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.

Extended-Synaptotagmin 1 Enhances Liver Cancer Progression Mediated by the Unconventional Secretion of Cytosolic Proteins.

Extended-synaptotagmin 1 (E-Syt1) is an endoplasmic reticulum membrane protein that is involved in cellular lipid transport. Our previous study identified E-Syt1 as a key factor for the unconventional protein secretion of cytoplasmic proteins in liver cancer, such as protein kinase C delta (PKCδ); however, it is unclear whether E-Syt1 is involved in tumorigenesis. Here, we showed that E-Syt1 contributes to the tumorigenic potential of liver cancer cells. E-Syt1 depletion significantly suppressed the proliferation of liver cancer cell lines. Database analysis revealed that E-Syt1 expression is a prognostic factor for hepatocellular carcinoma (HCC). Immunoblot analysis and cell-based extracellular HiBiT assays showed that E-Syt1 was required for the unconventional secretion of PKCδ in liver cancer cells. Furthermore, deficiency of E-Syt1 suppressed the activation of insulin-like growth factor 1 receptor (IGF1R) and extracellular-signal-related kinase 1/2 (Erk1/2), both of which are signaling pathways mediated by extracellular PKCδ. Three-dimensional sphere formation and xenograft model analysis revealed that E-Syt1 knockout significantly decreased tumorigenesis in liver cancer cells. These results provide evidence that E-Syt1 is critical for oncogenesis and is a therapeutic target for liver 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.

DYRK2 maintains genome stability via neddylation of cullins in response to DNA damage.

Neural precursor cell-expressed developmentally down-regulated 8 (NEDD8), an ubiquitin-like protein, is an essential regulator of the DNA damage response. Numerous studies have shown that neddylation (conjugation of NEDD8 to target proteins) dysfunction causes several human diseases, such as cancer. Hence clarifying the regulatory mechanism of neddylation could provide insight into the mechanism of genome stability underlying the DNA damage response (DDR) and carcinogenesis. Here, we demonstrate that dual-specificity tyrosine-regulated kinase 2 (DYRK2) is a novel regulator of neddylation and maintains genome stability. Deletion of DYRK2 leads to persistent DNA double-strand breaks (DSBs) and subsequent genome instability. Mechanistically, DYRK2 promotes neddylation through forming a complex with NAE1, which is a component of NEDD8-activating enzyme E1, and maintaining its protein level by suppressing polyubiquitylation. The present study is the first to demonstrate that DYRK2 controls neddylation and is necessary for maintaining genome stability. This article has an associated First Person interview with the first author of the paper.

Extracellular PKCδ signals to epidermal growth factor receptor for tumor proliferation in liver cancer cells.

Protein kinase C delta (PKCδ) is a multifunctional PKC family member and has been implicated in many types of cancers, including liver cancer. Recently, we have reported that PKCδ is secreted from liver cancer cells, and involved in cell proliferation and tumor growth. However, it remains unclear whether the extracellular PKCδ directly regulates cell surface growth factor receptors. Here, we identify epidermal growth factor receptor (EGFR) as a novel interacting protein of the cell surface PKCδ in liver cancer cells. Imaging studies showed that secreted PKCδ interacted with EGFR-expressing cells in both autocrine and paracrine manners. Biochemical analysis revealed that PKCδ bound to the extracellular domain of EGFR. We further found that a part of the amino acid sequence on the C-terminal region of PKCδ was similar to the putative EGFR binding site of EGF. In this regard, the point mutant of PKCδ in the binding site lacked the ability to bind to the extracellular domain of EGFR. Upon an extracellular PKCδ-EGFR association, ERK1/2 activation, downstream of EGFR signaling, was apparently induced in liver cancer cells. This study indicates that extracellular PKCδ behaves as a growth factor and provides a molecular basis for extracellular PKCδ-targeting therapy for liver cancer.

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.

Unconventional Secretion of PKCδ Exerts Tumorigenic Function via Stimulation of ERK1/2 Signaling in Liver Cancer.

