Oncofetal IGF2BP3-mediated control of microRNA structural diversity in the malignancy of early-stage lung adenocarcinoma.

The nature of microRNA (miRNA) dysfunction in carcinogenesis remains controversial because of the complex connection between miRNA structural diversity and biological processes. Here, we found that oncofetal IGF2BP3 regulates the selective production of a subset of 3'-isoforms (3'-isomiRs), including miR-21-5p and Let-7 family, which induces significant changes in their cellular seed occupancy and structural components, establishing a cancer-specific gene expression profile. The D-score, reflecting dominant production of a representative miR-21-5p+C (a 3'-isomiR), discriminated between clinical early-stage lung adenocarcinoma (LUAD) cases with low and high recurrence risks, and was associated with molecular features of cell cycle progression, epithelial-mesenchymal transition pressure, and immune evasion. We found that IGF2BP3 controls the production of miR-21-5p+C by directing the nuclear Drosha complex to select the cleavage site. IGF2BP3 was also involved in the production of 3'-isomiRs of miR-425-5p and miR-454-3p. IGF2BP3-regulated these three miRNAs are suggested to be associated with the regulation of p53, TGF-ß, and TNF pathways in LUAD. Knockdown of IGF2BP3 also induced a selective upregulation of Let-7 3'-isomiRs, leading to increased cellular Let-7 seed occupancy and broad repression of its target genes encoding cell cycle regulators. The D-score is an index that reflects this cellular situation. Our results suggest that the aberrant regulation of miRNA structural diversity is a critical component for controlling cellular networks, thus supporting the establishment of a malignant gene expression profile in early stage LUAD.

Recurrence-free survival as a surrogate endpoint for overall survival after neoadjuvant chemotherapy and surgery for oesophageal squamous cell carcinoma.

BACKGROUND: Overall survival is considered as one of the most important endpoints of treatment efficacy but often requires long follow-up. This study aimed to determine the validity of recurrence-free survival as a surrogate endpoint for overall survival in patients with surgically resectable advanced oesophageal squamous cell carcinoma (OSCC). METHODS: Patients with OSCC who received neoadjuvant cisplatin and 5-fluorouracil, or docetaxel, cisplatin and 5-fluorouracil, at 58 Japanese oesophageal centres certified by the Japan Esophageal Society were reviewed retrospectively. The correlation between recurrence-free and overall survival was assessed using Kendall's τ. RESULTS: The study included 3154 patients. The 5-year overall and recurrence-free survival rates were 56.6 and 47.7% respectively. The primary analysis revealed a strong correlation between recurrence-free and overall survival (Kendall's τ 0.797, 95% c.i. 0.782 to 0.812) at the individual level. Subgroup analysis showed a positive relationship between a more favourable pathological response to neoadjuvant chemotherapy and a higher τ value. In the meta-regression model, the adjusted R2 value at the institutional level was 100 (95% c.i. 40.2 to 100)%. The surrogate threshold effect was 0.703. CONCLUSION: There was a strong correlation between recurrence-free and overall survival in patients with surgically resectable OSCC who underwent neoadjuvant chemotherapy, and this was more pronounced in patients with a better response to neoadjuvant chemotherapy.

Analysis of operative duration of image-guided brachytherapy for cervical cancer.

PURPOSE: The present study aimed to analyze the operative duration of image-guided brachytherapy (IGBT) for cervical cancer performed at our institution. METHODS: We enrolled cervical cancer patients who had undergone tandem and ovoid-based intracavitary brachytherapy (ICBT) or intracavitary and interstitial brachytherapy (IC/ISBT) between 2020 and 2024. Cone beam computed tomography (CBCT), CT, or CT + MRI were used for IGBT. For each IGBT session, we retrospectively reviewed the following: application time (AT-defined as the duration from entry into the operating room to the initial image acquisition); planning time (PT-defined as the duration from the initial image acquisition to the start of irradiation); and total operation time (TOT- defined as the duration from entry to exit of the operating room). RESULTS: We analyzed a total of 126 sessions in 36 patients, consisting of 99 ICBT-only sessions and 27 IC/ISBT sessions. The IC/ISBT sessions had a significantly longer mean operative duration than the ICBT-only sessions. The IC/ISBT sessions with three or more interstitial needles had significantly longer AT and TOT. However, the IC/ISBT sessions with one needle showed no significant difference in operative duration compared to ICBT-only sessions. CBCT, CT, and CT + MRI were used in 42, 76, and 8 sessions, respectively. In the ICBT patients, CT + MRI had the longest PT. However, there was no significant differences in TOT among CBCT, CT, and CT + MRI. CONCLUSIONS: IC/ISBT sessions with one needle had no significant difference in operative duration compared to ICBT-only sessions. There was no significant difference in TOT between CT + MRI-based IGBT and CT-based IGBT.

