Prognostic Value of Serum Neutrophil to Lymphocyte Ratio and SUVmax in Stage I and II Colon Cancer.

OBJECTIVE: This study aimed to evaluate the correlation between maximal standardized uptake value (SUVmax) of primary colon cancer and serum neutrophil-to-lymphocyte ratio (NLR), and to assess the prognostic value of SUVmax and serum NLR in stage I and II colon cancer patients. METHODS: In this retrospective study a total of 128 patients with pathologically confirmed stage I and II colon cancer diagnosed between January 2014 and December 2017 were included. All patients underwent F-18 Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and differential white blood cell (WBC) counts before surgery. The correlations between SUVmax and NLR were assessed. The prognostic value of SUVmax and NLR for predicting recurrence-free survival (RFS) was investigated. RESULTS: The mean NLR was 2.2 ± 1.2, and the mean SUVmax of primary tumor was 15.2 ± 7.9. There was significant correlation between NLR and SUVmax (rho=0.2, p=0.02). Mean follow-up period was 59.8 ± 19.2 months and 12 patients experienced a recurrence. In univariable analysis, NLR (p=0.0084, HR=5.0223, 95% CI=1.5117-16.6853), C-reactive protein (CRP) (p=0.021, HR=4.1115, 95% CI=1.2380-13.6551), carbohydrate antigen 19-9 (CA19-9) (p=0.0134, HR=4.2683, 95% CI=1.3519-13.4766), and Kirsten ras sarcoma viral oncogene (KRAS) mutation (p=0.0338, HR=3.4703, 95% CI=1.0998-10.9499) were significant prognostic factors for the recurrence. In multivariable analysis, NLR (p=0.0256, HR=4.1155, 95% CI=1.1887-14.2490) and CA19-9 (p=0.0257, HR=4.139, 95% CI=1.1880-14.4200) were independent prognostic factors for the recurrence. CONCLUSIONS: Significant correlation was observed between SUVmax of primary colon cancer and serum NLR. Furthermore, in the multivariable analysis conducted on early colon cancer cases, NLR and CA19-9 were found to be independently associated with RFS. This suggested that NLR could be used as a supplementary tool for identifying patients at high risk of recurrence in early colon cancer. However, SUVmax was not associated with prognosis, suggesting that it cannot be used for predicting prognosis in early colon cancer.

Short-term outcomes of Early versus conventional adjuvant chemotherapy in stage III colon cancer: randomized clinical trial.

BACKGROUND: Evidence is lacking regarding the earliest timing of initiating adjuvant chemotherapy to maximize its efficacy safely. A trial was designed and conducted to evaluate the safety and oncological efficacy of early adjuvant chemotherapy compared with conventional adjuvant chemotherapy. The short-term outcomes are reported here. METHODS: A multicentre, randomized (1 : 1), open-label, phase III trial was conducted comparing early adjuvant chemotherapy with conventional adjuvant chemotherapy in patients with stage III colon cancer. Patients who underwent radical surgery who had stage III colon cancer confirmed by histopathological assessment were screened and randomized into the early adjuvant chemotherapy arm or the conventional adjuvant chemotherapy arm. The primary endpoint was 3-year disease-free survival. The adjuvant chemotherapy with FOLFOX was delivered between postoperative day 10 and 14 in the early adjuvant chemotherapy arm, and between postoperative day 24 and 28 in the conventional adjuvant chemotherapy arm. Toxicity and quality of life were evaluated. RESULTS: Between 9 September 2011 and 6 March 2020, 443 patients consented to randomization at eight sites. The intention-to-treat population included 423 patients (209 in the early adjuvant chemotherapy arm and 214 in the conventional adjuvant chemotherapy arm), and the safety population included 380 patients (192 in the early adjuvant chemotherapy arm and 188 in the conventional adjuvant chemotherapy arm). There was no statistically significant difference in overall toxicity (28.1 per cent in the early adjuvant chemotherapy arm and 28.2 per cent in the conventional adjuvant chemotherapy arm, P = 0.244), surgical complications, and quality of life between the two arms. CONCLUSION: Adjuvant chemotherapy can be safely initiated 2 weeks after surgery with toxicity and quality of life comparable to conventional adjuvant chemotherapy for stage III colon cancer.

