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This Review presents a comprehensive analysis of the amounts and distribution of public and philanthropic global cancer research funding between 2016 and 2023, including patterns of international collaboration and downstream research output, with an emphasis on the Commonwealth. We show that annual investment decreased globally each year, apart from a rise in 2021. Network analysis revealed that grant and publication collaborations between the Commonwealth, the USA, and the EU are facilitated by linkages through a core group of Commonwealth countries, including the UK, Australia, and Canada. There are inequities in research investment and low funding for treatment modalities for many cancers. These inequities also manifest in the central positioning of high-income Commonwealth countries in research collaborations, but also point to opportunities for high-income Commonwealth countries to facilitate linkages with low-income countries and support active cancer research in the USA and the EU. There is an urgent need to review research investment priorities, both within the Commonwealth and globally, to align with population needs and promote collaborative strategies that can build research skills and infrastructure in low-income settings to impact global cancer control. Finite resources should be invested wisely to achieve maximum improvements in mortality and alleviate the cancer burden.

Purpose UK NICE guidelines recommend axillary node clearance (ANC) should be performed in all patients with biopsy-proven node-positive breast cancer having primary surgery. There is, however, increasing evidence such extensive surgery may not always be necessary. Targeted axillary dissection (TAD) may be an effective alternative in patients with low-volume nodal disease who are clinically node negative (cN0) but have abnormal nodes detected radiologically. This survey aimed to explore current management of this group to inform feasibility of a future trial. Methods An online survey was developed to explore current UK management of patients with low-volume axillary disease and attitudes to a future trial. The survey was distributed via breast surgery professional associations and social media from September to November 2022. One survey was completed per unit and simple descriptive statistics used to summarise the results. Results 51 UK breast units completed the survey of whom 78.5% ( n  = 40) reported performing ANC for all patients with biopsy-proven axillary nodal disease having primary surgery. Only 15.7% of units currently performed TAD either routinely ( n  = 6, 11.8%) or selectively ( n  = 2, 3.9%). There was significant uncertainty (83.7%, n  = 36/43) about the optimal surgical management of these patients. Two-thirds ( n  = 27/42) of units felt an RCT comparing TAD and ANC would be feasible. Conclusions ANC remains standard of care for patients with low-volume node-positive breast cancer having primary surgery in the UK, but considerable uncertainty exists regarding optimal management of this group. This survey suggests an RCT comparing the outcomes of TAD and ANC may be feasible.

In protein folding and secretion disorders, activation of endoplasmic reticulum (ER) stress signaling (ERSS) protects cells, alleviating stress that would otherwise trigger apoptosis. Whether the stress-surviving cells resume normal function is not known. We studied the in vivo impact of ER stress in terminally differentiating hypertrophic chondrocytes (HCs) during endochondral bone formation. In transgenic mice expressing mutant collagen X as a consequence of a 13-base pair deletion in Col10a1 (13del), misfolded alpha1(X) chains accumulate in HCs and elicit ERSS. Histological and gene expression analyses showed that these chondrocytes survived ER stress, but terminal differentiation is interrupted, and endochondral bone formation is delayed, producing a chondrodysplasia phenotype. This altered differentiation involves cell-cycle re-entry, the re-expression of genes characteristic of a prehypertrophic-like state, and is cell-autonomous. Concomitantly, expression of Col10a1 and 13del mRNAs are reduced, and ER stress is alleviated. ERSS, abnormal chondrocyte differentiation, and altered growth plate architecture also occur in mice expressing mutant collagen II and aggrecan. Alteration of the differentiation program in chondrocytes expressing unfolded or misfolded proteins may be part of an adaptive response that facilitates survival and recovery from the ensuing ER stress. However, the altered differentiation disrupts the highly coordinated events of endochondral ossification culminating in chondrodysplasia.

