Molecular differences of angiogenic versus vessel co-opting colorectal cancer liver metastases at single-cell resolution.

BACKGROUND: Colorectal cancer liver metastases (CRCLM) are associated with a poor prognosis, reflected by a five-year survival rate of 14%. Anti-angiogenic therapy through anti-VEGF antibody administration is one of the limited therapies available. However, only a subgroup of metastases uses sprouting angiogenesis to secure their nutrients and oxygen supply, while others rely on vessel co-option (VCO). The distinct mode of vascularization is reflected by specific histopathological growth patterns (HGPs), which have proven prognostic and predictive significance. Nevertheless, their molecular mechanisms are poorly understood. METHODS: We evaluated CRCLM from 225 patients regarding their HGP and clinical data. Moreover, we performed spatial (21,804 spots) and single-cell (22,419 cells) RNA sequencing analyses to explore molecular differences in detail, further validated in vitro through immunohistochemical analysis and patient-derived organoid cultures. RESULTS: We detected specific metabolic alterations and a signature of WNT signalling activation in metastatic cancer cells related to the VCO phenotype. Importantly, in the corresponding healthy liver of CRCLM displaying sprouting angiogenesis, we identified a predominantly expressed capillary subtype of endothelial cells, which could be further explored as a possible predictor for HGP relying on sprouting angiogenesis. CONCLUSION: These findings may prove to be novel therapeutic targets to the treatment of CRCLM, in special the ones relying on VCO.

Preoperative Radiochemotherapy in Esophageal Squamous Cell Cancer with 5-Fluorouracil/Cisplatin or Carboplatin/Paclitaxel: Treatment Practice over a 20-Year Period and Implications for the Individual Treatment Modalities.

We retrospectively studied outcomes in patients treated with preoperative radiochemotherapy and surgery for esophageal squamous cell cancer. We put special focus on the comparison of patients treated with 5-fluorouracil/cisplatin ('Walsh') or carboplatin/paclitaxel ('CROSS'). We compared characteristics between patients treated according to 'Walsh' vs. 'CROSS'. Cox regression was performed to test for an association of parameters with outcomes. Study eligibility was met by 90 patients. First, the higher age and more comorbidities of the 'CROSS' patients, along with a shorter intensive care/intermediate care stay, might reflect an improvement in supportive and surgical/perioperative procedures over the periods. Second, the 'CROSS' patients experienced more hematologic toxicity and were less likely to complete chemotherapy as per protocol. This indicates that efforts should be taken to guide patients through a toxic treatment regimen by supportive measures. Third, the negative prognostic impact of radiochemotherapy-related toxicities (i.e., dysphagia and hematologic toxicities) and the duration of the intensive care/intermediate care unit stay underlines that further optimization of treatment procedures remains an important goal. We found no differences in tumor downstaging and survival between treatment regimen. Toxicity profiles could be improved by tailoring the regimen to individual patients (e.g., careful use of the taxane-based regimen in elderly patients).