries.

RCAN1 knockout and overexpression recapitulate an ensemble of rest-activity and circadian disruptions characteristic of Down syndrome, Alzheimer's disease, and normative aging.

BACKGROUND: Regulator of calcineurin 1 (RCAN1) is overexpressed in Down syndrome (DS), but RCAN1 levels are also increased in Alzheimer's disease (AD) and normal aging. AD is highly comorbid among individuals with DS and is characterized in part by progressive neurodegeneration that resembles accelerated aging. Importantly, abnormal RCAN1 levels have been demonstrated to promote memory deficits and pathophysiology that appear symptomatic of DS, AD, and aging. Anomalous diurnal rest-activity patterns and circadian rhythm disruptions are also common in DS, AD, and aging and have been implicated in facilitating age-related cognitive decline and AD progression. However, no prior studies have assessed whether RCAN1 dysregulation may also promote the age-associated alteration of rest-activity profiles and circadian rhythms, which could in turn contribute to neurodegeneration in DS, AD, and aging. METHODS: The present study examined the impacts of RCAN1 deficiency and overexpression on the photic entrainment, circadian periodicity, intensity and distribution, diurnal patterning, and circadian rhythmicity of wheel running in young (3-6 months old) and aged (9-14 months old) mice of both sexes. RESULTS: We found that daily RCAN1 levels in the hippocampus and suprachiasmatic nucleus (SCN) of light-entrained young mice are generally constant and that balanced RCAN1 expression is necessary for normal circadian locomotor activity rhythms. While the light-entrained diurnal period was unaltered, RCAN1-null and RCAN1-overexpressing mice displayed lengthened endogenous (free-running) circadian periods like mouse models of AD and aging. In light-entrained young mice, RCAN1 deficiency and overexpression also recapitulated the general hypoactivity, diurnal rest-wake pattern fragmentation, and attenuated amplitudes of circadian activity rhythms reported in DS, preclinical and clinical AD, healthily aging individuals, and rodent models thereof. Under constant darkness, RCAN1-null and RCAN1-overexpressing mice displayed altered locomotor behavior indicating circadian clock dysfunction. Using the Dp(16)1Yey/+ (Dp16) mouse model for DS, which expresses three copies of Rcan1, we found reduced wheel running activity and rhythmicity in both light-entrained and free-running young Dp16 mice like young RCAN1-overexpressing mice. Critically, these diurnal and circadian deficits were rescued in part or entirely by restoring Rcan1 to two copies in Dp16 mice. We also found that RCAN1 deficiency but not RCAN1 overexpression altered protein levels of the clock gene Bmal1 in the SCN. CONCLUSIONS: Collectively, this study's findings suggest that both loss and aberrant gain of RCAN1 precipitate anomalous light-entrained diurnal and circadian activity patterns emblematic of DS, AD, and possibly aging.