Purpose
Colorectal cancer (CRC) rarely occurs in children and adolescents. This study aimed to perform a retrospective analysis and disclose more detailed information about CRC in patients under ...20 years old.
Methods
Medical records of CRCs in patients under 20 years old referred to three tertiary hospitals in China from September 2000 to July 2019 were retrospectively reviewed. Clinicopathological characteristics, treatment processes and laboratory findings were summarized and treatment outcomes and prognostic factors were analyzed.
Results
A total of 33,394 CRC medical records were analyzed, and we identified seventy (0.21%) CRCs in patients under 20. The most common primary tumor location was the left hemicolon (35.7%). The prominent pathological types were mucinous adenocarcinoma (22.9%) and signet ring cell carcinoma (22.9%). Nearly half (47.1%) of the patients presented with distant metastasis at diagnosis. The fractions of patients with deficient mismatch repair (dMMR) protein expression and microsatellite instability-high (MSI-H) were 23.8% (5/21) and 71.4% (5/7), respectively. Forty-four patients underwent radical surgery. Fifty-five patients received chemotherapy and six patients received radiotherapy. One dMMR/MSI-H rectal cancer patient received immunotherapy and achieved a clinically complete response. The median overall survival (OS) time was 80 months. The 3-year and 5-year OS rates were 61.8% and 57.2%, respectively. An absence of distant metastasis was a favorable factor for OS. For stage II/III CRCs, classic adenocarcinoma and radical surgery were favorable factors for OS. For stage IV CRCs, primary location at the colon was a favorable factor for OS.
Conclusion
Child and adolescent CRC patients are likely to have distant metastasis, undifferentiated, left hemicolon location, and a dMMR/MSI-H phenotype at diagnosis. Additional efforts are needed to improve their survival outcomes.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
BackgroundDickkopf 1 (DKK1) is associated with tumor progression. However, whether DKK1 influences the tumor response to programmed cell death protein 1 (PD-1) blockade in colorectal cancers (CRCs) ...with deficient mismatch repair (dMMR) or microsatellite instability (MSI) has never been clarified.MethodsTumor tissues from 80 patients with dMMR CRC were evaluated for DKK1 expression and immune status via immunohistochemistry. Serum DKK1 was measured in another set of 43 patients who received PD-1 blockade therapy. CT26 cells and dMMR CRC organoids were cocultured with T cells, and CT26-grafted BALB/c mice were also constructed. T-cell cytotoxicity was assessed by apoptosis assays and flow cytometry. The pathway through which DKK1 regulates CD8+ T cells was investigated using RNA sequencing, and chromatin immunoprecipitation and luciferase reporter assays were conducted to determine the downstream transcription factors of DKK1.ResultsElevated DKK1 expression was associated with recurrence and decreased CD8+ T-cell infiltration in dMMR CRCs, and patients with high-serum DKK1 had a poor response to PD-1 blockade. RNA interference or neutralization of DKK1 in CRC cells enhanced CD8+ T-cell cytotoxicity, while DKK1 decreased T-bet expression and activated GSK3β in CD8+ T cells. In addition, E2F1, a downstream transcription factor of GSK3β, directly upregulated T-bet expression. In organoid models, the proportion of apoptotic cells was elevated after individual neutralization of PD-1 or DKK1 and was further increased on combined neutralization of PD-1 and DKK1.ConclusionsDKK1 suppressed the antitumor immune reaction through the GSK3β/E2F1/T-bet axis in CD8+ T cells. Elevated serum DKK1 predicted poor tumor response to PD-1 blockade in dMMR/MSI CRCs, and DKK1 neutralization may restore sensitivity to PD-1 blockade.
Background:
To date, the prognostic significance of acellular mucin pools in tumors from patients with locally advanced rectal cancer (LARC) undergoing preoperative chemoradiotherapy (CRT) and ...subsequently obtaining pathological complete response (pCR) has not been well determined. Our current study aimed to explore the prognostic impact on these patients of acellular mucin pools.