Anastomotic leak after minimally invasive anterior resection for rectal cancer with high versus low ligation of the inferior mesenteric artery: a study protocol for a multicentre randomized clinical trial.

BACKGROUND: Although many efforts have been made to decrease the incidence of anastomotic leak (AL), it remains one of the most serious complications of rectal cancer surgery. Many previous studies have reported an association between the ligation level of the inferior mesenteric artery (IMA) (high or low) and the incidence of AL after rectal cancer surgery. However, we cannot draw a solid conclusion because of the low quality and heterogeneity of those studies. Therefore, this study aims to investigate the impact of the IMA ligation level on the occurrence of AL after minimally invasive anterior resection of rectal cancer. METHODS/DESIGN: Patients with primary rectal cancer without distant metastases will be included after screening. They will be randomly assigned (1:1) to receive high or low ligation of the IMA. The primary endpoint is AL incidence; secondary endpoints are quality of life; urinary, sexual, and defecatory functions; and 3-year disease-free survival. We hypothesized that the incidence rate of AL would be 15% and 5% in the high- and low-ligation groups, respectively. With a two-sided α of 0.05 and a power of 0.8, the sample size is calculated to be 314 patients (157 per group), considering a 10% dropout rate. DISCUSSION: Although many studies have compared the short- and long-term outcomes of high and low ligation of the IMA in rectal cancer surgery, it is still debatable. This trial aims to help draw a more solid conclusion regarding the association between the IMA ligation level and AL incidence after rectal cancer surgery. We also hope to contribute to standardizing the method of rectal cancer surgery in this trial. TRIAL REGISTRATION: Clinical Research Information Service KCT0003523. Registered on February 18, 2019.

15-Prostaglandin Dehydrogenase Inhibition Enhances Colon Cancer Metastasis by Up-regulation of Epithelial-to-Mesenchymal Transition Genes.

BACKGROUND/AIM: Most deaths from colon cancer are due to metastasis. Recently, PGE2 was found to influence colon cancer invasion and metastasis. 15-PGDH, an enzyme that metabolizes PGE2, is known as a tumor suppressor in colonic carcinogenesis. This study investigated the effect of 15-PGDH on colon cancer metastasis. MATERIALS AND METHODS: 15-PGDH expression by immunohistochemical staining, clinicopathologic features, and 5-year cancer-specific survival were investigated in colon cancer patients. Liver metastasis was examined by assaying 15-PGDH activity in an animal model. Changes in PGE2, proliferation, migration, and invasion of the colorectal cancer cell line HCT116, were examined using a 15-PGDH inhibitor (SW033291) or enhancer (CDDO-ME). The expression of genes involved in the epithelial-to-mesenchymal transition (EMT) was also studied. RESULTS: The absence of 15-PGDH expression significantly correlated with advanced-stage, lymph node metastasis, and decreased cancer-specific survival in colon cancer patients. Inhibition of 15-PGDH increased colon cancer liver metastasis in the animal model. The 15-PGDH inhibitor, SW033291, increased PGE2 and decreased 15-PGDH expression on HCT116. However, treatment with CDDO-ME, a substance that enhances 15-PGDH, showed the opposite results. Inhibition of 15-PGDH increased cell proliferation, migration, and invasion, but activation of 15-PGDH showed the opposite effect. Inhibition of 15-PGDH also affected the EMT markers, N-cadherin, Snail, and Twist2. CONCLUSION: 15-PGDH inhibition increased colon cancer metastasis by inducing changes in EMT-related genes via an increase in PGE2 expression and could be a promising biomarker for anticancer treatment.

Real-world experience of safety and effectiveness of regorafenib for treatment of metastatic colorectal cancer, advanced gastrointestinal stromal tumors, and hepatocellular carcinoma: a post-marketing surveillance study in Korea.

