Background: Synchronous metastatic para-aortic lymph node (mPALN) dissectionin colorectal cancer has relatively good oncological outcomes, though many patients develop recurrence. Universal prognostic factor remain unclear and no definitive perioperative chemotherapy is available, making the treatment of mPALN controversial. In the present study, we aimed to establish a treatment strategy for synchronous mPALN.Methods: This retrospective study involved 20 patients with pathological mPALN below the renal vein who underwent R0 resection. Long-term outcomes, recurrence type, and prognostic factors for survival were investigated.Results: The 5-year overall survival and recurrence-free survival rates were 39% and 25%, respectively. Seventeen patients (85%) developed recurrence, including 13 (76%) within 1 year after surgery, and ~70% of all recurrences were multiple recurrences. Four patients (20%) survived >5 years. Pathological T stage (p=0.011), time to recurrence (p=0.007), and recurrence resection (p=0.009) were identified as prognostic factors for long-term survival.Conclusions: R0 resection of synchronous mPALN in colorectal cancer resulted in acceptable oncological outcomes, though we found a high rate of early unresectable recurrence. If the recurrence occurs late or isolated, surgical resection should be considered for longer survival.
Background Synchronous metastatic para-aortic lymph node (mPALN) dissectionin colorectal cancer has relatively good oncological outcomes, though many patients develop recurrence. Universal prognostic factor remain unclear and no definitive perioperative chemotherapy is available, making the treatment of mPALN controversial. In the present study, we aimed to establish a treatment strategy for synchronous mPALN. Methods This retrospective study involved 20 patients with pathological mPALN below the renal vein who underwent R0 resection. Long-term outcomes, recurrence type, and prognostic factors for survival were investigated. Results The 5-year overall survival and recurrence-free survival rates were 38% and 25%, respectively. Seventeen patients (85%) developed recurrence, including 13 (76%) within 1 year after surgery, and ~ 70% of all recurrences were multiple recurrences. Four patients (20%) survived > 5 years. Pathological T stage (p = 0.016), time to recurrence (p = 0.006), and recurrence resection (p = 0.008) were identified as prognostic factors for long-term survival. Conclusions R0 resection of synchronous mPALN in colorectal cancer resulted in acceptable oncological outcomes, though we found a high rate of early unresectable recurrence. If the recurrence occurs late or isolated, surgical resection should be considered for longer survival.
It is thought that a few treatment-resistant cells form heterogenous recurrences and metastases, but what cells make complex tumor lineage is unexplored in colorectal cancer (CRC). To elucidate the cells that escape from treatment and form recurrences and metastases, the gene expression landscape, and drug susceptibility were explored using patient-derived organoids (PDOs). Drug sensitivities of 16 PDOs including eight PDOs derived from patients with distant metastases were evaluated. t-SNE analysis clearly showed four clusters, including two clusters based on response to therapy (good and poor). RNA sequence analysis showed that poor-response PDOs were enriched in gene sets related to distant metastasis, recurrence, and treatment resistance compared with good-response PDOs. Expression of nine genes (CBS, E2F8, GCNT1, NETO2, PLPP5, POU5F1, XRCC2, RECQL4, and ZNF681) were characteristic in the poor-response PDOs. Among them, we focused on POU5F1 gene that characterized liver metastasis in CRC from our previous report. Further analysis revealed that POU5F1-positive cells survive after anticancer drug treatment, and they were produced from POU5F1-expressing cells, not POU5F1-negative cells. Notably, isolated single POU5F1-expressing cell produced a heterogeneous population of cells expressing various differentiation markers both in vitro and in vivo. Single POU5F1-expressing cell also reconstructed ductal structure with mucus-producing ability. Cells produced from POU5F1-expressing cells were thought to construct tumor diversity remaining various differentiation stage. Single-cell RNA sequencing was performed to reveal the heterogeneous population with treatment resistance. The seven characteristic clusters were identified and the number of cells in clusters 2, 4, and 6 increased at the time of tumor re-growth after anticancer drug treatment. Cluster 2 was characterized by cell-cycle score. When cluster 4 was set as the root of the proliferative trajectory, the trajectory of cluster 4→3→6 emerged with characteristic gene expression profiles. The Wnt signaling pathway was enriched in cluster 4, suggesting stem cell characteristics. Moreover, Glycolysis, HIF-1 signaling, and ferroptosis pathways, which are also reported as properties of persister cells were enriched in cluster 6. Herein, we report the features derived from single-cell RNA seq analysis and further examinations in vitro, in vivo, and in clinical specimens. Citation Format: Shiki Fujino, Aya Ito, Masayoshi Yasui, Chu Matsuda, Masayuki Ohue, Masafumi Horie, Shinichi Yachida, Yuichiro Doki, Hidetoshi Eguchi, Norikatsu Miyoshi. Single-cell RNA sequencing of patient-derived organoid reveals treatment-induced tumor resistance through cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 892.
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