WNT/ß-catenin Signaling and CD8+ Tumor-infiltrating Lymphocytes in Tremelimumab Plus Durvalumab for Advanced Hepatocellular Carcinoma.

BACKGROUND/AIM: Tremelimumab plus durvalumab is an approved first-line therapy for advanced hepatocellular carcinoma (HCC). Previous studies identified WNT/ß-catenin mutations or CD8+ tumor-infiltrating lymphocytes (TILs) as biomarkers that can predict responsiveness to immune checkpoint inhibitor therapy in HCC. However, biomarkers for effectiveness of tremelimumab plus durvalumab in HCC have not been reported. This study investigated whether evaluation of WNT/ß-catenin signaling and CD8+ TILs by immunohistochemical staining of tumor biopsy tissues can predict the response to tremelimumab plus durvalumab in patients with HCC. PATIENTS AND METHODS: Fifteen HCC patients who underwent tumor biopsies were classified into three groups based on WNT/ß-catenin signal activation and CD8+ TIL infiltration. The clinical responses to treatment in the groups were evaluated. RESULTS: Four patients had HCC with WNT/ß-catenin signal inactivation and high-level CD8+ TIL infiltration, four patients had HCC with WNT/ß-catenin signal activation and low-level CD8+ TIL infiltration, and seven patients had WNT/ß-catenin signal activation and high-level CD8+ TIL infiltration or WNT/ß-catenin signal inactivation and low-level CD8+ TIL infiltration. A better response rate was observed in the WNT/ß-catenin signal inactivation and high-level CD8+ TIL infiltration group, and a worse response rate was observed in the WNT/ß-catenin signal activation and low-level CD8+ TIL infiltration group. CONCLUSION: Although the present study involved a small number of patients, the findings suggest that the efficacy of tremelimumab plus durvalumab may be affected by WNT/ß-catenin signaling and CD8+ TIL infiltration.

Safety and efficacy of underwater EMR for 10- to 20-mm colorectal serrated lesions (SEA CLEAR study).

BACKGROUND AND AIMS: Colorectal serrated lesions (SLs) are precursors of colorectal carcinoma via the serrated neoplasia pathway. However, the success rate of endoscopic resection of large SLs is low. Therefore, this study aimed to determine the safety and efficacy of underwater EMR (UEMR) for SLs sized 10 to 20 mm. METHODS: This 2-center, prospective, observational study included patients with at least 1 SL sized 10 to 20 mm. We resected the SLs by UEMR and performed tattooing at the resection site. Surveillance colonoscopy was performed 12 months postoperatively to evaluate local recurrence. The primary outcome was the complete resection rate of UEMR, which was defined as en bloc resection with no serrated tissue in the 4 marginal biopsy samples and histologically negative margins. RESULTS: UEMR was performed for 65 SLs in 58 patients, with a median lesion size of 14 mm. The en bloc, R0 resection, and complete resection rates were 87.7% (57 of 65), 61.5% (40 of 65), and 60.0% (39 of 65), respectively. Adverse events included 1 (1.5%) immediate bleeding and 1 (1.5%) delayed perforation. Surveillance colonoscopy was performed in 50 patients with 57 scars, and the rates of identification for tattoos and scars were 94.7% (54 of 57) and 100% (57 of 57), respectively. The recurrence rate was 5.3% (3 of 57), and all 3 recurrent lesions were completely resected endoscopically. CONCLUSIONS: This 2-center prospective study demonstrated that UEMR for SLs sized 10 to 20 mm was comparable to previous conventional EMR outcomes.

Naldemedine for Opioid-Induced Constipation in Patients With Cancer: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial.