Purpose: This regulatory post-marketing surveillance (PMS) study was performed to evaluate the safety and effectiveness of regorafenib on Korean patients with colorectal cancer (CRC), gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma (HCC) in a real-world clinical setting. Methods: This PMS was conducted as a multi-center, prospective, observational study at 34 centers in Korea from August 2013 to August 2019. The primary objective was to evaluate the safety of regorafenib in real-world practice, with the secondary objective to investigate its effectiveness, including its overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: In total, 301 patients were included in the analysis (254 patients with CRC, 14 patients with GIST, and 33 patients with HCC). The incidence rates of adverse events (AEs) were 85.0%, 78.6%, and 81.8% in patients with CRC, GIST, and HCC, respectively. The most frequent AE related to regorafenib in the three cancer types was palmar-plantar erythrodysesthesia syndrome (PPES). The ORRs of patients with CRC, GIST, and HCC were 4.7%, 0%, and 41.4%, respectively. The median PFS and OS were 2.1 and 6.1 months for CRC, respectively; 9.2 and 16.4 months for GIST, respectively; and 5.5 months and not estimated (NE) for HCC, respectively. Patients who experienced a dose modification or discontinuation of regorafenib showed significantly shorter median PFS and OS (2.2 vs. 2.6 months, respectively, P = 0.0335 for PFS; 5.3 vs. 8.5 months, respectively, P = 0.0010 for OS). Conclusion: This PMS study, which is the largest surveillance study of CRC in Korea, found no newly identified safety concerns for patients who received regorafenib in the real-world setting. Additionally, the results of this study were consisted with those previously reported in phase III trials.

Complete response of MSI-high metastatic colon cancer following treatment with regorafenib: A case report.

Regorafenib has been demonstrated to prolong survival in patients with metastatic colorectal cancer refractory to standard chemotherapy. However, overall survival is limited to 2.5 months. The present report describes a unique case of metastatic colon cancer, which showed a complete response to regorafenib. A 54-year-old woman was diagnosed with right colon cancer obstruction with peritoneal seeding. The patient underwent laparoscopic right hemicolectomy, and the pathology was T4aN2bM1, moderately differentiated adenocarcinoma with high microsatellite instability (MSI-H) and wild-type KRAS/NRAS. The first-line chemotherapy was fluorouracil, leucovorin and irinotecan with cetuximab. After 12 cycles, recurrence at the anastomotic site was identified. The patient underwent palliative colectomy, and superior mesenteric artery (SMA) lymph node metastases were evident. The patient received second-line chemotherapy of fluorouracil, leucovorin and oxaliplatin with bevacizumab. Progression of metastasis to the right common iliac lymph nodes was detected after only four cycles of therapy. Thereafter, the patient received regorafenib as third-line therapy, starting with 160 mg for two cycles and reducing the dose thereafter, for a total of 17 cycles. The previously confirmed SMA lymph node metastasis had disappeared after the seventh cycle, and the right common iliac lymph node metastasis was not visible on CT after the 16th cycle. The patient decided to terminate regorafenib and has not experienced recurrence 2 years since treatment cessation. This is the first report of refractory metastatic colon cancer with MSI-H showing a complete response to regorafenib. Further studies are required to investigate the efficacy of regorafenib in refractory metastatic colon cancer with MSI-H and to elucidate the mechanism of remission.

15-Hydroxyprostaglandin dehydrogenase inhibitor prevents contrast-induced acute kidney injury.