Methods:
We collected clinical data from 117 consecutive LARC patients who achieved pCR after preoperative CRT and then underwent radical resection. Two groups of patients were generated, according to the presence or absence of acellular mucin pools. The 5-year disease-free survival (DFS) and overall survival (OS) rates were compared between the two groups of patients.
Results:
A total of 27 (23.1%) patients presented with acellular mucin pools. At a median follow-up period of 64 months, patients with acellular mucin pool showed a 5-year DFS rate (96.3% versus 83.7%, p = 0.110) and 5-year OS rate (100% versus 87.5%, p = 0.054) statistically similar to those of patients without acellular mucin pools. In univariable and multivariable Cox regression analyses, the presence of acellular mucin pools was not determined as an independent risk factor for DFS hazard ratio (HR): 0.222; 95% confidence interval (CI): 0.029–1.864; p = 0.145 or OS (HR: 0.033; 95% CI: 0.000–9.620; p = 0.238).
Conclusions:
Acellular mucin pools had no significant prognostic impact on LARC patients showing pCR after preoperative CRT.
Background:
Several issues on neoadjuvant imatinib therapy remain controversial despite its widespread application for rectal gastrointestinal stromal tumors (GIST). We aimed to describe the ...clinicopathological characteristics of this specific population, and compare the surgical and oncologic outcomes between patients with or without neoadjuvant imatinib therapy.
Patients and methods:
A cohort of 58 consecutive locally advanced rectal GIST patients receiving surgical treatment between January 2007 and July 2019 at Sun Yat-sen University Cancer Center and Yunnan Cancer Hospital was retrospectively analyzed. Recurrence-free survival (RFS) and overall survival (OS) were estimated using Kaplan-Meier method.
Results:
There were 33 (56.9%) patients who received neoadjuvant imatinib therapy. Among them, 20 (60.6%) patients had partial response (PR) as their best response, 11 (33.3%) patients had stable disease (SD), and 2 (6.1%) patients had progressive disease (PD). The median tumor size reduced from 5.2 to 4.0 cm after treatment (
p
< 0.001), and an attained “maximal response” was primarily achieved (32/33) on the 12th month after treatment. The most common adverse event was anemia. There were 27 adverse events occurred, most of which were grade 1 (19/27). With respect to intraoperative and postoperative surgical outcomes, no significant difference was found between patients with or without neoadjuvant Imatinib therapy except that patients with neoadjuvant treatment had a significant higher rate of preventive ileostomy (
p
= 0.004). Patients received neoadjuvant treatment had a superior 2-years RFS outcome than those without, though the difference was no significant (91.7% vs. 78.9%,
p
= 0.203). There were no significant differences in the 2-years OS rates (95.2% vs. 91.3%,
p
= 0.441).
Conclusion:
Neoadjuvant imatinib therapy is an effective and safe treatment for locally advanced rectal GISTs. Further studies are warranted to validate the long-term prognostic benefit for patients with rectal GISTs receiving neoadjuvant imatinib therapy.