PURPOSE: Opioid-induced constipation is the most frequent and non-self-limiting adverse effect of opioid analgesia, reducing adherence and interfering with pain relief. This clinical trial aimed to clarify the preventive effect of naldemedine versus placebo for constipation in patients with cancer starting regularly dosed strong opioids therapy. METHODS: This multicenter, double-blinded, randomized, placebo-controlled, confirmatory trial was conducted between July 2021 and May 2023 at four academic hospitals in Japan (ClinicalTrials.gov identifier: jRCTs031200397). Patients with cancer starting a first-time regularly dosed strong opioid for cancer pain and age 20+ years were included. Eligible patients were randomly assigned to the naldemedine (Symproic 0.2 mg) or placebo group in a 1:1 ratio for 14 days with protocol treatment. The primary end point was the proportion of patients with a Bowel Function Index (BFI) of <28.8 on day 14. The secondary end points included frequency of spontaneous bowel movements (SBM), quality of life (QOL), and frequency of opioid-induced nausea and vomiting (OINV). RESULTS: Of the 103 patients assessed for eligibility, 99 received either naldemedine (n = 49) or placebo (n = 50). A BFI of <28.8 on day 14 was significantly more likely to occur in the naldemedine group (64.6%; 95% CI, 51.1 to 78.1) versus placebo (17.0%; 95% CI, 6.3 to 27.8), and the difference between groups was 47.6% (95% CI, 30.3 to 64.8; P < .0001). The frequency of SBM, QOL, and the severity of OINV were nominally significant in the naldemedine group than in the control group. CONCLUSION: Naldemedine prevented constipation and improved constipation-related QOL, with possible preventive effect on OINV in patients with cancer starting regularly dosed opioids therapy.

Similar Efficacy Between Atezolizumab Plus Bevacizumab Versus Hepatic Arterial Infusion Chemotherapy For Unresectable Hepatocellular Carcinoma With Portal Vein Tumor Thrombus: A Retrospective Cohort Study.

BACKGROUND/AIM: The landscape of treatments for hepatocellular carcinoma (HCC), including immune checkpoint inhibitors, has expanded significantly. However, unresectable HCC patients with portal vein tumor thrombus (PVTT) continue to face a poor prognosis. This investigation examined the survival outcomes and determinants influencing survival rates in advanced HCC patients with PVTT undergoing treatment with atezolizumab plus bevacizumab (ATZ+BEV) or hepatic arterial infusion chemotherapy (HAIC). PATIENTS AND METHODS: Between December 2003 and June 2023, 48 advanced HCC with PVTT underwent treatment with either ATZ+BEV (16 patients) or HAIC (32 patients). RESULTS: The analysis revealed no significant disparities in overall survival (OS) or treatment efficacy between the ATZ+BEV and HAIC groups (ATZ+BEV: 10.0 months, HAIC: 15.3 months). Treatment with either ATZ+BEV or HAIC resulted in minimal alterations in the ALBI score and preserved hepatic function. Independent prognostic factors for OS, identified via multivariate logistic regression, included serum α-fetoprotein levels >400 ng/ml [hazard ratio (HR)=1.94; p=0.001], the existence of more than five tumors (HR=1.55; p=0.043), and the Child-Pugh score (HR=2.53; p=0.002). CONCLUSION: This investigation revealed no significant variance in OS and response rates between patients receiving ATZ+BEV and those treated with HAIC. The survival of advanced HCC patients with PVTT is intricately linked to the preservation of liver function, emphasizing the necessity for additional research to enhance treatment approaches for this patient population.

Chronological alterations in de novo malignancies after living-donor liver transplantation: A cohort study of 1781 recipients using annual comparisons of standardized incidence ratios.

BACKGROUND: De novo malignancies (DNMs) are a major adverse event after solid organ transplantation; however, their characteristics and recent trends after living-donor liver transplantation (LDLT) remain unclear. METHODS: We retrospectively reviewed 1781 primary LDLT recipients (1990-2020) and annually calculated standardized incidence ratios (SIRs) of DNMs compared to the age-adjusted Japanese general population. RESULTS: After 21 845 person-years follow-up, 153 DNM lesions (8.6%) were identified in 131 patients (7.4%). The incidence was 0.007 person-years. DNMs included 81 post-transplant lymphoproliferative disorders (PTLDs), 14 colorectal, 12 lung, and 12 gastric cancers, and so on. Comorbid DNMs significantly worsened recipient survival than those without (p < .001). The 5- and 10-year recipient survival after DNM diagnosis were 65% and 58%, respectively. Notably, SIR1993-1995: 8.12 (95% CI: 3.71-15.4, p < .001) and SIR1996-1998: 3.11 (1.34-6.12, p = .01) were significantly high, but had decreased time-dependently to SIR2005-2007: 1.31 (0.68-2.29, p = .42) and SIR2008-2010: 1.34 (0.75-2.20, p = .33), indicating no longer significant difference in DNMs development. Currently, however, SIR2014-2016: 2.27 (1.54-3.22, p < .001) and SIR2017-2019: 2.07 (1.40-2.96, p < .001) have become significantly higher again, reflecting recent aging of recipients (>50 years) and resultant increases in non-PTLD DNMs. Furthermore, characteristically in LDLT, the fewer the donor-recipient HLA-mismatches, the less the post-transplant DNMs development. CONCLUSION: DNM development after LDLT was significantly higher than in the general population due to higher PTLD incidence (1993-1998), but once became equivalent (2005-2013), then significantly increased again (2014-2019) due to recent recipient aging and resultant increase in solid cancers.