The two primary mechanisms by which iodinated contrast media (CM) causes contrast-induced acute kidney injury (CIAKI) are the hemodynamic effect causing intrarenal vasoconstriction and the tubular toxic effect causing acute tubular necrosis. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which degrades prostaglandin E2 (PGE2), promotes tissue repair and regeneration in many organs. PGE2 causes intrarenal arterial vasodilation. In this study, we investigated whether a 15-PGDH inhibitor can act as a candidate for blocking these two major mechanisms of CIAKI. We established a CIAKI mouse model by injecting a 10 gram of iodine per body weight (gI/kg) dose of iodixanol into each mouse tail vein. A 15-PGDH inhibitor (SW033291), PGE1, or PGE2 were administered to compare the renal functional parameters, histologic injury, vasoconstriction, and renal blood flow changes. In addition, human renal proximal tubular epithelial cells were cultured in a CM-treated medium. SW033291, PGE1, or PGE2 were added to compare any changes in cell viability and apoptosis rate. CIAKI mice that received SW033291 had lower serum levels of creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1 (p < 0.001); lower histologic injury score and TUNEL positive rates (p < 0.001); and higher medullary arteriolar area (p < 0.05) and renal blood flow (p < 0.001) than CM + vehicle group. In cell culture experiments, Adding SW033291 increased the viability rate (p < 0.05) and decreased the apoptosis rate of the tubular epithelial cells (p < 0.001). This 15-PGDH inhibitor blocks the two primary mechanisms of CIAKI, intrarenal vasoconstriction and tubular cell toxicity, and thus has the potential to be a novel prophylaxis for CIAKI. Abbreviations: 15-PGDH: 15-hydroxyprostaglandin dehydrogenase; AMP: adenosine monophosphate; CIAKI: contrast-induced acute kidney injury; CM: contrast media; EP: prostaglandin E2 receptor; hRPTECs: human-derived renal proximal tubule epithelial cells; KIM-1: kidney injury molecule-1; MTT: 3-(4,5-Dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide; NGAL: neutrophil gelatinase-associated lipocalin; PBS: phosphate-buffered saline; PGE1: prostaglandin E1; PGE2: prostaglandin E2; RBF: renal blood flow; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; α-SMA: α-Smooth muscle actin.

Low albumin level and longer interval to closure increase the early complications after ileostomy closure.

BACKGROUND: Loop ileostomy has an important role in mitigating the serious effects of anastomotic leakage in colorectal surgery. However, the morbidity and mortality associated with ileostomy reversal cannot be overlooked. We investigated the possible risk factors for complications following ileostomy reversal. METHODS: All patients who underwent loop ileostomy closure between 2008 and 2017 at Inje University Busan Paik Hospital were identified. Medical records on patient characteristics, preoperative management, surgical techniques, postoperative management, chemotherapy/radiotherapy, and complications were retrospectively analyzed in a prospectively collected database. RESULTS: A total of 354 patients underwent loop ileostomy closure. The overall complication rate was 23.7%, with Clavien-Dindo grade I as the most common (15.8%), 5.6% in grade II, 2.2% in grade III-V, and three patients died. The two most common complications were wound infection (11.6%) and small bowel obstruction (4.8%). In univariable and multivariable analyses, closure technique or chemotherapy did not affect the outcome, but low serum albumin <3.5 g/dL (OR 7.248, CI 2.416-22.838, p < 0.001) and longer interval to ileostomy closure (OR 1.977, CI 1.167-3.350, p = 0.0113) were independent contributing factors for morbidities of ileostomy closure. CONCLUSIONS: Closure technique or chemotherapy did not affect the complication of ileostomy closure. However, serum albumin <3.5 g/dL and a longer interval to ileostomy closure were identified as risk factors for morbidity of ileostomy closure. These two factors should be corrected and planned before ileostomy closure.

Inhibition of 15-PGDH prevents ischemic renal injury by the PGE2/EP4 signaling pathway mediating vasodilation, increased renal blood flow, and increased adenosine/A2A receptors.