Introduction: DNA ploidy (P), stroma fraction (S), and nucleotyping (N) collectively known as PSN, have proven prognostic accuracy in stage II colorectal cancer (CRC). However, few studies have ...reported on the prognostic value of the PSN panel in stage III colon cancer patients receiving capecitabine and oxaliplatin adjuvant chemotherapy. Objectives: This study aimed to validate PSN’s prognostic impact on stage III colon cancer, identifying candidates for optimized adjuvant chemotherapy duration. Design: A retrospective analysis was conducted on a cohort of stage III colon cancer patients from April 2008 to June 2020. Methods: Postoperative pathological samples from stage III colon cancer patients who underwent radical surgery and postoperative adjuvant chemotherapy at Sun Yat-sen University Cancer Center were retrospectively collected. Automated digital imaging assessed PSN, categorizing risk groups. Kaplan–Meier, Cox regression, and time-dependent receiver operating characteristic analysis compared model validity. Results: Significant differences in 5-year disease-free survival (DFS) and overall survival (OS) were noted among PSN-based low-, moderate-, and high-risk groups (DFS: 92.10% versus 83.62% versus 79.80%, p = 0.029; OS: 96.69% versus 93.99% versus 90.12%, p = 0.016). PSN emerged as an independent prognostic factor for DFS hazard ratio (HR) = 1.409, 95% confidence interval (CI): 1.002–1.981, p = 0.049 and OS (HR = 1.720, 95% CI: 1.127–2.624, p = 0.012). The PSN model, incorporating perineural invasion and tumor location, displayed superior area under the curve for 5-year (0.692 versus 0.553, p = 0.020) and 10-year (0.694 versus 0.532, p = 0.006) DFS than TNM stage. In the PSN high-risk group, completing eight cycles of adjuvant chemotherapy significantly improved 5-year DFS and OS compared to four to seven cycles (DFS: 89.43% versus 71.52%, p = 0.026; OS: 96.77% versus 85.46%, p = 0.007). Conclusion: The PSN panel effectively stratifies stage III colon cancer, aiding in optimized adjuvant chemotherapy duration determination.
Objectives:
Gamma glutamyl-transpeptidase (GGT) has been shown as a prognostic marker in many cancers. The aim of this study was to explore whether serum GGT could predict tumor recurrence in ...patients with liver-confined colorectal cancer liver metastases (CRCLM) undergoing R0 resection.
Methods:
We reviewed patients who had underwent liver surgery for CRCLM. Patients with liver-only metastases that underwent R0 resection were included. Pre-operative serum GGT were classified into either high or low using a cut-off value of 33 U/L for female and 51 U/L for male. Relapse-free survival (RFS) was compared in relation to GGT and other clinicopathological factors.
Results:
Of the 350 patients included, 108 (30.9%) had a high serum GGT. Patients with metachronous liver metastases, number of metastases ⩾2, size of the largest metastasis ⩾3 cm, or a history of neoadjuvant chemotherapy had a higher GGT level (p = 0.001, 0.027, 0.001, and 0.002, respectively). In survival analyses, patients with a high GGT had a shorter RFS than those with a low GGT, with a median RFS of 11.8 versus 30.3 months (p < 0.001). RFS was also associated with the number of metastases, size of the largest metastasis and the delivery of neoadjuvant chemotherapy. In multivariate analysis, GGT remained an independent prognostic factor of RFS.
Conclusions:
Our study demonstrates that the serum GGT level before liver surgery is an adverse prognostic factor of RFS for patients with liver-confined CRCLM.
Histopathological growth patterns (HGPs) have shown important prognostic values for patients with colorectal cancer liver metastases, but the potential molecular mechanisms remain largely unknown.
We ...performed an exploratory analysis by conducting the RNA sequencing of primary colorectal lesions, colorectal liver metastatic lesions and normal liver tissues.
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.
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.
Gad2 encodes GAD65, which is present preferentially in presynaptic terminals for synthesis of GABA for vesicle release. Gad2 is a regulatory target of cell activities in various brain functions and ...in GABA perturbation-related neurological diseases. However, our understanding of how Gad2 is transcriptionally regulated and how Gad2 transcription responds to changing cell environment under these conditions is still limited. This review discusses recent advances in the regulatory mechanisms for Gad2 transcription and highlights the characteristics of TATA-less Gad2 promoters and regulation of Gad2 transcription by CREB and by activity-dependent epigenetic modification of the chromatin structure in regulatory elements of the Gad2 gene.
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BFBNIB, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
The number of colorectal cancer liver metastases (CRLMs) is usually considered a contradictory indicator to surgical resection. However, some patients with initially unresectable CRLMs can ...receive radical local treatment after conversion therapy. This study aimed to evaluate the effect of radical local treatment after conversion therapy and the prognosis of patients with more than 10 initially unresectable CRLMs.