Impact of thoracic shape on the surgical outcomes of laparoscopic-assisted living donor hepatectomy.

Background: Although laparoscopic-assisted donor hepatectomy (LADH) has become the definitive procedure for harvesting living donor livers, its surgical outcomes in association with donor body shape have not been elucidated. Methods: The impact of donor factors, including thoracic shape, on LADH outcomes was retrospectively investigated. Thoracic anthropometric data were examined in all LADHs with a left/right graft between 2013 and 2022. Results: The study included 210 LADHs, consisting of 106 left- and 104 right-lobe donors with similar blood loss and similar operation time. Males have greater thoracic depth and greater thoracic width compared with females, respectively. Thoracic depth was associated with graft weight (p < 0.001), blood loss (p < 0.001), and operation time (p < 0.001). On multivariate analyses, blood loss >500 mL and operation time >8 h were associated with graft weight in the left-lobe donors, and blood loss >500 mL was associated with thoracic depth in the right-lobe donors. Conclusion: The greater thoracic depth is associated with massive blood loss in right-lobe donors. Anthropometric parameters might be helpful for estimating LADH outcomes.

Dynamics of the neutrophil­to­lymphocyte ratio during lenvatinib treatment for unresectable hepatocellular carcinoma.

Lenvatinib is an approved therapy for advanced hepatocellular carcinoma (HCC). Recently, immune checkpoint inhibitors have been approved as frontline chemotherapies for HCC, and the tumor immune microenvironment (TIME) has been demonstrated to significantly affect HCC treatment. The neutrophil-to-lymphocyte ratio (NLR) is associated with the TIME, and the dynamics of the NLR are associated with prognosis or treatment efficacy in various cancer types. The present study investigated the dynamics of the TIME using the NLR in 101 patients with HCC treated with lenvatinib. Immunostaining for CD8+ tumor-infiltrating lymphocytes (TILs) was also performed in 9 patients who underwent liver tumor biopsy prior to subsequent chemotherapy for progression or discontinuation due to adverse events on lenvatinib treatment. The NLR values measured at the start of treatment (SOT), after 1 month of treatment and after 3 months of treatment were 2.78±2.20, 2.61±1.86 and 2.66±2.36, respectively (P=0.733). Among the patients with no reduction in the initial dose, there was no significant difference between the NLR after 1 month (2.34±0.25) and that at the SOT (2.86±2.33) (P=0.613). In patients who achieved a complete or partial response, the NLR at the time of the best tumor response was 1.65±0.56, which was significantly lower than that at the SOT (2.05±0.78) (P=0.023). In patients who did not respond to lenvatinib, the NLR at the time of disease progression was 3.68±3.19, which was significantly higher than that at the SOT (2.78±1.79) (P=0.043). Overall, 5 out of the 6 patients who did not respond to lenvatinib had low CD8+ TIL counts at disease progression. Although the present study included a limited number of patients, the NLR was associated with the therapeutic effects of lenvatinib. These findings suggest the potential of lenvatinib as an immunomodulator.

LTK mutations responsible for resistance to lorlatinib in non-small cell lung cancer harboring CLIP1-LTK fusion.

The CLIP1-LTK fusion was recently discovered as a novel oncogenic driver in non-small cell lung cancer (NSCLC). Lorlatinib, a third-generation ALK inhibitor, exhibited a dramatic clinical response in a NSCLC patient harboring CLIP1-LTK fusion. However, it is expected that acquired resistance will inevitably develop, particularly by LTK mutations, as observed in NSCLC induced by oncogenic tyrosine kinases treated with corresponding tyrosine kinase inhibitors (TKIs). In this study, we evaluate eight LTK mutations corresponding to ALK mutations that lead to on-target resistance to lorlatinib. All LTK mutations show resistance to lorlatinib with the L650F mutation being the highest. In vitro and in vivo analyses demonstrate that gilteritinib can overcome the L650F-mediated resistance to lorlatinib. In silico analysis suggests that introduction of the L650F mutation may attenuate lorlatinib-LTK binding. Our study provides preclinical evaluations of potential on-target resistance mutations to lorlatinib, and a novel strategy to overcome the resistance.

