Cornelis Verhoef

Systemic anti-tumour immunity results from T cell priming in tumour-draining lymph nodes (TDLNs) ^1–4 . Although the suppression of T cells in tumours is well characterized ^5–8 , whether this occurs in TDLNs—and if so, through which mechanisms—remains poorly understood. Here, using imaging mass cytometry of TDLNs from patients with melanoma, we identify a spatial neighbourhood in the TDLN paracortex that is linked to the development of distant metastases. Targeted spatial transcriptomics of cells inside this neighbourhood revealed activated CD8 ⁺ T cells engaging with myeloid cells that expressed high levels of the immunosuppressive secretory phospholipase PLA2G2D. PLA2G2D ⁺ myeloid cells were substantially more abundant in TDLNs than they were in primary tumours or metastases. Genetic loss-of-function or antibody-mediated inhibition of PLA2G2D reduced tumour growth markedly, and single-cell transcriptomics in melanoma-bearing mice revealed that expression of Pla2g2d is confined to lymph-node macrophages. Mechanistically, PLA2G2D directly suppressed the early proliferation of T cells in vitro, and inhibiting PLA2G2D resulted in an expansion of tumour-specific T cells in TDLNs, leading to an increase in these T cells in the circulation and subsequently in tumours. Notably, PLA2G2D and PD-1 act as non-redundant immune checkpoints, with combination treatment showing additive or synergistic efficacy in humanized mice treated with human-specific antibodies. Collectively, our in-depth spatial profiling identifies PLA2G2D as a TDLN-centred targetable immune checkpoint for cancer immunotherapy.

Objective: Mitotane is the first-line medical treatment for adrenocortical carcinoma (ACC). Mitotane has substantial drawbacks, including severe toxicity and contralateral gland destruction while effective in only 25%-30% of ACCs. To improve patient selection for mitotane therapy, this study aimed to identify tissue biomarkers associated with in vitro mitotane response. Design: Retrospective cohort study. Methods: We performed transcriptomic and proteomic analyses on fresh–frozen human ACC tissues classified as responders (n = 13), partial responders (n = 10), or nonresponders (n = 7) based on in vitro mitotane-induced inhibition of cell proliferation. Results: Responders showed distinct transcriptomic and proteomic signatures compared with partial and nonresponders, whereas fewer differences were found between the latter groups. Integrating transcriptomic and clinicopathological data indicated that responders frequently had cortisol-producing ACC with metastases or nodal involvement. Furthermore, their transcriptomes aligned with aggressive, proliferative ACC subtypes described previously. Differential expression analysis identified 718 genes and 60 proteins that distinguished responders from nonresponders. Pathway and network analyses revealed upregulation of cell cycle and collagen-related genes and downregulation of mitochondria-related genes and proteins in responders. Conclusions: In summary, transcriptomic and proteomic profiling offers promise to predict mitotane response in ACC. Our findings suggest that responders exhibit features of aggressive ACC, with distinct molecular characteristics that could serve as biomarkers for treatment selection.

Aim: To investigate surgeons' perspectives on the management of right‐sided obstructing colon cancer, with particular focus on their views regarding bridge‐to‐surgery strategies. Methods: A national cross‐sectional descriptive survey study was conducted in the Netherlands between January and October 2024. Questionnaires were distributed among surgeons with an interest in colorectal surgery and surgical trainees specialising in gastrointestinal surgery. Results: Fifty completed questionnaires were analysed; 80% of the respondents were surgeons, 20% were surgical trainees. Emergency resection was reported as the sole treatment option for right‐sided obstructing colon cancer in 4% ( n = 2), while 64% ( n = 32) indicated that emergency resections were performed alongside other treatment strategies. The majority of the respondents preferred a bridge‐to‐surgery strategy, with bowel decompression with nasogastric tube (38%) and ileostomy (38%) being the most favoured strategies. Endoscopic stenting was not offered in 90%, largely due to the lack of trained endoscopists. Conclusion: Management of right‐sided obstructing colon cancer varies considerably, though most surgeons and surgical trainees favour bridge‐to‐surgery approaches. Greater consistency may be achieved through further research and guideline development.