In the present study, we demonstrated the marked activity of SW033291, an inhibitor of 15-hydoxyprostaglandin dehydrogenase (15-PGDH), in preventing acute kidney injury (AKI) in a murine model of ischemia-reperfusion injury. AKI due to ischemic injury represents a significant clinical problem. PGE2 is vasodilatory in the kidney, but it is rapidly degraded in vivo due to catabolism by 15-PGDH. We investigated the potential of SW033291, a potent and specific 15-PGDH inhibitor, as prophylactic treatment for ischemic AKI. Prophylactic administration of SW033291 significantly increased renal tissue PGE2 levels and increased post-AKI renal blood flow and renal arteriole area. In parallel, prophylactic SW033291 decreased post-AKI renal morphology injury scores and tubular apoptosis and markedly reduced biomarkers of renal injury that included blood urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Prophylactic SW033291 also reduced post-AKI induction of proinflammatory cytokines, high-mobility group box 1, and malondialdehyde. Protective effects of SW033291 were mediated by PGE2 signaling, as they could be blocked by pharmacological inhibition of PGE2 synthesis. Consistent with activation of PGE2 signaling, SW033291 induced renal levels of both EP4 receptors and cAMP, along with other vasodilatory effectors, including AMP, adenosine, and the adenosine A2A receptor. The protective effects of SW0333291 could largely be achieved with a single prophylactic dose of the drug. Inhibition of 15-PGDH may thus represent a novel strategy for prophylaxis of ischemic AKI in multiple clinical settings, including renal transplantation and cardiovascular surgery.

An Animal Model of Colorectal Cancer Liver Metastasis With a High Metastasis Rate and Clonal Dynamics.

BACKGROUND: Various animal models have been introduced into the study of liver metastasis of colorectal cancer, but they have not been compared under the same conditions. The aim of this study was to identify an optimized mouse model that showed a high rate of hepatic metastasis and expression of clonal dynamics. MATERIALS AND METHODS: Athymic nude mice (n=30) were divided into two equal groups for the creation of a splenic injection model (SIM) and surgically orthotopic implantation model (SOIM) of liver metastasis of colorectal cancer using HCT116 cells. Hepatic metastasis was confirmed by gross and microscopic examinations. Expression of MET transcriptional regulator MACC1 (MACC1) in colon cancer cell lines and metastatic tumors in the group with a higher liver metastasis rate was confirmed by quantitative reverse-transcription-polymerase chain reaction. RESULTS: The observation time was significantly shorter for SIM than for SOIM (33.0±6.8 vs. 41.2±7.2 days, p<0.001). The rate of hepatic metastasis was significantly higher in SIM than in SOIM (76.9% vs. 38.4%, p=0.038). MACC1 was expressed in Colo201, HCT116, HT29, LS513, SW620, and WiDr cells but not in SW480 cells. All hepatic metastases in SIM mice expressed MACC1, and metastatic HCT116 cells had significantly greater expression than did the original HCT116 cells (p<0.001). CONCLUSION: With a higher rate of hepatic metastasis with clonal dynamics in a shorter observation time than the SOIM, SIM appears to be a good animal model for identifying new targets and in drug development for colorectal cancer liver metastasis. SOIM should also be considered for the study of the full steps of metastasis.

Association between epidermal growth factor (EGF) and EGF receptor gene polymorphisms and end-stage renal disease and acute renal allograft rejection in a Korean population.

Purpose: Epidermal growth factor (EGF) has been found to be associated with the development and repair mechanisms of several renal diseases. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) in EGF or its receptor genes might have an association with end-stage renal disease (ESRD) or acute renal allograft rejection (AR) in a Korean population.Methods: Three-hundred and forty seven recipients of the first renal transplants for ESRD, including 63 AR patients along with 289 healthy adults were included in the study. Five EGF gene SNPs (rs11568835, rs11568943, rs2237051, rs11569017, and rs3756261) and four EGFR gene SNPs (rs1140475, rs2293347, rs1050171, and rs6965469) were analyzed. The genotypes of these SNPs were analyzed using the AxiomTM genome-wide human assay. Statistical analysis was performed using SNPStats and Haploview version 4.2 software. Multiple logistic regression models (codominant, dominant, recessive, and Log-additive) were used to estimate the odds ratio (OR), 95% confidence interval (CI), and P value.Results: One SNP (rs11569017) in the EGF gene showed significant association with ESRD but not with AR. Another SNP (rs11568835) in the EGF gene showed significant association with susceptibility to AR but not with ESRD. One SNP (rs1050171) in the EGFR gene showed significant association with susceptibility to AR but not with ESRD.Conclusion: Our findings suggest that SNPs in the EGF and EGFR gene may be associated with the risk of ESRD and AR development in the Korean population.

Bio-orthogonal Supramolecular Latching inside Live Animals and Its Application for in Vivo Cancer Imaging.

