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2024, 36(6): 587-591.
doi: 10.21147/j.issn.1000-9604.2024.06.01
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Abstract:
2024, 36(6): 592-595.
doi: 10.21147/j.issn.1000-9604.2024.06.02
Abstract:
Microbiota and urinary tumor immunity: Mechanisms, therapeutic implications, and future perspectives
2024, 36(6): 596-615.
doi: 10.21147/j.issn.1000-9604.2024.06.03
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2024, 36(6): 616-651.
doi: 10.21147/j.issn.1000-9604.2024.06.04
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Exhausted T cell (Tex) is a specific state of T cell dysfunction, in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation. The enrichment of exhausted CD8+ T cell (CD8+ Tex) in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy. Recent studies have reported many reasons leading to the CD8+ T cell exhaustion. In addition to cancer cells, myeloid cells can also contribute to T cell exhaustion via many ways. In this review, we discuss the history of the concept of exhaustion, CD8+ T cell dysfunction states, the heterogeneity, origin, and characteristics of CD8+ Tex. We then focus on the effects of myeloid cells on CD8+ Tex, including tumor-associated macrophages (TAMs), dendritic cells (DCs) and neutrophils. Finally, we systematically summarize current strategies and recent advancements in therapies reversing and CD8+ T cell exhaustion.
Exhausted T cell (Tex) is a specific state of T cell dysfunction, in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation. The enrichment of exhausted CD8+ T cell (CD8+ Tex) in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy. Recent studies have reported many reasons leading to the CD8+ T cell exhaustion. In addition to cancer cells, myeloid cells can also contribute to T cell exhaustion via many ways. In this review, we discuss the history of the concept of exhaustion, CD8+ T cell dysfunction states, the heterogeneity, origin, and characteristics of CD8+ Tex. We then focus on the effects of myeloid cells on CD8+ Tex, including tumor-associated macrophages (TAMs), dendritic cells (DCs) and neutrophils. Finally, we systematically summarize current strategies and recent advancements in therapies reversing and CD8+ T cell exhaustion.
2024, 36(6): 652-668.
doi: 10.21147/j.issn.1000-9604.2024.06.05
Abstract:
Lipid metabolic reprogramming is considered one of the most prominent metabolic abnormalities in cancer, and fatty acid metabolism is a key aspect of lipid metabolism. Recent studies have shown that fatty acid metabolism and its related lipid metabolic pathways play important roles in the malignant progression of nasopharyngeal carcinoma (NPC). NPC cells adapt to harsh environments by enhancing biological processes such as fatty acid metabolism, uptake, production, and oxidation, thereby accelerating their growth. In addition, the reprogramming of fatty acid metabolism plays a central role in the tumor microenvironment (TME) of NPC, and the phenotypic transformation of immune cells is closely related to fatty acid metabolism. Moreover, the reprogramming of fatty acid metabolism in NPC contributes to immune escape, which significantly affects disease treatment, progression, recurrence, and metastasis. This review explores recent advances in fatty acid metabolism in NPC and focuses on the interconnections among metabolic reprogramming, tumor immunity, and corresponding therapies. In conclusion, fatty acid metabolism represents a potential target for NPC treatment, and further exploration is needed to develop strategies that target the interaction between fatty acid metabolic reprogramming and immunotherapy.
Lipid metabolic reprogramming is considered one of the most prominent metabolic abnormalities in cancer, and fatty acid metabolism is a key aspect of lipid metabolism. Recent studies have shown that fatty acid metabolism and its related lipid metabolic pathways play important roles in the malignant progression of nasopharyngeal carcinoma (NPC). NPC cells adapt to harsh environments by enhancing biological processes such as fatty acid metabolism, uptake, production, and oxidation, thereby accelerating their growth. In addition, the reprogramming of fatty acid metabolism plays a central role in the tumor microenvironment (TME) of NPC, and the phenotypic transformation of immune cells is closely related to fatty acid metabolism. Moreover, the reprogramming of fatty acid metabolism in NPC contributes to immune escape, which significantly affects disease treatment, progression, recurrence, and metastasis. This review explores recent advances in fatty acid metabolism in NPC and focuses on the interconnections among metabolic reprogramming, tumor immunity, and corresponding therapies. In conclusion, fatty acid metabolism represents a potential target for NPC treatment, and further exploration is needed to develop strategies that target the interaction between fatty acid metabolic reprogramming and immunotherapy.
