Phallus preservation and reconstruction: 5-year outcomes of national penile cancer centralisation in the Republic of Ireland.

INTRODUCTION: Penile cancer is a rare urological malignancy with an age-standardised incidence of 0.8 per 100,000 person-years [1]. Given this low incidence it has been suggested that centralised care may improve patient outcomes in relation to phallus sparing surgery and nodal assessment [2]. We aim to assess the outcomes after 5-years of national centralisation of penile cancer care. METHODS: A retrospective analysis of prospectively collected data was performed. All patients undergoing penile cancer surgery from January 2018 to December 2022 following centralisation of care were included. The primary outcome was proportion of phallus sparing procedures performed. Secondary outcomes were patient characteristics, histologic outcomes and procedures performed. RESULTS: 124 patients underwent surgery in the study period. Mean age was 64.49 (±13.87). Overall, 82.3% of patients underwent phallus sparing surgery. This remained stable over the 5-year period from 2018 to 2022 â€‹at 92%, 85%, 76%, 79% and 78% respectively (p â€‹= â€‹0.534). 62.7% had reconstruction performed, including split-thickness skin graft neoglans formation, (57.8% [n â€‹= â€‹37]), preputial flap (32.8% [n â€‹= â€‹21]), glans resurfacing (4.7% [n â€‹= â€‹3]), shaft advancement flap (1.6% [n â€‹= â€‹1]), penile shaft skin graft (1.6% [n â€‹= â€‹1]), and partial penectomy with urethral centralisation (1.6% [n â€‹= â€‹1]). Phallus preservation was not affected by positive nodal status (OR 0.75 [95% CI 0.249-2.266], p â€‹= â€‹0.564) or T-stage ≥1b (OR 0.51 [95% CI 0.153-1.711], p â€‹= â€‹0.276). There has been a significant reduction in Nx nodal status from 64% in 2017 to 15% in 2021 (p â€‹= â€‹0.009). CONCLUSION: Centralisation of treatment for rare malignancies such as penile cancer may improve oncologic outcomes and rates of phallus preservation. This study has shown centralisation to has a high rate of phallus preservation. Further long-term analysis of outcomes in Ireland is required.

Colorectal cancer survivorship care plans: Variations in documentation and posttreatment surveillance recommendations.

BACKGROUND: Survivorship care plans (SCP) should outline pertinent information about cancer treatment and follow-up. METHODS: We descriptively analyzed the content of 74 colorectal cancer SCPs completed as part of a randomized, controlled trial of SCPs at an academic and community cancer center. Surveillance recommendations were compared with American Cancer Society, American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines. RESULTS: SCP information provided in >80% of the plans included participant age, cancer diagnosis, details, and side-effects of treatment (surgery, chemotherapy, radiation) and health promotion recommendations. SCP content documented less frequently included predisposing conditions, genetic counseling/testing information and staging. Posttreatment surveillance recommendations were documented in >90% SCPs. For stage 2-3 cancer, rates of guideline concordant recommendations were 100% for colonoscopy surveillance (Year 1 only), 87% for imaging surveillance, 65% for carcinoembryonic antigen surveillance, and 33% for follow-up visits. Excluding colonoscopy, >15 unique recommendations were listed for each modality across stages and sites, with more variation at the academic site. CONCLUSIONS: SCPs consistently recorded information about cancer diagnosis and treatment but omitted critical information about cancer-specific details denoting risk. Surveillance recommendations varied considerably between cancer centers. Future work to improve the consistency of surveillance recommendations documented in SCPs may be needed.

Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.

BACKGROUND: Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. METHODS: In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed. FINDINGS: Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6-21·3). 38 (35·5% [95% CI 26·5-45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. INTERPRETATION: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. FUNDING: Incyte Corporation.

Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)-a small-molecule targeted inhibitor of mutated IDH1-in patients with previously treated IDH1-mutant cholangiocarcinoma. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. FINDINGS: Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8-10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6-4·2] vs 1·4 months [1·4-1·6]; hazard ratio 0·37; 95% CI 0·25-0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. INTERPRETATION: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. FUNDING: Agios Pharmaceuticals.

