Factors associated with favourable pathological tumour response after neoadjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma.

INTRODUCTION: Pathological response of pancreatic ductal adenocarcinoma (PDAC) to neoadjuvant chemotherapy (NAT) has been associated with oncological outcome. The aim of the study was to investigate factors associated with favourable tumour regression in patients undergoing pancreatic resection for PDAC. METHODS: Patients who received NAT before undergoing PDAC resection at two institutions were reviewed. Tumour regression grading (TRG) was scored according to the College of American Pathologists (CAP) system. Interactions between chemotherapy, tumour and surgical factors with TRG were explored. RESULTS: 54 patients were identified, with 12 (22%) displaying a favourable response to NAT. The type of chemotherapy agent received, the number of cycles or a dose reduction during NAT course was not significantly different between the groups. The time from diagnosis to chemotherapy and time from end of chemotherapy to surgery were also similar between the groups. A favourable TRG was associated with greater disease-free survival median 33.2 months vs. 10.3 months; p = 0.0) but not overall survival (median 43.8 months vs. 32.3 months; p = 0.200), which may be due to small sample size. CONCLUSIONS: Chemotherapy factors were not significantly related to a favourable response to NAT. Future studies should seek to identify modifiable factors associated with a favourable TRG.

SIMAP500: A novel risk score to identify recipients at higher risk of hepatocellular carcinoma recurrence following liver transplantation.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) has a devastating influence on recipients' survival; however, the risk of recurrence is not routinely stratified. Risk stratification is vital with a long LT waiting time, as that could influence the recurrence despite strict listing criteria. AIM: This study aims to identify predictors of recurrence and develop a novel risk prediction score to forecast HCC recurrence following LT. METHODS: A retrospective review of LT for HCC recipients at University Hospitals Birmingham between July 2011 and February 2020. Univariate and multivariate analyses were performed to identify recurrence predictors, based on which the novel SIMAP500 (satellite nodules, increase in size, microvascular invasion, AFP > 500, poor differentiation) risk score was proposed. RESULTS: 234 LTs for HCC were performed with a median follow-up of 5.3 years. Recurrence developed in 25 patients (10.7%). On univariate analyses, RETREAT score > 3, α-fetoprotein (AFP) at listing 100-500 and > 500, bridging, increased tumour size between imaging at the listing time and explant histology, increase in the size of viable tumour between listing and explant, presence of satellite nodules, micro- and macrovascular invasion on explant and poor differentiation of tumours were significantly associated with recurrence, based on which, the SIMAP500 risk score is proposed. The SIMAP500 demonstrated an excellent predictive ability (c-index = 0.803) and outperformed the RETREAT score (c-index = 0.73). SIMAP500 is indicative of the time to disease recurrence. CONCLUSION: SIMAP500 risk score identifies the LT recipients at risk of HCC recurrence. Risk stratification allows patient-centric post-transplant surveillance programs. Further validation of the score is recommended.

Pembrolizumab-induced Myasthenia Gravis and Myocarditis.

As the use of immune checkpoint inhibitors (ICPi) such as pembrolizumab is rapidly expanding in the field of immuno-oncology, it is crucial for healthcare providers to be aware of their immune-related adverse events (irAE) which are thought to be driven by augmented immune response of T-cells. While neurologic irAE are underrepresented in literature, their consequences could lead to fatal outcomes. In this report, we describe the case of a patient with excellent performance status prior to pembrolizumab therapy who subsequently suffered myasthenic crisis eventually requiring tracheostomy and long-term mechanical ventilation.

Histopathological findings from the investigation of paediatric acute hepatitis of unknown aetiology, United Kingdom 2022.