2024, 36(6): 669-682.
doi: 10.21147/j.issn.1000-9604.2024.06.06
Abstract:
Gastric cancer (GC) ranks 3rd in incidence rate and mortality rate among malignant tumors in China, and the age-standardized five-year net survival rate of patients with GC was 35.9% from 2010 to 2014. The tumor immune microenvironment (TIME), which includes T cells, macrophages, natural killer (NK) cells and B cells, significantly affects tumor progression, immunosuppression and drug resistance in patients with GC. In recent years, immunotherapy has become the first-line or second-line treatment for GC. Lysine-specific demethylase 1 (LSD1, also known as KDM1A) was the first identified human histone demethylase, and high expression of LSD1 in GC is closely related to the dysfunction of the above types of immune cells. Therefore, LSD1 inhibitors could regulate the cytotoxic effects of immune cells against tumor cells through a variety of mechanisms to control tumor progression. In this review, we discuss the effects of LSD1 inhibitors on immune cells in GC and propose LSD1 as a new potential target for immunotherapy in GC.
Gastric cancer (GC) ranks 3rd in incidence rate and mortality rate among malignant tumors in China, and the age-standardized five-year net survival rate of patients with GC was 35.9% from 2010 to 2014. The tumor immune microenvironment (TIME), which includes T cells, macrophages, natural killer (NK) cells and B cells, significantly affects tumor progression, immunosuppression and drug resistance in patients with GC. In recent years, immunotherapy has become the first-line or second-line treatment for GC. Lysine-specific demethylase 1 (LSD1, also known as KDM1A) was the first identified human histone demethylase, and high expression of LSD1 in GC is closely related to the dysfunction of the above types of immune cells. Therefore, LSD1 inhibitors could regulate the cytotoxic effects of immune cells against tumor cells through a variety of mechanisms to control tumor progression. In this review, we discuss the effects of LSD1 inhibitors on immune cells in GC and propose LSD1 as a new potential target for immunotherapy in GC.
2024, 36(6): 683-699.
doi: 10.21147/j.issn.1000-9604.2024.06.07
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As a key component of tumor microenvironment, the microbiota has gradually played a key role in cancer research. Particularly in colorectal cancer, the specific population of microbiota within the tumor shows a strong association with the tumor type. Although the existence and potential role of microbiota in tumors have been recognized, the specific associations between the microbiota and tumor tissue and the mechanism of action still need to be further explored. This paper reviews the discovery, origin, and emerging role of the intratumor microbiota in the immune microenvironment and systematically outlines the oncogenic and metastasis-promoting strategies of the intratumor microbiota. Moreover, it comprehensively and holistically evaluates therapeutic strategies and prognostic performance on the basis of the intratumor microbiota, with the goal of providing strong support for future research and clinical practice.
As a key component of tumor microenvironment, the microbiota has gradually played a key role in cancer research. Particularly in colorectal cancer, the specific population of microbiota within the tumor shows a strong association with the tumor type. Although the existence and potential role of microbiota in tumors have been recognized, the specific associations between the microbiota and tumor tissue and the mechanism of action still need to be further explored. This paper reviews the discovery, origin, and emerging role of the intratumor microbiota in the immune microenvironment and systematically outlines the oncogenic and metastasis-promoting strategies of the intratumor microbiota. Moreover, it comprehensively and holistically evaluates therapeutic strategies and prognostic performance on the basis of the intratumor microbiota, with the goal of providing strong support for future research and clinical practice.
2024, 36(6): 700-712.
doi: 10.21147/j.issn.1000-9604.2024.06.08
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ObjectiveThis study investigated the clinical significance of DICER1 mutations in patients with distant metastatic follicular cell-derived thyroid cancer (FDTC). MethodsThis study included 310 Chinese patients with distant metastatic FDTC. We analyzed the interactions between DICER1 mutations and other gene alterations and compared the clinicopathological characteristics of patients with pathogenic (P) or likely pathogenic (LP) DICER1 mutations (n=9), other gene alterations (n=253), and no gene alterations (n=37). To compare FDTCs with different drivers, isolated BRAFV600E, RAS mutations, and RET fusions were compared with isolated DICER1 mutations. ResultsThe prevalence of DICER1 mutations was 6.5% (20/310) in the patient cohort. Among patients with DICER1 mutations, 45% (9/20) harbored P or LP DICER1 variants and 55% (11/20) harbored DICER1 variants of uncertain significance (VUS). The coexistence of DICER1 mutations and other gene alterations was detected in 65% (13/20) of patients. Compared with VUS, P or LP DICER1 variants were almost mutually exclusive with early driver alterations (such as BRAFV600E) (11.1% vs. 81.8%, P=0.002) and more coexisted with late-hit events, particularly TP53 mutations (44.4% vs. 27.3%, P=0.642). Clinically, compared with the no alteration and other alteration groups, the DICER1 mutation group exhibited larger primary tumors, higher poorly differentiated thyroid cancer proportion, more extrathyroidal extension, more extrapulmonary metastases, and higher radioactive iodine-refractory proportion (all P<0.05). Cases with isolated DICER1 mutations differed from those with isolated BRAFV600E and RET fusions in terms of tumor size, poorly differentiated thyroid cancer proportion, and metastatic sites, but were similar to cases with isolated RAS mutations in the high proportion of follicular thyroid cancer, N0, and extrapulmonary metastases. ConclusionsMutation of DICER1 gene is a non-negligible molecular event and it may represent an aggressive subset of FDTCs. DICER1 has RAS-like clinical characteristics and DICER1-mutant tumors exhibit more aggressive clinical behaviors compared with those with BRAFV600E and RET fusions.
