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1.
EMBO J ; 41(22): e110712, 2022 11 17.
Article in English | MEDLINE | ID: mdl-36254590

ABSTRACT

Bone marrow (BM)-resident hematopoietic stem and progenitor cells (HSPCs) are often activated following bacterial insults to replenish the host hemato-immune system, but how they integrate the associated tissue damage signals to initiate distal tissue repair is largely unknown. Here, we show that acute gut inflammation expands HSPCs in the BM and directs them to inflamed mesenteric lymph nodes through GM-CSFR activation for further expansion and potential differentiation into Ly6C+ /G+ myeloid cells specialized in gut tissue repair. We identified this process to be mediated by Bacteroides, a commensal gram-negative bacteria that activates innate immune signaling. These findings establish cross-organ communication between the BM and distant inflamed sites, whereby a certain subset of multipotent progenitors is specified to respond to imminent hematopoietic demands and to alleviate inflammatory symptoms.


Subject(s)
Hematopoietic Stem Cells , Inflammation , Humans , Hematopoietic Stem Cells/physiology , Inflammation/pathology , Cell Differentiation , Signal Transduction , Myeloid Cells/pathology
2.
Lancet ; 404(10447): 55-66, 2024 Jul 06.
Article in English | MEDLINE | ID: mdl-38876133

ABSTRACT

BACKGROUND: Neoadjuvant therapy is the standard treatment for patients with locally advanced oesophageal squamous cell carcinoma (OSCC). However, the prognosis remains poor and more intensive neoadjuvant treatment might be needed to improve patient outcomes. We therefore aimed to compare the efficacy and safety of neoadjuvant doublet chemotherapy, triplet chemotherapy, and doublet chemotherapy plus radiotherapy in patients with previously untreated locally advanced OSCC. METHODS: In this randomised, open-label, phase 3 trial, patients aged 20-75 years with previously untreated locally advanced OSCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 44 centres across Japan. Patients were randomly assigned (1:1:1) centrally via a web-based system to receive neoadjuvant doublet chemotherapy (two courses of fluorouracil [800 mg/m2 per day intravenously on days 1-5] and cisplatin [80 mg/m2 per day on day 1] separated by an interval of 3 weeks [NeoCF]), triplet chemotherapy (three courses of fluorouracil [750 mg/m2 per day on days 1-5], cisplatin [70 mg/m2 per day on day 1], and docetaxel [70 mg/m2 per day on day 1] repeated every 3 weeks [NeoCF+D]), or doublet chemotherapy (two courses of fluorouracil [1000 mg/m2 per day on days 1-4] and cisplatin [75 mg/m2 per day on day 1] separated by an interval of 4 weeks) plus 41·4 Gy radiotherapy [NeoCF+RT]) followed by oesophagectomy with regional lymph node dissection. Randomisation was stratified by T stage and institution. Participants, investigators, and those assessing outcomes were not masked to group assignment. The primary endpoint was overall survival, analysed by intention to treat. Analysis of safety included all patients who received at least one course of chemotherapy, and analysis of surgical complications included those who also underwent surgery. This study is registered with the Japan Registry of Clinical Trials, jRCTs031180202, and the trial is complete. FINDINGS: A total of 601 patients (529 male individuals and 72 female individuals) were randomly assigned between Dec 5, 2012, and July 20, 2018, with 199 patients in the NeoCF group, 202 patients in the NeoCF+D group, and 200 patients in the NeoCF+RT group. Compared with the NeoCF group, during a median follow-up period of 50·7 months (IQR 23·8-70·7), the 3-year overall survival rate was significantly higher in the NeoCF+D group (72·1% [95% CI 65·4-77·8] vs 62·6% [55·5-68·9]; hazard ratio [HR] 0·68, 95% CI 0·50-0·92; p=0·006) but not in the NeoCF+RT group (68·3% [61·3-74·3]; HR 0·84, 0·63-1·12; p=0·12). Grade 3 or higher febrile neutropenia occurred in two (1%) of 193 patients in the NeoCF group, 32 (16%) of 196 patients in the NeoCF+D group, and nine (5%) of 191 patients in the NeoCF+RT group. Treatment-related adverse events leading to termination of neoadjuvant therapy were more common in the NeoCF+D group (18 [9%] of 202 participants) than in the NeoCF+RT group (12 [6%] of 200) and NeoCF group (eight [4%] of 199). There were three (2%) treatment-related deaths during neoadjuvant therapy in the NeoCF group, four (2%) deaths in the NeoCF+D group, and two (1%) deaths in the NeoCF+RT group. Grade 2 or higher postoperative pneumonia, anastomotic leak, and recurrent laryngeal nerve paralysis were reported in 19 (10%), 19 (10%), and 28 (15%) of 185 patients, respectively, in the NeoCF group; 18 (10%), 16 (9%), and 19 (10%) of 183 patients, respectively, in the NeoCF+D group; and 23 (13%), 23 (13%), and 17 (10%) of 178 patients, respectively, in the NeoCF+RT group. The in-hospital deaths following surgery included three deaths in the NeoCF group, two deaths in the NeoCF+D group, and one in the NeoCF+RT group. INTERPRETATION: Neoadjuvant triplet chemotherapy followed by oesophagectomy resulted in a statistically significant overall survival benefit compared with doublet chemotherapy and might be the new standard of care for locally advanced OSCC who are in good condition in Japan. Neoadjuvant doublet chemotherapy plus radiotherapy did not show significant improvement of survival compared with doublet chemotherapy. FUNDING: Japan Agency for Medical Research and Development and National Cancer Center Research and Development Fund.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Cisplatin , Docetaxel , Esophageal Neoplasms , Fluorouracil , Neoadjuvant Therapy , Humans , Middle Aged , Esophageal Neoplasms/therapy , Esophageal Neoplasms/pathology , Esophageal Neoplasms/mortality , Male , Female , Neoadjuvant Therapy/methods , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Fluorouracil/administration & dosage , Fluorouracil/therapeutic use , Aged , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Docetaxel/administration & dosage , Docetaxel/therapeutic use , Adult , Esophageal Squamous Cell Carcinoma/therapy , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/mortality , Chemoradiotherapy/methods , Esophagectomy
3.
Int J Cancer ; 155(3): 582-594, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-38380807