Readmission Adversely Affects Survival in Surgical Rectal Cancer Patients.

BACKGROUND: Readmission has received attention as a potential healthcare quality metric. No studies have investigated the relationship between readmission and survival in patients undergoing rectal cancer surgery. The aims of this study were to identify factors associated with 30-day readmission after rectal cancer surgery and to determine the impact of readmission on overall survival (OS). METHODS: Patients who underwent surgical treatment for rectal/rectosigmoid adenocarcinoma stages I-IV were identified using the National Cancer Database (2004-2014). Multivariable logistic regression was used to identify factors for readmission. 2:1 nearest neighbor caliper matching without replacement was used to ensure similarity of patients being compared. Survival analyses were performed using Kaplan-Meier method along with log-rank test and Cox proportional hazards model. RESULTS: Of 110,167 patients, 7045 (6.39%) were readmitted. Factors associated with readmission included higher Charlson comorbidity score, non-private or no insurance, procedure type, hospitals in the Northeast, South, and Midwest regions, and prolonged length of stay. Within the matched cohort (13,756 non-readmitted and 6878 readmitted), readmitted patients had worse 5- and 10-year OS regardless of cancer stage (p < 0.001) and procedure type. Five- and 10-year OS were 58.98% and 41.01% for readmitted patients, 64.96% and 43.50% for non-readmitted patients. Readmitted patients had shorter OS by 13.14 months and increased risk of mortality (HR 1.20, 95% CI 1.15-1.25, p < 0.001). CONCLUSIONS: Thirty-day readmission after rectal cancer surgery is associated with decreased OS. Efforts to reduce readmissions should be considered to advance cancer care and enhance the potential for improved patient survival.

Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma.

OBJECTIVE: Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastro-oesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival. DESIGN: Thirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein-Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour-stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density. RESULTS: 12% of resections showed tumour cell membranous PD-L1 expression and 44% showed expression within the immune stroma. Two cases (6%) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (>500/mm2) were associated with worse progression-free survival (PFS) and overall survival (OS). CONCLUSIONS: PD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immune-based therapy.

The use of vascularised bone capping to prevent and treat amputation stump spiking in the paediatric population.

BACKGROUND: Overgrowth of the stump skeleton is a major complication seen in children after an amputation. In advanced cases, perforation of the bone spike through the skin can occur. Many surgical treatments have been employed to treat and prevent this, with best results seen when non-vascularised osteo-chondral bone grafts are placed to try to mimic a trans-articular amputation. We reviewed our outcomes using vascularized bone flaps to prevent and treat spiking. PATIENTS AND METHODS: Between 2000 and 2016 we carried out six vascularised osteo-cartilaginous bone capping procedures. Five patients underwent the procedure as an adjunct to primary amputation and in a single patient it was used to treat established bone spiking. Trauma accounted for three cases, with the other three being tumour, vascular malformation and ischemia. Three patients had pedicled bone flaps placed on the amputation stump and three underwent free tissue transfer (free calcaneus, free scapular angle, and free proximal tibia). Five cases involved lower limb amputations, with one in the upper limb. RESULTS: One patient had an early post-operative complication in the form of partial skin flap necrosis that required debridement and skin grafting. All bone flaps survived. Mean follow-up was 6.5 years. All patients had bony union with no development of stump spiking. Two patients required further procedures unrelated to the bone flaps. CONCLUSION: Vascularised bone flaps to cap amputation stumps may be a safe and effective method of preventing and treating long-bone stump spiking following amputation in children.

Mismatch Repair Deficiency and Response to Immune Checkpoint Blockade.