2024, 36(6): 713-728.
doi: 10.21147/j.issn.1000-9604.2024.06.09
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ObjectiveBased on the findings of the KEYNOTE-048 study, pembrolizumab in combination with platinum and fluorouracil is the standard first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). The efficacy and safety of pembrolizumab combined with nab-paclitaxel and platinum in such patients remain unexplored. MethodsThis single-arm phase 2 study enrolled patients with R/M HNSCC who received pembrolizumab (200 mg), nab-paclitaxel (260 mg/m²), and either cisplatin (75 mg/m²) or carboplatin [area under the curve (AUC) 5] every 21 d for up to six cycles, followed by pembrolizumab maintenance therapy. The primary endpoint was the objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. Exploratory multi-omics analyses were conducted. ResultsBetween April 23, 2021, and August 20, 2023, a total of 67 patients with R/M HNSCC were enrolled and received the study treatment. By the data cut-off date of March 2, 2024, 62 (92.5%) patients had received cisplatin, while five (7.5%) patients had received carboplatin. The median follow-up duration was 12.7 (range: 2.3−34.8) months. The ORR was 62.7%, and the DCR was 88.1%. The median PFS, DoR, and OS were 9.7, 13.0, and 18.7 months, respectively. The most common grade 3 adverse events (AEs) were leukopenia (22.4%) and neutropenia (28.4%). Genomic alterations correlated with efficacy outcomes, and dynamic changes in 17 plasma proteins were associated with treatment response. Upregulation of serum interferon (IFN)-γ and interleukin (IL) 8 levels was linked to treatment-related AEs. ConclusionsPembrolizumab in combination with nab-paclitaxel and platinum demonstrated promising efficacy and a manageable safety profile in patients with R/M HNSCC. Future studies are warranted to confirm these findings.
2024, 36(6): 729-741.
doi: 10.21147/j.issn.1000-9604.2024.06.10
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ObjectiveTo explore the prognosis-predictive influence of human epidermal growth factor receptor 2 (HER2)-low status in breast cancer patients after neoadjuvant therapy (NAT). MethodsConsecutive patients with invasive breast cancer who underwent NAT and surgery from January 2009 to December 2020 at multiple centers were included. A modified CPS+EG scoring system that integrates HER2-low status, CPS+EGHlow was developed. Multiple scoring systems were compared via receiver operating characteristic curves with the area under curve (AUC), the Akaike information criterion, the C-index, and calibration curves. ResultsA total of 2,141 patients were included: 1,074, 640, and 427 patients in the training, internal validation, and external validation groups, respectively. HER2-low patients had a significantly better breast cancer-specific survival (BCSS, P=0.008) and recurrence-free interval (RFI, P=0.030) compared to HER2-zero patients (P=0.038) but inferior outcomes than HER2-amplified ones (BCSS, P=0.002; RFI, P<0.001). The CPS+EGHlow (AUC: 0.846, 0.817, 0.901) could stratify patients according to BCSS in training, internal validation, and external validation group, respectively, overperforming pathological stage (PS) (AUC: 0.746, 0.779, 0.754), CPS+EG (AUC: 0.771, 0.752, 0.748), and Neo-Bioscore (AUC: 0.783, 0.777, 0.786, all P<0.05). ConclusionsHER2-low status showed a significant prognostic value in breast cancer patients after NAT. The CPS+EGHlow model significantly outperformed PS, CPS+EG, and Neo-Bioscore in clinical outcome prediction, which may guide further therapy targeting HER2-low.
2024, 36(6): 742-751.
