Photoreceptor loss does not recruit neutrophils despite strong microglial activation.

In response to central nervous system (CNS) injury, tissue resident immune cells such as microglia and circulating systemic neutrophils are often first responders. The degree to which these cells interact in response to CNS damage is poorly understood, and even less so, in the neural retina which poses a challenge for high resolution imaging in vivo. In this study, we deploy fluorescence adaptive optics scanning light ophthalmoscopy (AOSLO) to study fluorescent microglia and neutrophils in mice. We simultaneously track immune cell dynamics using label-free phase-contrast AOSLO at micron-level resolution. Retinal lesions were induced with 488 nm light focused onto photoreceptor (PR) outer segments. These lesions focally ablated PRs, with minimal collateral damage to cells above and below the plane of focus. We used in vivo (AOSLO, SLO and OCT) imaging to reveal the natural history of the microglial and neutrophil response from minutes-to-months after injury. While microglia showed dynamic and progressive immune response with cells migrating into the injury locus within 1-day after injury, neutrophils were not recruited despite close proximity to vessels carrying neutrophils only microns away. Post-mortem confocal microscopy confirmed in vivo findings. This work illustrates that microglial activation does not recruit neutrophils in response to acute, focal loss of photoreceptors, a condition encountered in many retinal diseases.

The impact of expanded access programs for systemic anticancer therapy in an Irish cancer centre.

BACKGROUND: Expanded access programs (EAPs) allow cancer patients with unmet clinical need to obtain access to pre-authorisation treatments. There is no standardised process for implementing these programs nationally, and real-world data on their impact is lacking. AIMS: This study aimed to evaluate the prevalence of such EAPs and their impact in a cancer centre. METHODS: Data relating to adult cancer patients treated via EAPs from 2011 to 2021 in three Cork university hospitals was collated. Descriptive statistics were employed to get an overview of the impact these programs currently have on cancer care provision. RESULTS: We identified 193 patients who accessed EAPs during the study period, availing of 33 separate drugs for a total of 50 different cancer indications. The prevalence of EAP usage was shown to have been trending upwards in recent years with a total of 189 programs being accessed throughout the period. Drugs provided were from a number of different anti-cancer drug classes, particularly targeted therapies (n = 18) and immune checkpoint inhibitors (n = 17). Cancers from a wide range of both solid and liquid tumour types were treated with EAP drugs, and patients treated were from across a broad spectrum of ages (26-82, SD 11.99). CONCLUSIONS: EAPs have an increasing role in accessing novel cancer therapies in our community and by extension nationally. Equity of EAP access would be facilitated by a national registry of available agents which we have established. Assessment of their benefits and toxicities would be enhanced by the requirement for a real-world database as a condition of EAP approval.

Room to Improve: An Audit of In-Hospital End-of-Life Care for Oncology Patients in a Tertiary Cancer Centre in Ireland During the COVID-19 Pandemic.

The COVID-19 pandemic compounded isolation for patients through social distancing measures and staff shortages. We were concerned about the impact of COVID-19 on the quality of care provided at end-of-life in 2021 in a national cancer centre, and instigated the first ever review of the care of the dying. Quality of care was assessed retrospectively using a validated instrument developed by the United Kingdom's National Quality Board. Sixty-six patient deaths occurred in our cancer centre in 2021. The 'risk of dying' was documented in 65.2% of records. Palliative care services were involved in 77%, and pastoral care in 10.6%. What was important to the patient was documented in 24.2%. The 'quality-of-death' score was satisfactory for most but poor in 21.2%. Our study prompted change, including appointment of an end-of-life coordinator, development of a checklist to ensure comprehensive communication, expansion of the end-of-life committee to include junior doctors, and regular audit.

Contributed Session II: In vivo imaging of immune cell activity in primate retina after photoreceptor ablation.