: More than 1.6 million new cases of cancer will be diagnosed in the U.S. in 2016, resulting in more than 500,000 deaths. Although chemotherapy has been the mainstay of treatment in advanced cancers, immunotherapy development, particularly with PD-1 inhibitors, has changed the face of treatment for a number of tumor types. One example is the subset of tumors characterized by mismatch repair deficiency and microsatellite instability that are highly sensitive to PD-1 blockade. Hereditary forms of cancer have been noted for more than a century, but the molecular changes underlying mismatch repair-deficient tumors and subsequent microsatellite unstable tumors was not known until the early 1990s. In this review article, we discuss the history and pathophysiology of mismatch repair, the process of testing for mismatch repair deficiency and microsatellite instability, and the role of immunotherapy in this subset of cancers. IMPLICATIONS FOR PRACTICE: Mismatch repair deficiency has contributed to our understanding of carcinogenesis for the past 2 decades and now identifies a subgroup of traditionally chemotherapy-insensitive solid tumors as sensitive to PD-1 blockade. This article seeks to educate oncologists regarding the nature of mismatch repair deficiency, its impact in multiple tumor types, and its implications for predicting the responsiveness of solid tumors to immune checkpoint blockade.

A Prevalence and Management Study of Acute Pain in Children Attending Emergency Departments by Ambulance.

Pain is the most common symptom in the emergency setting and remains one of the most challenging problems for emergency care providers, particularly in the pediatric population. The primary objective of this study was to determine the prevalence of acute pain in children attending emergency departments (EDs) in Ireland by ambulance. In addition, this study sought to describe the prehospital and initial ED management of pain in this population, with specific reference to etiology of pain, frequency of pain assessment, pain severity, and pharmacological analgesic interventions. A prospective cross-sectional study was undertaken over a 12-month period of all pediatric patients transported by emergency ambulance to four tertiary referral hospitals in Ireland. All children (<16 years) who had pain as a symptom (regardless of cause) at any stage during the prehospital phase of care were included in this study. Over the study period, 6,371 children attended the four EDs by emergency ambulance, of which 2,635 (41.4%, 95% confidence interval 40.2-42.3%) had pain as a documented symptom on the ambulance patient care report (PCR) form. Overall 32% (n = 856) of children who complained of pain were subject to a formal pain assessment during the prehospital phase of care. Younger age, short transfer time to the ED, and emergency calls between midnight and 6 am were independently associated with decreased likelihood of having a documented assessment of pain intensity during the prehospital phase of care. Of the 2,635 children who had documented pain on the ambulance PCR, 26% (n = 689) received some form of analgesic agent prior to ED arrival. Upon ED arrival 54% (n = 1,422) of children had a documented pain assessment and some form of analgesic agent was administered to 50% (n = 1,324). Approximately 41% of children who attend EDs in Ireland by ambulance have pain documented as their primary symptom. This study suggests that the management of acute pain in children transferred by ambulance to the ED in Ireland is currently poor, with documentary evidence of only 26% receiving prehospital analgesic agents.

Development of key performance indicators for prehospital emergency care.

INTRODUCTION: Key performance indicators (KPIs) are used to monitor and evaluate critical areas of clinical and support functions that influence patient outcome. Traditional prehospital emergency care performance monitoring has focused solely on response time metrics. The landscape of emergency care delivery in Ireland is in the process of significant national reconfiguration. The development of KPIs is therefore considered one of the key priorities in prehospital research. AIMS: The aim of this study was to develop a suite of KPIs for prehospital emergency care in Ireland. METHODS: A systematic literature review of prehospital care performance measurement was undertaken followed by a three-round Delphi consensus process facilitated by a broad-based multidisciplinary group of panellists. The consensus process was conducted between June 2012 and October 2013. Each candidate indicator on the Delphi survey questionnaire was rated using a 5-point Likert-type rating scale. Agreement was defined as at least 70% of responders rating an indicator as 'agree' or 'strongly agree' on the rating scale. Data were analysed using descriptive statistics. Sensitivity of the ratings was examined for robustness by bootstrapping the original sample. RESULTS: Of the 78 citations identified by the systematic review, 5 relevant publications were used to select candidate indicators for the Delphi round 1 questionnaire. Response rates in Delphi rounds 1 and 2 were 89% and 83%, respectively. Following the consensus development conference, 101 KPIs reached consensus. Based on the Donabedian framework for quality-of-care indicators, 7 of the KPIs which reached agreement were structure KPIs, 74 were process KPIs and 20 were outcome KPIs. The highest ranked indicator was a process KPI ('Direct transport of ST-elevation myocardial infarction patients to a primary percutaneous intervention (PCI)-capable facility for ECG to PCI time <90 min'). CONCLUSION: Improving the quality of prehospital care requires the development and implementation of performance measurement using scientifically valid and reliable KPIs. Employing a Delphi panel of key multidisciplinary Emergency Medical Service stakeholders, it was feasible to develop a suite of 101 KPIs for performance monitoring of prehospital emergency care in Ireland. This suite of KPIs may contribute to a framework for achieving safer, better care in the prehospital environment.