ABSTRACT

The proto-oncogene MYCN expression marked a cancer stem-like cell population in hepatocellular carcinoma (HCC) and served as a therapeutic target of acyclic retinoid (ACR), an orally administered vitamin A derivative that has demonstrated promising efficacy and safety in reducing HCC recurrence. This study investigated the role of MYCN as a predictive biomarker for therapeutic response to ACR and prognosis of HCC. MYCN gene expression in HCC was analyzed in the Cancer Genome Atlas and a Taiwanese cohort (N = 118). Serum MYCN protein levels were assessed in healthy controls (N = 15), patients with HCC (N = 116), pre- and post-surgical patients with HCC (N = 20), and a subset of patients from a phase 3 clinical trial of ACR (N = 68, NCT01640808). The results showed increased MYCN gene expression in HCC tumors, which positively correlated with HCC recurrence in non-cirrhotic or single-tumor patients. Serum MYCN protein levels were higher in patients with HCC, decreased after surgical resection of HCC, and were associated with liver functional reserve and fibrosis markers, as well as long-term HCC prognosis (>4 years). Subgroup analysis of a phase 3 clinical trial of ACR identified serum MYCN as the risk factor most strongly associated with HCC recurrence. Patients with HCC with higher serum MYCN levels after a 4-week treatment of ACR exhibited a significantly higher risk of recurrence (hazard ratio 3.27; p = .022). In conclusion, serum MYCN holds promise for biomarker-based precision medicine for the prevention of HCC, long-term prognosis of early-stage HCC, and identification of high-response subgroups for ACR-based treatment.


Subject(s)
Biomarkers, Tumor , Carcinoma, Hepatocellular , Liver Neoplasms , N-Myc Proto-Oncogene Protein , Neoplasm Recurrence, Local , Proto-Oncogene Mas , Adult , Aged , Female , Humans , Male , Middle Aged , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/blood , Liver Neoplasms/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/prevention & control , Liver Neoplasms/pathology , N-Myc Proto-Oncogene Protein/genetics , Neoplasm Recurrence, Local/prevention & control , Neoplasm Recurrence, Local/blood , Prognosis
4.
Cancer Sci ; 115(1): 247-256, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38013627

ABSTRACT

The long interspersed nuclear element-1 (LINE-1) retrotransposons are a major family of mobile genetic elements, comprising approximately 17% of the human genome. The methylation state of LINE-1 is often used as an indicator of global DNA methylation levels and it regulates the retrotransposition and somatic insertion of the genetic element. We have previously reported the significant relationship between LINE-1 hypomethylation and poor prognosis in upper gastrointestinal (GI) cancers. However, the causal relationships between LINE-1 hypomethylation, retrotransposition, and tumor-specific insertion in upper GI cancers remain unknown. We used bisulfite-pyrosequencing and quantitative real-time PCR to verify LINE-1 methylation and copy number in tissue samples of 101 patients with esophageal and 103 patients with gastric cancer. Furthermore, we analyzed the LINE-1 retrotransposition profile with an originally developed L1Hs-seq. In tumor samples, LINE-1 methylation levels were significantly lower than non-tumor controls, while LINE-1 copy numbers were markedly increased. As such, there was a significant inverse correlation between the LINE-1 methylation level and copy number in tumor tissues, with lower LINE-1 methylation levels corresponding to higher LINE-1 copy numbers. Of particular importance is that somatic LINE-1 insertions were more numerous in tumor than normal tissues. Furthermore, we observed that LINE-1 was inserted evenly across all chromosomes, and most often within genomic regions associated with tumor-suppressive genes. LINE-1 hypomethylation in upper GI cancers is related to increased LINE-1 retrotransposition and tumor-specific insertion events, which may collectively contribute to the acquisition of aggressive tumor features through the inactivation of tumor-suppressive genes.