The non-human primate (NHP) is the gold standard animal model for preclinical development of gene and cell based therapies for vision restoration. However, the ocular immune response to these interventions remains poorly understood. We conducted a proof of concept study using offset aperture adaptive optics scanning light ophthalmoscopy (AOSLO) to visualize cellular-scale changes in the primate retina following photoreceptor (PR) ablation. Ultrafast 730nm laser exposure at 26.6 - 32.5 J/cm2 was used to create six lesions in four NHPs. Offset aperture images focused on retinal vascular layers were collected with an offset distance of ~10 Airy Disk Diameters from 15 minutes up to three hours after PR ablation. We observed putative immune cells in and around vessels supplying the lesioned areas. Consistent with previous findings in murine models, cells within vessels adhered to the inner wall, exhibited crawling behavior, and had a diameter ranging from ~9.3 - 11.5 µm. Additionally, we observed the emergence of cellular-scale structures above the PR layer that originated in the center of the lesion 15 minutes post-insult and gradually radiated outward. Vascular perfusion was maintained in these regions. Our data suggest that offset aperture imaging offers cellular-scale, label free, in vivo assessment of the retinal response to insult in NHPs and could be employed to advance our understanding of the ocular immune response provoked by disease and therapeutic interventions.

Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial.

BACKGROUND: The optimum curative approach to adenocarcinoma of the oesophagus and oesophagogastric junction is unknown. We aimed to compare trimodality therapy (preoperative radiotherapy with carboplatin plus paclitaxel [CROSS regimen]) with optimum contemporaneous perioperative chemotherapy regimens (epirubicin plus cisplatin or oxaliplatin plus fluorouracil or capecitabine [a modified MAGIC regimen] before 2018 and fluorouracil, leucovorin, oxaliplatin, and docetaxel [FLOT] subsequently). METHODS: Neo-AEGIS (CTRIAL-IE 10-14) was an open-label, randomised, phase 3 trial done at 24 centres in Europe. Patients aged 18 years or older with clinical tumour stage T2-3, nodal stage N0-3, and M0 adenocarcinoma of the oesophagus and oesophagogastric junction were randomly assigned to perioperative chemotherapy (three preoperative and three postoperative 3-week cycles of intravenous 50 mg/m2 epirubicin on day 1 plus intravenous 60 mg/m2 cisplatin or intravenous 130 mg/m2 oxaliplatin on day 1 plus continuous infusion of 200 mg/m2 fluorouracil daily or oral 625 mg/m2 capecitabine twice daily up to 2018, with four preoperative and four postoperative 2-week cycles of 2600 mg/m2 fluorouracil, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin, and 50 mg/m2 docetaxel intravenously on day 1 as an option from 2018) or trimodality therapy (41·4 Gy in 23 fractions on days 1-5, 8-12, 15-19, 22-26, and 29-31 with intravenous area under the curve 2 mg/mL per min carboplatin plus intravenous 50 mg/m2 paclitaxel on days 1, 8, 15, 22, and 29). The primary endpoint was overall survival, assessed in all randomly assigned patients who received at least one dose of study drug, regardless of which study drug they received, by intention to treat. Secondary endpoints were disease-free survival, site of treatment failure, operative complications, toxicity, pathological response (complete [ypT0N0] and major [tumour regression grade 1 and 2]), margin-free resection (R0), and health-related quality of life. Toxicity and safety data were analysed in the safety population, defined as patients who took at least one dose of study drug, according to treatment actually received. The initial power calculation was based on superiority of trimodality therapy (n=366 patients); it was adjusted after FLOT became an option to a non-inferiority design with a margin of 5% for perioperative chemotherapy (n=540). This study is registered with ClinicalTrials.gov, NCT01726452. FINDINGS: Between Jan 24, 2013, and Dec 23, 2020, 377 patients were randomly assigned, of whom 362 were included in the intention-to treat population (327 [90%] male and 360 [99%] White): 184 in the perioperative chemotherapy group and 178 in the trimodality therapy group. The trial closed prematurely in December, 2020, after the second interim futility analysis (143 deaths), on the basis of similar survival metrics and the impact of the COVID-19 pandemic. At a median follow-up of 38·8 months (IQR 16·3-55·1), median overall survival was 48·0 months (95% CI 33·6-64·8) in the perioperative chemotherapy group and 49·2 months (34·8-74·4) in the trimodality therapy group (3-year overall survival 55% [95% CI 47-62] vs 57% [49-64]; hazard ratio 1·03 [95% CI 0·77-1·38]; log-rank p=0·82). Median disease-free survival was 32·4 months (95% CI 22·8-64·8) in the perioperative chemotherapy group and 24·0 months (18·0-40·8) in the trimodality therapy group [hazard ratio 0·89 [95% CI 0·68-1·17]; log-rank p=0·41). The pattern of recurrence, locoregional or systemic, was not significantly different (odds ratio 1·35 [95% CI 0·63-2·91], p=0·44). Pathological complete response (odds ratio 0·33 [95% CI 0·14-0·81], p=0·012), major pathological response (0·21 [0·12-0·38], p<0·0001), and R0 rates (0·21 [0·08-0·53], p=0·0003) favoured trimodality therapy. The most common grade 3-4 adverse event was neutropenia (49 [27%] of 183 patients in the perioperative chemotherapy group vs 11 [6%] of 178 patients in the trimodality therapy group), followed by diarrhoea (20 [11%] vs none), and pulmonary embolism (ten [5%] vs nine [5%]). One (1%) patient in the perioperative chemotherapy group and three (2%) patients in the trimodality therapy group died from serious adverse events, two (one in each group) of which were possibly related to treatment. No differences were seen in operative mortality (five [3%] deaths in the perioperative chemotherapy group vs four [2%] in the trimodality therapy group), major morbidity, or in global health status at 1 and 3 years. INTERPRETATION: Although underpowered and incomplete, Neo-AEGIS provides the largest comprehensive randomised dataset for patients with adenocarcinoma of the oesophagus and oesophagogastric junction treated with perioperative chemotherapy (predominantly the modified MAGIC regimen), and CROSS trimodality therapy, and reports similar 3-year survival and no major differences in operative and health-related quality of life outcomes. We suggest that these data support continued clinical equipoise. FUNDING: Health Research Board, Cancer Research UK, Irish Cancer Society, Oesophageal Cancer Fund, and French National Cancer Institute.