Immunotherapy in upper GI malignancies.

OPINION STATEMENT: A comprehensive analysis of the interactions that can occur amongst three complex systems-the tumor cell, tissue microenvironment, and the immune response, is required if we are to realize the potential of immunotherapeutics in gastroesophageal cancer. For many years, epithelial cancers were believed to originate due to the transformation of tissue stem cells. Recently however, it has suggested that bone marrow-derived cells (BMDCs), which are frequently recruited to sites of tissue injury and inflammation, might also represent a potential source of malignancy. The link between infection, chronic inflammation, and cancer has long been recognized in gastric cancer with its close association with Helicobacter pylori as a class I carcinogen. The long-term consequences of recruiting pluripotent cells to areas of chronic inflammation which can result in altered cell signaling and differentiation needs to be defined, but this work provides a fascinating insight into the pivotal role played by the immune system in the development of upper GI tumors. Here, we discuss many of the immunotherapeutic strategies that have been assessed in gastroesophageal cancer in the last two decades. At the time of writing, the use of checkpoint inhibitors represents the most exciting approach and displays the greatest potential for widespread adoption in the clinic. Preliminary data suggest that programmed death ligand-1 (PD-L1) expression ranges from approximately 18 to 42% in gastroesophageal cancer. Phase II and phase III clinical trials involving either single agent PD-1/PD-L1 inhibition or combined with CTLA-4 inhibitors are currently enrolling, and it is expected that checkpoint inhibition will become a new standard of care in the management of advanced disease in the near future.

Intranasal fentanyl for the management of acute pain in children.