In 2022, there were global reports of increased numbers of acute hepatitis not explained by hepatitis A-E virus infection in children. This manuscript summarises histopathology results from 20 patients in the United Kingdom who underwent liver transplant or had a liver biopsy as part of aetiological investigations. All available histopathological samples were reviewed centrally as part of the outbreak investigation. A working group comprised of infection specialists, hepatologists and histopathologists met virtually to review the cases, presentation, investigations and histopathology. All 20 liver samples had evidence of inflammation without significant interface activity, and submassive confluent pan-lobular or multilobular hepatocellular necrosis. Overall, the predominant histopathological findings were of acute nonspecific hepatitis with submassive hepatic necrosis and central vein perivenulitis and endothelitis. Histopathological findings were a poor indicator of aetiology.

Evaluating whether Prostate Cancer UK's risk checker is a help or hindrance to prostate-specific antigen testing policy: a mixed-methods study.

BACKGROUND: The UK has an informed choice testing policy for prostate cancer. The prostate-specific antigen (PSA) blood test is available for free to any man aged ≥50 years who requests it and has been informed of the harms and benefits. This policy leads to differences in PSA testing rates, which can exacerbate health inequalities. AIM: To assess whether Prostate Cancer UK's risk checker helps men at risk of prostate cancer make an informed choice about the PSA test. DESIGN & SETTING: Mixed-methods study in the UK. METHOD: In total, 1181 men at risk, their partners, and clinical experts participated in surveys, focus groups, and one-to-one interviews. Data on risk checker completions by sociodemographic factors were analysed over time. Data from general practices that sent the risk checker to their patients were collected and analysed for service monitoring purposes. RESULTS: There was a strong assumption that testing must be good, and therefore a need to emphasise the pros and cons of the test and that having it was the patient's decision. Men believed their GP would invite them for PSA testing. On the impact of the risk checker, 79.6% of men who completed it had at least one prostate cancer risk factor; the average time they interacted with the information in the tool was 9 minutes 28 seconds; and 75.7% felt the tool had equipped them to make an informed choice. CONCLUSION: Online decision-making tools, such as the risk checker, can help reach men at high risk of prostate cancer and support them in making an informed choice about the PSA test.

Interplay in galectin expression predicts patient outcomes in a spatially restricted manner in PDAC.

BACKGROUND: Galectins (Gal's) are a family of carbohydrate-binding proteins that are known to support the tumour microenvironment through their immunosuppressive activity and ability to promote metastasis. As such they are attractive therapeutic targets, but little is known about the cellular expression pattern of galectins within the tumour and its neighbouring stromal microenvironment. Here we investigated the cellular expression pattern of Gals within pancreatic ductal adenocarcinoma (PDAC). METHODS: Galectin gene and protein expression were analysed by scRNAseq (n=4) and immunofluorescence imaging (n=19) in fibroblasts and epithelial cells of pancreatic biopsies from PDAC patients. Galectin surface expression was also assessed on tumour adjacent normal fibroblasts and cancer associated primary fibroblasts from PDAC biopsies using flow cytometry. RESULTS: scRNAseq revealed higher Gal-1 expression in fibroblasts and higher Gal-3 and -4 expression in epithelial cells. Both podoplanin (PDPN+, stromal/fibroblast) cells and EpCAM+ epithelial cells expressed Gal-1 protein, with highest expression seen in the stromal compartment. By contrast, significantly more Gal-3 and -4 protein was expressed in ductal cells expressing either EpCAM or PDPN, when compared to the stroma. Ductal Gal-4 cellular expression negatively correlated with ductal Gal-1, but not Gal-3 expression. Higher ductal cellular expression of Gal-1 correlated with smaller tumour size and better patient survival. CONCLUSIONS: In summary, the intricate interplay and cell-specific expression patterns of galectins within the PDAC tissue, particularly the inverse correlation between Gal-1 and Gal-4 in ducts and its significant association with patient survival, highlights the complex molecular landscape underlying PDAC and provides valuable insights for future therapeutic interventions.

Real-world efficacy of single-agent belantamab mafodotin in relapsed systemic AL amyloidosis.