Subject(s)
Gastrointestinal Neoplasms , Stomach Neoplasms , Humans , DNA Methylation/genetics , Gastrointestinal Neoplasms/genetics , Long Interspersed Nucleotide Elements/genetics , Stomach Neoplasms/genetics , Esophagus
5.
Cancer Sci ; 2024 Sep 25.
Article in English | MEDLINE | ID: mdl-39321028

ABSTRACT

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor "immunophenotypes" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.

6.
Br J Cancer ; 131(5): 797-807, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38992099

ABSTRACT

BACKGROUND: Fusobacterium nucleatum inhabits the oral cavity and affects the progression of gastrointestinal cancer. Our prior findings link F. nucleatum to poor prognosis in oesophageal squamous cell carcinoma via NF-κB pathway. However, its role in oesophagogastric junction and gastric adenocarcinoma remains unexplored. We investigated whether F. nucleatum influences these cancers, highlighting its potential impact. METHODS: Two cohorts of EGJ and gastric adenocarcinoma patients (438 from Japan, 380 from the USA) were studied. F. nucleatum presence was confirmed by qPCR, FISH, and staining. Patient overall survival (OS) was assessed based on F. nucleatum positivity. EGJ and gastric adenocarcinoma cell lines were exposed to F. nucleatum to study molecular and phenotypic effects, validated in xenograft mouse model. RESULTS: In both cohorts, F. nucleatum-positive EGJ or gastric adenocarcinoma patients had notably shorter OS. F. nucleatum positivity decreased in more acidic tumour environments. Cancer cell lines with F. nucleatum showed enhanced proliferation and NF-κB activation. The xenograft model indicated increased tumour growth and NF-κB activation in F. nucleatum-treated cells. Interestingly, co-occurrence of F. nucleatum and Helicobacter pylori, a known risk factor, was rare. CONCLUSIONS: F. nucleatum can induce the NF-κB pathway in EGJ and gastric adenocarcinomas, leading to tumour progression and poor prognosis.


Subject(s)
Adenocarcinoma , Esophageal Neoplasms , Esophagogastric Junction , Fusobacterium Infections , Fusobacterium nucleatum , NF-kappa B , Stomach Neoplasms , Humans , Stomach Neoplasms/microbiology , Stomach Neoplasms/pathology , Stomach Neoplasms/mortality , Animals , Esophageal Neoplasms/microbiology , Esophageal Neoplasms/pathology , Esophageal Neoplasms/mortality , Mice , Esophagogastric Junction/pathology , Esophagogastric Junction/microbiology , Male , Female , Adenocarcinoma/microbiology , Adenocarcinoma/pathology , Adenocarcinoma/mortality , NF-kappa B/metabolism , Cell Line, Tumor , Fusobacterium Infections/complications , Fusobacterium Infections/microbiology , Aged , Middle Aged , Prognosis , Cell Proliferation , Tumor Microenvironment , Xenograft Model Antitumor Assays
7.
Ann Surg Oncol ; 31(5): 2983-2995, 2024 May.
Article in English | MEDLINE | ID: mdl-38006530

ABSTRACT

BACKGROUND: The expression of programmed death-ligand 1 (PD-L1) in tumor cells is a leading cause of tumor immune escape; however, the precise mechanism underlying the regulation of PD-L1 expression in gastric cancer (GC) cells remains unknown. In this study, we aimed to investigate the potential mechanism of cancer-associated fibroblasts (CAFs) regulating PD-L1 expression in GC cells. METHODS: We evaluated the immunomodulatory effects of CAFs in GC cells in vitro via the transwell co-culture system, cytometric bead array, and Western blotting. We detected the role of interleukin (IL)-8 in affecting underlying pathways in GC cells via transfecting IL-8 small-interfering RNA (siRNA), and the protection effects of CAFs on GC cells exposed to CD8+ T cells via cytotoxicity assays. RESULTS: The results revealed that CAFs upregulated PD-L1 expression of GC cells. IL-8 expression was increased after KATO III or MKN45 cells co-cultured with CAF. Additionally, CAF-derived IL-8 promoted PD-L1 expression in GC cells through the P38, JNK, and NF-κB pathways. Besides, repertaxin, an IL-8 receptors (CXCR1/2) inhibitor, reduced PD-L1 expression in GC cells by blocking the P38, JNK, and NF-κB pathways. Furthermore, the expressions of p-P38, p-JNK, and p-NF-κB decreased after GC cells co-cultured with siIL-8-treated CAF. Moreover, repertaxin attenuated the protection of CAFs to cancer cells that were resistant to CD8+ T-cell cytotoxicity, and improved the antibody effects of anti-PD-L1 facilitating CD8+ T-cell cytotoxicity by targeting IL-8. CONCLUSION: Targeting CAF-derived IL-8 may defeat PD-L1 upregulation-mediated immune resistance in GC cells, which provides a novel approach to improve the immunotherapeutic efficacies of patients with GC.