Here, we demonstrate a supramolecular latching tool for bio-orthogonal noncovalent anchoring of small synthetic molecules in live animal models using a fully synthetic high-affinity binding pair between cucurbit[7]uril (CB[7]) and adamantylammonium (AdA). This supramolecular latching system is small (∼1 kDa), ensuring efficient uptake into cells, tissues, and whole organisms. It is also chemically robust and resistant to enzymatic degradation and analogous to well-characterized biological systems in terms of noncovalent binding. Occurrence of fluorescence resonance energy transfer (FRET) between cyanine 3-CB[7] (Cy3-CB[7]) and boron-dipyrromethene 630/650X-AdA (BDP630/650-AdA) inside a live worm (Caenorhabditis elegans) indicates efficient in situ high-affinity association between AdA and CB[7] inside live animals. In addition, selective visualization of a cancer site of a live mouse upon supramolecular latching of cyanine 5-AdA (Cy5-AdA) on prelocalized CB[7]-conjugating antibody on the cancer site demonstrates the potential of this synthetic system for in vivo cancer imaging. These findings provide a fresh insight into the development of new chemical biology tools and medical therapeutic systems.

Decursinol angelate ameliorates 12-O-tetradecanoyl phorbol-13-acetate (TPA) -induced NF-κB activation on mice ears by inhibiting exaggerated inflammatory cell infiltration, oxidative stress and pro-inflammatory cytokine production.

Decursinol angelate (DA) is a pyranocoumarin purified from the roots of Angelica gigas. Here, we synthesized DA and determined its anti-inflammatory potential on TPA-induced mice ear inflammation. First, we evaluated the non-toxic behaviour of DA on HaCaT cells. Additionally, we observed the free radical scavenging potential of DA at 60 µM to be 50%. This finding was further supported by nitric oxide assay, malondialdehyde assay, H2DCFDA staining and western blotting analysis of antioxidant enzymes. DA also suppressed the activation and polarization of macrophage phagocytic activity on RAW 264.7 cells. We further evaluated the expression of ICAM-1, MCP-1, MIP-2 and MIP-1ß on in-vivo model system. Consequently, DA significantly reduced the production of NF-κB and COX-2 induced proinflammatory cytokine levels on TPA induced ear edema. Inhibition of MAPK and transcriptional factor NF-κB was also validated by western blotting analysis of p-ERK, p-p38, IKKα, IKKγ, IκBα, NF-κB-p65. Immunohistochemistry and immunofluorescence staining of NFκB-p65, TNF-α and IL-1ß were also performed to support the findings. Conclusively, these results suggest that topical administration of DA significantly inhibited the expression of pro-inflammatory cytokines by blocking the canonical NF-κB and MAPK pathway. Therefore, we suggest DA as a potent therapeutic compound against skin inflammation related diseases.

Oncological outcomes of complete versus conventional mesocolic excision in laparoscopic right hemicolectomy.

BACKGROUND: Complete mesocolic excision (CME) has been proposed for colon cancer to improve oncological outcomes. The risks and benefits of laparoscopic CME have not been examined fully. We compared short- and long-term outcomes of CME with a conventional mesocolic excision (non-CME) in laparoscopic right hemicolectomy (RHC) for right-sided colon cancer. METHODS: In total, 115 patients who underwent laparoscopic RHC with stage I-III right-sided colon cancer at Busan Paik Hospital from August 2007 to October 2011 were enrolled in this case-control study. Three trained colorectal surgeons reviewed videos of the surgeries; patients were divided into two groups: those who underwent a CME (CME group, n = 34) and those who underwent a conventional mesocolic excision (non-CME group, n = 81). RESULTS: There was no significant difference between the CME and non-CME groups in operative time, post-operative complications, or hospital stay. However, the CME group had more lymph nodes harvested (P < 0.001) and lower blood loss (P = 0.016) versus the non-CME group. There was no difference in 5-year disease-free survival rate between the groups, but 5-year overall survival rate was 100% in the CME group and 89.49% in the non-CME group (P < 0.05). CONCLUSIONS: Laparoscopic RHC with CME is safe and associated with better 5-year overall survival rate than non-CME for patients with stage I-III right-sided colon cancer. Implementation of CME surgery might improve oncological outcomes for patients with right-sided colon cancer.