A pilot project investigating the use of ONCOpatient®-An electronic patient-reported outcomes app for oncology patients.

Purpose: To investigate the feasibility of implementing a remote patient monitoring system using an electronic patient-reported outcomes (ePROs) platform in a tertiary cancer center in the Republic of Ireland. Methods: Patients receiving oral chemotherapy and oncology clinicians were invited to participate in the study. Patients were asked to submit weekly symptom questionnaires through an ePRO mobile phone application (app)-ONCOpatient®. Clinical staff were invited to use the ONCOpatient® clinician interface. After 8 weeks all participants submitted evaluation questionnaires. Results: Thirteen patients and five staff were enrolled in the study. The majority of patients were female (85%) with a median age of 48 years (range 22-73). Most (92%) were enrolled over telephone requiring on average 16 minutes. Compliance with the weekly assessments was 91%. Alerts were triggered by 40% of patients who then required phone calls to aid with symptom management. At the end of study, 87% of patients reported they would use the app frequently, 75% reported that the platform met their expectations, and 25% that it exceeded their expectations. Similarly, 100% of staff reported they would use the app frequently, 60% reported that it met their expectations, and 40% that it exceeded their expectations. Conclusions: Our pilot study showed that it is feasible to implement ePRO platforms in the Irish clinical setting. Small sample bias was recognized as a limitation, and we plan to confirm our findings on a larger cohort of patients. In the next phase we will integrate wearables including remote blood pressure monitoring.

The Changing Face of Lung Cancer: Oligometastatic Renal Metastasis Post Chemo-Immunotherapy Combination.