Methods
Data for a total of 229 patients with initially unresectable CRLMs were retrospectively reviewed between December 2012 and January 2020. Among these patients, 107 had ≥10 CRLMs, and 122 had <10 CRLMs. Overall survival (OS) and progression‐free survival (PFS) were used to reflect the prognosis of different groups of patients. Conversion therapy was defined as an initially unresectable liver metastasis converted into an R0 resectable lesion after systemic chemotherapy. Radical local treatment included hepatectomy and radiofrequency ablation (RFA).
Results
Patients with ≥10 CRLMs had a lower conversion rate (42.7% vs. 56.6%, p = 0.001). Baseline clinical N stage 1–2, ≥8 first‐line chemotherapy courses, and stable disease (SD) according to the Response Evaluation Criteria in Solid Tumours (RECIST) were independent factors predictive of conversion failure. Primary tumour location in the right colon, RECIST response of SD, and the absence of targeted therapy were independent factors predictive of unfavourable OS. The survival curves revealed that the OS of patients with or without conversion could be distinguished only among patients with <10 CRLMs (89.9% 95% CI, 82.5%–98.0% vs. 58.9% 95% CI, 45.2%–76.7%, p < 0.001); this cut‐off point could also distinguish patients with a successful conversion outcome according to OS (89.9% 95% CI, 82.5–98.0% vs. 58.2% 95% CI, 42.2–80.4%, p = 0.008).
Conclusion
For CRLMs ≥ 10, patients with a successful conversion outcome cannot be distinguished from those without successful conversion outcome according to OS. Thus, conversion therapy with the intent to perform radical local treatment may not be suitable for patients with 10 or more liver metastases from colorectal cancer.
In clinical practice, radical local treatment is still doutble for the primary treatment option for patients with more than 10 initially unresectable liver metastases from colorectal cancer.We find out conversion therapy with the intent to perform radical local treatment may not be suitable for patients with 10 or more liver metastases from colorectal cancer.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Our previous study reported the favorable efficacy and good tolerance associated with a modified XELOX adjuvant chemotherapy with eight cycles of capecitabine and six cycles of oxaliplatin for ...operated stage III colon cancer. The current study aimed to confirm the feasibility of modified XELOX chemotherapy for treating specific high-risk (T4, N2, or both) stage III colon cancer.
We selected 142 consecutive patients with high-risk stage III colon cancer who received colon tumor resection followed by modified XELOX or standard full-cycle XELOX chemotherapy from November 2007 to June 2016 at Sun Yat-sen University Cancer Center. Disease-free survival (DFS), overall survival (OS), and adverse events of patients treated with the two chemotherapy regimens were compared.
Seventy-four (52.1%) patients received standard XELOX chemotherapy, and 68 (47.8%) received modified XELOX chemotherapy. Neurotoxicity was the most common adverse event in 99 (69.7%) patients. Grade 2-3 neurotoxicity, grade 2-4 thrombocytopenia and grade 3-4 leucopenia were the major severe adverse events related to the decision to treat patients with modified XELOX chemotherapy. After a median follow-up of 69 months, the modified XELOX group presented a comparable 5-year DFS rate (79.0 vs. 80.3%, P = 0.891) and 5-year OS rate (93.8 vs. 87.8%, P = 0.446) as those in the standard XELOX group. Univariate survival analysis indicated that poor tumor differentiation (HR: 2.381, 95% CI: 1.141-4.968, P = 0.021) was the only significant risk factor for DFS, but no significant prognostic factor was identified for OS.
The modified XELOX adjuvant chemotherapy presented a comparable oncologic efficacy as standard XELOX chemotherapy for high-risk stage III colon cancer. The modified XELOX adjuvant chemotherapy could be an alternative treatment for patients suffering severe adverse events, especially severe neurotoxicity.
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