Impact of the Combination of Anamorelin and Rehabilitation on Functional and Nutritional Outcomes in Patients with Cancer Cachexia.

Cancer cachexia, characterized by the progressive loss of skeletal muscle mass, leads to functional impairment and poor prognosis. Anamorelin is approved for treating cancer cachexia in Japan; however, the factors influencing its discontinuation and the impact of combining anamorelin with rehabilitation remain unclear. Therefore, we retrospectively analyzed 82 patients with cancer cachexia to identify factors associated with anamorelin discontinuation and assess changes in nutritional status and motor function using non-dominant handgrip strength after 12 wk. Patients received outpatient rehabilitation, combining resistance and aerobic training every two weeks, alongside anamorelin therapy. Our findings indicate that patients with an ECOG performance status of 1 or 2 were less likely to continue anamorelin therapy for 12 wk compared to those with a performance status of 0 (odds ratio 2.71; 95% CI 1.05 - 7.00; p = 0.040). Significant improvements were observed in body weight (48.8 to 53.7 kg, p < 0.001), skeletal muscle mass (6.4 to 6.9 kg/m2, p < 0.001), FAACT score (11.5 to 18.0, p < 0.001), and non-dominant handgrip strength (20.5 to 21.7 kg, p = 0.018) after 12 wk. Early initiation of anamorelin with regular rehabilitation is recommended to enhance nutritional status and motor function in patients with cancer cachexia.

Evaluation of the prognostic impact of pathologic tumor regression grade on patients with colorectal cancer after preoperative chemoradiotherapy.

BACKGROUND: The prognostic value of the pathological response to preoperative chemoradiotherapy (CRT) in rectal cancer (RC) remains unknown. OBJECTIVES: We aimed to assess the predictive value of the response to CRT that was derived from an evaluation of the histological findings (whole-section vs. representative-section sampling) and attempted to determine an objective cut-off value for the tumor regression grade (TRG). METHODS: We examined the association of the TRG with the outcomes (recurrence-free survival [RFS] and overall survival [OS]) of 78 patients with RC. Patients with RC treated with preoperative CRT were divided into development (30 cases) and validation (48 cases) cohorts. The TRG was classified as grades I (Ia, Ib), II, and III. The cut-off value was determined by receiver operating characteristic (ROC) curve analysis. RESULTS: The TRG determined from whole-section sampling versus representative-section sampling was more strongly correlated with patient survival. We found that in both cohorts, patients with a cut-off value of <73% had a poor prognosis. Finally, the cut-off value was found to be an independent predictive factor in both univariate and multivariate analysis. CONCLUSIONS: The TRG that was used to evaluate patients with RC who underwent preoperative CRT was an independent prognostic factor for outcome.

Appropriate timing for the removal of urinary catheters in gastrointestinal surgery with epidural anesthesia: a randomized controlled trial.