Targeting PRPK and TOPK for skin cancer prevention and therapy.

Solar ultraviolet (sUV) irradiation is a major environmental carcinogen that can cause inflammation and skin cancer. The costs and morbidity associated with skin cancer are increasing, and therefore identifying molecules that can help prevent skin carcinogenesis is important. In this study, we identified the p53-related protein kinase (PRPK) as a novel oncogenic protein that is phosphorylated by the T-LAK cell-originated protein kinase (TOPK). Knockdown of TOPK inhibited PRPK phosphorylation and conferred resistance to solar-simulated light (SSL)-induced skin carcinogenesis in mouse models. In the clinic, acute SSL irradiation significantly increased epidermal thickness as well as total protein and phosphorylation levels of TOPK and PRPK in human skin tissues. We identified two PRPK inhibitors, FDA-approved rocuronium bromide (Zemuron®) or betamethasone 17-valerate (Betaderm®) that could attenuate TOPK-dependent PRPK signaling. Importantly, topical application of either rocuronium bromide or betamethasone decreased SSL-induced epidermal hyperplasia, neovascularization, and cutaneous squamous cell carcinoma (cSCC) development in SKH1 (Crl: SKH1-Hrhr) hairless mice by inhibiting PRPK activation, and also reduced expression of the proliferation and oncogenesis markers, COX-2, cyclin D1, and MMP-9. This study is the first to demonstrate that targeting PRPK could be useful against sUV-induced cSCC development.

Korean Society of Coloproctology (KSCP) trial of cONsolidation Chemotherapy for Locally advanced mid or low rectal cancer after neoadjUvant concurrent chemoraDiothErapy: a multicenter, randomized controlled trial (KONCLUDE).

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) has been a standard treatment option for locally advanced rectal cancer with improved local control. However, systemic recurrence despite neoadjuvant CRT remained unchanged. The only significant prognostic factor proven to be important was pathologic complete response (pCR) after neoadjuvant CRT. Several efforts have been tried to improve survival of patients who treated with neoadjuvant CRT and to achieve more pCR including adding cytotoxic chemotherapeutic agents, chronologic modification of chemotherapy schedule or adding chemotherapy during the perioperative period. Consolidation chemotherapy is adding several cycles of chemotherapy between neoadjuvant CRT and TME. It could increase pCR rate, subsequently could show better oncologic outcomes. METHODS: Patients with advanced mid or low rectal cancer who received neoadjuvant CRT will be included after screening. They will be randomized and assigned to undergo TME followed by 8 cycles of adjuvant chemotherapy (control arm) or receive 3 cycles of consolidation chemotherapy before TME, and receive 5 cycles of adjuvant chemotherapy (experimental arm). The primary endpoints are pCR and 3-year disease-free survival (DFS), and the secondary endpoints are radiotherapy-related complications, R0 resection rate, tumor response rate, surgery-related morbidity, and peripheral neuropathy at 3 year after the surgery. The authors hypothesize that the experimental arm would show a 15% improvement in pCR (15 to 30%) and in 3-year DFS (65 to 80%), compared with the control arm. The accrual period is 2 years and the follow-up period is 3 years. Based on the superiority design, one-sided log-rank test with α-error of 0.025 and a power of 80% was conducted. Allowing for a drop-out rate of 10%, 358 patients (179 per arm) will need to be recruited. Patients will be followed up at every 3 months for 2 years and then every 6 months for 3 years after the last patient has been randomized. DISCUSSION: KONCLUDE trial aims to investigate whether consolidation chemotherapy shows better pCR and 3-year DFS than adjuvant chemotherapy alone for the patients who received neoadjuvant CRT for locally advanced rectal cancer. This trial is expected to provide evidence to support clear treatment guidelines for patients with locally advanced rectal cancer. TRIAL REGISTRATION: Clinicaltrials.gov NCT02843191 (First posted on July 25, 2016).