BACKGROUND: Pain is the most common symptom in the emergency setting; however, timely management of acute pain in children continues to be suboptimal. Intranasal drug delivery has emerged as an alternative method of achieving quicker drug delivery without adding to the distress of a child by inserting an intravenous cannula. OBJECTIVES: We identified and evaluated all randomized controlled trials (RCTs) and quasi-randomized trials to assess the effects of intranasal fentanyl (INF) versus alternative analgesic interventions in children with acute pain, with respect to reduction in pain score, occurrence of adverse events, patient tolerability, use of "rescue analgesia," patient/parental satisfaction and patient mortality. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 1); MEDLINE (Ovid SP, from 1995 to January 2014); EMBASE (Ovid SP, from 1995 to January 2014); the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO Host, from 1995 to January 2014); the Latin American and Caribbean Health Science Information Database (LILACS) (BIREME, from 1995 to January 2014); Commonwealth Agricultural Bureaux (CAB) Abstracts (from 1995 to January 2014); the Institute for Scientific Information (ISI) Web of Science (from 1995 to January 2014); BIOSIS Previews (from 1995 to January 2014); the China National Knowledge Infrastructure (CNKI) (from 1995 to January 2014); International Standard Randomized Controlled Trial Number (ISRCTN) (from 1995 to January 2014); ClinicalTrials.gov (from 1995 to January 2014); and the International Clinical Trials Registry Platform (ICTRP) (to January 2014). SELECTION CRITERIA: We included RCTs comparing INF versus any other pharmacological/non-pharmacological intervention for the treatment of children in acute pain (aged < 18 years). DATA COLLECTION AND ANALYSIS: Two independent review authors assessed each title and abstract for relevance. Full copies of all studies that met the inclusion criteria were retrieved for further assessment. Mean difference (MD), odds ratio (OR) and 95% confidence interval (CI) were used to measure effect sizes. Two review authors independently assessed and rated the methodological quality of each trial using the tool of The Cochrane Collaboration to assess risk of bias, as per Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: Three studies (313 participants) met the inclusion criteria. One study compared INF versus intramuscular morphine (IMM); another study compared INF versus intravenous morphine (IVM); and another study compared standard concentration INF (SINF) versus high concentration INF (HINF). All three studies reported a reduction in pain score following INF administration. INF produced a greater reduction in pain score at 10 minutes post administration when compared with IMM (INF group pain score: 1/5 vs IMM group pain score: 2/5; P value 0.014). No other statistically significant differences in pain scores were reported at any other time point. When INF was compared with IVM and HINF, no statistically significant differences in pain scores were noted between treatment arms, before analgesia or at 5, 10, 20 and 30 minutes post analgesia. Specifically, when INF was compared with IVM, both agents were seen to produce a statistically significant reduction in pain score up to 20 minutes post analgesia. No further reduction in pain score was noted after this time. When SINF was compared with HINF, a statistically and clinically significant reduction in pain scores over study time was observed (median decrease for both groups 40 mm, P value 0.000). No adverse events (e.g. opiate toxicity, death) were reported in any study following INF administration. One study described better patient tolerance to INF compared with IMM, which achieved statistical significance. The other studies described reports of a "bad taste" and vomiting with INF. Overall the risk of bias in all studies was considered low. AUTHORS' CONCLUSIONS: INF may be an effective analgesic for the treatment of patients with acute moderate to severe pain, and its administration appears to cause minimal distress to children. However, this review of published studies does not allow any definitive conclusions regarding whether INF is superior, non-inferior or equivalent to intramuscular or intravenous morphine. Limitations of this review include the following: few eligible studies for inclusion (three); no study examined the use of INF in children younger than three years of age; no study included children with pain from a "medical" cause (e.g. abdominal pain seen in appendicitis); and all eligible studies were conducted in Australia. Consequently, the findings may not be generalizable to other healthcare settings, to children younger than three years of age and to those with pain from a "medical" cause.

A qualitative study of the barriers to prehospital management of acute pain in children.

INTRODUCTION: Effective pain management in the prehospital setting is gaining momentum as a potential key performance indicator by many emergency medical service systems, but historically has been shown to be inadequate, particularly in the paediatric population. This study aimed to identify the barriers, as perceived by a national cohort of advanced paramedics (APs), to achieving optimal prehospital management of acute pain in children. METHODS: A qualitative approach was employed to capture data through two focus group interviews. Sixteen APs were invited to participate in this study. Both focus groups were audio recorded, transcribed and analysed using Attride-Stirling's framework for thematic network analysis. RESULTS: The global theme 'Understanding Barriers to the Prehospital Management of Acute Pain in Children' emerged from three organising themes as follows: AP education and training; current clinical practice guidelines for paediatric pain management; realities of prehospital practice. Limited exposure to children in the prehospital setting, difficulty assessing pain intensity in small children, and challenges in administering oral or inhaled analgesic agents to distressed and uncooperative children were highlighted by participants. Short transfer times to the emergency department, and a 'medical' cause of pain were also implicated as examples of when children are less likely to receive analgesia from practitioners. CONCLUSIONS: The pathway to improving care must include an emphasis on improvements in practitioner education and training, offering alternatives to assessing pain in preverbal children, exploring the intranasal route of drug delivery in managing acute severe pain, and robustly developed evidence-based guidelines that are practitioner friendly and patient-focused.