This report describes a rare case of oligometastatic renal disease in a 69 year-old Caucasian male with non-small cell lung cancer (NSCLC). Diagnosed with Stage IIIb, NSCLC he completed chemoradiotherapy followed by 1 year of immunotherapy. Surveillance CT scans after nearly three years showed an ill-defined lesion in the left kidney. Biopsy results were consistent with metastasis from the known lung carcinoma. Following neo-adjuvant Pembrolizumab (200mg, q3w), the patient underwent a left radical nephrectomy, without complications. One year post-operatively, CT of the thorax, abdomen and pelvis (TAP) did not identify any recurrence. Renal metastases were historically demonstrated predominantly by autopsy studies[1]. Any mass manifesting in the kidney in the context of previous NSCLC warrants comprehensive investigations. The combination of immunotherapy followed by definitive treatment appears to be a promising management strategy[2]. With regards to local curative options, the advantages and disadvantages of surgery and radiotherapy have been well described[3-4]. LEARNING POINTS: With improved treatment strategies for advanced malignancies, rare cases will continue to emerge and thus, maintaining a high index of suspicion is fundamentalThis case demonstrates that immunotherapy increases the efficacy of definitive treatment.

Are CT-Derived Muscle Measurements Prognostic, Independent of Systemic Inflammation, in Good Performance Status Patients with Advanced Cancer?

The present study examined the relationships between CT-derived muscle measurements, systemic inflammation, and survival in advanced cancer patients with good performance status (ECOG-PS 0/1). Data was collected prospectively from patients with advanced cancer undergoing anti-cancer therapy with palliative intent. The CT Sarcopenia score (CT-SS) was calculated by combining the CT-derived skeletal muscle index (SMI) and density (SMD). The systemic inflammatory status was determined using the modified Glasgow Prognostic Score (mGPS). The primary outcome of interest was overall survival (OS). Univariate and multivariate Cox regressions were used for survival analysis. Three hundred and seven patients met the inclusion criteria, out of which 62% (n = 109) were male and 47% (n = 144) were ≥65 years of age, while 38% (n = 118) were CT-SS ≥ 1 and 47% (n = 112) of patients with pre-study blood were inflamed (mGPS ≥ 1). The median survival from entry to the study was 11.1 months (1-68.1). On univariate analysis, cancer type (p < 0.05) and mGPS (p < 0.001) were significantly associated with OS. On multivariate analysis, only mGPS (p < 0.001) remained significantly associated with OS. In patients who were ECOG-PS 0, mGPS was significantly associated with CT-SS (p < 0.05). mGPS may dominate the prognostic value of CT-derived sarcopenia in good-performance-status patients with advanced cancer.

Real-world outcomes and toxicity of adjuvant chemotherapy in NSCLC: a single-center experience.

Aim: Adjuvant chemotherapy in NSCLC is associated with modest benefits and significant toxicity. We sought to evaluate the toxicity of adjuvant chemotherapy and disease-specific outcomes in a real-world population. Methods: We performed a retrospective analysis of patients undergoing adjuvant chemotherapy for NSCLC in an Irish center over a 7-year period. We described treatment-associated toxicity, recurrence-free survival and overall survival. Results: 62 patients underwent adjuvant chemotherapy. Treatment-associated hospitalisation occurred in 29% of patients. Relapse was recorded in 56% of patients and median recurrence-free survival was 27 months. Conclusion: High rates of disease recurrence and treatment-associated morbidity were observed in patients receiving adjuvant chemotherapy for NSCLC. Novel therapeutic strategies are required to improve outcomes in this population.

Early NSCLC is primarily managed with lung cancer surgery. Chemotherapy is offered to some patients with early NSCLC after surgery depending on the size of the tumor and lymph node involvement. The benefit of post-surgery (adjuvant) chemotherapy in reducing the chance of cancer recurrence has been shown to be relatively small in previous studies. Large studies of post-surgery chemotherapy in NSCLC have included limited numbers of older patients, and patients with significant medical issues. This study looked to evaluate the safety and treatment-associated side effects of adjuvant chemotherapy in a group of patients more reflective of everyday clinical practice, and to assess the rates of cancer recurrence in these patients. In our study of 62 patients who underwent adjuvant chemotherapy for NSCLC, nearly 1 in 3 patients required hospital admission due to treatment-associated side effects. Almost 40% of patients experienced significant blood test abnormalities (including anaemia, reduced platelets, and reduced white blood cells). Approximately 1 in 4 patients required a reduction in the doses of their treatment due to treatment-associated side effects. More than half of the patients in our study experienced a recurrence of their cancer. Our study demonstrates the significant side effects associated with adjuvant chemotherapy in NSCLC and highlights the need for better-tolerated treatment strategies to reduce cancer recurrence in early NSCLC.

