Laparoscopic Colorectal Surgery with Anatomical Recognition with Artificial Intelligence Assistance for Nerves and Dissection Layers.

BACKGROUND: In digestive tract surgery, dissection of an avascular space consisting of loose connective tissue (LCT) appearing by countertraction improves oncological outcomes and reduces complications.1-3 Kumazu et al.4 described a deep learning approach that automatically segments LCT to help surgeons.4 During left colorectal surgery, lumbar splanchnic, hypogastric, and pelvic visceral nerve injuries cause sexual dysfunction and/or urinary issues.5 As nerve preservation is critical for functional preservation, the AI model Kumazu reported is named Eureka (Anaut Inc., Tokyo, Japan) and was developed to separate nerves automatically. The educative efficacy of intraoperative nerve visualization has been described.6 Artificial intelligence (AI) assisted navigation is expected to aid in the anatomical recognition of nerves and the safe dissection layers surrounding nerves in the future. METHODS: We used Eureka as an educational tool for surgeons' training during laparoscopic colorectal surgery. The laparoscopic system used was Olympus VISERA ELITE3 (Tokyo, Japan). RESULTS: Total mesorectal excision (TME) was safely performed with nerve preservation. No postoperative complications occurred. Automatic segmentation and highlighting of LCT in the dissected layers, lumbar splanchnic, hypogastric, and pelvic visceral nerves (S3, S4), were performed in real time. CONCLUSIONS: In colorectal cancer surgery, the nerves are vital anatomical structures serving as landmarks for dissection. Lumbar splanchnic, hypogastric, and pelvic visceral nerve injuries (S3, S4) cause sexual dysfunction or urinary disorders.5 Nerve preservation is important for functional preservation. AI-assisted navigation methods are noninvasive, user-friendly, and expected to improve in accuracy in the future. They have the potential to develop nerve-guided TME.

High-output stoma is a risk factor for stoma outlet obstruction in defunctioning loop ileostomies after rectal cancer surgery.

PURPOSE: Defunctioning loop ileostomy has been reported to reduce symptomatic anastomotic leakage after rectal cancer surgery; however, stoma outlet obstruction (SOO) is a serious postileostomy complication. We, therefore, explored novel risk factors for SOO in defunctioning loop ileostomy after rectal cancer surgery. METHODS: This is a retrospective study that included 92 patients who underwent defunctioning loop ileostomy with rectal cancer surgery at our institution. Among them, 77 and 15 ileostomies were created at the right lower abdominal and umbilical sites, respectively. We defined the output volumeMAX as the maximum output volume the day before the onset of SOO or-for those without SOO-that was observed during hospitalization. Univariate and multivariate analyses were performed to evaluate risk factors for SOO. RESULTS: SOO was observed in 24 cases, and the median onset was 6 days postoperatively. The stoma output volume in the SOO group was consistently higher than that in the non-SOO group. In the multivariate analysis, the rectus abdominis thickness (p < 0.01) and output volumeMAX (p < 0.01) were independent risk factors for SOO. CONCLUSION: A high-output stoma may predict SOO in patients with defunctioning loop ileostomy for rectal cancer. Considering that SOO occurs even at umbilical sites with no rectus abdominis, a high-output stoma may trigger SOO primarily.

Increased risk of incisional hernia after stoma closure in patients with colorectal cancer.

PURPOSE: Stoma construction and closure are common surgical strategies in patients with colorectal cancer. The present study evaluated the influence of multiple incisional sites resulting from stoma closure on incisional hernia after colorectal cancer surgery. METHODS: The study included 1681 patients who underwent colorectal cancer surgery. Multiple incisional sites were defined as the coexistence of incisions at the midline and stoma closure sites. We retrospectively investigated the relationship between the presence of multiple incisional sites and incisional hernia development in patients with colorectal cancer. RESULTS: Among the 1681 patients, 420 (25%) underwent stoma construction, with a stoma closure-to-construction ratio of 33% (139/420), and 155 (9.2%) developed incisional hernias after colorectal cancer surgery. In the multivariate analysis, female sex (p < 0.001), body mass index (p < 0.001), multiple incisional sites (p = 0.001), wound infection (p = 0.003), and postoperative chemotherapy (p = 0.030) were independent predictors of incisional hernia. In the multiple incisional sites group, the age (p < 0.001), surgical approach (laparoscopic) (p = 0.013), wound infection rate (p = 0.046), small bowel obstruction rate (p < 0.001), and anastomotic leakage rate (p = 0.008) were higher in those in the single incisional site group. CONCLUSIONS: Multiple incisional sites resulting from stoma closure are associated with the development of incisional hernia following colorectal cancer surgery.