PURPOSE: The purpose of this randomized controlled trial was to evaluate whether early urinary catheter removal is feasible during epidural anesthesia during gastrointestinal surgery in male patients at high risk for urinary retention. METHODS: Male patients who underwent radical surgery for gastric or colon cancer were enrolled in this randomized controlled trial. Patients were randomized 1:1 into 2 groups: the early group, in which the urinary catheter was removed before removal of the epidural catheter on the second or third postoperative day, and the late group, in which the urinary catheter was removed after removal of the epidural catheter. The randomization adjustment factors were age (≥ 65 or < 65 years) and operative site (gastric or colon). The primary endpoint was urinary retention. The secondary endpoints were the incidence of urinary tract infection and length of postoperative hospital stay. RESULTS: Seventy-three patients were enrolled between March 2020 and February 2024 and assigned to the Early (n = 37) and Late (n = 36) groups. Four patients withdrew their consent after randomization. The intention-to-treat analysis showed that urinary retention occurred in 4 patients (11.1%) in the early group and 1 patient (3.0%) in the late group (P = 0.20). Urinary tract infection occurred in 1 patient (3.0%) in the late group. The median postoperative hospital stay was 9 days in both groups. CONCLUSION: Early urinary catheter removal in male patients undergoing gastrointestinal surgery with epidural anesthesia could increase urinary retention within the expected acceptable range. TRIAL REGISTRATION NUMBER: UMIN000040468, Date of registration: May 21, 2020.

Biomarker-oriented chemo-immunotherapy for advanced gastric cancer.

The biomarker-oriented chemo-immunotherapy is useful and promising in the development of new anticancer agents, since the responders can be enriched by selecting patients with biomarkers. Compared to colorectal and lung cancers, the development of biomarker-driven molecular-targeted therapeutics for gastric cancers has been straggled. However, several new biomarkers in gastric cancers have been discovered and clinical trials in enrichment design with certain biomarkers have been conducted. Therefore, there are currently several treatment options to treat gastric cancer patients based on individual biomarker-oriented strategies. In the present review, we describe the useful biomarkers in gastric cancer, with focusing on HER2, PD-L1, and Claudin18.2, in relation to their clinical significance and associated targeted agents.

Prognostic impact and survival outcomes of colon perforation in patients with metastatic colorectal cancer: a multicenter retrospective cohort study.

BACKGROUND: Colon perforation caused by colorectal cancer (CRC) is a fatal condition requiring emergency intervention. For patients with metastatic lesions, surgeons face difficult decisions regarding whether to resect the primary and metastatic lesions. Moreover, there is currently no established treatment strategy for these patients. This study aimed to investigate the clinical practice and long-term outcomes of patients with metastatic CRC diagnosed with the onset of colon perforation. METHODS: We performed a population-based multicenter cohort study. Consecutive patients diagnosed with stage IV CRC between 2008 and 2015 at all designated cancer hospitals in Fukushima Prefecture, Japan, were enrolled in this study. We evaluated the impact of colon perforation on the survival outcomes of patients with metastatic CRC. The main outcome was the adjusted hazard ratio (aHR) of perforation for overall survival (OS). Survival time and HRs were estimated using Kaplan‒Meier and Cox proportional regression analyses. RESULTS: A total of 1258 patients were enrolled (perforation: n = 46; non-perforation: n = 1212). All but one of the patients with perforation underwent primary resection or colostomy and 25 cases were able to receive chemotherapy. The median OS for the perforation and non-perforation groups was 19.0 and 20.0 months, respectively (p = 0.96). Moreover, perforation was not an independent prognostic factor (aHR: 0.99; 95% confidence interval: 0.61-1.28). CONCLUSIONS: In metastatic CRC, perforation is not necessarily a poor prognostic factor. Patients with perforation who undergo primary tumor resection or colostomy and prompt initiation of systemic chemotherapy might be expected to have a survival time similar to that of patients with non-perforated colon.

The real-world data of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study.

BACKGROUND: The real-world efficacy, feasibility, and prognostic factors of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer are not fully established. METHODS: This multi-institutional retrospective cohort study evaluated 71 consecutive patients treated with immune-checkpoint inhibitor combination therapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, safety, and long-term survival. RESULTS: In patients with measurable lesions, the response rate was 58%, and the disease control rate for all enrolled patients was 80%. Five patients (7.0%) underwent successful conversion surgery. Grade 3 or higher immune-related adverse events occurred in 13% of patients, and one patient (1.4%) died due to cholangitis. Median progression-free survival was 9.7 (95% confidence interval: 6.5-not reached). C-reactive protein levels and performance status were identified as significant predictors of progression-free survival through Cox proportional hazards analysis. CONCLUSIONS: Immune-checkpoint inhibitor combination therapy for esophageal cancer demonstrated comparable tumor response, safety, and long-term survival to previous randomized clinical trials. Patients with good performance status and low C-reactive protein levels may be suitable candidates for this treatment.