High-resolution structural and functional retinal imaging in the awake behaving mouse.

The laboratory mouse has provided tremendous insight to the underpinnings of mammalian central nervous system physiology. In recent years, it has become possible to image single neurons, glia and vascular cells in vivo by using head-fixed preparations combined with cranial windows to study local networks of activity in the living brain. Such approaches have also succeeded without the use of general anesthesia providing insights to the natural behaviors of the central nervous system. However, the same has not yet been developed for the eye, which is constantly in motion. Here we characterize a novel head-fixed preparation that enables high-resolution adaptive optics retinal imaging at the single-cell level in awake-behaving mice. We reveal three new functional attributes of the normal eye that are overlooked by anesthesia: 1) High-frequency, low-amplitude eye motion of the mouse that is only present in the awake state 2) Single-cell blood flow in the mouse retina is reduced under anesthesia and 3) Mouse retinae thicken in response to ketamine/xylazine anesthesia. Here we show key benefits of the awake-behaving preparation that enables study of retinal physiology without anesthesia to study the normal retinal physiology in the mouse.

Cost and public reimbursement of cancer medicines in the UK and the Republic of Ireland.

INTRODUCTION/AIMS: There are disparities in the availability of systemic anticancer therapies (SACTs) globally. We set out to investigate the cost and reimbursement of SACTs in the United Kingdom (UK) and the Republic of Ireland (ROI) in conjunction with efficacy and licensing authority decisions in the United States (US) and the European Union (EU). METHODS: We sought data pertaining to licensing in the EU, reimbursement in ROI/UK and cost/efficacy of SACTs licensed by the Food and Drug Administration (FDA) between January 2015 and May 2021. Independent samples t tests, chi-square test and Pearson's correlation were used for statistical analysis. RESULTS: We identified that the majority of FDA-approved regimens are licensed by the European Medicines Agency (EMA) (n = 91, 67.9%). However, only a minority of these are currently reimbursed in the UK (n = 60, 45%) or the ROI (n = 28, 21%) as of the 1st of May 2021. In addition, only a minority of regimens have demonstrated a statistically significant OS benefit (n = 54, 40%). There was no association between cost of regimens and either the presence (t = 0.846, p = 0.40) or duration of OS benefit (t = - 0.84, p = 0.64). CONCLUSIONS: Our study highlights that many licensed systemic anticancer treatments are not currently reimbursed in ROI/UK. The high cost of these medicines is independent of the presence of an OS benefit. Collaboration between regulatory agencies, governments and industry partners is needed to ensure health expenditure is directed towards the most effective treatments.

Consensus statement on the surveillance of patients with gastrointestinal malignancies.

BACKGROUND: Improvements in early detection, screening and treatment of cancer have resulted in a significant improvement in cancer mortality and an increase in the number of cancer survivors globally. Accordingly, a significant rise in the number of cancer survivors in Ireland has been observed. The surveillance of survivors of gastrointestinal malignancies in Ireland is heterogeneous and represents an unmet need for standardisation. AIMS: There are currently no national guidelines in Ireland to guide follow-up practices for these patients. The aim of this study was to establish homogeneity nationally with respect to follow-up of these patients by medical oncologists. METHODS/RESULTS: A consensus group consisting of Irish oncologists with an interest in gastrointestinal malignancies was created to address this issue, and determined that it would be reasonable to adopt the NCCN guidelines for this purpose, but that this recommendation would not be prescriptive, and should be individualised to each patient. CONCLUSION: We hope that this initiative may help to homogenise survivorship practices in this cohort of Irish patients, and may support the implementation of survivorship initiatives by the National Cancer Control Programme (NCCP).

Lactate dehydrogenase: relationship with the diagnostic GLIM criterion for cachexia in patients with advanced cancer.