DYRK2 promotes chemosensitivity via p53-mediated apoptosis after DNA damage in colorectal cancer.

Dual-specificity tyrosine-regulated kinase 2 (DYRK2) is a protein kinase that phosphorylates p53-Ser46 and induces apoptosis in response to DNA damage. However, the relationship between DYRK2 expression and chemosensitivity after DNA damage in colorectal cancer has not been well investigated. The aim of the present study was to examine whether DYRK2 could be a novel marker for predicting chemosensitivity after 5-fluorouracil- and oxaliplatin-induced DNA damage in colorectal cancer. Here we showed that DYRK2 knockout decreased the chemosensitivity to 5-fluorouracil and oxaliplatin in p53 wild-type colorectal cancer cells, whereas the chemosensitivity remained unchanged in p53-deficient/mutated colorectal cancer cells. In addition, no significant differences in chemosensitivity to 5-fluorouracil and oxaliplatin between scramble and siDYRK2 p53(-/-) colorectal cancer cells were observed. Conversely, the combination of adenovirus-mediated overexpression of DYRK2 with 5-fluorouracil or oxaliplatin enhanced apoptosis and chemosensitivity through p53-Ser46 phosphorylation in p53 wild-type colorectal cancer cells. Furthermore, DYRK2 knockout decreased chemosensitivity to 5-fluorouracil and oxaliplatin in p53 wild-type xenograft mouse models. Taken together, these findings demonstrated that DYRK2 expression was associated with chemosensitivity to 5-fluorouracil and oxaliplatin in p53 wild-type colorectal cancer, suggesting the importance of evaluating the p53 status and DYRK2 expression as a novel marker in therapeutic strategies for colorectal cancer.

Inhibition of protein kinase C delta leads to cellular senescence to induce anti-tumor effects in colorectal cancer.

Protein kinase C delta (PKCδ) is a multifunctional serine-threonine kinase implicated in cell proliferation, differentiation, tumorigenesis, and therapeutic resistance. However, the molecular mechanism of PKCδ in colorectal cancer (CRC) remains unclear. In this study, we showed that PKCδ acts as a negative regulator of cellular senescence in p53 wild-type (wt-p53) CRC. Immunohistochemical analysis revealed that PKCδ levels in human CRC tissues were higher than those in the surrounding normal tissues. Deletion studies have shown that cell proliferation and tumorigenesis in wt-p53 CRC is sensitive to PKCδ expression. We found that PKCδ activates p21 via a p53-independent pathway and that PKCδ-kinase activity is essential for p21 activity. In addition, both repression of PKCδ expression and inhibition of PKCδ activity induced cellular senescence-like phenotypes, including increased senescence-associated ß-galactosidase (SA-ß-gal) staining, low LaminB1 expression, large nucleus size, and senescence-associated secretory phenotype (SASP) detection. Finally, a kinase inhibitor of PKCδ suppressed senescence-dependent tumorigenicity in a dose-dependent manner. These results offer a mechanistic insight into CRC survival and tumorigenesis. In addition, a novel therapeutic strategy for wt-p53 CRC is proposed.

Enforced dual-specificity tyrosine-regulated kinase 2 expression by adenovirus-mediated gene transfer inhibits tumor growth and metastasis of colorectal cancer.

Colorectal cancer is one of the most common gastrointestinal tumors with good outcomes; however, with distant metastasis, the outcomes are poor. Novel treatment methods are urgently needed. Our in vitro studies indicate that dual-specificity tyrosine-regulated kinase 2 (DYRK2) functions as a tumor suppressor in colorectal cancer by regulating cell survival, proliferation, and apoptosis induction. In addition, DYRK2 expression is decreased in tumor tissues compared to nontumor tissues in colorectal cancer, indicating a correlation with clinical prognosis. In this context, we devised a novel therapeutic strategy to overexpress DYRK2 in tumors by adenovirus-mediated gene transfer. The present study shows that overexpression of DYRK2 in colon cancer cell lines by adenovirus inhibits cell proliferation and induces apoptosis in vitro. Furthermore, in mouse subcutaneous xenograft and liver metastasis models, enforced expression of DYRK2 by direct or intravenous injection of adenovirus to the tumor significantly inhibits tumor growth. Taken together, these findings show that adenovirus-based overexpression of DYRK2 could be a novel gene therapy for liver metastasis of colorectal cancer.