TGFß-Responsive Stromal Activation Occurs Early in Serrated Colorectal Carcinogenesis.

Activated TGFß signaling in the tumor microenvironment, which occurs independently of epithelial cancer cells, has emerged as a key driver of tumor progression in late-stage colorectal cancer (CRC). This study aimed to elucidate the contribution of TGFß-activated stroma to serrated carcinogenesis, representing approximately 25% of CRCs and often characterized by oncogenic BRAF mutations. We used a transcriptional signature developed based on TGFß-responsive, stroma-specific genes to infer TGFß-dependent stromal activation and conducted in silico analyses in 3 single-cell RNA-seq datasets from a total of 39 CRC samples and 12 bulk transcriptomic datasets consisting of 2014 CRC and 416 precursor samples, of which 33 were serrated lesions. Single-cell analyses validated that the signature was expressed specifically by stromal cells, effectively excluding transcriptional signals derived from epithelial cells. We found that the signature was upregulated during malignant transformation and cancer progression, and it was particularly enriched in CRCs with mutant BRAF compared to wild-type counterparts. Furthermore, across four independent precursor datasets, serrated lesions exhibited significantly higher levels of TGFß-responsive stromal activation compared to conventional adenomas. This large-scale analysis suggests that TGFß-dependent stromal activation occurs early in serrated carcinogenesis. Our study provides novel insights into the molecular mechanisms underlying CRC development via the serrated pathway.

[Regulation of the Tumor Microenvironment through HER2 Signaling-Insights from Gastric Cancer Cases with Heterogeneous HER2 Overexpression].

HER2, a member of the human epidermal growth factor receptor(HER)family, exhibits gene amplification, protein overexpression, or both in 13-27% of gastric cancer(GC)cases. Through the activation of downstream Akt and ERK pathways, HER2 promotes the survival and proliferation of gastric cancer cells. The impact of HER2 signaling on the tumor microenvironment(TME)in GC remains unclear, and the heterogeneity of HER2 overexpression in GC tissues is considered a contributing factor. In this study, we focused on differences in the TME between HER2-positive and HER2-negative areas in HER2-positive GC and found that HER2 signaling, particularly the HER2-Akt cascade, may suppress stimulator of interferon genes (STING)expression and reduce CD8+ T cell infiltration in tumor cells. Overall, our findings suggest the potential for a novel therapeutic approach to activate the anti-tumor immune response in HER2-positive GC.

[365 Days in Newly Opened Cancer Treatment Center in Core Hospital of Mountainous Area].

The declining birthrate and aging population is one of the social issues in mountainous area in Japan. One regional core hospital at Aizu area in Fukushima prefecture opened cancer treatment center in these area in July, 2022. A high-performance radiation therapy system was newly installed and operated with the staff of Fukushima Medical University, and several supportive therapy for cancer chemotherapy including appearance care became possible in the center. The patients living in Aizu area can receive advanced treatments including radiation therapy without moving to long-distant bigger cities now. We report multiple preparations and several trials that we have made during one year since the opening of the center.

Outcomes of patients with esophageal squamous cell carcinoma who achieved a pathological complete response in the primary lesion by neoadjuvant treatment: a Japanese nationwide cohort study.

