Transcriptomic Maps of Colorectal Liver Metastasis: Machine Learning of Gene Activation Patterns and Epigenetic Trajectories in Support of Precision Medicine

Background Many attempts have been made to induce limb salvage as an alternative to amputation for primary bone cancer in the extremities, but efforts to establish its benefits over amputation yielded inconsistent results with regard to outcomes and functional recovery. This study aimed to investigate the prevalence and therapeutic efficiency of limb-salvage tumor resection in patients with primary bone cancer in the extremities, and to compare it with extremity amputation. Methods Patients diagnosed with T1-T2/N0/M0 primary bone cancer in the extremities between 2004 and 2019 were retrospectively identified from the Surveillance, Epidemiology, and End Results program database. Cox regression models were used to test for statistical differences between overall survival (OS) and disease-specific survival (DSS). The cumulative mortality rates (CMRs) for non-cancer comorbidities were also estimated. The evidence level in this study was Level IV. Results A total of 2,852 patients with primary bone cancer in the extremities were included in this study, among which 707 died during the study period. Of the patients, 72.6% and 20.4% underwent limb-salvage resection and extremity amputation, respectively. In patients with T1/T2-stage bone tumors in the extremities, limb-salvage resection was associated with significantly better OS and DSS than extremity amputation (OS: adjusted HR, 0.63; 95% confidence interval [CI], 0.55–0.77; p < 0.001; DSS: adjusted HR, 0.70; 95% CI, 0.58–0.84; p < 0.001). Limb-salvage resection was associated with significantly better OS and DSS than extremity amputation for patients with limb osteosarcoma (OS: adjusted HR, 0.69; 95% CI, 0.55–0.87; p = 0.001; DSS: adjusted HR, 0.73; 95% CI, 0.57–0.94; p = 0.01). Mortality from cardiovascular diseases and external injuries was remarkably declined in primary bone cancer in the extremities patients who underwent limb-salvage resection (cardiovascular diseases, p = 0.005; external injuries, p = 0.009). Conclusion Limb-salvage resection exhibited excellent oncological superiority for T1/2-stage primary bone tumors in the extremities. We recommend that patients with resectable primary bone tumors in the extremities undergo limb-salvage surgery as the first choice of treatment.

https://www.frontiersin.org/articles/10.3389/fsurg.2023.1147372/pdf

Limb-salvage surgery versus extremity amputation for early-stage bone cancer in the extremities: a population-based study

Background Second primary colorectal cancer (CRC) is attributed to a crucial component of the CRC population. Still, its treatments remain unclear due to the troublesome conditions originating from multiple primary cancers and the lack of quality evidence. This study aimed to determine that which type of surgical resection is the eligible treatment for second primary CRC among patients with a prior cancer history. Methods This cohort study retrospectively collected patients with second primary stage 0-III CRC in the Surveillance, Epidemiology, and End Results database from 2000 to 2017. Prevalence of surgical resection in second primary CRC, overall survival (OS) and disease-specific survival (DSS) of patients who received different surgical interventions were estimated. Results A total of 38,669 patients with second primary CRC were identified. Most of the patients (93.2%) underwent surgical resection as initial treatment. Approximately 39.2% of the second primary CRCs (N = 15,139) were removed with segmental resection, while 54.0% (N = 20,884) were removed through radical colectomy/proctectomy. Surgical resection was associated with a significantly favorable OS and DSS compared to those not receiving any surgical operations for second primary CRC [OS: adjusted Hazard ratios (adjusted HR): 0.35; 95% CI: 0.34–0.37, p < 0.001; DSS: adjusted HR: 0.27; 95% CI: 0.25–0.29, p < 0.001]. Segmental resection considerably outperformed radical resection in terms of OS and DSS (OS: adjusted HR: 0.97; 95% CI: 0.91–1.00, p = 0.07; DSS: adjusted HR: 0.92; 95% CI: 0.87–0.97, p = 0.002). Segmental resection was also associated with a significantly reduced cumulative mortality of postoperative non-cancer comorbidities. Conclusion Surgical resection demonstrated excellent oncological superiority for second primary CRC and was used to remove the vast majority of second primary CRCs. In comparison to radical resection, segmental resection offered a better prognosis and reduced postoperative non-cancer complications. The second primary colorectal cancers should be resected if the patients can afford surgical operations.

https://www.frontiersin.org/articles/10.3389/fmed.2023.1167777/pdf

Surgical resection for second primary colorectal cancer: a population-based study

