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Objectives: To compare a novel method of methadone rotation used in a specialist palliative care inpatient unit (SPCU) in Cork, Ireland, with rapid titration methods using Perth and Brisbane Protocols as well as the Edmonton method of methadone rotation., Methods: A retrospective chart review was performed in March-June 2022. All patients who completed rotation to methadone during 2018-2019 in the SPCU were included. 2018-2019 was selected to study a population not affected by the coronavirus pandemic. Oral morphine equivalent (OME) was calculated using the opioid conversion chart. From the OME, the expected daily methadone dose was calculated using the Perth, Brisbane and Edmonton methods. These figures were then compared directly with the actual methadone doses achieved using our dosing schedule., Results: A comparison of the expected doses using the Perth and Brisbane rapid titration protocols and stable daily dose achieved revealed that the stable methadone dose was significantly lower than both rapid titration protocols (p=<0.0001) and (p=0.0035, respectively). However, a comparison of the expected dose using the Edmonton method and the dose achieved did not determine any significant difference (p=0.7602)., Conclusions: This is the first evaluation of a novel Irish method of methadone rotation and demonstrates a lower overall daily methadone dose compared with established protocols., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: This timely study assesses the immunosuppressive effects of surgery on cytotoxic Th1-like immunity and investigates if immune checkpoint blockade (ICB) can boost Th1-like immunity in the perioperative window in upper gastrointestinal cancer (UGI) patients., Methods: PBMCs were isolated from 11 UGI patients undergoing tumour resection on post-operative days (POD) 0, 1, 7 and 42 and expanded ex vivo using anti-CD3/28 and IL-2 for 5 days in the absence/presence of nivolumab or ipilimumab. T cells were subsequently immunophenotyped via flow cytometry to determine the frequency of T helper (Th)1-like, Th1/17-like, Th17-like and regulatory T cell (Tregs) subsets and their immune checkpoint expression profile. Lymphocyte secretions were also assessed via multiplex ELISA (IFN-γ, granzyme B, IL-17 and IL-10). The 48h cytotoxic ability of vehicle-, nivolumab- and ipilimumab-expanded PBMCs isolated on POD 0, 1, 7 and 42 against radiosensitive and radioresistant oesophageal adenocarcinoma tumour cells (OE33 P and OE33 R) was also examined using a cell counting kit-8 (CCK-8) assay to determine if surgery affected the killing ability of lymphocytes and whether the use of ICB could enhance cytotoxicity., Results: Th1-like immunity was suppressed in expanded PBMCs in the immediate post-operative setting. The frequency of expanded circulating Th1-like cells was significantly decreased post-operatively accompanied by a decrease in IFN-γ production and a concomitant increase in the frequency of expanded regulatory T cells with an increase in circulating levels of IL-10. Interestingly, PD-L1 and CTLA-4 immune checkpoint proteins were also upregulated on expanded Th1-like cells post-operatively. Additionally, the cytotoxic ability of expanded lymphocytes against oesophageal adenocarcinoma tumour cells was abrogated post-surgery. Of note, the addition of nivolumab or ipilimumab attenuated the surgery-mediated suppression of lymphocyte cytotoxicity, demonstrated by a significant increase in tumour cell killing and an increase in the frequency of Th1-like cells and Th1 cytokine production., Conclusion: These findings support the hypothesis of a surgery-mediated suppression in Th1-like cytotoxic immunity and highlights a rationale for the use of ICB within the perioperative setting to abrogate tumour-promoting effects of surgery and ameliorate the risk of recurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Davern, Gaughan, O’ Connell, Moran, Mylod, Sheppard, Ramjit, Yun-Tong Kung, Phelan, Davey, Ryan, Butler, Quinn, Howard, Tone, Phoenix, Butt, Lynam-Lennon, Maher, Ravi, Donohoe, Reynolds, Lysaght and Donlon.)