Systemic Chemotherapy for Advanced Hepatocellular Carcinoma in Patients With Child-Pugh class B.

Background/Aim: Numerous agents, including immune checkpoint inhibitors, are now available for hepatocellular carcinoma (HCC) treatment. Most trials involving systemic chemotherapy have included patients with Child-Pugh class A, while excluding or minimally enrolling those with Child-Pugh class B, due to liver dysfunction-related mortality. This study aimed to identify prognostic factors for survival in Child-Pugh class B patients receiving sorafenib (SOR), lenvatinib (LEN), atezolizumab plus bevacizumab (ATZ+BEV), or hepatic arterial infusion chemotherapy (HAIC). Patients and Methods: From December 2003 to June 2023, 137 patients with advanced HCC receiving systemic chemotherapies (SOR: n=43, LEN: n=16, ATZ+BEV: n=18, HAIC: n=60) were enrolled. Results: Overall survival (OS) and response rates did not differ significantly across treatments (SOR: 8.3 months, LEN: 10.2 months, ATZ+BEV: 8.5 months, HAIC: 7.3 months). Patients on HAIC and LEN had a lower rate of discontinuing treatment within three months compared to those on ATZ+BEV and SOR. HAIC was associated with fewer changes in ALBI score and better preservation of liver function. Multivariate logistic regression identified serum α-fetoprotein >400 ng/ml [hazard ratio (HR)=1.94; p=0.001], tumor count >5 (HR=1.55; p=0.043), and Child-Pugh score (HR=2.53; p=0.002) as independent predictors of OS. Conclusion: OS and response rates were similar across systemic chemotherapies. Prognosis for HCC in Child-Pugh class B patients was associated with liver function, necessitating further research for optimal treatment.

The serum thioredoxin-1 levels are not associated with bronchopulmonary dysplasia and retinopathy of prematurity.

BACKGROUND: We hypothesized that the serum TRX-1 in extremely preterm infants (EPIs) after birth was associated with the development of severe bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP). METHODS: This single-centered retrospective study enrolled EPIs treated at our institution. Serum TRX-1 concentrations of the residual samples taken on admission, day 10-20 of life, and 36-40 weeks of postmenstrual age (PMA) were measured with an enzyme-linked immunosorbent assay. RESULTS: The serum TRX-1 levels on admission were not different between the severe BPD (n = 46) and non-severe BPD groups (n = 67): [median (interquartile range) 147 (73.0-231) vs. 164 (80.5-248) ng/mL] (P = 0.57). These had no significant difference between the severe ROP (n = 47) and non-severe ROP groups (n = 66): [164 (71.3-237) vs. 150 (80.9-250) ng/mL] (P = 0.93). The TRX-1 levels at 10-20 days of life and 36-40 weeks of PMA also had no association with the development of severe BPD and ROP. CONCLUSION: The serum TRX-1 levels after birth are not predictive of severe BPD and ROP. IMPACT: Serum thioredoxin-1 levels in extremely preterm infants on the day of birth are lower than those in term or near-term infants hospitalized for transient tachypnea of the newborn. In extremely preterm infants, the serum thioredoxin-1 levels on the day of birth, at 10-20 days of life, and at postmenstrual age of 36-40 weeks were not associated with severe bronchopulmonary dysplasia and retinopathy of prematurity. The thioredoxin system is under development in extremely preterm infants; however, the serum thioredoxin-1 level is not predictive for severe bronchopulmonary dysplasia and retinopathy of prematurity.

Water intake, baseline biopsy, and graft function after living donor kidney transplantation.