Wilhelmy equation revisited: A lightweight method to measure liquid-vapor, solid-liquid, and solid-vapor interfacial tensions from a single molecular dynamics simulation.

We have given theoretical expressions for the forces exerted on a so-called Wilhelmy plate, which we modeled as a quasi-2D flat and smooth solid plate immersed in a liquid pool of a simple liquid. All forces given by the theory, the local forces on the top, the contact line, and the bottom of the plate as well as the total force, showed an excellent agreement with the MD simulation results. The force expressions were derived by a purely mechanical approach, which is exact and ensures the force balance on the control volumes arbitrarily set in the system, and are valid as long as the solid-liquid (SL) and solid-vapor (SV) interactions can be described by mean-fields. In addition, we revealed that the local forces around the bottom and top of the solid plate can be related to the SL and SV interfacial tensions γSL and γSV, and this was verified through the comparison with the SL and SV works of adhesion obtained by the thermodynamic integration (TI). From these results, it has been confirmed that γSL and γSV as well as the liquid-vapor interfacial tension γLV can be extracted from a single equilibrium MD simulation without the computationally demanding calculation of the local stress distributions and the TI.

Dual-specificity tyrosine-regulated kinase 2 exerts anti-tumor effects by induction of G1 arrest in lung adenocarcinoma.

OBJECTIVES: Lung cancer is a leading cause of cancer-related mortality and remains one of the most poorly prognosed disease worldwide. Therefore, it is necessary to identify novel molecular markers with potential therapeutic effects. Recent findings have suggested that dual-specificity tyrosine-regulated kinase 2 (DYRK2) plays a tumor suppressive role in colorectal, breast, and hepatic cancers; however, its effect and mechanism in lung cancer remain poorly understood. Therefore, this study aimed to investigate the tumor-suppressive role and molecular mechanism of DYRK2 in lung adenocarcinoma (LUAD) by in vitro experiments and xenograft models. MATERIALS AND METHODS: The evaluation of DYRK2 expression was carried out using lung cancer cell lines and normal bronchial epithelial cells. Overexpression of DYRK2 was induced by an adenovirus vector, and cell proliferation was assessed through MTS assay and Colony Formation Assay. Cell cycle analysis was performed using flow cytometry. Additionally, proliferative capacity was evaluated in a xenograft model by subcutaneously implanting A549 cells into SCID mice (C·B17/Icr-scidjcl-scid/scid). RESULTS: Immunoblotting assays showed that DYRK2 was downregulated in most LUAD cell lines. DYRK2 overexpression using adenovirus vectors significantly suppressed cell proliferation compared with that in the control group. Additionally, DYRK2 overexpression suppressed tumor growth in a murine subcutaneous xenograft model. Mechanistically, DYRK2 overexpression inhibited the proliferation of LUAD cells via p21-mediated G1 arrest, which was contingent on p53. CONCLUSION: Taken together, these findings suggest that DYRK2 may serve as potential prognostic biomarker and therapeutic target for LUAD.

Prognostic usefulness of the C-reactive protein-albumin-lymphocyte (CALLY) index as a novel biomarker in patients undergoing colorectal cancer surgery.

