Anti-Cancer Effects of CDK4/6 Inhibitor LEE011 and Chemotherapy Drugs on Lymphocytic Leukemia L1210 Cells.

BACKGROUND/AIM: Chronic lymphocytic leukemia is a slowly-progressing disease in which symptoms often do not manifest until years after disease onset. In advanced stages, infection and bleeding are common. Past studies have shown that the interaction between CDK4/6 inhibitors and chemotherapy drugs can enhance the anti-tumor efficacy of drugs and limit toxicity. Therefore, in this study, the treatment effects of combining the CDK4/6 inhibitor LEE011 with chemotherapy drugs bendamustine or hydroxyurea were investigated in vitro. MATERIALS AND METHODS: The mouse lymphocytic leukemia cell line L1210 was treated with LEE011 combined with hydroxyurea or bendamustine. Western blot and flow cytometry were performed to elucidate the mechanisms behind tumor suppression. RESULTS: LEE011 combined with hydroxyurea or bendamustine significantly inhibited proliferation of L1210 cell lines in a concentration- and time-dependent manner as well as increased the arrest of cells in G1 and S phases. The combination of LEE011 with hydroxyurea also reduced the phosphorylation of Rb while increased the expression of total Rb protein. Furthermore, reduced expression of GPX4, which is a key protein in ferroptosis, indicates that the tumor suppression effects of this drug combination could involve ferroptosis. CONCLUSION: CDK4/6 inhibitor LEE011 treatment alone may not be a suitable treatment option for lymphocytic leukemia; however, our findings in vitro support the combination of LEE011 with chemotherapy drugs to enhance anti-tumor activity in lymphocytic leukemia.

5-Methoxytryptophan enhances the sensitivity of sorafenib on the inhibition of proliferation and metastasis for lung cancer cells.

BACKGROUND: Lung cancer is a leading cause of cancer-related mortality worldwide, and effective therapies are limited. Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective therapy. Sorafenib is a multi-tyrosine kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clinical application. This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5-methoxytryptophan (5-MTP) on cell growth and metastasis of Lewis lung carcinoma (LLC) cells. METHOD: The anticancer effect of the combination treatment of sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combination treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combination treatment on the tumorigenic ability of LLC cells. RESULT: Our results demonstrated that the sorafenib and 5-MTP combination synergistically reduced viability and proliferation compared to sorafenib or 5-MTP treatment alone. Reduction of cyclin D1 expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthermore, the sorafenib-5-MTP combination significantly increased the inhibitory effect on migration and invasion of LLC cells compared to the single treatments. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on proliferation and metastasis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of sorafenib alone. CONCLUSIONS: In conclusion, our data indicate that 5-MTP sensitizes the antitumor activity of sorafenib in LLC cells in vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer.

Medium-term surgical outcomes and health-related quality of life after laparoscopic vs open colorectal cancer resection: SF-36 health survey questionnaire.

BACKGROUND: Previous studies that compared the postoperative health-related quality of life (HRQoL) outcomes after receiving laparoscopic resection (LR) or open resection (OR) in patients with colorectal cancer (CRC) have different conclusions. AIM: To explore the medium-term effect of postoperative HRQoL in such patients. METHODS: This study randomized 567 patients undergoing non-metastatic CRC surgery managed by one surgeon to the LR or OR groups. HRQoL was assessed during the preoperative period and 3, 6, and 12 mo postoperative using a modified version of the 36-Item Short Form (SF-36) Health Survey questionnaire, emphasizing eight specific items. RESULTS: This cohort randomly assigned 541 patients to receive LR (n = 296) or OR (n = 245) surgical procedures. More episodes of postoperative urinary tract infection (P < 0.001), wound infection (P < 0.001), and pneumonia (P = 0.048) were encountered in the OR group. The results demonstrated that the LR group subjectively gained mildly better general health (P = 0.045), moderately better physical activity (P = 0.006), and significantly better social function recovery (P = 0.0001) 3 mo postoperatively. Only the aspect of social function recovery was claimed at 6 mo, with a significant advantage in the LR group (P = 0.001). No clinical difference was found in HRQoL during the 12 mo. CONCLUSION: Our results demonstrated that LR resulted in better outcomes, including intra-operative blood loss, surgery-related complications, course of recovery, and especially some health domains of HRQoL at least within 6 mo postoperatively. Patients should undergo LR if there is no contraindication.