doi: 10.21147/j.issn.1000-9604.2024.06.11
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ObjectiveThe laparoscopic approach for locally advanced gastric cancer has recently been adopted based on the results of several randomized controlled trials (RCTs). However, findings from RCTs have not been examined at the national level. This study aimed to investigate the external validity of the Korean Laparoscopic Gastrointestinal Surgery Study-02 (KLASS-02) trial involving 13 tertiary hospitals, using data from the Korean Gastric Cancer Association (KGCA)-led nationwide survey involving 68 tertiary or general hospitals. MethodsData on patients who underwent laparoscopic or open distal gastrectomy for pathological stage IB−IIIC gastric cancer under the same conditions were collected from the KLASS-02 trial and the KGCA nationwide survey datasets. Surgical outcomes were assessed for each dataset and multivariable analyses were performed to examine the effect of the laparoscopic approach on surgical outcomes. ResultsThe laparoscopic group had a lower overall complication rate than the open group in both KLASS-02 and KGCA datasets (16.1% vs. 23.5% for the KLASS-02 and 12.6% vs. 19.6% for the KGCA). Moreover, the laparoscopic group had fewer wound problems, and fewer grade II, IIIa, and IV complications than the open group in the KGCA data (0.8% vs. 3.4%, 5.8% vs. 10.4%, 2.3% vs. 3.7%, and 0.5% vs. 1.4%, respectively), which were not observed in the KLASS-02 data. Multivariable analyses revealed that the laparoscopic approach was not associated with overall complications, but reduced wound problems and more harvested lymph nodes in the KGCA survey data (adjusted odds ratios, 0.19 for wound problems, adjusted β coefficient 4.39 for number of harvested lymph nodes), which were not shown in the KLASS-02 data. ConclusionsThe safety and feasibility of the laparoscopic approach for locally advanced gastric cancer were validated at a national level. The laparoscopic approach for locally advanced gastric cancer can be implemented in the Republic of Korea.
2024, 36(6): 752-767.
doi: 10.21147/j.issn.1000-9604.2024.06.12
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ObjectiveData on the global, regional and national changes in the trends of colorectal cancer (CRC) are analyzed to understand the trends in its burden, in order to assist policymakers in allocating healthcare resources and developing prevention and control strategies. MethodsThis study analyzed trends in age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), and disability-adjusted life years (DALYs) for CRC from 1990 to 2021 using data from the Global Burden of Disease (GBD) 2021 database. The trends of burden and effectiveness of control strategies were assessed using jointpoint regression analysis, decomposition analysis and frontier analysis. ResultsGlobally, the ASMR and age-standardized DALYs for CRC have shown a declining trend, but the ASIR was still increasing. The number of new cases of CRC in 2021 was higher in males than in females, the values were 1,263.46 thousands [95% confidence interval (95% CI): 1,146.50, 1,400.38] vs. 930.68 thousands (95% CI: 824.67, 1,017.65). The change in DALYs was mainly due to population growth (111.42%). The high socio-demographic index (SDI) region had an ASIR of 40.52 (95% CI: 37.45, 42.45), and the low SDI region had an ASIR of 7.39 (95% CI: 6.65, 8.19). The ASIR for CRC showed an upward trend in all SDI regions before age of 40 years. Among the four world regions, only America showed a downward trend in ASIR, with an estimated annual percentage change (EAPC) of −0.62 (95% CI: −0.71, −0.53). Among the 204 countries and territories, Netherlands, Monaco, and Bermuda were the top 3 countries with the highest ASIR in 2021. In the frontier analysis of DALYs, the 10 countries with the longest effective distances all had SDI levels above 0.70. ConclusionsAlthough ASMR and age-standardized DALYs are declining, ASIR is still increasing globally and in many regions. The burden of CRC varies significantly across the globe, and more targeted screening strategies and prevention measures are needed to address the problem of CRC.
2024, 36(6): 768-780.
doi: 10.21147/j.issn.1000-9604.2024.06.13
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ObjectiveColorectal cancer (CRC) surgeries can be performed using either laparoscopic or open laparotomy approaches. However, the long-term outcomes based on tumor location and age remain unclear. This study compared the long-term outcomes of laparoscopic and laparotomy surgeries in patients with CRC, focusing on tumor location and age to identify suitable subgroups and determine an optimal cut-off age. MethodsThis retrospective study analyzed 2,014 patients with CRC who underwent radical surgery. Patients were categorized into laparoscopy and laparotomy groups, and propensity score matching (PSM) was performed. Kaplan-Meier analysis, log-rank tests, and Cox regression models were used to identify the independent factors affecting overall survival (OS). ResultsAnalysis results before PSM indicated higher OS in the laparoscopy group (P=0.035); however, it was no significant difference in mean OS between the two groups after PSM analysis. Cox regression analysis identified several factors influencing the OS of patients with CRC, with age, T stage, nodal involvement, poorly differentiated adenocarcinoma, ascites, preoperative intestinal obstruction, and local tumor spread as independent risk factors. Family history was a protective factor [hazard ratio (HR)=0.33; 95% CI, 0.16−0.68; P=0.002], and the surgical modality did not independently affect OS. The subgroup analysis highlighted the advantages of laparoscopic surgery in specific subgroups. ConclusionsOverall, laparoscopic and laparotomy surgeries resulted in similar mid- and long-term prognoses for patients with CRC. Laparoscopic surgery showed better outcomes in specific subgroups, particularly in patients aged >60 years and in those with right-sided colon carcinoma. This study suggests that age >64 years might be the optimal cut-off age for laparoscopic surgery.
