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Background: Management of patients with colorectal liver metastases (CRLMs) requires a multidisciplinary approach. For patients with progression of RAS mutant tumors, the choice of angiogenesis inhibitors can be controversial. Here, we report a patient with RAS mutant CRLMs achieving long-term disease-free survival with repeated R0 resections and perioperative treatment, especially aflibercept + FOLFIRI (5-fluorouracil, levofolinate, irinotecan), which may have prevented long-term recurrence., Case Presentation: The patient was a 37 year-old woman diagnosed with RAS mutant transverse colon cancer with 19 LMs. As the metastases were limited to the liver, we introduced systemic chemotherapy aiming at conversion surgery. After six cycles of bevacizumab + FOLFOXIRI (5-fluorouracil, levofolinate, oxaliplatin, irinotecan), we performed partial hepatectomy for all LMs, and left hemicolectomy for the primary tumor after another four cycles of bevacizumab + FOLFIRI. Three months after surgery, the patient presented with massive ovarian metastases with carcinomatous ascites. We conducted bilateral oophorectomy, and initiated aflibercept + FOLFIRI therapy considering the possibility of resistance to bevacizumab. The patient was recurrence-free for 2 years during aflibercept + FOLFIRI treatment. After its discontinuation, two distant metastases developed. Both were resectable and the patient achieved recurrence-free survival of 2 years and 3 months after the last operation (6 years since initiation of treatment), without additional chemotherapy., Conclusions: We believe that multidisciplinary treatment aimed at complete resection could lead to long-term survival even in patients with repeated recurrence of CRLMs. Aflibercept + FOLFIRI could be effective in controlling metastasis of RAS mutant colon cancer even after treatment with bevacizumab., (© 2024. The Author(s).)

Intracellular delivery of biomolecules is a prerequisite for genetic techniques such as recombinant engineering and genome editing. Realizing the full potential of this technology requires the development of safe and effective methods for delivering protein tools into cells. In this study, we demonstrated the spontaneous internalization of exogenous proteins into intact cells and root tissue of whole plants of Arabidopsis thaliana. We termed this internalization phenomenon as protein Delivery Independent of Vehicles or Equipment (DIVE), which efficiently delivered genome engineering proteins including Cre recombinase and zinc-finger nucleases (ZFN) into plant cells. Using protein DIVE, we achieved less toxic protein delivery than electroporation with up to 94% efficiency in Arabidopsis cell culture and 19% genome modification in Arabidopsis plants that was maintained in regenerated tissue. This work illustrates the potential of protein DIVE for a wide range of applications, including genome engineering in plants., (© 2024. The Author(s).)

Aims: Impella has become a new option for mechanical circulatory support in patients with cardiogenic shock (CS); however, prognostic models for patients after Impella are lacking. We aimed to identify the factors that predict in-hospital mortality in patients with CS requiring Impella and develop a new risk prediction model., Methods and Results: We utilized the J-PVAD registry, which includes all cases where Impella was implanted in Japan. Two-thirds of the patients in the J-PVAD registry were randomly assigned to the derivation cohort (n = 1701), and the other third was assigned to the validation cohort (n = 850). A backward stepwise logistic regression model was developed to identify factors associated with in-hospital mortality. In the derivation cohort, 956 patients were discharged alive, and 745 patients (43.8%) died during hospitalization. Among 29 candidate variables, 12 were independently associated with in-hospital mortality and were applied as components of the risk model, including age, sex, body mass index, fulminant myocarditis aetiology, cardiac arrest in hospital, baseline veno-arterial extracorporeal membrane oxygenation use, mean arterial pressure, lactate, lactate dehydrogenase, total bilirubin, creatinine, and albumin levels. The comparison of predicted and observed in-hospital mortality according to the 7th quantiles using the J-PVAD risk score showed good calibration. The area under the curve for the J-PVAD risk score was 0.76 (95% confidence interval 0.73-0.78). In the validation cohort, the J-PVAD risk score showed good calibration and discrimination ability., Conclusions: The J-PVAD risk score can be calculated using variables easily obtained in routine clinical practice. It helps the accurate stratification of mortality risk and facilitates clinical decision-making., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Fontan-associated liver disease (FALD) encompasses hepatic complications following the Fontan procedure, ranging from fibrosis to hepatocellular carcinoma (HCC). Despite advancements in surgical techniques and perioperative care, robot-assisted laparoscopic hepatectomy (RALH) for HCC in patients with FALD has not been previously reported owing to concerns about the Fontan circulation., Case Presentation: We present the first case of RALH for recurrent HCC in a 45-year-old man after the Fontan procedure. The preoperative evaluation confirmed good cardiac function. The procedure involved meticulous monitoring and management of central venous pressure and was successfully completed with minimal blood loss. Postoperative recovery was uneventful. With thorough preoperative cardiac assessment and close collaboration between cardiologists and anesthesiologists, RALH can be safely performed in selected patients with FALD., Conclusions: Even if a patient has a history of FALD, RALH can be safely performed in selected patients under appropriate conditions., (© 2024. The Author(s).)

