A functional personalised oncology approach against metastatic colorectal cancer in matched patient derived organoids.

Globally, colorectal cancer (CRC) is the third most frequently occurring cancer. Progression on to an advanced metastatic malignancy (metCRC) is often indicative of poor prognosis, as the 5-year survival rates of patients decline rapidly. Despite the availability of many systemic therapies for the management of metCRC, the long-term efficacies of these regimens are often hindered by the emergence of treatment resistance due to intratumoral and intertumoral heterogeneity. Furthermore, not all systemic therapies have associated biomarkers that can accurately predict patient responses. Hence, a functional personalised oncology (FPO) approach can enable the identification of patient-specific combinatorial vulnerabilities and synergistic combinations as effective treatment strategies. To this end, we established a panel of CRC patient-derived organoids (PDOs) as clinically relevant biological systems, of which three pairs of matched metCRC PDOs were derived from the primary sites (ptCRC) and metastatic lesions (mCRC). Histological and genomic characterisation of these PDOs demonstrated the preservation of histopathological and genetic features found in the parental tumours. Subsequent application of the phenotypic-analytical drug combination interrogation platform, Quadratic Phenotypic Optimisation Platform, in these pairs of PDOs identified patient-specific drug sensitivity profiles to epigenetic-based combination therapies. Most notably, matched PDOs from one patient exhibited differential sensitivity patterns to the rationally designed drug combinations despite being genetically similar. These findings collectively highlight the limitations of current genomic-driven precision medicine in guiding treatment strategies for metCRC patients. Instead, it suggests that epigenomic profiling and application of FPO could complement the identification of novel combinatorial vulnerabilities to target synchronous ptCRC and mCRC.

Systematic review of isolated disseminated carcinomatosis of bone marrow from colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) metastasis commonly occurs in the liver and lungs with bone metastasis rarely occurring in isolation. Disseminated carcinomatosis of bone marrow (DCBM) is extremely rare in CRC. We conducted a systematic review to provide more information on the diagnosis, treatment options, and prognosis of the condition. METHODS: Studies were identified by performing searches on MEDLINE and EMBASE electronic databases according to the PRISMA statement standards. We included a single patient whom we treated for metastatic CRC presenting with DCBM in our study. Statistical analysis was performed using SPSS software version 23.0. RESULTS: A search through 5502 unique studies yielded 14 studies that were eventually included. There was a total of 17 cases of DCBM in CRC with back pain and constitutional symptoms as the most common presenting complaints. DCBM in CRC was associated with markedly elevated CEA of 275.57 (95% CI 17.13-534.00). There was no predilection for site of primary tumour. Overall median survival was 120 days (95% CI 64.43-175.58). The median survival for patients who received chemotherapy was 240 days (95% CI 71.11-408.89), as compared to 9 days (95% CI 1.80-16.20) for patients who received best supportive treatment. CONCLUSION: DCBM from CRC is extremely rare. Bone marrow examination remains the gold standard for diagnosis. Colonic stenting or surgical diversion may be more appropriate than primary resection in obstructed CRC in view of the poor prognosis. Systemic chemotherapy shows promise in increasing median survival.

Propensity-score-matched analysis of D2 and D3 right hemicolectomy for colon cancer.

BACKGROUND: Complete mesocolic excision with D3 lymph node dissection in right-sided colon cancer is associated with improved oncological outcomes, but can potentially be associated with higher rates of complications compared to conventional D2 right hemicolectomy. This study aims to evaluate the oncological and perioperative outcomes of patients who underwent D3 right hemicolectomy, comparing to conventional right hemicolectomy. METHODS: From 2015 to 2020, 360 patients underwent right hemicolectomy for colonic malignancies. Data was retrospectively analysed from a prospectively collected database. A propensity-score-matched analysis was performed between the two groups to evaluate their outcomes. RESULTS: About 88(24.4%) patients underwent D3 right hemicolectomy, with the rest undergoing D2 right hemicolectomy. After propensity-matched analysis, D3 right hemicolectomy had a higher lymph node yield (median of 26 versus 23, p = 0.005), lower overall recurrence rate (11.7% versus 25.7%, p = 0.03), and lower overall mortality rate (14.5% versus 30.1%, p = 0.02) There were no significant differences in the complication rates. There were no anastomotic leaks. D3 right hemicolectomy was associated with an improved 3-year disease-free survival (DFS) with a hazard ratio of 0.63 (P = 0.21), and also an improved 3-year overall survival (OS) with a hazard ratio of 0.68 (P = 0.31). CONCLUSION: D3 right hemicolectomy is associated with a higher lymph node yield, without increasing morbidity or mortality. It is also associated with significantly lower recurrence and overall mortality rates in this study. Short term 3-year DFS and OS also trend towards favouring D3 right hemicolectomy. However, this study is limited by the small sample size and retrospective nature.