Systemic light chain (AL) amyloidosis is a relapsing plasma cell disorder. Therapy is limited, particularly for triple-class refractory disease. We report the use of belantamab mafodotin, a BCMA-directed drug-antibody conjugate, for relapsed AL amyloidosis, including patients traditionally excluded from clinical trials. Thirty-one patients were reviewed, with a median of three prior lines of therapy. The median follow-up was 12 months (95% CI 4-19), and a median of five doses were delivered. The best haematological overall response rate was 71%, and the complete/very good partial response was 58%. Sixty-eight percent had keratopathy and improved in all. Belantamab mafodotin has high efficacy and good tolerability in patients with relapsed AL amyloidosis.

Investigating misdiagnosis of suspected cancer among patients undergoing pancreatoduodenectomy: three decades of experience.

BACKGROUND: Diagnostic error can result in pancreatoduodenectomy (PD) being mistakenly performed for benign disease. The aims of this study were to observe the error rate in PD over three decades and identify characteristics of benign disease that can mimic malignancy. METHODS: Patients with a benign histological diagnosis after having PD performed for suspected malignancy between 1988 and 2019 were selected for review. Preoperative clinical features, imaging and pathological samples were reviewed alongside resection specimens to identify features that may have led to misdiagnosis. RESULTS: Over the study period, 1812 patients underwent PD for suspected malignancy and 97 (5.2 %) of these had a final benign diagnosis. The rate of benign cases reduced across the study period. Some 62 patients proceeded to surgery without a preoperative tissue diagnosis; the decision to operate was made upon clinical and radiologic features alone. There were six patients who had a preoperative pathological sample suspicious for malignancy, of which two had autoimmune pancreatitis in the postoperative histology specimen. DISCUSSION: Benign conditions, notably autoimmune and chronic pancreatitis, can mimic malignancy even with the use of EUS-FNA. The results of all available diagnostic modalities should be interpreted by a multidisciplinary team and honest discussions with the patient should follow.

Developing and Validating a Multivariable Prognostic-Predictive Classifier for Treatment Escalation of Oropharyngeal Squamous Cell Carcinoma: The PREDICTR-OPC Study.

PURPOSE: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC. EXPERIMENTAL DESIGN: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort. RESULTS: A total of 985 subjects (median follow-up 5.03 years, range: 4.73-5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16-0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14-1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17-0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1-2.38, P = 0.384. The concordance index was 0.73. CONCLUSIONS: We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption.

Vein Wall Invasion Is a More Reliable Predictor of Oncological Outcomes than Vein-Related Margins after Pancreaticoduodenectomy for Early Stages of Pancreatic Ductal Adenocarcinoma.

Pancreaticoduodenectomy (PD) with vein resection is the only potentially curative option for patients with pancreatic ductal adenocarcinoma (PDAC) with venous involvement. The aim of our study was to assess the oncological prognostic significance of the different variables of venous involvement in patients undergoing PD for resectable and borderline-resectable with venous-only involvement (BR-V) PDAC. We performed a retrospective analysis of prospectively acquired data over a 10-year period. Of the 372 patients included, 105 (28%) required vein resection and vein wall involvement was identified in 37% of those. A multivariable analysis failed to identify the vein-related resection margins as independent predictors for OS, DFS or LR. Vein wall tumour involvement was an independent predictor of OS (risk x1.7-2) and DFS (risk x1.9-2.2) in all models, while it replaced overall surgical margin positivity as the only parameter independently predicting LR during an analysis of separate resection margins (risk x2.4). Vein wall tumour invasion may be a more reliable predictor of oncological outcomes compared to traditionally reported parameters. Future studies should focus on possible pre-operative investigations that could identify these cases and management pathways that could yield a survival benefit, such as the use of neoadjuvant treatments.

Invitation methods for Indigenous New Zealand Maori in lung cancer screening: Protocol for a pragmatic cluster randomized controlled trial.