BACKGROUND: Minimal data was reported regarding the characteristics, risks of lymph node metastasis, and prognostic factors in esophageal cancer patients who achieved remarkable response in the primary lesion to neoadjuvant treatment (NAT). METHODS: This study evaluated the nationwide data of esophageal squamous cell carcinoma (ESCC) patients who underwent surgery following NAT in Japan. Of 4484 patients, 300 (6.7%) had ypT0 following NAT and curative esophagectomy. Factors associated with lymph node metastasis and prognosis were analyzed. RESULTS: Neoadjuvant chemotherapy (NAC) and neoadjuvant chemoradiotherapy (NACRT) were administered in 260 (86.2%) and 40 (13.8%) patients, respectively. Pathologically, 72 (24.0%) had lymph node metastasis (residual nodal disease; RND), and pretherapeutic lymph node metastasis was the independent risk factor for RND (odd ratio [OR]: 3.21; 95% confidence interval [CI]: 1.44-8.20; P = 0.008). The 5-year overall and relapse-free survivals were significantly longer in patients with pathological complete response (pCR) than in those with RND (both P < 0.001). Pretherapeutic cT3 or T4a tumors (hazard ratio [HR]: 1.71; 95% CI: 1.02-2.88; P = 0.043), RND (HR: 3.30; 95% CI: 1.98-5.50; P < 0.001), and operative blood loss (Liter, HR: 1.53; 95% CI: 1.07-2.19; P = 0.021) were independent risk factors affecting relapse-free survival in multivariable analysis. CONCLUSIONS: Of patients with ypT0 after NAT, 24.0% had RND, and pretherapeutic lymph node metastasis was the risk factor. In addition, pretherapeutic cT3, or T4a tumors, RND, and operative blood loss were the poor prognosticators in patients with ypT0 after NAT.

Outcome research on esophagectomy analyzed using nationwide databases in Japan: evidences generated from real-world data.

Esophagectomy for esophageal cancer is a highly invasive gastrointestinal surgical procedure. The National Clinical Database (NCD) of Japan, initiated in 2011, has compiled real-world data on esophagectomy, one of nine major gastroenterological surgeries. This review examines outcomes after esophagectomy analyzed using the Japanese big databases. Certification systems by the Japanese Society of Gastroenterological Surgery (JSGS) and the Japan Esophageal Society (JES) have shown that institutional certification has a greater impact on short-term surgical outcomes than surgeon certification. Minimally invasive esophagectomy has emerged as a viable alternative to open esophagectomy, although careful patient selection is crucial, especially for elderly patients with advanced tumors. The NCD has significantly contributed to the assessment and enhancement of surgical quality and short-term outcomes, while studies based on Comprehensive Registry of Esophageal Cancer in Japan (CRECJ) have provided data on patient characteristics, treatments, and long-term outcomes. The JES has conducted various questionnaire-based retrospective clinical reviews in collaboration with authorized institutions certified by JES. The Diagnosis Procedure Combination (DPC) database provides administrative claims data including itemized prices for surgical, pharmaceutical, laboratory, and other inpatient services. Analyzing these nationwide databases can offer precise insights into surgical quality for esophageal cancer, potentially leading to improved treatment outcomes.

The tumor cell-intrinsic cGAS-STING pathway is associated with the high density of CD8+ T cells after chemotherapy in esophageal squamous cell carcinoma.

BACKGROUND: Chemotherapy has the potential to induce CD8+ T-cell infiltration in the tumor microenvironment (TME) and activate the anti-tumor immune response in several cancers including esophageal squamous cell carcinoma (ESCC). The tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been known as a critical component for regulating immune cell activation in the TME. However, its effect on the infiltration of immune cells induced by chemotherapy in the ESCC TME has not been investigated. METHODS: We examined the effect of the tumor-cell intrinsic cGAS-STING pathway on the infiltration of CD8+ T cells induced by chemotherapy in ESCC using ESCC cell lines and surgically resected ESCC specimens from patients who received neoadjuvant chemotherapy (NAC). RESULTS: We found that chemotherapeutic agents, including 5-fluorouracil (5-FU) and cisplatin (CDDP), activated the cGAS-STING pathway, consequently inducing the expression of type I interferon and T-cell-attracting chemokines in ESCC cells. Moreover, the tumor cell-intrinsic expression of cGAS-STING was significantly and positively associated with the density of CD8+ T cells in ESCC after NAC. However, the tumor cell-intrinsic expression of cGAS-STING did not significantly impact clinical outcomes in patients with ESCC after NAC. CONCLUSION: Our findings suggest that the tumor cell-intrinsic cGAS-STING pathway might contribute to chemotherapy-induced immune cell activation in the ESCC TME.

Comparison of proton-based definitive chemoradiotherapy and surgery-based therapy for esophageal squamous cell carcinoma: a multi-center retrospective Japanese cohort study.