Response rates to immune checkpoint blockade (ICB) remain low in oesophageal adenocarcinoma (OAC). Combining ICB with immunostimulatory chemotherapies to boost response rates is an attractive approach for converting 'cold' tumours into 'hot' tumours. This study profiled immune checkpoint (IC) expression on circulating and tumour-infiltrating T cells in OAC patients and correlated these findings with clinical characteristics. The effect of first-line chemotherapy regimens (FLOT and CROSS) on anti-tumour T cell immunity was assessed to help guide design of ICB and chemotherapy combinations in the first-line setting. The ability of ICB to enhance lymphocyte-mediated cytolysis of OAC cells in the absence and presence of post-FLOT and post-CROSS chemotherapy tumour cell secretome was assessed by a CCK-8 assay. Expression of ICs on T cells positively correlated with higher grade tumours and a subsequent poor response to neoadjuvant treatment. First-line chemotherapy regimens substantially altered IC expression profiles of T cells increasing PD-1, A2aR, KLRG-1, PD-L1, PD-L2 and CD160 and decreasing TIM-3 and LAG-3. In addition, pro-inflammatory T cell cytokine profiles were enhanced by first-line chemotherapy regimens. T cell activation status was significantly altered; both chemotherapy regimens upregulated co-stimulatory markers ICOS and CD69 yet downregulated co-stimulatory marker CD27. However, ICB attenuated chemotherapy-induced downregulation of CD27 on T cells and promoted differentiation of effector memory T cells into a terminally differentiated state. Importantly, dual nivolumab-ipilimumab treatment increased lymphocyte-mediated cytolysis of OAC cells, an effect further enhanced in the presence of post-FLOT tumour cell secretome. These findings justify a rationale to administer ICBs concurrently with first-line chemotherapies., (Copyright © 2022. Published by Elsevier Inc.)

Recent studies have demontrated that immune checkpoint receptors are expressed on the surface of oesophageal adenocarcinoma (OAC) cells and might confer a survival advantage. This study explores the role of PD-1 and TIGIT signalling in OAC cells in either promoting or inhibiting the survival of OAC cells under characteristic features of the tumour microenvironment including nutrient-deprivation and hypoxia. PD-1 and TIGIT are expressed in normal and pre-malignant oesophageal epithelial cells and this expression significantly decreases along the normal- Barrett's Oesophagus- OAC disease sequence. However, glucose-deprivation and hypoxia significantly upregulated PD-1 and TIGIT on the surface of OAC cells in vitro. PD-1 blockade decreased OAC cell proliferation under normoxia but enhanced proliferation and decreased cell death in OAC cells under hypoxia and glucose-deprivation. TIGIT blockade decreased proliferation and induced OAC cell death, an effect that was maintained under nutrient-deprivation and hypoxia. Basal respiration and glycolytic reserve were enhanced and GLUT1 was upregulated on the surface of a subpopulation of OAC cells following PD-1 blockade. In contrast, TIGIT blockade enhanced a glycolytic phenotype in OAC cells, yet decreased other metabolic parameters including oxidative phosphorylation and basal respiration. Interestingly, inhibition of oxidative phosphorylation significantly upregulated TIGIT expression and inhibition of oxidative phosphorylation and glycolysis significantly decreased PD-1 on the surface of a subpopulation of OAC cells in vitro. These findings suggest an immune-independent mechanism for PD-1 inhibitor resistance in hypoxic tumours and suggest that TIGIT might be a more effective therapeutic target in OAC compared with PD-1 for treating hypoxic tumours., (Copyright © 2022. Published by Elsevier Inc.)

Endobronchial ultrasound (EBUS) has long been a common diagnostic tool used in the diagnosis of pulmonary pathologies. In the last decade, increased interest has been shown in its usage via the oesophagus for sampling lesions inaccessible via the airways. We describe three cases in which we used this modality to biopsy lesions not visualised via conventional EBUS and which would be too risky to be attempted via a CT-guided biopsy with a high likelihood of complications. More focused education on using EBUS via the oesophagus for respiratory trainees could greatly improve overall clinical practice. It improves the diagnostic yield of lesions and prevents subsequent referral to gastrointestinal colleagues which may delay diagnosis especially during the COVID-19 pandemic as was the case in our patient cohort where services are already limited. EBUS, due to its smaller size, is less irritant to the upper airways and requires less sedation than endoscopic ultrasound (EUS) scopes. It is also shorter than an EUS scope improving manoeuvrability. Each of our cases resulted in early histological diagnosis and subsequent appropriate treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

We describe a 5-day-old infant who fulfilled the diagnostic criteria for Sweet's syndrome, and the concurrent histologic and autoantibody features supporting the diagnosis of neonatal lupus. To our knowledge, this is the youngest case of Sweet's syndrome reported in the literature. Importantly, our findings further support the hypothesis that lupus erythematosus should be considered in the differential diagnosis of a nonbullous neutrophilic dermatosis, as it may represent the initial manifestation of the disease.