Aim: To identify distinct health‐related quality of life (HRQoL) profiles among colorectal cancer (CRC) patients using patient‐reported outcome measures (PROMs), with the aim of informing more personalised follow‐up strategies. Methods: Baseline HRQoL data from CRC patients enrolled in the FUTURE‐primary study, a multicentre implementation study on home‐based follow‐up, were analysed. Patients completed the EORTC QLQ‐C30 and QLQ‐CR29 questionnaires. Aggregated symptom and function scales were developed using factor analysis and expert consensus. Latent profile analysis (LPA) was applied to identify subgroups based on PROM responses. Model selection was guided by the Bayesian Information Criterion (BIC), entropy, average posterior probabilities (AvePP), class sizes, clinical interpretability, and additional sensitivity and stability analyses. Results: Three HRQoL profiles were identified: low HRQoL ( n = 62), intermediate HRQoL ( n = 95), and high HRQoL ( n = 42). The profiles followed a gradient‐like pattern, with consistently high, moderate, or low scores across symptom burden and functional outcomes. Classification quality was high, as indicated by high entropy (>0.93) and average posterior probabilities (>0.96), although profile assignment should be interpreted probabilistically. Conclusion: This study highlights variation in HRQoL among CRC patients. LPA identified three profiles that primarily reflected differences in overall symptom burden and functioning. These profiles may provide a preliminary framework for describing differences in supportive care needs, but their clinical applicability for tailoring follow‐up or allocating care resources requires longitudinal validation. Implications for Cancer Survivors: Identifying HRQoL profiles may support more personalised follow‐up, ensuring targeted care for those with higher symptom burden and lower functional scores, while reducing unnecessary interventions for others.

Background: Rectal cancer with mesorectal fascia involvement (MRF+) requires neoadjuvant downstaging and/or induction therapy, followed by (beyond) total mesorectal excision and/or multivisceral resection (MVR) depending on response. Decisions on the need for MVR and plane of dissection vary. This nationwide cross-sectional study aimed to evaluate treatment and oncological outcomes in MRF+ primary rectal cancer and the impact of MVR types. Methods: Using collaborative research, extensive clinical data on all rectal cancer resections in 2016 across 67 Dutch hospitals were retrospectively collected. Patients with cT3-4 MRF+ primary rectal cancer and standardized re-assessment of primary and restaging magnetic resonance imaging were selected. Patients were categorized by radiologically involved structures or organs and by MVR type. The primary outcome measures were microscopically positive margin (R1) resection rate, 4-year cumulative local recurrence, and 4-year overall survival. Results: Of 3178 patients registered, 571 cT3-4 MRF+ were selected resections, 125 of which were MVR. Tumours remained MRF+ on restaging magnetic resonance imaging in 76.4%. The overall R1 rate was 11.8% (9.7% in cT3/4a MRF+ and 17.9% in cT4b tumours). The R1 rate after MVR was 20.8%. Overall, the 4-year local recurrence rate was 15.1% and 4-year overall survival 67.5%. When comparing total mesorectal excision with MVR and/or beyond total mesorectal excision, the local recurrence rate was 12.7% versus 24.2% (P = 0.001), and overall survival 71.3% versus 53.7% (P < 0.001). Patients with radiological anterior involvement seemed to have a higher R1 rate compared with other locations. Anterior resections in both men and women appeared to be associated with relatively low local recurrence and high overall survival, whereas other resections resulted in numerically lower R1 rates, but worse long-term oncological outcomes. However, neither anatomical location of MRF+ and/or ingrowth nor MVR type was significantly associated with the primary outcomes. Pelvic sepsis (hazard ratio 1.533, 95% confidence interval 1.0 to 2.3) and positive margins (hazard ratio 1.837, 1.2 to 2.8) were independent predictors of worse overall survival. Conclusion: Oncological outcomes of MRF+ rectal cancer were not significantly influenced by the anatomical location of MRF involvement or MVR type.