Subject(s)
B7-H1 Antigen , Cancer-Associated Fibroblasts , Interleukin-8 , Stomach Neoplasms , Humans , B7-H1 Antigen/metabolism , Cancer-Associated Fibroblasts/pathology , CD8-Positive T-Lymphocytes , Cell Line, Tumor , Interleukin-8/metabolism , NF-kappa B/metabolism , RNA, Small Interfering , Stomach Neoplasms/metabolism , Sulfonamides
8.
Ann Surg Oncol ; 2024 Jul 09.
Article in English | MEDLINE | ID: mdl-38981990

ABSTRACT

BACKGROUND: Tumor-associated macrophages (TAM), a major component of the tumor microenvironment, play key roles in tumor formation and progression; however, mechanisms underlying TAM-induced tumor progression are complex and not well known. We previously reported that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) functions as a tumor promoter in some cancer contexts. METHODS: We examined ANGPTL2 expression in paraffin-embedded tumor samples from resected specimens of 221 patients with esophageal cancer. Patients were subdivided into four groups based on immunohistochemistry scores described above: ANGPTL2-low/TAM-low, ANGPTL2-low/TAM-high, ANGPTL2-high/TAM-low, and ANGPTL2-high/TAM-high groups. Gene expression datasets of esophageal cancer cell lines were obtained from the cancer cell line encyclopedia public database. RESULTS: In this study, we demonstrate that TAM infiltration is associated with poor prognosis in patients with esophageal cancer whose tumor cells show relatively higher ANGPTL2 expression levels; however, TAM infiltration did not affect prognosis in patients with ANGPTL2-low-expressing esophageal cancer, suggesting that ANGPTL2 expression in esophageal cancer cells is required for TAM-induced tumor progression. Our analysis of public datasets indicates a potential positive correlation of ANGPTL2 expression levels with that of transforming growth factor (TGF)-ß, a TAM-activating factor, in esophageal cancer cell lines. CONCLUSION: We conclude that ANGPTL2 signaling in tumor cells supports TAM-induced tumor progression and contributes to poor prognosis in patients with esophageal cancer. These findings overall provide novel insight into pro-tumor ANGPTL2 functions and illustrate the essential role of cancer cell/TAM crosstalk in cancer progression.

9.
Ann Surg Oncol ; 31(6): 3839-3849, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38421531

ABSTRACT

BACKGROUND: Obesity is associated with increased mortality in various cancers, but the relationship between obesity and clinical outcomes in unresectable or recurrent esophageal cancer who receive immune checkpoint inhibitors (ICIs) remains unknown. This study investigated the association between body composition and clinical outcomes in patients with unresectable or recurrent esophageal cancer who received ICIs. METHODS: Utilizing an unbiased database of 111 unresectable or recurrent esophageal cancers, we evaluated the relationships between body composition (body mass index, waist circumference, psoas major muscle volume, and subcutaneous and visceral fat areas) at the initiation of ICI treatment and clinical outcomes including the disease control rate and progression-free survival (PFS). RESULTS: Waist circumference was significantly associated with the disease control rate at the first assessment (P = 0.0008). A high waist circumference was significantly associated with favorable PFS in patients treated with nivolumab. In an univariable model, for 5-cm increase of waist circumference in the outcome category of PFS, univariable hazard ratio (HR) was 0.73 (95% confidence interval [CI], 0.61-0.87; P = 0.0002). A multivariable model controlling for potential confounders yielded a similar finding (multivariable HR, 0.56; 95% CI, 0.33-0.94; P = 0.027). We observed the similar finding in esophageal cancer patients treated with pembrolizumab+CDDP+5-FU (P = 0.048). In addition, waist circumference was significantly associated with the prognostic nutritional index (P = 0.0073). CONCLUSIONS: A high waist circumference was associated with favorable clinical outcomes in ICI-treated patients with unresectable or recurrent esophageal cancer, providing a platform for further investigations on the relationships among body composition, nutrition, and the immune status.


Subject(s)
Body Composition , Esophageal Neoplasms , Immune Checkpoint Inhibitors , Humans , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/pathology , Esophageal Neoplasms/mortality , Immune Checkpoint Inhibitors/therapeutic use , Male , Female , Aged , Middle Aged , Survival Rate , Prognosis , Follow-Up Studies , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Retrospective Studies , Aged, 80 and over , Body Mass Index , Obesity/complications , Waist Circumference , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/mortality , Adult , Nivolumab/therapeutic use
10.
J Surg Res ; 301: 640-646, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39096553