BACKGROUND: The C-reactive protein (CRP)-albumin-lymphocyte (CALLY) index is a novel immuno-nutritional biomarker based on the levels of CRP, serum albumin, and lymphocyte count. This study examined the prognostic value of the CALLY index in patients with colorectal cancer undergoing curative surgery. METHODS: Between 2010 and 2017, 578 patients with stage II-III colorectal cancer who underwent curative resection were enrolled. The CALLY index was defined as (albumin × lymphocyte)/(CRP × 104). We investigated the association of the CALLY index with disease-free survival (DFS) and overall survival (OS). RESULTS: The cutoff value of the CALLY index was determined to be 2. Of the 578 patients, 175 (30%) had a preoperative CALLY index <2. In multivariate analysis, the pre-operative carcinoembryonic antigen (CEA) level (p = 0.003), cell differentiation (p = 0.045), venous invasion (p = 0.036), Tumor-Node-Metastasis stage (p < 0.001), and CALLY index score <2 (p = 0.006) were independent predictors of DFS. Meanwhile, preoperative carbohydrate antigen (CA)19-9 levels (p = 0.019), lymphatic invasion (p = 0.018), preoperative platelet (p = 0.037), and CALLY index score <2 (p = 0.007) were independent predictors of OS. CONCLUSION: The CALLY index may be an independent prognostic biomarker for long-term outcomes in patients with colorectal cancer.

Clinical Significance of Controlling Nutritional Status (CONUT) Score in Patients With Colorectal Liver Metastases After Hepatectomy.

BACKGROUND/AIM: The prognostic outcome of the controlling nutritional status (CONUT) score in patients with colorectal liver metastases (CRLM) who underwent hepatectomy has not been investigated. The aim of this study was to investigate the prognostic value of preoperative CONUT score and other systemic inflammation-related biomarkers in patients who underwent hepatectomy for CRLM. PATIENTS AND METHODS: The subjects included 145 patients with CRLM who underwent hepatectomy and retrospectively investigated the association of preoperative CONUT score with disease-free survival (DFS), surgical failure-free survival (SFS), and overall survival (OS) using univariate and multivariate analyses. RESULTS: In this study, the cut-off of the CONUT score was 4. In the univariate analysis, the high CONUT score was associated with worse SFS and OS (p=0.01, 0.01). The multivariate analysis showed significant and independent predictors of OS were lymph node metastases (p=0.03) and a high CONUT score (p=0.04). In patients with a high CONUT score, postoperative complications due to infections were significantly more than in those with a low CONUT score (27% vs. 9%, p=0.04). CONCLUSION: The CONUT score can be useful for predicting not only short-term but also long-term outcomes in patients with CRLM after hepatectomy.

Evaluation of the Outcome of Local Surgery for Stomal Prolapse.

We reviewed the results of local surgical treatment of stoma prolapse, a long-term complication of stoma construction. Fifteen patients treated for stomal prolapse between 2009 and 2020 at the authors' and affiliated hospitals were included in this study. The treatment comprised local laparotomic stomal reconstruction (LLSR) in nine patients and stapling repair (SR) in six. We compared and evaluated the clinical and surgical information and postoperative complications. Operation time was significantly shorter in the SR group than in the LLSR group: 20 and 53 min, respectively (p = 0.036). The duration of postoperative hospitalization was shorter in the SR group than in the LLSR group: 5.5 and 8 days, respectively; the difference was not significant (p = 0.088). No short-term complications were found in either group. Regarding long-term, postoperative complications, parastomal hernias developed after 2.5 years in one patient in the LLSR group and after 6 months in one patient in the SR group; both patients had histories of parastomal hernia surgery and had relatively high body mass indices. Local surgery for stomal prolapse was minimally invasive and performed safely. In patients with a history of surgery for parastomal hernia, attention must be paid to the potential of parastomal hernia developing as a postoperative complication.

Comparison of Strength of Anastomosis Between Four Different Techniques for Colorectal Surgery.

BACKGROUND/AIM: Advances in stapling devices have led to their widespread use in colorectal surgery. We compared the strength of four types of anastomoses using bursting pressure. MATERIALS AND METHODS: We created stapled anastomosis models [double stapling technique (DST), functional end-to-end anastomosis (FEEA) unbuttressed or buttressed, and triangulating anastomosis (TA) with two- or three-row stapling] and a hand-sewn anastomosis model. Bursting pressures of each method were measured. The primary end point was the bursting pressure. The effectiveness of buttressing and three-row stapling were the secondary endpoints. RESULTS: The DST group had significantly lower bursting pressure than TA with three-row stapling, FEEA buttressed, and hand-sewn groups. No significant difference was found between the bursting pressure of the FEEA unbuttressed and FEEA buttressed groups and that of the TA with two-row and three-row stapling groups. CONCLUSION: DST has the lowest bursting pressure compared to other anastomotic techniques. Buttressing suture and three-row stapling have no effect on the strength of anastomosis.