Out-of-hospital cardiac arrest in Cork, Ireland.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) in Ireland accounts for approximately 5000 deaths annually. Little published evidence exists on survival from OHCA in this country to date. We aimed to characterise and describe 'presumed cardiac' OHCA in Cork City and County attended by the Ambulance Service. METHODS: Dispatch records, ambulance patient records and hospital records for a 1-year period were examined for patient demographics, OHCA characteristics, interventions and patient outcomes. RESULTS: There were 231 'presumed cardiac' OHCAs attended over the study period; 130 (56%) were in urban locations and 101 (44%) in rural. OHCAs were lay-witnessed in 20% (n=46), and 22% (n=50) received bystander CPR. Shockable rhythm was present in 36 cases (16%) on initial assessment, and there was no difference in presence of shockable rhythm between urban and rural OHCAs (18% vs 13%, p=0.31). Resuscitation was attempted in 176 cases (77.5%), of whom 27 (15%) achieved return of spontaneous circulation and 13 (7.4%) survived to leave hospital. Survival when the initial rhythm was shockable was 16.7% (6 of 36 patients). Despite longer response times for rural compared with urban OHCAs (median (IQR) 16.5 (11.0-23.5) vs 9 (7-12) min, p<0.001), survival to leave hospital alive where resuscitation was attempted was similar (7.4% vs 7.4%, p=0.99, respectively). CONCLUSION: A survival rate of 16.7% in shockable rhythms indicates scope for improvement which would influence the overall survival rate which was found to be 7.4%. Real-time feedback of performance and quality of the continuum of patient care through a clinical-quality cardiac arrest registry would monitor and incentivise such initiatives.

A study of using epigenetic modulators to enhance response to pembrolizumab (MK-3475) in microsatellite stable advanced colorectal cancer.

BACKGROUND: Approximately 95% of advanced colorectal cancer patients (CRC) have mismatch repair MMR-proficient (MMRp) tumors, which do not respond to PD1 blockade alone. Preclinical studies have shown that combined histone deacetylases (HDAC) and/or DNA methyltransferases (DNMT) inhibition can induce susceptibility to immune checkpoint therapy and inhibit tumor growth. We conducted a pilot trial evaluating PD-1 immune checkpoint inhibitor therapy in combination with DNMT and HDAC inhibitors in MMRp CRC. The study was designed with a biological endpoint of change in immune cell infiltration, to determine the optimal epigenetic combination that optimizes the tumor microenvironment. This trial was designed to test that hypothesis. RESULTS: From January 2016 to November 2018, 27 patients were enrolled with median age of 57 (range 40-69) years. Median progression-free survival and overall survival were 2.79 months and 9.17, respectively. One patient in Arm C achieved a durable partial response by RECIST criteria, lasting for approximately 19 months. The most common treatment-related hematological adverse events in all arms were anemia (62%), lymphopenia (54%) and thrombocytopenia (35%), and non-hematological AEs were anorexia (65%), nausea (77%), and vomiting (73%). CONCLUSIONS: The combination of 5-azacitidine and romidepsin with pembrolizumab was safe and tolerable in patients with advanced MMRp CRC, but with a minimal activity. Further mechanistic investigations are needed to understand epigenetic-induced immunologic shift and to expand the potential applicability of checkpoint inhibitors in this setting.

The cost of cancer care: how far would you go for a trial?

BACKGROUND: Clinical trials are often considered the gold standard in cancer care. However, patients face barriers in trial participation including distances to cancer centres and personal costs including changing employment status, cost of medications, inpatient admissions, and parking tariffs. AIM: Our aim was to compare the distances patients travelled for clinical trials compared to those receiving standard systemic anticancer therapy (SACT). We also investigated the additional costs associated with this. METHODS: This was a retrospective review of electronic patient medical records. The distance from the patients' home address to Beaumont was calculated as a one-way journey in kilometres. Patients attending for clinical trials were compared to those receiving standard of care SACT. RESULTS: A total of 271 patients receiving standard SACT over a 5-day period and 111 patients enrolled on 24 clinical trials were included. The median one-way distance travelled by patients enrolled in clinical trials was 41.4 km, compared to 14 km in those patients' receiving standard of care SACT. The median estimated cost was €13 vs €4.20 for those enrolled on clinical trials compared to those receiving standard of care treatment, respectively. CONCLUSION: Patients enrolled on clinical trials often travel more than twice as far to receive their anti-cancer treatment compared to those receiving standard of care SACT and incur an increased cost of travel expenses.