Lung cancer screening can significantly reduce mortality from lung cancer. Further evidence about how to optimize lung cancer screening for specific populations, including Aotearoa New Zealand (NZ)'s Indigenous Maori (who experience disproportionately higher rates of lung cancer), is needed to ensure it is equitable. This community-based, pragmatic cluster randomized trial aims to determine whether a lung cancer screening invitation from a patient's primary care physician, compared to from a centralized screening service, will optimize screening uptake for Maori. Participating primary care practices (clinics) in Auckland, Aotearoa NZ will be randomized to either the primary care-led or centralized service for delivery of the screening invitation. Clinic patients who meet the following criteria will be eligible: Maori; aged 55-74 years; enrolled in participating clinics in the region; ever-smokers; and have at least a 2% risk of developing lung cancer within six years (determined using the PLCOM2012 risk prediction model). Eligible patients who respond positively to the invitation will undertake shared decision-making with a nurse about undergoing a low dose CT scan (LDCT) and an assessment for Chronic Obstructive Pulmonary Disease (COPD). The primary outcomes are: 1) the proportion of eligible population who complete a risk assessment and 2) the proportion of people eligible for a CT scan who complete the CT scan. Secondary outcomes include evaluating the contextual factors needed to inform the screening process, such as including assessment for Chronic Obstructive Pulmonary Disease (COPD). We will also use the RE-AIM framework to evaluate specific implementation factors. This study is a world-first, Indigenous-led lung cancer screening trial for Maori participants. The study will provide policy-relevant information on a key policy parameter, invitation method. In addition, the trial includes a nested analysis of COPD in the screened Indigenous population, and it provides baseline (T0 screen round) data using RE-AIM implementation outcomes.

Impacts of EU Tobacco Products Directive regulations on use of e-cigarettes in adolescents in Great Britain: a natural experiment evaluation.

Background: E-cigarettes are a popular smoking-cessation tool. Although less harmful than tobacco, use of e-cigarettes by non-smokers should be prevented. There is concern about the use of e-cigarettes by young people and that e-cigarettes may renormalise smoking. In May 2016, Tobacco Products Directive regulations aimed to reduce e-cigarettes' appeal to young people. Aims: To examine the effects of the Tobacco Products Directive regulations on young people's use of e-cigarettes, and the role of e-cigarettes in renormalising smoking. Design: A mixed-method natural experimental evaluation combining secondary analyses of survey data, with process evaluation, including interviews with young people, policy stakeholders, retailers and trading standards observers, and observations of retail settings. Settings: Wales, Scotland and England. Participants: Survey participants were aged 13-15 years, living in England, Scotland or Wales and participated in routinely conducted surveys from 1998 to 2019. Process evaluation participants included 14- to 15-year-olds in England, Scotland and Wales, policy stakeholders, trading standards offices and retailers. Intervention: Regulation of e-cigarettes, including bans on cross-border advertising, health warnings and restrictions on product strength. Comparison group: Interrupted time series design, with baseline trends as the comparator. Main outcome measures: The primary outcome was ever e-cigarette use. Secondary outcomes included regular use, ever and regular smoking, smoking attitudes, alcohol and cannabis use. Data capture and analysis: Our primary statistical analysis used data from Wales, including 91,687 young people from the 2013-19 Health Behaviour in School-aged Children and School Health Research Network surveys. In Scotland, we used the Scottish Schools Adolescent Lifestyle and Substance Use Survey and in England we used the Smoking Drinking and Drug Use surveys. The process evaluation included interviews with 73 young people in 2017 and 148 young people in 2018, 12 policy stakeholders, 13 trading standards officers and 27 retailers. We observed 30 retail premises before and after implementation. Data were integrated using the Medical Research Council's process evaluation framework. Results: Ever smoking continued to decline alongside the emergence of e-cigarettes, with a slight slowing in decline for regular use. Tobacco Products Directive regulations were described by stakeholders as well implemented, and observations indicated good compliance. Young people described e-cigarettes as a fad and indicated limited interaction with the components of the Tobacco Products Directive regulations. In primary statistical analyses in Wales [i.e. short (to 2017) and long term (to 2019)], growth in ever use of e-cigarettes prior to Tobacco Products Directive regulations did not continue after implementation. Change in trend was significant in long-term analysis, although of similar magnitude at both time points (odds ratio 0.96). Data from England and Scotland exhibited a similar pattern. Smoking followed the opposite pattern, declining prior to the Tobacco Products Directive regulations, but plateauing as growth in e-cigarette use stalled. Limitations: Alternative causal explanations for changes cannot be ruled out because of the observational design. Conclusions: Young people's ever and regular use of e-cigarettes appears to have peaked around the time of the Tobacco Products Directive regulations and may be declining. Although caution is needed in causal attributions, findings are consistent with an effect of regulations. Our analysis provides little evidence that e-cigarettes renormalise smoking. More recent data indicate that declines in smoking are plateauing. Future work: International comparative work to understand differences in use of e-cigarettes, and tobacco, within varying regulatory frameworks is a priority. Study registration: This study is registered as ResearchRegistry4336. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 11, No. 5. See the NIHR Journals Library website for further project information.