<title>Abstract</title> The behaviour of metastases in patients with liver-metastatic colorectal cancer (CRC) is still not adequately considered during treatment planning. However, studies in large cohorts have shown that the disease course in these patients depends on the histopathological growth pattern (HGP) of the liver metastases, with the desmoplastic (or encapsulated) pattern responsible for a favourable outcome and the replacement pattern for an unfavourable course. To increase our knowledge of cancer biology in general as well as to design clinical trials that take into account the diverse behaviour of liver metastases, it is necessary to know the cellular and molecular determinants of these growth patterns. For that purpose, we compared the transcriptome of tumour tissue (n = 57) sampled very precisely at the transition of metastasis and adjacent liver, between the desmoplastic and replacement HGP. In addition, the mutational profiles for 46 genes related to CRC were extracted from the RNA sequencing reads. First, we show that the genetic constitution of a liver metastasis from colorectal cancer does not determine its HGP. Second, we show clear differences between HGPs regarding the expression of genes belonging to the Molecular Signatures Database hallmark gene sets. Biological themes of the replacement HGP reflect cancer cell proliferation and glucose metabolism, while the desmoplastic HGP is characterized by inflammation and immune response, and angiogenesis. This study supports the view that HGPs are a reflection of the biology of CRC liver metastases and suggests the HGPs are driven epigenetically rather than by specific gene mutations. 

Molecular characterization of the histopathological growth patterns of colorectal cancer liver metastases by RNA sequencing of targeted samples at the tumor-liver interface

The growth pattern of oropharyngeal squamous cell carcinomas (OPSCC) varies from compact tumor cell aggregates to diffusely infiltrating tumor cell-clusters. The influence of the growth pattern on local tumor control and survival has been studied mainly for surgically treated oral cavity carcinomas on a visual basis. In this study, we used multiplex immunofluorescence staining (mIF) to examine the antigens pan-cytokeratin, p16INK4a, Ki67, CD271, PD-L1, and CD8 in pretherapeutic biopsies from 86 OPSCC. We introduce Tumor-stroma contact ratio (TSC), a novel parameter, to quantify the relationship between tumor cells in contact with the stromal surface and the total number of epithelial tumor cells. mIF tumor cores were analyzed at the single-cell level, and tumor-stromal contact area was quantified using the R package "Spatstat". TSC was correlated with the visually assessed invasion pattern by two independent investigators. Furthermore, TSC was analyzed in relation to clinical parameters and patient survival data to evaluate its potential prognostic significance. Higher TSC correlated with poor response to (chemo-)radiotherapy (r = 0.3, p < 0.01), and shorter overall (OS) and progression-free (PFS) survival (median OS: 13 vs 136 months, p < 0.0001; median PFS: 5 vs 85 months, p < 0.0001). Visual categorization of growth pattern according to established criteria of tumor aggressiveness showed interobserver variability increasing with more nuanced categories (2 categories: k = 0.7, 95 %-CI: 0.55 - 0.85; 4 categories k = 0.48, 95 %-CI: 0.35 - 0.61). In conclusion, TSC is an objective and reproducible computer-based parameter to quantify tumor-stroma contact area. We demonstrate its relevance for the response of oropharyngeal carcinomas to primary (chemo-)radiotherapy. 

Tumor-stroma contact ratio - a novel predictive factor for tumor response to chemoradiotherapy in locally advanced oropharyngeal cancer

Endoscopic excision as a viable alternative to major resection for early duodenal cancers: A population-based cohort study.

Background Histopathological growth patterns (HGPs) have shown important prognostic values for patients with colorectal cancer liver metastases, but the potential molecular mechanisms remain largely unknown. Methods We performed an exploratory analysis by conducting the RNA sequencing of primary colorectal lesions, colorectal liver metastatic lesions and normal liver tissues. Findings We found that desmoplastic HGPs of the metastatic lesions were significantly enriched in EMT, angiogenesis, stroma, and immune signaling pathways, while replacement HGPs were enriched in metabolism, cell cycle, and DNA damage repair pathways. With the exception of immune-related genes, the differentially expressed genes of the two HGPs from colorectal liver metastases were mostly inherited from the primary tumor. Moreover, normal liver tissue in the desmoplastic HGP subgroup was markedly enriched in the fibrinous inflammation pathway. Conclusions We surmised that HGPs are observable morphological changes resulting from the regulation of molecular expressions, which is the combined effect of the heterogeneity and remodeling of primary tumors seeds and liver soils.

/pdf/delineating-the-molecular-landscape-of-different-2wrp5qjc.pdf

Delineating the molecular landscape of different histopathological growth patterns in colorectal cancer liver metastases

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Endoscopic excision as a viable alternative to major resection for early duodenal cancers: A population-based cohort study.

Delineating the molecular landscape of different histopathological growth patterns in colorectal cancer liver metastases