Targeting PRPK Function Blocks Colon Cancer Metastasis.

The biological functions of the p53-related protein kinase (PRPK) remain unclear. We have previously demonstrated that PRPK is phosphorylated by the T-LAK cell-originated protein kinase (TOPK) and that phosphorylated PRPK (p-PRPK) promotes colon cancer metastasis. Here, we analyzed colon adenocarcinomas from 87 patients and found that higher expression levels of p-PRPK were associated with later stages of metastatic dissemination (stage III and IV) as compared with earlier stages (stages I and II). Indeed, levels of p-PRPK were higher in metastatic versus malignant human colon adenocarcinomas. Knocking down PRPK expression attenuated colorectal liver and lung metastasis of colon cancer cells in vivo An in vitro kinase assay indicated that active PRPK does not phosphorylate p53 directly. We found that PRPK phosphorylates survivin, a regulator of colon cancer metastasis. PRPK phosphorylates survivin at Thr34, which is important for survivin stability. Taken together, our data strongly suggest that the PRPK signaling pathway promotes colon cancer metastasis by modulating survivin stability, and that PRPK could be a new prognostic marker for the survival of colon cancer patients. In addition, we identified an FDA-approved bacteriostatic antibiotic, fusidic acid sodium salt (fusidic acid or FA) as an inhibitor of PRPK, and show that FA combined with 5-fluorouracil (5-FU) inhibited PRPK activity and colon cancer metastasis to the lung in mice. We contend that the combination of FA with 5-FU could be an alternative therapeutic strategy to traditional chemotherapy for colon cancer patients with poor prognosis. Mol Cancer Ther; 17(5); 1101-13. ©2018 AACR.

Prognostic value of positron emission tomography/computed tomography for adjuvant chemotherapy of colon cancer.

BACKGROUND: To assess the prognostic value of preoperative 18 F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with high-risk stage II or stage III colon cancer who underwent FOLFOX chemotherapy. METHODS: The study included 166 patients with high-risk stage II or stage III colon cancer who received FOLFOX4 chemotherapy. Retrospective patient data were analysed including pathological stage, histology, disease-free survival (DFS) and the maximum standardized uptake value (SUVmax ) of the primary tumour on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. The primary end point was DFS. RESULTS: There were recurrences in 29 of the 166 patients (17.4%). Measuring the area under the receiver operating characteristic curve, the cut-off value of SUVmax with maximum sensitivity and specificity was 10.95. Using the Kaplan-Meier method, the DFS of the patients categorized by SUVmax tended to differ (P = 0.055). In univariate analyses, the risk factors for DFS were age over 70 years, higher N stage and neural invasion. SUVmax ≤ 10.95 showed a tendency, but was not significant (P = 0.0604). In multivariate analyses, the risk factors for DFS were age over 70 and neural invasion. CONCLUSIONS: The results of this study suggest that high fluorodeoxyglucose uptake of the primary mass in high-risk stage II and stage III colon cancer does not significantly correlate with DFS.

Serine 347 Phosphorylation by JNKs Negatively Regulates OCT4 Protein Stability in Mouse Embryonic Stem Cells.

The POU transcription factor OCT4 is critical for maintaining the undifferentiated state of embryonic stem cells (ESCs) and generating induced pluripotent stem cells (iPSCs), but its precise mechanisms of action remain poorly understood. Here, we investigated the role of OCT4 phosphorylation in the biological functions of ESCs. We observed that c-Jun N-terminal kinases (JNKs) directly interacted with and phosphorylated OCT4 at serine 347, which inhibited the transcriptional activity of OCT4. Moreover, phosphorylation of OCT4 induced binding of FBXW8, which reduced OCT4 protein stability and enhanced its proteasomal degradation. We also found that the mutant OCT4 (S347A) might delay the differentiation process of mouse ESCs and enhance the efficiency of generating iPSCs. These results demonstrated that OCT4 phosphorylation on serine 347 by JNKs plays an important role in its stability, transcriptional activities, and self-renewal of mouse ESCs.