BACKGROUND: Although suggestive of dysregulated metabolism, the relationship between serum LDH level, phenotypic/aetiologic diagnostic Global Leadership Initiative on Malnutrition (GLIM) criteria and survival in patients with advanced cancer has yet to examined. METHODS: Prospectively collected data from patients with advanced cancer, undergoing anti-cancer therapy with palliative intent, across nine sites in the UK and Ireland between 2011-2016, was retrospectively analysed. LDH values were grouped as <250/250-500/>500 Units/L. Relationships were examined using χ2 test for linear-by-linear association and binary logistics regression analysis. RESULTS: A total of 436 patients met the inclusion criteria. 46% (n = 200) were male and 59% (n = 259) were ≥65 years of age. The median serum LDH was 394 Units/L and 33.5% (n = 146) had an LDH > 500 Units/L. LDH was significantly associated with ECOG-PS (p < 0.001), NLR (p < 0.05), mGPS (p < 0.05) and 3-month survival (p < 0.001). LDH was significantly associated with 3-month survival independent of weight loss (p < 0.01), BMI (p < 0.05), skeletal muscle mass (p < 0.01), metastatic disease (p < 0.05), NLR (p < 0.05) and mGPS (p < 0.01). DISCUSSION: LDH was associated with performance status, systemic inflammation and survival in patients with advanced cancer. LDH measurement may be considered as an aetiologic criteria and become a potential therapeutic target in the treatment of cancer cachexia.

Cost-Effectiveness of First-Line Pembrolizumab Monotherapy Versus Chemotherapy in High Programmed Death-Ligand 1 Advanced Non-Small Cell Lung Cancer in the Irish Healthcare Setting.

OBJECTIVES: This study aimed to assess the cost-effectiveness of pembrolizumab monotherapy in the first-line treatment of advanced non-small cell lung cancer (NSCLC) in adults whose tumors expressed programmed death-ligand 1 (PD-L1) with a tumor proportion score (TPS) ≥ 50% in the Irish healthcare setting. METHODS: Effectiveness inputs were derived from the 5-year analysis of KEYNOTE-024 phase III clinical trial. The intervention was pembrolizumab monotherapy; the comparator was a weighted average of the 5 chemotherapy regimens from the trial. The population included those with previously untreated advanced PD-L1 TPS ≥ 50% NSCLC. A de novo partitioned survival model was developed. Survival modeling was done using Bayesian model averaging on fitted parametric functions. Costs included drug acquisition, treatment initiation, administration and monitoring, adverse events, subsequent treatments, and terminal care. Costs and health state utilities were sourced from the literature and Irish sources. The model had a 20-year time horizon. The perspective taken was the Health Service Executive. A 4% discount rate was applied. Outcomes were expressed as an incremental cost-effectiveness ratio (ICER), measured in terms of incremental costs per quality-adjusted life-year (QALY). Probabilistic sensitivity analysis and 1-way sensitivity analyses were conducted. RESULTS: The model estimated a base case ICER of €54 237 per QALY. The probabilistic sensitivity analysis estimated an average ICER of €54 568 per QALY and a 11% probability of cost-effectiveness at the Irish cost-effectiveness threshold of €45 000 per QALY. CONCLUSION: At the current list price, first-line pembrolizumab monotherapy is not considered cost-effective for the treatment of advanced PD-L1 TPS ≥ 50% NSCLC in the Irish healthcare setting.

A large, multi-centre prospective study demonstrating high prevalence of malnutrition associated with reduced survival in ambulatory systemic anti-cancer therapy patients.