Background: The preoperative serum creatine kinase (CK) concentration is a prognostic factor for malignant diseases. We investigated the significance of CK in surgically resected thymic epithelial tumors and the relationship between CK and clinicopathological factors., Methods: We retrospectively evaluated the relationship between preoperative CK levels and prognosis in 120 patients with thymic epithelial tumors who underwent surgical resection at two centers. The cutoff for CK was determined by the standard value in our institution (<62 IU/L for men and <45 IU/L for women). The paravertebral muscle at the Th12 level was used to assess skeletal muscle area to investigate sarcopenia., Results: Eighteen patients (15.0%) were categorized into the low CK group. The CK level was not associated with age, sex, performance status, myasthenia gravis, and pathological findings. Preoperative serum albumin and total cholesterol concentrations were significantly lower in the low CK group than in the normal CK group (both P<0.001). Moreover, the Th12 muscle index was lower in the low CK group (P=0.03), indicating that low CK was related to sarcopenia. Kaplan-Meier curve analysis illustrated that patients in the low CK group had significantly shorter disease-free survival (DFS) and overall survival (OS) than those in the normal CK group (P=0.03 and P=0.002, respectively). Multivariate analysis identified low CK as an independent prognostic factor for DFS (P=0.03) and OS (P=0.005)., Conclusions: Preoperative serum CK might reflect the host nutritional status in patients with resected thymic epithelial tumors; therefore, CK could be a biomarker of postoperative prognosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1797/coif). The authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Background: Cell-cell interaction factors that facilitate the progression of adenoma to sporadic colorectal cancer (CRC) remain unclear, thereby hindering patient survival., Methods: We performed spatial transcriptomics on five early CRC cases, which included adenoma and carcinoma, and one advanced CRC. To elucidate cell-cell interactions within the tumour microenvironment (TME), we investigated the colocalisation network at single-cell resolution using a deep generative model for colocalisation analysis, combined with a single-cell transcriptome, and assessed the clinical significance in CRC patients., Findings: CRC cells colocalised with regulatory T cells (Tregs) at the adenoma-carcinoma interface. At early-stage carcinogenesis, cell-cell interaction inference between colocalised adenoma and cancer epithelial cells and Tregs based on the spatial distribution of single cells highlighted midkine (MDK) as a prominent signalling molecule sent from tumour epithelial cells to Tregs. Interaction between MDK-high CRC cells and SPP1+ macrophages and stromal cells proved to be the mechanism underlying immunosuppression in the TME. Additionally, we identified syndecan4 (SDC4) as a receptor for MDK associated with Treg colocalisation. Finally, clinical analysis using CRC datasets indicated that increased MDK/SDC4 levels correlated with poor overall survival in CRC patients., Interpretation: MDK is involved in the immune tolerance shown by Tregs to tumour growth. MDK-mediated formation of the TME could be a potential target for early diagnosis and treatment of CRC., Funding: Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research; OITA Cancer Research Foundation; AMED under Grant Number; Japan Science and Technology Agency (JST); Takeda Science Foundation; The Princess Takamatsu Cancer Research Fund., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)