The spatiotemporal proteome of the intervertebral disc (IVD) underpins its integrity and function. We present DIPPER, a deep and comprehensive IVD proteomic resource comprising 94 genome-wide profiles from 17 individuals. To begin with, protein modules defining key directional trends spanning the lateral and anteroposterior axes were derived from high-resolution spatial proteomes of intact young cadaveric lumbar IVDs. They revealed novel region-specific profiles of regulatory activities and displayed potential paths of deconstruction in the level- and location-matched aged cadaveric discs. Machine learning methods predicted a ‘hydration matrisome’ that connects extracellular matrix with MRI intensity. Importantly, the static proteome used as point-references can be integrated with dynamic proteome (SILAC/degradome) and transcriptome data from multiple clinical samples, enhancing robustness and clinical relevance. The data, findings, and methodology, available on a web interface ( http://www.sbms.hku.hk/dclab/DIPPER/ ), will be valuable references in the field of IVD biology and proteomic analytics. The backbone of vertebrate animals consists of a series of bones called vertebrae that are joined together by disc-like structures that allow the back to move and distribute forces to protect it during daily activities. It is common for these intervertebral discs to degenerate with age, resulting in back pain and severely reducing quality of life. The mechanical features of intervertebral discs are the result of their proteins. These include extracellular matrix proteins, which form the external scaffolding that binds cells together in a tissue, and signaling proteins, which allow cells to communicate. However, how the levels of different proteins in each region of the disc vary with time has not been fully examined. To establish how protein composition changes with age, Tam, Chen et al. quantified the protein levels and gene activity (which leads to protein production) of intervertebral discs from young and old deceased individuals. They found that the position of different mixtures of proteins in the intervertebral disc changes with age, and that young people have high levels of extracellular matrix proteins and signaling proteins. Levels of these proteins decreased as people got older, as did the amount of proteins produced. To determine which region of the intervertebral disc different proteins were in, Tam, Chen et al. also performed magnetic resonance imaging (MRI) of the samples to correlate image intensity (which represents water content) with the corresponding protein signature. The data obtained provides a high-quality map of how the location of different proteins changes with age, and is available online under the name DIPPER. This database is an informative resource for research into skeletal biology, and it will likely advance the understanding of intervertebral disc degeneration in humans and animals, potentially leading to the development of new treatment strategies for this condition.

CNS relapse in the brain parenchyma, eyes, or leptomeninges is an uncommon but devastating complication of diffuse large B-cell lymphoma. CNS prophylaxis strategies, typically involving intrathecal or high-dose antimetabolites, have been developed in the front-line treatment setting with the aim to reduce this subsequent risk. Clinical and biological features associated with elevated risk are increasingly well defined and are discussed in this Review. This Review summarises both the historical and current developments in this challenging field, provides a nuanced discussion regarding current reasons for and against standard prophylactic measures, outlines evidence for the timing of prophylactic measures when delivered, and reflects on possible future developments.

The integrated stress response (ISR) is activated by diverse forms of cellular stress, including endoplasmic reticulum (ER) stress, and is associated with diseases. However, the molecular mechanism(s) whereby the ISR impacts on differentiation is incompletely understood. Here, we exploited a mouse model of Metaphyseal Chondrodysplasia type Schmid (MCDS) to provide insight into the impact of the ISR on cell fate. We show the protein kinase RNA-like ER kinase (PERK) pathway that mediates preferential synthesis of ATF4 and CHOP, dominates in causing dysplasia by reverting chondrocyte differentiation via ATF4-directed transactivation of Sox9. Chondrocyte survival is enabled, cell autonomously, by CHOP and dual CHOP-ATF4 transactivation of Fgf21. Treatment of mutant mice with a chemical inhibitor of PERK signaling prevents the differentiation defects and ameliorates chondrodysplasia. By preventing aberrant differentiation, titrated inhibition of the ISR emerges as a rationale therapeutic strategy for stress-induced skeletal disorders.

PurposeUsing consumption value theory, this study aims to examine the impact of tourists’ perceived consumption value dimensions of tea beverages offered by Hong Kong (HK)-style cafés, including taste value, price value, health value and emotional value, on tourists’ memorable experience (ME), satisfaction and revisit intention.Design/methodology/approachUsing an online survey, this study collected 225 usable data from tourists who had experience in visiting HK-style cafés. Partial least squares–structural equation modelling was used to examine the importance of tourists’ value dimensions, including taste value, price value, health value and emotional value, on tourists’ ME, satisfaction and revisit intention.FindingsThe results revealed that taste value, price value, health value and emotional value are significant predictors of tourists’ ME in HK-style cafés, which in turn drive their satisfaction and revisit intention.Research limitations/implicationsThis study focusses on a single context: HK-style cafés. Future research may enhance the generalisability of the findings by replicating the model in other countries with diverse cultures.Practical implicationsTourism marketers may strengthen tourists’ ME, satisfaction and revisit intention by promoting tea beverages as well as HK-style cafés. Tourism marketers are recommended to communicate taste value, price value, health value and emotional value of HK-style tea beverages, which in turn encourages tourists to learn about the features of tea beverages. Subsequently, it drives tourists’ ME and satisfaction, thereby strengthening their intention to revisit.Originality/valueThis study contributes to the tourism marketing literature by providing an understanding of the role of tea beverage value in driving tourists’ ME, satisfaction and revisit intention. By empirically testing a research model, this study confirms that specific consumption value elements of tea beverages, namely, taste value, price value, health value and emotional value, are critical drivers in driving tourists’ ME, satisfaction and revisit intention.