BACKGROUND & AIMS: The nutritional status of cancer patients is highly variable, and known to impact on clinical outcomes. To date, no large study evaluating the nutritional status of Irish cancer patients has been reported. The aim of this study was to describe the nutritional status, using gold standard methods, of a large cohort of ambulatory oncology patients receiving Systemic Anti-Cancer Therapy and to assess the impact of abnormal body composition phenotypes on survival. METHODS: A prospective study in adults undergoing Systemic Anti-Cancer Therapy for solid tumours enrolled patients between 2012 and 2016. Baseline details were collected incorporating demographics, cancer pathology, lifestyle, body composition (by computed tomography (CT), and inflammatory status. Skeletal muscle index (SMI) and mean muscle attenuation (MA) were obtained from CT images and categorised to low muscle mass and low MA using previously published sex specific cut points. Survival was monitored for a median of 25 months [IQR:10-46 months]. Survival analyses were conducted using multivariate Cox Proportional Hazards Models. RESULTS: Of 1015 patients recruited, 940 patients with an evaluable CT were included in this analysis. Median age was 64 years [IQR 55-71] and 56% were male. Colorectal cancer (28%) and gastro-oesophageal (16%) were the most common diagnoses and 58% of patients had stage IV disease. Despite 56% being overweight or obese (BMI >25 kg/m2), 52% were weight losing and 17% had lost >10% body weight. Cancer Cachexia (CC) was present in 42%, 39% had low muscle mass (MM) (sarcopenia) and 45% had low MA. Overall, 73% of patients exhibited an abnormal body composition (BC) phenotype (≥1 of CC, low MM/MA). Overall survival was significantly lower in those with abnormal BC phenotype, independent of site, stage, sex, ECOG and mGPS (HR: 1.416 [95% CI: 1.069-1.875], p = 0.015). CONCLUSIONS: Malnutrition and abnormal body composition phenotypes are common in cancer, but are often masked by adiposity. Appropriate screening and diagnostic tools should consider this co-presentation of overweight and obesity, alongside muscle depletion. Given that abnormal body composition phenotypes detectable only via CT are associated with reduced survival, these should be more widely employed to identify patients at risk of poor prognosis, and allow potentially more effective, early intervention.

Pembrolizumab-associated erythema nodosum in the treatment of metastatic melanoma.

A 66-year-old woman receiving pembrolizumab for metastatic melanoma presented with tender red nodules on her shins and forearms. Biopsy was consistent with erythema nodosum (EN). The eruption responded to oral minocycline and potent topical steroids. Subsequent investigations detected bihilar lymphadenopathy, biopsied as granulomatous lymphadenitis, confirming the diagnosis of pembrolizumab-associated sarcoidosis. Pembrolizumab was stopped for two cycles and was restarted without recrudescence of EN or bihilar lymphadenopathy. Immunotherapy-associated sarcoidosis is a rare but recognized adverse event related to therapy with immune checkpoint inhibitors. EN is an uncommon manifestation of immunotherapy-induced sarcoidosis. New-onset bihilar lymphadenopathy in the context of immunotherapy requires prompt histological evaluation to differentiate between immunotherapy-associated sarcoidosis and metastatic progression. We review the literature related to immunotherapy-associated EN.

Pembrolizumab (trade name Keytruda^®) is a type of immune therapy that stimulates the body's immune system to fight cancer cells. This immune therapy can cause a variety of rashes. In this article, we describe a patient who developed a red lumpy rash on her limbs that is not commonly described with pembrolizumab. A woman was diagnosed with advanced melanoma and was treated with pembrolizumab. She developed a red lumpy rash on her arms and legs, and a biopsy showed signs of a condition called erythema nodosum. Treatment with an antibiotic tablet and strong steroid ointment were helpful. Scans of her chest showed signs of sarcoidosis in her lungs, which can be associated with erythema nodosum. Pembrolizumab was stopped, and both the rash and lung sarcoidosis stayed away when it was restarted. This type of rash has rarely been described with this kind of immune therapy, and it can be a sign of lung involvement.

In Vivo Capillary Structure and Blood Cell Flux in the Normal and Diabetic Mouse Eye.

Purpose: To characterize the early structural and functional changes in the retinal microvasculature in response to hyperglycemia in the Ins2Akita mouse. Methods: A custom phase-contrast adaptive optics scanning light ophthalmoscope was used to image retinal capillaries of 9 Ins2Akita positive (hyperglycemic) and 9 Ins2Akita negative (euglycemic) mice from postnatal weeks 5 to 18. A 15 kHz point scan was used to image capillaries and measure red blood cell flux at biweekly intervals; measurements were performed manually. Retinal thickness and fundus photos were captured monthly using a commercial scanning laser ophthalmoscope/optical coherence tomography. Retinal thickness was calculated using a custom algorithm. Blood glucose and weight were tracked throughout the duration of the study. Results: Elevated blood glucose (>250 mg/dL) was observed at 4 to 5 weeks of age in Ins2Akita mice and remained elevated throughout the study, whereas euglycemic littermates maintained normal glucose levels. There was no significant difference in red blood cell flux, capillary anatomy, lumen diameter, or occurrence of stalled capillaries between hyperglycemic and euglycemic mice between postnatal weeks 5 and 18. Hyperglycemic mice had a thinner retina than euglycemic littermates (p < 0.001), but retinal thickness did not change with duration of hyperglycemia despite glucose levels that were more than twice times normal. Conclusions: In early stages of hyperglycemia, retinal microvasculature structure (lumen diameter, capillary anatomy) and function (red blood cell flux, capillary perfusion) were not impaired despite 3 months of chronically elevated blood glucose. These findings suggest that hyperglycemia alone for 3 months does not alter capillary structure or function in profoundly hyperglycemic mice.