Increased water intake is recommended for kidney transplant recipients; however, its efficacy remains controversial. We hypothesized that pre-existing histological findings of the allograft might modulate the impact of water intake. We retrospectively analyzed 167 adults with living-donor kidney transplants (April 2011-May 2020; median observation period, 77 months) whose baseline biopsy data were available. We compared the chronic-change group (n = 38) with the control group (n = 129) to assess the impact of self-reported daily water intake on the estimated glomerular filtration rate (eGFR). The range distribution of water intake was as follows: - 1000 ml (n = 4), 1000-1500 ml (n = 23), 1500-2000 ml (n = 64), 2000-2500 ml (n = 57), 2500-3000 ml (n = 16), and 3000 - ml (n = 3). Donor age was significantly higher in the chronic-change group. In the control group, the ΔeGFR/year increase was correlated with water intake. However, the increase in the water intake of the chronic-change group significantly decreased ΔeGFR/year (1000-1500 ml: + 1.95 ml/min/1.73 m2 and > 2000 ml: - 1.92 ml/min/1.73 m2, p = 0.014). This study suggested a potential influence of increased water intake on recipients with marginal grafts in living donor kidney transplantation.

Neutrophil-to-Lymphocyte Ratio Predicts Immune-related Adverse Events in Patients With Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab.

Background/Aim: Atezolizumab in combination with bevacizumab is an approved systemic chemotherapy regimen for advanced hepatocellular carcinoma (HCC). However, immune checkpoint inhibitors (ICIs), such as atezolizumab, frequently lead to immune-related adverse events (irAEs). The identification of biomarkers that can predict the occurrence of irAEs is crucial for the optimal management of patients undergoing ICI treatment. Patients and Methods: Between October 2020 and June 2023, we conducted a study involving 69 patients with advanced HCC who received treatment with atezolizumab plus bevacizumab. We conducted an analysis of blood-based biomarkers to identify independent risk factors associated with irAEs. Results: In our study, 12 out of 69 patients (17.4%) experienced irAEs. Our investigation into blood-based biomarkers revealed that a neutrophil-to-lymphocyte ratio (NLR) <2.04 at three weeks after the initiation of treatment had high predictive power (area under the curve: 0.77) for irAEs. Furthermore, multivariate logistic analysis identified NLR at three weeks (hazard ratio=0.23; p=0.037) and non-viral infection (hazard ratio=4.47; p=0.037) as independent factors contributing to the occurrence of irAEs. Patients who developed irAEs demonstrated a more favorable overall response rate (75.0% vs. 28.1%, p=0.005), disease control rate (91.6% vs. 52.6%, p=0.016), and progression-free survival (12.1 months vs. 6.0 months, p=0.010) than those who did not experience irAEs. Conclusion: An NLR <2.04 at three weeks after the initiation of treatment may serve as a valuable biomarker for predicting irAEs in patients with HCC undergoing atezolizumab plus bevacizumab therapy.

[Preparation of Nanoplastic Particles as Potential Standards for the Study of Nanoplastics].

Nanoplastics (NPs) are plastic fragments that are small enough to be absorbed by organisms through ingestion or inhalation. Recent studies indicate that nanoplastics can be ubiquitous in the environment, and there are growing concerns regarding the impacts of nanoplastics on the health of humans and other organisms. However, quantitative information on nanoplastics in the environment is still very limited, and most previous toxicity studies have used only polystyrene (PS) particles because of a lack of appropriate model particles of other plastics. We developed a nanoprecipitation-based method for the preparation of nanoplastic particles of five major polymers: low-density polyethylene (LDPE), high-density polyethylene (HDPE), polypropylene (PP), polyvinyl chloride (PVC), and polystyrene. A major advantage of our method is that the nanoplastic particles are prepared without using reagents that can remain in the particles as impurities. Analysis of the prepared particles' molecular weight (Mw) distributions, crystallinities, and thermal properties revealed that their compositions and constitutions were within the general ranges for commercial products. The mechanisms underlying the formation of low-density polyethylene particles via our method were investigated by means of a simple population balance model, and particle diameter was found to be linearly correlated with the suspension density of the nanoplastic dispersion up to 0.4 mg·mL-1. Future studies should focus on improving our method to allow for precise, scale-independent production of nanoplastic particles. Methods for the preparation of labeled particles are also needed so that such particles can be used in nanoplastic risk assessments.

The Prevalence and Characteristics of Symptomatic Uncomplicated Diverticular Disease Among Asian Patients With Unexplained Abdominal Symptoms.