ABSTRACT

INTRODUCTION: Acute care surgeons are experts in trauma treatment, emergency surgery, and critical surgical care. Here, we analyzed the association of acute care surgeons on postoperative outcomes of emergency general surgery. METHODS: This retrospective study included 92 patients who underwent emergency general surgery at our institution between January 2020 and September 2021. Propensity score matching was used to analyze postoperative outcomes. The primary outcome was postoperative complications, while secondary outcomes included perioperative management and surgery-related and postoperative complications. Logistic regression analysis was used to estimate the odds ratios for all complications. In this study, acute care surgeons were defined as acute care surgery (ACS)-certified surgeons by the Japanese Society for Acute Care Surgery. RESULTS: Overall, 30 patients were treated by an acute care surgeon and general surgeons (ACS group), and 62 patients were treated by general surgeons (non-ACS group), respectively. Propensity score matching identified 30 patients with balanced baseline covariates, in each group. The ACS group had lower complication rates (Clavien-Dindo classification ≥2) than the non-ACS group (17% versus 40%, P = 0.08). The ACS group had a significantly shorter surgery duration than the non-ACS group (75 min versus 96 min, P = 0.014). In the logistic analysis, acute care surgeon involvement was identified as an independent predictor for the decrease in all complications (odds ratio, 0.15; 95% confidence interval, 0.02-0.64). CONCLUSIONS: It was suggested that the involvement of acute care surgeons may reduce the overall complication rate in emergency general surgery.


Subject(s)
Postoperative Complications , Propensity Score , Surgeons , Humans , Male , Retrospective Studies , Female , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/prevention & control , Middle Aged , Aged , Surgeons/statistics & numerical data , Adult , Japan/epidemiology , Critical Care/statistics & numerical data , Aged, 80 and over
11.
Gastric Cancer ; 27(2): 235-247, 2024 03.
Article in English | MEDLINE | ID: mdl-38142463

ABSTRACT

BACKGROUND: Imatinib contributes to improving prognosis of high-risk or unresectable gastrointestinal stromal tumors (GISTs). As therapeutic efficacy is limited by imatinib resistance and toxicity, the exploration of predictive markers of imatinib therapeutic efficacy that enables patients to utilize more effective therapeutic strategies remains urgent. METHODS: The correlation between FBXW7 and imatinib resistance via FBXW7-MCL1 axis was evaluated in vitro and in vivo experiments. The significance of FBXW7 as a predictor of imatinib treatment efficacy was examined in 140 high-risk patients with GISTs. RESULTS: The ability of FBXW7 to predict therapeutic efficacy of adjuvant imatinib in high-risk GIST patients was determined through 5-year recurrence-free survival (RFS) rates analysis and multivariate analysis. FBXW7 affects imatinib sensitivity by regulating apoptosis in GIST-T1 cells. FBXW7 targets MCL1 to regulate apoptosis. MCL1 involves in the regulation of imatinib sensitivity through inhibiting apoptosis in GIST-T1 cells. FBXW7 regulates imatinib sensitivity by down-regulating MCL1 to enhance imatinib-induced apoptosis in vitro. FBXW7 regulates imatinib sensitivity of GIST cells by targeting MCL1 to predict efficacy of imatinib treatment in vivo. CONCLUSIONS: FBXW7 regulates imatinib sensitivity by inhibiting MCL1 to enhance imatinib-induced apoptosis in GIST, and predicts efficacy of imatinib treatment in high-risk GIST patients treated with imatinib.


Subject(s)
Antineoplastic Agents , F-Box-WD Repeat-Containing Protein 7 , Gastrointestinal Neoplasms , Gastrointestinal Stromal Tumors , Imatinib Mesylate , Stomach Neoplasms , Humans , Antineoplastic Agents/therapeutic use , F-Box-WD Repeat-Containing Protein 7/metabolism , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/pathology , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/pathology , Imatinib Mesylate/therapeutic use , Myeloid Cell Leukemia Sequence 1 Protein/therapeutic use , Stomach Neoplasms/drug therapy
12.
Gastric Cancer ; 2024 Jul 19.
Article in English | MEDLINE | ID: mdl-39028419

ABSTRACT

BACKGROUND: The significance of reinforcement of the duodenal stump with seromuscular sutures and the effectiveness of reinforced staplers in preventing duodenal stump leakage remain unclear. We aimed to explore the importance of duodenal stump reinforcement and determine the optimal reinforcement method for preventing duodenal stump leakage. METHODS: This retrospective cohort study was conducted between January 1, 2012 and December 31, 2021, with data analyzed between December 1, 2022 and September 30, 2023. This multicenter study across 57 institutes in Japan included 16,475 patients with gastric cancer who underwent radical gastrectomies. Elective open or minimally invasive (laparoscopic or robotic) gastrectomy was performed in patients with gastric cancer. RESULTS: Duodenal stump leakage occurred in 153 (0.93%) of 16,475 patients. The proportions of males, patients aged ≥ 75 years, and ≥ pN1 were higher in patients with duodenal stump leakage than in those without duodenal stump leakage. The incidence of duodenal stump leakage was significantly lower in the group treated with reinforcement by seromuscular sutures or using reinforced stapler than in the group without reinforcement (0.72% vs. 1.19%, p = 0.002). Duodenal stump leakage incidence was also significantly lower in high-volume institutions than in low-volume institutions (0.70% vs. 1.65%, p = 0.047). The rate of duodenal stump leakage-related mortality was 7.8% (12/153). In the multivariate analysis, preoperative asthma and duodenal invasion were identified as independent preoperative risk factors for duodenal stump leakage-related mortality. CONCLUSIONS: The duodenal stump should be reinforced to prevent duodenal stump leakage after radical gastrectomy in patients with gastric cancer.