BACKGROUND: Proton-based, definitive chemoradiotherapy (P-CRT) for esophageal squamous cell carcinoma (ESCC) previously showed comparable survival outcomes with the surgery-based therapy, i.e., neoadjuvant chemotherapy followed by esophagectomy (NAC-S), in a single-institutional study. This study aimed to validate this message in a Japanese multicenter study. METHODS: Eleven Japanese esophageal cancer specialty hospitals have participated. A total of 518 cases with clinical Stage I-IVA ESCC between 2010 and 2019, including 168 P-CRT and 350 NAC-S patients, were enrolled and long-term outcomes were evaluated. Propensity-score weighting analyses with overlap weighting for confounding adjustment were used. RESULTS: The 3-year overall survival (OS) of the P-CRT group was equivalent to the NAC-S group (74.8% vs. 72.7%, hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.61-1.25). Although, the 3-year P-CRT group progression-free survival (PFS) was inferior to the NAC-S group (51.4% vs. 59.6%, HR 1.39, 95% CI 1.04-1.85), the progression P-CRT group cases showed better survival than the NAC-S group (HR 0.58, 95% CI 0.38-0.88), largely because of salvage surgery or endoscopic submucosal dissection for local progression. The survival advantage of P-CRT over NAC-S was more pronounced in the cT1-2 (HR 0.61, 95% CI 0.29-1.26) and cStage I-II (HR 0.50, 95% CI 0.24-1.07) subgroups, although this trend was not evident in other populations, such as cT3-4 and cStage III-IVA. CONCLUSIONS: Proton-based CRT for ESCC showed equivalent OS to surgery-based therapy. Especially for patients with cT1-2 and cStage I-II disease, proton-based CRT has the potential to serve as a first-line treatment.

A nationwide survey on the safety of cricothyrotomy: a multicenter retrospective study in Japan.

BACKGROUND: Cricothyrotomy is a widely performed potentially life-saving treatment to secure an airway in emergencies. It is also a pneumonia-preventing treatment to secure an expectorant route in patients with difficulty self-expelling sputum; however, its safety and usefulness remain unclear. Thus, we conducted a nationwide survey of cricothyrotomy. METHODS: We retrospectively collected and analyzed cricothyrotomy data from the institutions certified by the Japan Broncho-Esophagological Society or the Japanese Esophageal Society. Ultimately, 116 facilities responded to the survey and the present study included 1001 patients from 26 facilities who underwent cricothyrotomies from January 1, 2010 to December 31, 2021. RESULTS: Cricothyrotomy was performed for sputum suctioning after esophagectomy or other surgical procedures in 945 (94.4%) cases and for emergency airway clearance in 48 (4.8%) cases. Complications during puncture were observed in 12 (1.2%) cases. We found significantly fewer complications during puncture for sputum suction (1.0%) compared with emergency airway clearance (4.2%) (p = 0.002), and also at the condition after esophagectomy (0.5%) compared with other surgical procedures (7.8%) (p < 0.001). Complications after puncture were observed in 45 (4.5%) cases, and we found significantly fewer complications after puncture at the condition after esophagectomy (4.2%) compared with other surgical procedures (11.8%) (p = 0.032). There were no significant differences in the type of kit used for complications during and after the puncture. CONCLUSIONS: Cricothyrotomy for prophylactic sputum suctioning after esophagectomy was safer compared to emergency airway clearance. However, future studies should verify the efficacy of cricothyrotomy.

Esophagectomy for esophageal cancer in patients with a history of total pharyngolaryngectomy: a Japanese nationwide retrospective cohort study.