Expression of human protein kinase C delta (PKCδ) protein has been linked to many types of cancers. PKCδ is known to be a multifunctional PKC family member and has been rigorously studied as an intracellular signaling molecule. Here we show that PKCδ is a secretory protein that regulates cell growth of liver cancer. Full-length PKCδ was secreted to the extracellular space in living liver cancer cells under normal cell culture conditions and in xenograft mouse models. Patients with liver cancer showed higher levels of serum PKCδ than patients with chronic hepatitis or liver cirrhosis or healthy individuals. In liver cancer cells, PKCδ secretion was executed in an endoplasmic reticulum (ER)-Golgi-independent manner, and the inactivation status of cytosolic PKCδ was required for its secretion. Furthermore, colocalization studies showed that extracellular PKCδ was anchored on the cell surface of liver cancer cells via association with glypican 3, a liver cancer-related heparan sulfate proteoglycan. Addition of exogenous PKCδ activated IGF-1 receptor (IGF1R) activation and subsequently enhanced activation of ERK1/2, which led to accelerated cell growth in liver cancer cells. Conversely, treatment with anti-PKCδ antibody attenuated activation of both IGF1R and ERK1/2 and reduced cell proliferation and spheroid formation of liver cancer cells and tumor growth in xenograft mouse models. This study demonstrates the presence of PKCδ at the extracellular space and the function of PKCδ as a growth factor and provides a rationale for the extracellular PKCδ-targeting therapy of liver cancer. SIGNIFICANCE: PKCδ secretion from liver cancer cells behaves as a humoral growth factor that contributes to cell growth via activation of proliferative signaling molecules, which may be potential diagnostic or therapeutic targets.

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.

Safety and Efficacy of Trifluridine-Tipiracil Hydrochloride Oral Combination (TAS-102) in Patients with Unresectable Colorectal Cancer.

AIM: To retrospectively examine efficacy and safety of oral combination of trifluridine and tipiracil hydrochloride (TAS-102) as the second-line therapeutic agent for unresectable colorectal cancer. PATIENT AND METHODS: Treatment outcomes of 17 patients who had received TAS-102 at our Institution from January 2015 to January 2017 were analyzed. The indications for second-line TAS-102 treatment were intolerance to other multi-drug combination (four patients) or patient refusal of the standard second-line therapy (13 patients). RESULTS: Among 17 patients who received TAS-102 as second-line therapy, partial response was observed in two (12%) and stable disease in two (12%). Outcomes of TAS-102 given as second-line therapy were: median overall survival of 5 months, response rate of 12% and disease control of 24%. Overall, no adverse events other than neutropenia were noted. CONCLUSION: Our findings suggest a beneficial role of TAS-102 in second-line therapy for unresectable colorectal carcinoma.

Risk Factors for Early Postoperative Small Bowel Obstruction After Anterior Resection for Rectal Cancer.

PURPOSE: The aim of the study was to evaluate risk factors for small bowel obstruction (SBO) in early postoperative period after anterior resection for rectal cancer. METHODS: Patients who underwent anterior resection (AR) [high AR (HAR) or low AR (LAR)] for rectal cancer between January 2009 and April 2016 were enrolled into the study after fulfilling selection criteria. In included patients, risk factors for early postoperative SBO (EPSBO) were analyzed by means of univariate and multivariate analysis. Cases with perioperative major complications other than intestinal obstruction and with simultaneous resection of other organs were excluded. The same analyses were also performed for cases of redo surgery due to EPSBO. EPSBO was defined as clinically and radiologically confirmed SBO that developed after resuming oral intake within 30 days following surgery. The logistic regression method was used for statistical analyses. RESULTS: In enrolled 180 patients, EPSBO occurred in 23 (12.8%). In univariate analysis, male sex [odds ratio (OR) = 2.17, 95% CI = 0.82-6.84, p < 0.0001], previous abdominal surgery (OR = 0.20, 95% CI = 0.03-0.73, p = 0.0117), low tumor (OR = 3.26, 95% CI = 1.28-8.13, p = 0.0140), LAR (OR = 17.25, 95% CI = 3.49-312.55, p < 0.0001), D3 node dissection (OR = 13.61, 95% CI = 2.75-246.69, p = 0.0002), defunctioning ileostomy (DI) formation (OR = 9.88, 95% = 3.80-29.14, p < 0.0001), and prolonged operation time (OR = 1.01, 95% CI = 1.00-1.01, p = 0.0122) were significantly related to EPSBO. Multivariate analysis demonstrated that D3 node dissection (OR = 10.93, 95% CI = 1.94-208.23, p = 0.0038) and DI formation (OR = 5.82, 95% CI = 1.55-25.31, p = 0.0083) were independent risk factors for EPSBO. Four cases (17.4%) with EPSBO required re-operation because conservative therapies failed; all were laparoscopic DI formation cases. In three of those four cases, stenosis of stoma at the level of the posterior sheath of rectus abdominis muscle was the reason of SBO, and in one case it was kinking of the stomal limb. CONCLUSIONS: D3 lymph node dissection and DI formation are independent risk factors for EPSBO in AR.