Background/Aims: The precise incidence of symptomatic uncomplicated diverticular disease (SUDD) and its effects on the quality of life (QOL) remain unclear, particularly in Asian patients with right-sided SUDD. We assess the prevalence of SUDD and its impact on QOL in a real-world population. Methods: Five institutional cohorts of patients who received outpatient treatment for unexplained abdominal symptoms from January 15, 2020 to March 31, 2022, were included. All patients underwent colonoscopy. SUDD was defined as the presence of recurrent abdominal symptoms, particularly pain in the lower right or left quadrant lasting > 24 hours in patients with diverticulosis at the site of pain. The 36-item short-form health survey was used to assess QOL. Results: Diverticula were identified in 108 of 361 patients. Among these 108 patients, 31% had SUDD, which was right-sided in 39% of cases. Of the 50 patients with right-sided diverticula, 36% had SUDD, as did 15 of 35 patients with left-sided diverticula (43%). Among the 33 patients with SUDD, diverticula were right-sided, left-sided, and bilateral in 39%, 45%, and 15% of patients, respectively. Diarrhea was more frequent in the SUDD group than in the non-SUDD group. Patients with SUDD had significantly lower physical, mental, and role/social component scores than those without SUDD. Conclusions: It is important to recognize that patients with SUDD account for as high as 31% of outpatients with unexplained abdominal symptoms; these patients have diarrhea and a low QOL. The presence of right-sided SUDD was characteristic of Asian patients.

Vascular Reconstruction with the Cuff Technique in Mouse Orthotopic Liver Transplantation.

Mouse orthotopic liver transplantation is an effective methodology for investigating the underlying mechanisms of liver ischemia and reperfusion injury. However, the technical challenges pose a barrier to utilizing this valuable experimental model and passing on these skills to the next generation. The most challenging aspect of this procedure is vascular reconstruction, including the portal vein (PV), infrahepatic inferior vena cava (IHIVC), and suprahepatic inferior vena cava. The use of plastic cuffs, rather than sutures, allows for smoother PV and IHIVC reconstruction. Vessels are reconstructed by attaching a cuff made from an intravenous catheter to the tip of the graft vessel and interposing the cuff into the recipient vessel. The two most crucial aspects are properly visualizing the inner lumen of the vessel and avoiding the use of excessive force. Our aim is to provide a technical overview of vascular reconstructions using the cuff technique in recipient surgery. These technical tips for the cuff technique are expected to help microsurgeons facilitate vascular reconstruction and advance their research.

Combined Ultrasound and Computed Tomography Guidance in Radiofrequency Ablation for Hepatocellular Carcinoma Reduces Local Recurrence Rate.

Background/Aim: In radiofrequency ablation (RFA) treatment of hepatocellular carcinoma (HCC), the therapeutic effect depends on the appropriate position of the electrode. To improve the accuracy of the electrode needle position, we currently perform RFA with combined ultrasound sonography (US) and computed tomography (CT) guidance. The purpose of this study was to evaluate the effectiveness of this US/CT-guided RFA method. Patients and Methods: This retrospective study recruited 97 patients with single tumors treated with transcatheter arterial chemoembolization and monopolar RFA between January 2013 and December 2017. Among these, 50 patients were treated with RFA under US/CT guidance (US/CT-guided group) and 47 were treated with RFA under US guidance alone (US-guided group). We analyzed the efficacy of US/CT guidance compared with US guidance alone. Results: The 1-, 2-, and 3-year local recurrence rates for the US/CT-guided and US-guided groups were 4.1%, 6.3%, and 8.6%, and 19.6%, 31.6%, and 41.9%, respectively. The local recurrence rate was lower in the US/CT-guided group (p=0.0030). Cox proportional hazards model for multivariate analysis demonstrated that the independent risk factors associated with local recurrence were tumor size (p=0.0028) and US/CT guidance (p=0.0037). Conclusion: US/CT-guided RFA for HCC reduced the local recurrence rate compared with US-guided RFA alone.

CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade.