Patients with colorectal cancer (CRC) frequently develop liver metastases^1-3. The prognosis of these patients is skewed by the histopathological heterogeneity of their liver metastases^4,5. Patients with 'replacement' metastases have a 5-year overall survival of less than 44.2%, compared with 73.4% in patients with 'encapsulated' (previously known as desmoplastic) metastases⁵; yet there are currently no approved therapies targeting replacement liver metastases. Here we show that treatment-naive patients with CRC with liver steatosis have an increased occurrence of replacement metastases compared with patients without steatosis. Mechanistically, we find that steatosis-promoted fatty acid oxidation increases formation of replacement metastases by increasing MYC stability through acetylation. In turn, MYC activates proline synthesis, fuelling collagen production, enabling growth of replacement metastases. Targeting MYC, P5CS or COL1A1 suppresses the occurrence and growth of replacement metastases in patient-derived organoids, mouse or patient-derived xenograft models. Spatial metabolite and protein analyses of liver metastases from patients with CRC further support this mechanism. In conclusion, we provide a mechanistic understanding of the emergence of liver metastases with poor prognosis in treatment-naive patients with CRC, identifying potential targets for therapeutic intervention.

Introduction: Colorectal cancer (CRC) incidence is rising, consequentially traditional follow-up care models are increasingly unsustainable. Patient-led, home-based follow-up (PHFU) may offer a promising alternative to reduce hospital visits while maintaining patient well-being. Methods: The DISTANCE trial is a stepped-wedge cluster randomised trial conducted in six hospitals in the Netherlands. A total of 354 stage I–III CRC survivors, disease-free at 12 months post-surgery, assigned to either PHFU or standard follow-up. The primary endpoint was the number of hospital contacts. Secondary endpoints included quality of life (QoL, EORTC QLQ-C30), cancer-related worry (CWS), and psychological distress (HADS). Results: In the intention-to-treat (ITT) analysis, no significant difference in hospital contacts was observed. In the as-treated (AT) analysis, PHFU reduced hospital contacts by 38% compared to standard follow-up (RR 0.62, 95% CI 0.51–0.75, p < 0.001). There was substantial crossover, with 117 patients assigned to PHFU receiving standard follow-up and 10 patients assigned to standard follow-up receiving PHFU. No significant differences were found in QoL or psychological distress between the two groups. Conclusion: The DISTANCE trial suggests that PHFU is a feasible and effective alternative to standard hospital-based follow-up for CRC survivors.TOC Summary

Background/Objectives: Intraoperative fluorescence imaging (FI) with tumor-targeted tracers offers a promising approach to improve surgical precision in cancer surgery. cRGD-ZW800-1, an integrin-targeted fluorescent tracer, has previously demonstrated safety, tumor specificity, and utility in detecting inadequate margins in oral cancer. During this study, we observed variability in background fluorescence between different subsites of the oral cavity. Therefore, this study aimed to systematically evaluate intraoperative in vivo and ex vivo mucosal contrast ratios across various oral cavity subsites using FI with cRGD-ZW800-1. Methods: Thirty-one patients with oral squamous cell carcinoma underwent intraoperative FI following intravenous injection of cRGD-ZW800-1 at least 18 h preoperatively. In vivo imaging was performed using the Quest Spectrum platform. In addition, ex vivo FI of the resected specimen was performed using the Pearl Trilogy Small Animal Imaging System. As these ex vivo images were obtained under uniform and controlled acquisition conditions, they allow for direct comparison with the intraoperative fluorescence signals. Fluorescence intensities and tumor-to-background ratios (TBRs) were assessed per oral subsite using manually drawn regions of interest (ROIs) on the tumor and adjacent healthy mucosa using Quest’s Spectrum Software, version 4.8.2, (in vivo images) and the Pearl’s integrated software ImageStudio version 6.2 (ex vivo images). A TBR ≥ 1.5 was considered sufficient. Results: Under uniform imaging settings, all samples exhibited adequate contrast (TBR ≥ 2.3), allowing clear tumor visualization and precise evaluation of mucosal margins on final histopathology. Notably, intraoperative in vivo contrast in the posterior located maxillary alveolar process was comparatively lower, which was attributable to suboptimal imaging conditions and subsite-specific background fluorescence. Conclusions: Our findings indicate that, although contrast varies across different oral subsites, all specimens exhibited sufficient ex vivo mucosal contrast to allow reliable tumor delineation. As in vivo imaging may be affected by subsite-specific background fluorescence and inherent limitations of intraoperative imaging geometry, fluorescence signals should be interpreted in conjunction with standard visual and tactile assessment. Due to anatomical constraints, different oral subsites may appear within the same field of view, which can influence perceived signal intensity. Therefore, intraoperative ex vivo fluorescence evaluation is recommended for signal interpretation.