13.
Langenbecks Arch Surg ; 409(1): 289, 2024 Sep 24.
Article in English | MEDLINE | ID: mdl-39316139

ABSTRACT

PURPOSE: It has reported that the prevalence of frailty in patients with pancreatic cancer is 45%. The number of patients with pancreatic cancer is increasing, and within this cohort, patients often suffer from impaired activities of daily living (ADLs). This study aimed to examine the association between perioperative Barthel Index (BI) scores, a validated measure of ADLs, and survival outcomes after pancreatectomy for pancreatic cancer. METHODS: We analyzed the data of 201 patients who underwent pancreatectomy for pancreatic cancer between 2010 and 2020. Preoperative and postoperative ADLs were assessed using the BI (range: 0-100; higher scores indicated greater independence). A preoperative or postoperative BI score ≤ 85 was defined as an impairment of perioperative ADLs. Cox proportional hazards regression was used to calculate the hazard ratios (HRs) after adjusting for potential confounders. RESULTS: Among the 201 patients, 14 (7.0%) had a preoperative BI score ≤ 85 and 50 (25%) had a postoperative BI score ≤ 85. Impairment of perioperative ADLs was independently associated with shorter overall survival (multivariable HR: 2.66, 95% confidence interval [95%CI]: 1.75-4.03, P < 0.001), cancer-specific survival (multivariable HR: 2.64, 95%CI: 1.15-4.25, P < 0.001), and recurrence-free survival (multivariable HR: 1.94, 95%CI: 1.08-3.50, P = 0.021). CONCLUSION: Impairment of perioperative ADLs is associated with poor prognosis following pancreatectomy for pancreatic cancer. The maintenance and improvement of perioperative ADLs could play an important role in providing favorable long-term outcomes in patients with pancreatic cancer.


Subject(s)
Activities of Daily Living , Pancreatectomy , Pancreatic Neoplasms , Humans , Pancreatic Neoplasms/surgery , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Pancreatectomy/adverse effects , Male , Female , Aged , Middle Aged , Prognosis , Retrospective Studies , Frailty/complications , Survival Rate , Aged, 80 and over
14.
Langenbecks Arch Surg ; 409(1): 56, 2024 Feb 09.
Article in English | MEDLINE | ID: mdl-38332380

ABSTRACT

BACKGROUND: Portal vein embolization (PVE) is often performed prior to right hemihepatectomy (RH) to increase the future liver remnants. However, intraoperative removal of portal vein thrombus (PVT) is occasionally required. An algorithm for treating the right branch of the PV using laparoscopic RH (LRH) after PVE is lacking and requires further investigation. METHODS: In our department, after the confirmation of a lack of extension of PVT to the main portal trunk or left branch on preoperative examination (ultrasound and contrast-enhanced computed tomography), a final evaluation was performed using intraoperative ultrasonography (IOUS). Here we present the cases of eight patients who underwent LRH after PVE and examine the safety of our treatment strategies. RESULTS: IOUS revealed PVT extension into the main portal trunk in two cases. For the other six patients without PVT extension, we continued the laparoscopic procedure. In contrast, in the two cases with PVT extension, we converted to laparotomy after hepatic transection and removed the PVT. The median operation time for hepatectomy was 562 min (421-659 min), the median blood loss was 293 mL (85-1010 mL), no liver-related postoperative complications were observed, and the median length of stay was 10 days (6-34 days). CONCLUSIONS: PVT evaluation and removal are important in cases of LRH after PVE. Our strategy is safe and IOUS is particularly useful for laparoscopically evaluating PVT extension.


Subject(s)
Embolization, Therapeutic , Laparoscopy , Liver Neoplasms , Thrombosis , Humans , Hepatectomy/methods , Portal Vein/surgery , Liver Neoplasms/surgery , Embolization, Therapeutic/methods , Thrombosis/surgery
15.
Langenbecks Arch Surg ; 409(1): 47, 2024 Jan 25.
Article in English | MEDLINE | ID: mdl-38267769

ABSTRACT

AIM: Patients with malignant tumors are prone to develop nutritional disorders. The Geriatric Nutritional Risk Index (GNRI) is a new prognostic indicator for assessing the nutritional status. This study was performed to evaluate whether the preoperative GNRI can serve as a prognostic factor in patients with intrahepatic cholangiocarcinoma (ICC) undergoing curative surgery. METHODS: This study included 123 consecutive patients with ICC who were treated with curative surgery. Kaplan-Meier analysis was performed to calculate the recurrence-free survival (RFS) and overall survival (OS), and Cox regression analysis was used to evaluate prognostic factors. RESULTS: Of the 123 patients, 82 were male and 41 were female. The median age of the patients was 70 years, and the median follow-up period was 37.0 months (interquartile range, 16.2-71.7 months). The patients were classified by the median GNRI into a low GNRI group (GNRI < 105) and high GNRI group (GNRI ≥ 105). The patients in the low GNRI group had a significantly poorer prognosis in terms of RFS and OS than the patients in the high GNRI group (RFS, p = 0.0201; OS, p < 0.0001). Lymph node metastasis [hazard ratio (HR), 4.66; 95% confidence interval (CI), 2.46-8.85], postoperative complications (HR, 2.38; 95% CI, 1.32-4.31), and a low GNRI (HR, 2.53; 95% CI, 1.42-4.50) were independent poor prognostic factors for OS. CONCLUSION: The GNRI may be a useful prognostic indicator in patients with ICC undergoing curative hepatectomy.


Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Humans , Female , Male , Aged , Infant , Child, Preschool , Child , Hepatectomy , Prognosis , Retrospective Studies , Cholangiocarcinoma/surgery , Bile Duct Neoplasms/surgery , Bile Ducts, Intrahepatic
16.
Int J Clin Oncol ; 29(1): 47-54, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37943377

ABSTRACT

BACKGROUND: With the rapid aging of populations worldwide, the number of vulnerable patients with liver metastasis from colorectal cancer has increased. This study aimed to examine the association between vulnerability and clinical outcomes in patients with colorectal liver metastasis (CRLM). METHODS: Consecutive 101 patients undergoing upfront hepatectomy for CRLM between 2004 and 2020 were included. The preoperative vulnerability was assessed using the Clinical Frailty Scale (CFS) score ranging from one (very fit) to nine (terminally ill), and frailty was defined as a CFS score of ≥ 4. A multivariable Cox proportional hazard regression model was utilized to investigate associations of frailty with disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS). RESULTS: Of the 101 patients, 12 (12%) had frailty. Associations between frailty and surgical outcomes, namely, the incidence of 90-day mortality and postoperative complications, were not statistically significant (P > 0.05). In the multivariable analyses, after adjusting for clinical risk scores calculated using six factors (timing of liver metastasis, primary tumor lymph node status, number of liver tumors, size of the largest tumor, extrahepatic metastatic disease, and carbohydrate antigen 19-9 level) to predict recurrence following hepatectomy for CRLM, preoperative frailty was found to be an independent risk factor for DFS (hazard ratio [HR]:2.37, 95% confidence interval [CI] 1.06-4.72, P = 0.036), OS (HR:4.17, 95% CI 1.43-10.89, P = 0.011), and CSS (HR:3.49, 95% CI 1.09-9.60, P = 0.036). CONCLUSION: Preoperative frailty was associated with worse DFS, OS, and CSS after upfront hepatectomy for CRLM. Assessment and improvement of patient vulnerability may provide a favorable prognosis for patients with CRLM.


Subject(s)
Colorectal Neoplasms , Frailty , Liver Neoplasms , Humans , Hepatectomy , Frailty/surgery , Colorectal Neoplasms/pathology , Retrospective Studies , Prognosis
17.
Int J Clin Oncol ; 2024 Sep 19.
Article in English | MEDLINE | ID: mdl-39297909

ABSTRACT

BACKGROUND: Biliary tract cancer (BTC) comprises a heterogeneous group of malignancies with poor prognosis because of the limited treatment options. With the recent advances of next generation sequencing technologies, comprehensive genomic profiling (CGP) tests have been widely introduced into daily clinical practice. PATIENTS AND METHODS: We performed a retrospective, multicenter, observation cohort study. The genomic and clinical data of 85 BTC patients, who underwent CGP testing from August 2021 to September 2023, were analyzed. RESULTS: There were 62 (73%) cases in which treatment recommendations were raised during expert meetings, including 34 intrahepatic cholangiocarcinoma (ICC), 20 extrahepatic cholangiocarcinoma (ECC) and 8 gall bladder carcinoma (GBC). The drug accessibility rate of the BTC patients was 15.3% (13 cases): ten ICCs, two ECCs, and one GBC. Five ICC patients (three male and two female) with the FGFR2 fusion gene were treated with pemigatinib. Those patients who received a genomically matched therapy had significantly longer median overall survival than those patients who not received. (n = 13; not reached [95% CI not reached-not reached] vs n = 72; 8.6 months [95% CI 6.6-10.0]; hazard ratio 0.24 [95% CI 0.12-0.49], p = 0.013). The median observation period of pemigatinib treatment was 15.4 months (range 10.1-27.4). The responses were classified as PR in three patients, SD in one patient and PD in one patient. The median progression free survival is 9.0 months. No patient had grade 3/4 AEs requiring discontinuation of the treatment. CONCLUSION: The drug accessibility rate of ICC is high and pemigatinib is effective and well-tolerated in ICC patients harboring FGFR2 gene fusions.