Much has been achieved in preventing young people smoking; however, e-cigarettes have emerged as a new issue. E-cigarettes can help smokers stop, but might also appeal to young people or make smoking look 'normal'. Until recently, In the United Kingdom, there were not many rules for e-cigarettes. In 2016, new rules came in as part of the European Union Tobacco Products Directive regulations. The Tobacco Products Directive regulations limited advertising and included rules about how e-cigarettes should be labelled. In our study, we wanted to know if (1) e-cigarettes make young people think smoking is 'normal' and (2) people's use of e-cigarettes changed after new rules. We included young people who took part in surveys in England, Scotland and Wales between 1998 and 2019. Overall, about 360,000 young people did one of the surveys and about 90,000 were included in our main analysis. We spoke with young people in 2017 and 2018. In addition, in 2018, we spoke with people involved in tobacco policy, trading standards officers and people who sold e-cigarettes. Young people held negative attitudes about smoking and said that friends disagreed with smoking. Young people approved of occasional social e-cigarette use, but not regular use. Stakeholders described a range of views on how e-cigarettes should be regulated. Retailers and trading standards officers said that some retailers did not get much information about Tobacco Products Directive regulations, but new rules were implemented well. The percentage of young people saying that they had tried e-cigarettes was growing, but the number had stopped growing after the new rules. Regular use remained low throughout. Our findings suggest that e-cigarettes are not making smoking look normal again and new rules may have helped stop growth in use of e-cigarettes by young people.

Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma has a poor clinical outcome and responses to immunotherapy are suboptimal. Stromal fibroblasts are a dominant but heterogenous population within the tumor microenvironment and therapeutic targeting of stromal subsets may have therapeutic utility. Here, we combine spatial transcriptomics and scRNA-Seq datasets to define the transcriptome of tumor-proximal and tumor-distal cancer-associated fibroblasts (CAFs) and link this to clinical outcome. Tumor-proximal fibroblasts comprise large populations of myofibroblasts, strongly expressed podoplanin, and were enriched for Wnt ligand signaling. In contrast, inflammatory CAFs were dominant within tumor-distal subsets and expressed complement components and the Wnt-inhibitor SFRP2. Poor clinical outcome was correlated with elevated HIF-1α and podoplanin expression whilst expression of inflammatory and complement genes was predictive of extended survival. These findings demonstrate the extreme transcriptional heterogeneity of CAFs and its determination by apposition to tumor. Selective targeting of tumor-proximal subsets, potentially combined with HIF-1α inhibition and immune stimulation, may offer a multi-modal therapeutic approach for this disease.