Immune cell atlas of cholangiocarcinomas reveals distinct tumor microenvironments and associated prognoses.

BACKGROUND: Immunotherapy has demonstrated a limited clinical efficacy in approximately 5% of cholangiocarcinoma. The main challenges for an effective immunotherapy response in cholangiocarcinoma arise from the tumor microenvironment, which is poorly understood. METHODS: For a comprehensive analysis of the tumor microenvironment in cholangiocarcinoma, we performed multiplex immunohistochemistry with two 15-marker immune panels and Nanostring assays for a comprehensive analysis of 104 surgically resected cholangiocarcinomas including intrahepatic, hilar, and distal cholangiocarcinoma. We also validated some key findings with a batch integration analysis of published single cell RNA sequencing data. RESULTS: This study found that natural killer cells occupy the largest immune cell compartment in cholangiocarcinoma. Granzyme-B+CD8+ effector T cells are significantly associated with better overall survival in both intrahepatic and distal cholangiocarcinoma. Above 85% of intrahepatic cholangiocarcinomas with higher density of PD-1-EOMES-CD8+ effector T cells are associated with long-term survival. However, only the density of PD-1-EOMES-CD8+ T cells in the tumor areas, but not in the peripheries of the tumors, is prognostic. In all three cholangiocarcinoma subtypes, T regulator cells are significantly associated with a poor prognosis; however, M1 and M2 tumor-associated macrophages or PD-L1+ tumor-associated macrophage demonstrate different prognostic values. Combining PD-L1+ M1 or M2, PD-L1- M1 or M2 tumor-associated macrophages, and T regulator cells to subgroup intrahepatic and distal cholangiocarcinoma, the prognosis is significantly better distinguished. Moreover, PD-L1- M2 tumor-associated macrophages is associated with a good prognosis in intrahepatic and distal cholangiocarcinoma, suggesting this subtype of M2 tumor-associated macrophages may be antitumoral. Interestingly, lower densities of various types of immunosuppressive cells are associated with decreased infiltration of effector T cells in distal and hilar cholangiocarcinoma, but not in intrahepatic cholangiocarcinoma. In intrahepatic cholangiocarcinoma, PD-L1+ tumor-associated macrophages exert their immunosuppressive function likely through promoting T cell exhaustion. CONCLUSIONS: This study suggests that the densities of Granzyme-B+CD8+ effector T cells and non-exhausted PD-1-EOMES-CD8+ T cells and the PD-L1 status in the tumor-associated macrophages are prognostic makers in cholangiocarcinomas. The study also supports targeting PD-L1+ tumor-associated macrophages as the immunotherapy for cholangiocarcinoma.

A telephone assessment and advice service within an ED physiotherapy clinic: a single-site quality improvement cohort study.