18.
Int J Clin Oncol ; 29(9): 1284-1292, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38833114

ABSTRACT

BACKGROUND: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. Using propensity score matching, we previously reported that the 3-year disease-free survival (DFS) rate was significantly higher in patients treated with uracil and tegafur plus leucovorin (UFT/LV) against surgery alone. We report the final results, including updated 5-year overall survival (OS) rates and risk factor analysis outcomes. METHODS: In total, 1902 high-risk stage II CC patients with T4, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, and/or < 12 dissected lymph nodes were enrolled in this prospective, non-randomized controlled study based on their self-selected treatment. Oral UFT/LV therapy was administered for six months after surgery. RESULTS: Of the 1880 eligible patients, 402 in Group A (surgery alone) and 804 in Group B (UFT/LV) were propensity score-matched. The 5-year DFS rate was significantly higher in Group B than in Group A (P = 0.0008). The 5-year OS rates were not significantly different between groups. The inverse probability of treatment weighting revealed significantly higher 5-year DFS (P = 0.0006) and 5-year OS (P = 0.0122) rates in group B than in group A. Multivariate analyses revealed that male sex, age ≥ 70 years, T4, < 12 dissected lymph nodes, and no adjuvant chemotherapy were significant risk factors for DFS and/or OS. CONCLUSION: The follow-up data from our prospective non-randomized controlled study revealed a considerable survival advantage in DFS offered by adjuvant chemotherapy with UFT/LV administered for six months over surgery alone in individuals with high-risk stage II CC. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019), UMIN Clinical Trials Registry: UMIN000007783 (date of registration: 18/04/2012).


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Colonic Neoplasms , Leucovorin , Neoplasm Recurrence, Local , Neoplasm Staging , Propensity Score , Tegafur , Uracil , Humans , Tegafur/administration & dosage , Tegafur/therapeutic use , Male , Female , Aged , Uracil/administration & dosage , Uracil/therapeutic use , Middle Aged , Leucovorin/therapeutic use , Leucovorin/administration & dosage , Chemotherapy, Adjuvant , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Prospective Studies , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Risk Factors , Neoplasm Recurrence, Local/drug therapy , Adult , Disease-Free Survival , Aged, 80 and over
19.
Surg Today ; 54(8): 927-934, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38583108

ABSTRACT

PURPOSE: The concept of oligometastasis, which represents limited metastatic disease, has recently gained interest, accompanied by a more detailed classification. This study aims to investigate the relationship between the treatment course and prognosis in patients with a recurrence of esophageal squamous cell carcinoma (ESCC) after curative esophagectomy. METHODS: 126 patients with ESCC recurrence after curative resection were enrolled in this study. Oligometastasis was defined as fewer than five recurrences in a single organ. Patients were classified as having oligometastatic recurrence (OLR) or polymetastatic recurrence (PLR). Patients were further classified into four subgroups according to lesion progression: persistent oligorecurrence (PER-OLR), converted polyrecurrence (CON-PLR), induced oligorecurrence (IND-OLR), and persistent polyrecurrence (PER-PLR). We analyzed the relationship between the recurrence patterns and prognosis according to the progression of oligometastatic lesions. RESULTS: OLR was identified in 58 (46%) of 126 patients with recurrence. Patients with OLR had a significantly better prognosis than those with PLR (P < 0.0001). A further subgroup analysis revealed that patients who underwent IND-OLR had a similar prognosis to those who underwent PER-OLR. CONCLUSIONS: This study suggests that OLR is a prognostic factor after recurrence following resection of ESCC and that PLR can be converted to OLR by therapeutic intervention to achieve a long-term survival.


Subject(s)
Disease Progression , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Esophagectomy , Neoplasm Metastasis , Neoplasm Recurrence, Local , Humans , Esophageal Neoplasms/pathology , Esophageal Neoplasms/surgery , Esophageal Neoplasms/mortality , Prognosis , Esophageal Squamous Cell Carcinoma/surgery , Esophageal Squamous Cell Carcinoma/secondary , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/mortality , Esophageal Squamous Cell Carcinoma/therapy , Male , Female , Middle Aged , Aged , Carcinoma, Squamous Cell/surgery , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/secondary , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/therapy
20.
Surg Today ; 2024 May 21.
Article in English | MEDLINE | ID: mdl-38771326

ABSTRACT

PURPOSE: To compare the short- and long-term outcomes of laparoscopic and open abdominal lymph node dissection using propensity score matching (PSM) analysis. METHODS: The subjects of this retrospective analysis were 459 patients who underwent curative resection for esophageal squamous cell carcinoma (ESCC) between May, 2005 and December, 2019, at our hospital. Patients were divided into two groups: the Laparoscopic (Lap group) and the Open (Open group). Post-PSM, 139 patients from each group were selected for the analysis to compare the short- and long-term outcomes between the groups. RESULTS: The Lap group experienced fewer Clavien-Dindo (CD) Grade ≥ 2 complications (28.1% vs. 40.3%, P = 0.04) and lower rates of abdominal surgical site infections (SSI) (2.9% vs. 7.9%, P = 0.02) than the Open group. The number of lymph nodes harvested was similar in the Lap and Open groups (14.8 ± 7.5 vs. 15.7 ± 8.6, P = 0.34). There was no significant difference in 3-year overall survival rates (81.2% vs. 69.5%, P = 0.12) or relapse-free survival rates (61.1% vs. 58.2%, P = 0.54) between the groups. CONCLUSIONS: Laparoscopic abdominal lymph node dissection for ESCC can be performed safely and appears to be beneficial.

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