Pancreatic cancer is one of the deadliest and most difficult cancers to treat. It responds poorly to immunotherapy for instance, despite this approach often succeeding in enlisting immune cells to fight tumours in other organs. This may be due, in part, to a type of cell called fibroblasts. Not only do these wrap pancreatic tumours in a dense, protective layer, they also foster complex relationships with the cancerous cells: some fibroblasts may fuel tumour growth, while other may help to contain its spread. These different roles may be linked to spatial location, with fibroblasts adopting different profiles depending on their proximity with cancer calls. For example, certain fibroblasts close to the tumour resemble the myofibroblasts present in healing wounds, while those at the periphery show signs of being involved in inflammation. Being able to specifically eliminate pro-cancer fibroblasts requires a better understanding of the factors that shape the role of these cells, and how to identify them. To examine this problem, Croft et al. relied on tumour samples obtained from pancreatic cancer patients. They mapped out the location of individual fibroblasts in the vicinity of the tumour and analysed their gene activity. These experiments helped to reveal the characteristics of different populations of fibroblasts. For example, they showed that the myofibroblast-like cells closest to the tumour exhibited signs of oxygen deprivation; they also produced podoplanin, a protein known to promote cancer progression. In contrast, cells further from the cancer produced more immune-related proteins. Combining these data with information obtained from patients' clinical records, Croft et al. found that samples from individuals with worse survival outcomes often featured higher levels of podoplanin and hypoxia. Inflammatory markers, however, were more likely to be present in individuals with good outcomes. Overall, these findings could help to develop ways to selectively target fibroblasts that support the growth of pancreatic cancer. Weakening these cells could in turn make the tumour accessible to immune cells, and more vulnerable to immunotherapies.

Case report: Acute liver failure in children and the human herpes virus 6-? A factor in the recent epidemic.

The 2022 worldwide epidemic of acute hepatitis and liver failure in young children has led to a focus on unusual causes for childhood acute hepatitis. In the UK epidemic, human herpes virus subtype 6B (HHV-6B) was detected along with adenovirus subtype-41F in severely affected children, especially in those requiring liver transplantation (LT). The lifting of COVID lock-down measures has coincided with the rise in these common childhood infections with a higher than expected rate of systemic complications. The sudden exposure of young children to common childhood infections from which they were protected during the pandemic may have induced an abnormal immune mediated response potentiated by multiple pathogen exposure. Primary HHV-6 infection is one such common childhood infection. Classically known as Roseola infantum due to the appearance of a widespread erythematous rash on fever subsidence (exanthema subitem), it has a peak incidence of 6-12 months of age and almost all children will have been infected by age 2. It is the virus most frequently associated with febrile convulsions but the more serious complications of hepatitis and liver failure are rare. We report on the historic cases of three female infants who had suspected primary HHV-6B infection, acute hepatitis and rapid progression to acute liver failure (ALF) requiring LT. Appearances of their native liver were identical to those described in children in the recent hepatitis epidemic. Deteriorating clinical trajectories of recurrent graft hepatitis and rejection-like episodes followed and all three succumbed to graft failure with HHV-6B detected posthumously in their liver allografts. Our case series and the serious complications observed with the recent rise in common childhood infections is a reminder that these routinely encountered pathogens can be deadly especially in the young immunologically untrained. We advocate for HHV-6 to be screened for routinely in children with acute hepatitis and the use of effective HHV-6 anti-viral prophylaxis to prevent recurrence post-transplant.

SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions.

Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP's contributions to sporadic CRC. In human single-cell cRNA-Seq (scRNA-Seq) data sets, we discovered that SELENOP expression rose as normal colon stem cells transformed into adenomas that progressed into carcinomas. We next examined the effects of Selenop KO in a mouse adenoma model that involved conditional, intestinal epithelium-specific deletion of the tumor suppressor adenomatous polyposis coli (Apc) and found that Selenop KO decreased colon tumor incidence and size. We mechanistically interrogated SELENOP-driven phenotypes in tumor organoids as well as in CRC and noncancer cell lines. Selenop-KO tumor organoids demonstrated defects in organoid formation and decreases in WNT target gene expression, which could be reversed by SELENOP restoration. Moreover, SELENOP increased canonical WNT signaling activity in noncancer and CRC cell lines. In defining the mechanism of action of SELENOP, we mapped protein-protein interactions between SELENOP and the WNT coreceptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6). Last, we confirmed that SELENOP-LRP5/6 interactions contributed to the effects of SELENOP on WNT activity. Overall, our results position SELENOP as a modulator of the WNT signaling pathway in sporadic CRC.