BACKGROUND: In response to issues with timely access and high non-attendance rates for Emergency Department (ED) physiotherapy, a telephone assessment and advice service was evaluated as part of a quality improvement project. This telehealth option requires minimal resources, with the added benefit of allowing the healthcare professional streamline care. A primary aim was to investigate whether this service model can reduce wait times and non-attendance rates, compared to usual care. A secondary aim was to evaluate service user acceptability. METHODS: This was a single-site quality improvement cohort study that compares data on wait time to first physiotherapy contact, non-attendance rates and participant satisfaction between patients that opted for a service based on initial telephone assessment and advice, versus routine face-to-face appointments. 116 patients were referred for ED physiotherapy over the 3-month pilot at the ED and out-patient physiotherapy department, XMercy University Hospital, Cork, Ireland. 91 patients (78%) opted for the telephone assessment and advice service, with 40% (n=36) contacting the service. 25 patients (22%) opted for the face-to-face service. Data on wait time and non-attendance rates was gathered using the hospital data reporting system. Satisfaction data was collected on discharge using a satisfaction survey adapted from the General Practice Assessment Questionnaire. Independent-samples t-test or Mann Whitney U Test was utilised depending on the distribution of the data. For categorical data, Chi-Square tests were performed. A level of significance of p ≤ 0.05 was set for this study. RESULTS: Those that contacted the telephone assessment and advice service had a significantly reduced wait time (median 6 days; 3-8 days) compared to those that opted for usual care (median 35 days; 19-39 days) (p ≤ 0.05). There was no significant between-group differences for non-attendance rates or satisfaction. CONCLUSION: A telephone assessment and advice service may be useful in minimising delays for advice for those referred to ED Physiotherapy for musculoskeleltal problems. This telehealth option appears to be broadly acceptable and since it can be introduced rapidly, it may be helpful in triaging referrals and minimising face-to-face consultations, in line with COVID-19 recommendations. However, a large scale randomised controlled trial is warranted to confirm these findings.

Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial.

IMPORTANCE: Isocitrate dehydrogenase 1 (IDH1) variations occur in up to approximately 20% of patients with intrahepatic cholangiocarcinoma. In the ClarIDHy trial, progression-free survival as determined by central review was significantly improved with ivosidenib vs placebo. OBJECTIVE: To report the final overall survival (OS) results from the ClarIDHy trial, which aimed to demonstrate the efficacy of ivosidenib (AG-120)-a first-in-class, oral, small-molecule inhibitor of mutant IDH1-vs placebo for patients with unresectable or metastatic cholangiocarcinoma with IDH1 mutation. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized, double-blind, placebo-controlled, clinical phase 3 trial was conducted from February 20, 2017, to May 31, 2020, at 49 hospitals across 6 countries among patients aged 18 years or older with cholangiocarcinoma with IDH1 mutation whose disease progressed with prior therapy. INTERVENTIONS: Patients were randomized 2:1 to receive ivosidenib, 500 mg, once daily or matched placebo. Crossover from placebo to ivosidenib was permitted if patients had disease progression as determined by radiographic findings. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival as determined by blinded independent radiology center (reported previously). Overall survival was a key secondary end point. The primary analysis of OS followed the intent-to-treat principle. Other secondary end points included objective response rate, safety and tolerability, and quality of life. RESULTS: Overall, 187 patients (median age, 62 years [range, 33-83 years]) were randomly assigned to receive ivosidenib (n = 126; 82 women [65%]; median age, 61 years [range, 33-80 years]) or placebo (n = 61; 37 women [61%]; median age, 63 years [range, 40-83 years]); 43 patients crossed over from placebo to ivosidenib. The primary end point of progression-free survival was reported elsewhere. Median OS was 10.3 months (95% CI, 7.8-12.4 months) with ivosidenib vs 7.5 months (95% CI, 4.8-11.1 months) with placebo (hazard ratio, 0.79 [95% CI, 0.56-1.12]; 1-sided P = .09). When adjusted for crossover, median OS with placebo was 5.1 months (95% CI, 3.8-7.6 months; hazard ratio, 0.49 [95% CI, 0.34-0.70]; 1-sided P < .001). The most common grade 3 or higher treatment-emergent adverse event (≥5%) reported in both groups was ascites (11 patients [9%] receiving ivosidenib and 4 patients [7%] receiving placebo). Serious treatment-emergent adverse events considered ivosidenib related were reported in 3 patients (2%). There were no treatment-related deaths. Patients receiving ivosidenib reported no apparent decline in quality of life compared with placebo. CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that ivosidenib was well tolerated and resulted in a favorable OS benefit vs placebo, despite a high rate of crossover. These data, coupled with supportive quality of life data and a tolerable safety profile, demonstrate the clinical benefit of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02989857.