Serine/threonine kinase, cell division cycle 7 (CDC7) is critical for initiating DNA replication. TAK-931 is a specific CDC7 inhibitor, which is a next-generation replication stress (RS) inducer. This study preclinically investigates TAK-931 antitumor efficacy and immunity regulation. TAK-931 induce RS, generating senescence-like aneuploid cells, which highly expressed inflammatory cytokines and chemokines (senescence-associated secretory phenotype, SASP). In vivo multilayer-omics analyses in gene expression panel, immune panel, immunohistochemistry, RNA sequencing, and single-cell RNA sequencing reveal that the RS-mediated aneuploid cells generated by TAK-931 intensively activate inflammatory-related and senescence-associated pathways, resulting in accumulation of tumor-infiltrating immune cells and potent antitumor immunity and efficacy. Finally, the combination of TAK-931 and immune checkpoint inhibitors profoundly enhance antiproliferative activities. These findings suggest that TAK-931 has therapeutic antitumor properties and improved clinical benefits in combination with conventional immunotherapy.

Multiple Gastric Neuroendocrine Tumors Associated with Long-term Use of a Proton Pump Inhibitor and a Potassium-competitive Acid Blocker.

A 52-year-old man who had been using a proton pump inhibitor (PPI) and a potassium-competitive acid blocker (P-CAB) for 14 years underwent esophagogastroduodenoscopy and was found to have three neuroendocrine tumors (NETs) in the gastric body. Following detailed examinations, parietal cell dysfunction was excluded, and the NETs did not meet the criteria for the Rindi classification types I-III. The lesions were ultimately considered to be associated with the long-term use of the PPI and P-CAB. We performed endoscopic submucosal dissection of the lesions, with no recurrence or new lesions noted after discontinuation of the PPI and P-CAB.

Antimicrobial peptides modulate lung injury by altering the intestinal microbiota.

BACKGROUND: Mammalian mucosal barriers secrete antimicrobial peptides (AMPs) as critical, host-derived regulators of the microbiota. However, mechanisms that support microbiota homeostasis in response to inflammatory stimuli, such as supraphysiologic oxygen, remain unclear. RESULTS: We show that supraphysiologic oxygen exposure to neonatal mice, or direct exposure of intestinal organoids to supraphysiologic oxygen, suppresses the intestinal expression of AMPs and alters intestinal microbiota composition. Oral supplementation of the prototypical AMP lysozyme to hyperoxia-exposed neonatal mice reduced hyperoxia-induced alterations in their microbiota and was associated with decreased lung injury. CONCLUSIONS: Our results identify a gut-lung axis driven by intestinal AMP expression and mediated by the intestinal microbiota that is linked to lung injury in newborns. Together, these data support that intestinal AMPs modulate lung injury and repair. Video Abstract.

Management of bronchopulmonary dysplasia in Japan: A nationwide survey.

BACKGROUND: The incidence of bronchopulmonary dysplasia (BPD) and respiratory management practices for extremely low birth weight infants (ELBWIs) widely vary among institutions and countries. AIMS: To clarify the variation and characteristics of the current practices of Japanese neonatologists managing patients with BPD. STUDY DESIGN: Questionnaire-based survey. PARTICIPANTS: Level II and III perinatal centers certified by the Japan Society of Perinatal and Neonatal Medicine. OUTCOME MEASURES: Policies of the neonatal intensive care units (NICUs) regarding respiratory care and medications for BPD prevention and treatment. RESULTS: A total of 76 % of facilities (207/274) responded to our survey. The response rates of level III and II facilities were 91 % (102/112) and 35 % (105/296), respectively. INtubation-SURfactant-Extubation and Less Invasive Surfactant Administration methods were performed in 23 % (47/206) and 1 % (3/206) of facilities, respectively. For the prophylactic purpose, systemic and inhaled steroids were administered "frequently" or "occasionally" in 14 % (28/205) and 42 % (86/204) of NICUs, respectively. For the therapeutic purpose, systemic and inhaled steroids were administered "frequently" or "occasionally" in 84 % (171/204) and 29 % (59/204) of NICUs, respectively. Approximately half of the NICUs (99/202) used volume-targeted ventilation (VTV) "frequently" or "occasionally" in progressing BPD. High-frequency oscillation ventilation (HFOV) was used for progressing BPD "frequently" and "occasionally" in 89 % (180/202) of the facilities. CONCLUSIONS: Our study provided an overview and characteristics of BPD management in Japan in recent years. Noninvasive approaches with surfactant administration remain not widely used in Japan. HFOV is a widely accepted management for progressing BPD.