Are dynamic or fixed FDG-PET measures of disease of greater prognostic value in patients with relapsed/refractory diffuse large B-cell lymphoma undergoing autologous haematopoietic stem cell transplantation?

Positron emission tomography (PET) response assessment using the Deauville score has prognostic utility in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem-cell transplantation (ASCT). Improved predictive methods are required to identify patients with poor outcomes who may be better considered for other salvage options. We investigated the prognostic value of mean tumour volume (MTV) and maximum standardised uptake value (SUVmax) at pre-salvage and pre-ASCT time-points, and the quantitative changes between scans (∆MTV and ∆SUVmax). One hundred and twenty-five patients with R/R DLBCL underwent salvage immunochemotherapy and ASCT: 80 patients had pre-salvage PET and 90 had pre-ASCT PET available. With a median follow-up of 5.6 years, 5-year progression-free survival (PFS) and overall survival (OS) were 52% and 65%, respectively. For patients with PET-positive residual disease after salvage therapy, pre-ASCT MTV was a significant negative prognosticator for PFS (HR 1.19 per 100 ml, p < 0.001) and OS (HR 1.78 per 100 ml, p < 0.001). Similarly, pre-ASCT SUVmax was negatively associated with PFS (HR 1.08, p < 0.001) and OS (HR 1.08, p < 0.001). Notably, pre-salvage MTV and SUVmax and ∆MTV and ∆SUVmax were not associated with PFS or OS. In conclusion, pre-ASCT MTV and SUVmax appear to be of greater predictive value than the degree of response. Potential application may exist for PET-directed management of R/R DLBCL patients.

Tissue-Resident Memory T Cells in Pancreatic Ductal Adenocarcinoma Coexpress PD-1 and TIGIT and Functional Inhibition Is Reversible by Dual Antibody Blockade.

Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and a much more detailed understanding of the tumor immune microenvironment is needed if this situation is to be improved. Here, we characterized tumor-infiltrating T-cell populations in patients with PDAC using cytometry by time of flight (CyTOF) and single-cell RNA sequencing. T cells were the predominant immune cell subset observed within tumors. Over 30% of CD4+ T cells expressed a CCR6+CD161+ Th17 phenotype and 17% displayed an activated regulatory T-cell profile. Large populations of CD8+ tissue-resident memory (TRM) T cells were also present and expressed high levels of programmed cell death protein 1 (PD-1) and TIGIT. A population of putative tumor-reactive CD103+CD39+ T cells was also observed within the CD8+ tumor-infiltrating lymphocytes population. The expression of PD-1 ligands was limited largely to hemopoietic cells whilst TIGIT ligands were expressed widely within the tumor microenvironment. Programmed death-ligand 1 and CD155 were expressed within the T-cell area of ectopic lymphoid structures and colocalized with PD-1+TIGIT+ CD8+ T cells. Combinatorial anti-PD-1 and TIGIT blockade enhanced IFNγ secretion and proliferation of T cells in the presence of PD-1 and TIGIT ligands. As such, we showed that the PDAC microenvironment is characterized by the presence of substantial populations of TRM cells with an exhausted PD-1+TIGIT+ phenotype where dual checkpoint receptor blockade represents a promising avenue for future immunotherapy.

Distinct roles for interleukin-23 receptor signaling in regulatory T cells in sporadic and inflammation-associated carcinogenesis.