Therapeutic Response Evaluation in Advanced Melanoma Patients Incorporating Plasma cfDNA, LDH, VEGF, PD-L1, and IFN-γ Measurements.

BACKGROUND/AIM: Current treatment strategies for advanced melanoma require serial assessment of disease status in affected patients. In this study, we sought to examine the relationship between radiographic tumour burden and blood borne biomarkers including plasma cfDNA, serum LDH, plasma VEGF, PD-L1 and IFN-γ in advanced melanoma patients receiving immunotherapy. We hypothesized that a combination of these explanatory variables in a suitable regression analysis model may predict changes in tumour burden during patient treatment. MATERIALS AND METHODS: We extracted and quantified circulating cfDNA, LDH, VEGF, PD-L1, and IFN-γ from thirty patients with stage IV melanoma at baseline and at six months. All participating patients were evaluated with paired blood sample collection and CT scan assessments during treatment. RESULTS: Changes in radiographic tumour burden correlated with changes in levels of cfDNA (p≤0.001), LDH (p≤0.001), VEGF (p≤0.001), and PD-L1 (p<0.05) during treatment. Multiple regression analysis consisting of the follow-up to baseline assessment ratios of cfDNA, LDH, VEGF and PD-L1 explained changes in tumour burden (F (4, 23)=32.05, p<0.001); with an R2 of 0.8479 (Y=ß0+ß1*B+ß2*C+ß3*D+ß4*E). CONCLUSION: A quantitative measure of cfDNA, LDH, VEGF and PD-L1 may complement current methods of assessing tumour burden in advanced melanoma patients.

The implication of BRAF mutation in advanced colorectal cancer.

BACKGROUND: Advanced colorectal cancer (CRC) is frequently a lethal disease. Mutations in the BRAF gene is a key driver in CRC pathogenesis and confers a poor prognosis. To date, Irish data on this molecular subtype of CRC is lacking. AIMS: Our aim was to compare the natural history of Irish patients with BRAF (BRAFMUT) metastatic CRC with a control group of metastatic CRC patients without BRAF mutation (BRAFWT wild- type). METHOD: A retrospective observational analysis of advanced CRC patients with known BRAFMUT was conducted by chart review. BRAFMUT patients were identified from the Cork University Hospital (CUH) histopathology database. Controls with known BRAFWT were randomly selected from the database. Demographic characteristics and clinicopathological data were recorded. Survival was assessed with Kaplan-Meier curve/Cox proportional hazard models. RESULTS: Twenty patients with BRAFMUT and 36 with BRAFWT were studied. BRAFMUT were more likely female (75% vs 33%, p = 0.007) and right-sided (65% vs 31.4%, p = 0.033). Median overall survival was lower in BRAFMUT group (17.3 months (95% CI 0-40.8)) compared to patients with BRAFWT (median survival not reached, log rank p = 0.001). On multivariate analysis, BRAFMUT was independently associated with an increased risk of mortality (HR 12.76 (95% CI 3.15-51.7), p < 0.001). CONCLUSION: BRAFMUT advanced colorectal cancer was associated with significantly reduced overall survival in this Irish CRC population. Knowledge of mutation status should now be considered standard of care and should dictate management. Surgeons should be aware of this genetic signature as the natural history of the disease may mitigate against an aggressive surgical strategy. A prospective study should be conducted to further corroborate these findings.