Abstract Background Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract. Due to an increased risk of developing colorectal cancer, regular surveillance for dysplastic lesions via colonoscopy is recommended. Invisible dysplasia is the abnormal development of cells noted on pathology with no visible lesion seen during colonoscopy. Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease leading to progressive stricturing and fibrosis of the bile ducts. There is significant association between PSC and IBD, as up to 80% of patients with PSC having underlying IBD. Drug induced liver injury (DILI) is a common cause of acute liver failure in most Western countries. Most cases of DILI are self-limited, with resolution of laboratory and clinical findings after cessation of the offending agent. Purpose To describe a case of invisible colonic malignancy and possible idiosyncratic drug-induced liver injury from vedolizumab (VDZ) in a patient with ulcerative colitis (UC), PSC and autoimmune hepatitis (AIH) overlap syndrome. Method Patient consent was obtained. Information from electronic records was extracted, including admission notes and procedural reports. A literature review was performed using Pubmed. Result(s) A 32-year-old Caucasian female with UC on VDZ with PSC and AIH had multiple colonoscopies performed demonstrating multifocal low-grade dysplasia. However, she remained resistant to surgery. She presented to clinic with tea-coloured urine, fatigue, and scleral icterus. Investigations revealed conjugated hyperbilirubinemia with elevation in hepatocellular liver enzymes. Imaging was consistent with large duct PSC, and liver biopsy showed grade 2 chronic hepatitis raising the possibility of large bile duct obstruction. She underwent liver transplant assessment and VDZ was held. Her bilirubin and liver enzymes recovered. Given multiple colonoscopies showing multifocal dysplastic changes and the patient declining other biologics, she would ultimately undergo total proctocolectomy with end ileostomy. Pathology demonstrated mucinous adenocarcinoma with a signet ring component. Conclusion(s) Both mucinous adenocarcinoma and signet ring carcinoma are more aggressive malignancies associated with poor prognosis. Found more often in younger patients, they are often diagnosed in later stages with lymphovascular invasion. Here, there was no evidence of metastases in any of the 40 lymph nodes examined, which indicated more favourable prognosis. The mechanism by which VDZ potentially causes liver injury is unknown. Multiple therapies for PSC-AIH overlap and IBD were entertained as causative agents. However, significant improvement in clinical symptoms and serologic parameters following cessation of VDZ was temporally suggestive. This case simultaneously highlights the importance of both timely colectomy in IBD patients with high-risk features during surveillance and early recognition and cessation of potential causative medications which induce liver injury. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Objective To compare the postoperative pulmonary complications (PPC) after minimally invasive or open transthoracic esophagectomy for esophageal cancer in an international, multicenter cohort. Summary of background data Ongoing debate exists around the optimal surgical approach for esophageal cancer, with limited data assessing the external validity of randomised trials on outcomes of MIE Methods Patients undergoing open (OE, n  = 744), hybrid (HE, n  = 500), and totally minimally invasive esophagectomy (TMIE, n  = 540) for esophageal cancer were identified from the international, prospective Oesophagogastric Anastomosis Audit (OGAA). Multivariable models were used to investigate PPC (primary outcome) as well as overall complications, major complications, anastomotic leak and 90-day mortality (secondary outcomes). Results PPC rates were lower after TMIE compared to OE and HE (28% vs 37% vs 39%, p  = 0.002), even on adjusted analyses compared to OE (odds ratio (OR): 0.60, CI 95% : 0.45—0.78). TMIE was also associated with significantly lower overall complications (OR: 0.68, CI 95% : 0.52—0.88) compared to OE, but not for major complications (OR: 0.90, CI 95% : 0.67—1.21), anastomotic leak (OR: 1.39, CI 95% : 0.96—2.01) and 90-day mortality (OR: 0.49, CI 95% : 0.22—1.04). Sensitivity analyses by underlying respiratory disease, neoadjuvant chemoradiotherapy or high-volume centers confirmed above findings. Conclusion This study provides real-world data that TMIE was associated with lower 90-day PPC than OE and HE approaches, especially in patients with underlying respiratory disease or receiving neoadjuvant chemoradiotherapy. These warrant a further review into causes and mechanisms in selected patients, and that quality assurance in delivery of TMIE is probably of major importance. The ideal surgical approach remains unclear, and ongoing trials will provide more evidence within a few years that may clarify the optimum approach to locally advanced esophageal cancers.