Introduction: The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal cancer (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R) signaling in CRC remain unknown. One of the cell types that highly expresses IL-23R are colonic regulatory T cells (Treg cells). The aim of this study was to define the contribution of Treg cell-specific IL-23R signaling in sporadic and inflammation-associated CRC. Methods: In mice, the role of IL-23R in Treg cells in colitis-associated cancer (CAC) was investigated using azoxymethane/dextran sodium sulphate in wild-type Treg cell reporter mice (WT, Foxp3 YFP-iCre), and mice harboring a Treg cell-specific deletion of IL-23 (Il23r ΔTreg). The role of IL-23R signaling in Treg cells in sporadic CRC was examined utilizing orthotopic injection of the syngeneic colon cancer cell line MC-38 submucosally into the colon/rectum of mice. The function of macrophages was studied using clodronate. Finally, single-cell RNA-seq of a previously published dataset in human sporadic cancer was reanalyzed to corroborate these findings. Results: In CAC, Il23r ΔTreg mice had increased tumor size and increased dysplasia compared to WT mice that was associated with decreased tumor-infiltrating macrophages. In the sporadic cancer model, Il23r ΔTreg mice had increased survival and decreased tumor size compared to WT mice. Additionally, MC-38 tumors of Il23r ΔTreg mice exhibited a higher frequency of pro-inflammatory macrophages and IL-17 producing CD4+ T cells. The decreased tumor size in Il23r ΔTreg mice was macrophage-dependent. These data suggest that loss of IL-23R signaling in Treg cells permits IL-17 production by CD4+ T cells that in turn promotes pro-inflammatory macrophages to clear tumors. Finally, analysis of TCGA data and single-cell RNA-seq analysis of a previously published dataset in human sporadic cancer, revealed that IL23R was highly expressed in CRC compared to other cancers and specifically in tumor-associated Treg cells. Conclusion: Inflammation in colorectal carcinogenesis differs with respect to the contribution of IL-23R signaling in regulatory T cells.

Para-aortic lymph node involvement should not be a contraindication to resection of pancreatic ductal adenocarcinoma.

BACKGROUND: Para-aortic lymph nodes (PALN) are found in the aortocaval groove and they are staged as metastatic disease if involved by pancreatic ductal adenocarcinoma (PDAC). The data in the literature is conflicting with some studies having associated PALN involvement with poor prognosis, while others not sharing the same results. PALN resection is not included in the standard lymphadenectomy during pancreatic resections as per the International Study Group for Pancreatic Surgery and there is no consensus on the management of these cases. AIM: To investigate the prognostic significance of PALN metastases on the oncological outcomes after resection for PDAC. METHODS: This is a retrospective cohort study of data retrieved from a prospectively maintained database on consecutive patients undergoing pancreatectomies for PDAC where PALN was sampled between 2011 and 2020. Statistical comparison of the data between PALN+ and PALN- subgroups, survival analysis with the Kaplan-Meier method and risk analysis with univariable and multivariable time to event Cox regression analysis were performed, specifically assessing oncological outcomes such as median overall survival (OS) and disease-free survival (DFS). RESULTS: 81 cases had PALN sampling and 17 (21%) were positive. Pathological N stage was significantly different between PALN+ and PALN- patients (P = 0.005), while no difference was observed in any of the other characteristics. Preoperative imaging diagnosed PALN positivity in one case. OS and DFS were comparable between PALN+ and PALN- patients with lymph node positive disease (OS: 13.2 mo vs 18.8 mo, P = 0.161; DFS: 13 mo vs 16.4 mo, P = 0.179). No difference in OS or DFS was identified between PALN positive and negative patients when they received chemotherapy either in the neoadjuvant or in the adjuvant setting (OS: 23.4 mo vs 20.6 mo, P = 0.192; DFS: 23.9 mo vs 20.5 mo, P = 0.718). On the contrary, when patients did not receive chemotherapy, PALN disease had substantially shorter OS (5.5 mo vs 14.2 mo; P = 0.015) and DFS (4.4 mo vs 9.8 mo; P < 0.001). PALN involvement was not identified as an independent predictor for OS after multivariable analysis, while it was for DFS doubling the risk of recurrence. CONCLUSION: PALN involvement does not affect OS when patients complete the indicated treatment pathway for PDAC, surgery and chemotherapy, and should not be considered as a contraindication to resection.