BACKGROUND: Second primary esophageal cancer often develops in patients with head and neck cancer, and esophagectomy in patients with a history of total pharyngolaryngectomy (TPL) is challenging. However, the clinical outcomes of these patients have yet to be examined in a multicenter setting. METHODS: We evaluated the surgical outcomes of a nationwide cohort of 62 patients who underwent esophagectomy for esophageal cancer with a history of TPL. RESULTS: Ivor-Lewis and McKeown esophagectomies were performed in 32 (51.6%) and 30 (48.4%) patients, respectively. Postoperatively, 23 patients (37.1%) developed severe complications, and 7 patients (11.3%) required reoperation within 30 days. Pneumonia and anastomotic leakage occurred in 13 (21.0%) and 16 (25.8%) patients, respectively. Anastomotic leakage occurred more frequently in the McKeown group than in the Ivor-Lewis group (46.7% vs. 6.2%, P < 0.001). The adjusted odds ratio for anastomotic leakage in the McKeown group was 9.64 (95% confidence intervals (CI), 2.11-70.82, P = 0.008). Meanwhile, the 5-year overall survival rates were comparable between the groups (41.8% for Ivor-Lewis and 42.7% for McKeown), and the adjusted hazard ratio of overall survival was 1.44 (95% CI, 0.64-3.29; P = 0.381; Ivor-Lewis as the reference). CONCLUSIONS: In our cohort, anastomotic leakage occurred more frequently after McKeown than Ivor-Lewis esophagectomy, and almost half of patients in the McKeown group experienced leakage. Ivor-Lewis esophagectomy is preferred for decreasing anastomotic leakage when oncologically and technically feasible.

M2 tumor-associated macrophages resist to oxidative stress through heme oxygenase-1 in the colorectal cancer tumor microenvironment.

M2 tumor-associated macrophages (M2-TAMs) promote cancer cell proliferation and metastasis in the TME. Our study aimed to elucidate the mechanism of increased frequency of M2-TAMs infiltration in the colorectal cancer (CRC)-TME, focusing on the resistance to oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we evaluated the correlation between M2-TAM signature and mRNA expression of antioxidant related genes using public datasets, and the expression level of antioxidants in M2-TAMs by flow cytometry and the prevalence of M2-TAMs expressing antioxidants by immunofluorescence staining using surgically resected specimens of CRC (n = 34). Moreover, we generated M0 and M2 macrophages from peripheral blood monocytes and evaluated their resistance to oxidative stress using the in vitro viability assay. Analysis of GSE33113, GSE39582, and The Cancer Genome Atlas (TCGA) datasets indicated that mRNA expression of HMOX1 (heme oxygenase-1 (HO-1)) was significantly positively correlated with M2-TAM signature (r = 0.5283, r = 0.5826, r = 0.5833, respectively). The expression level of both Nrf2 and HO-1 significantly increased in M2-TAMs compared to M1- and M1/M2-TAMs in the tumor margin, and the number of Nrf2+ or HO-1+M2-TAMs in the tumor stroma significantly increased more than those in the normal mucosa stroma. Finally, generated M2 macrophages expressing HO-1 significantly resisted to oxidative stress induced by H2O2 in comparison with generated M0 macrophages. Taken together, our results suggested that an increased frequency of M2-TAMs infiltration in the CRC-TME is related to Nrf2-HO-1 axis mediated resistance to oxidative stress.

ARID1A deficiency is targetable by AKT inhibitors in HER2-negative gastric cancer.

BACKGROUND: The PI3K/AKT signaling pathway is frequently activated in gastric cancer (GC); however, AKT inhibitors are not effective in unselected GC patients in clinical trials. Mutations in AT-rich interactive domain 1A (ARID1A), which are found in approximately 30% of GC patients, activate PI3K/AKT signaling, suggesting that targeting the ARID1A deficiency-activated PI3K/AKT pathway is a therapeutic candidate for ARID1A-deficient GC. METHODS: The effect of AKT inhibitors was evaluated using cell viability and colony formation assays in ARID1A-deficient and ARID1A knockdown ARID1A-WT GC cells as well as in HER2-positive and HER2-negative GC. The Cancer Genome Atlas cBioPortal and Gene Expression Omnibus microarray databases were accessed to determine the extent of dependence of GC cell growth on the PI3K/AKT signaling pathway. RESULTS: AKT inhibitors decreased the viability of ARID1A-deficient cells and the inhibitory effect was greater in ARID1A-deficient/HER2-negative GC cells. Bioinformatics data suggested that PI3K/AKT signaling plays a greater role in proliferation and survival in ARID1A-deficient/HER2-negative GC cells than in ARID1A-deficient/HER2-positive cells, supporting the higher therapeutic efficacy of AKT inhibitors. CONCLUSIONS: The effect of AKT inhibitors on cell proliferation and survival is affected by HER2 status, providing a rationale for exploring targeted therapy using AKT inhibitors in ARID1A-deficient/HER2-negative GC.