Synergistic and Antagonistic Antiproliferative Effects of Ribociclib (Lee011) and Irinotecan (SN38) on Colorectal Cancer Cells.

BACKGROUND/AIM: Colorectal cancer (CRC) is one of the most common malignancies and cause of cancer-related deaths worldwide. The combination of chemotherapeutics working with different mechanisms enhances the therapeutic effects and delays the development of resistance. This study investigated the anticancer effect of the combination of ribociclib (LEE011) and irinotecan (SN38) on CRC cells. MATERIALS AND METHODS: HT-29 and SW480 cells were treated with LEE011, SN38, or the combination of LEE011 and SN38. Cell viability and cell cycle distribution were analyzed. The expression of cell cycle- and apoptosis-related proteins was determined using western blot. RESULTS: The combination of LEE011 and SN38 elicited a synergistic antiproliferative effect on HT-29 (PIK3CAP449T mutation) cells, and an antagonistic antiproliferative effect on SW480 (KRASG12V mutation) cells. LEE011 inhibited retinoblastoma protein (Rb) phosphorylation and led to G1 arrest in HT-29 and SW480 cells. SN38 treatment caused a significant increase in the phosphorylation levels of Rb, cyclin B1, and CDC2 in SW480 cells and induced S phase arrest. Furthermore, SN38 treatment increased the phosphorylation levels of p53 and activated caspase-3 and caspase-8 in HT-29 and SW480 cells. LEE011-induced G1 arrest contributed to its synergistic antiproliferative effect with SN38 in HT-29 cells through the down-regulation of the phosphorylation of Rb. In addition, it elicited an antagonistic effect with SN38 in SW480 cells by changing the phosphorylation levels of Rb and activating caspase-8. CONCLUSION: The effects of the combination of LEE011 and conventional chemotherapy drugs on CRC depend on the chemotherapy drug and the specific gene mutation harbored by tumor cells.

The impact of a multispecialty operative team on colorectal cancer surgery: A retrospective study from a would-be medical center in Taiwan.

Some studies showed that when distant metastasis or locally advanced tumors were observed, the participation of 2 or more operating surgeons (combined surgery) in the operation could improve the prognosis of patients. The multispecialty operative team would perform combined surgery in colon cancer patients with some complications since 2015. The goal of this study is to confirm performing combined surgery would improve the outcomes of colon cancer patients. A retrospective observational study was conducted, which involved all colon cancer patients between November 2015 and December 2019 at one would-be medical center. Patients were divided into 3 cohorts: those with complicated cases and had combined surgery (C_2S), those with complicated cases and had surgery performed by a single surgeon (C_1S), and those with uncomplicated cases and had surgery performed by a single surgeon (NC_1S). Overall survival and disease-free survival were compared among the 3 groups. A total of 296 colon cancer patients during the study period. Among them, 35 were C_2S, 87 were C_1S, and 174 were NC_1S. Patients in the NC_1S group had significantly higher 12-, 24-, and 36-month OS rates compared to those in the C_1S group (P < .01). In contrast, there was no significant difference in overall survival among patients in the NC_1S and C_2S group (P =.15). The quality of surgery must be impact the prognosis, especially in the individual who was complicated case, the survival in patients who had surgery performed by multispecialty operative team would be improved.

Mesentery solitary fibrous tumor with postoperative recurrence and sarcomatosis: A case report and review of literature.

BACKGROUND: Solitary fibrous tumors are rare neoplasms of mesenchymal origin. They are often of low malignant potential and rarely metastasize. They frequently arise from the pleura and can occur at any soft tissue site in the body. However, these tumors rarely develop in the mesentery, peritoneal cavity or peritoneum. CASE SUMMARY: We report on a scarce case of solitary fibrous tumor of the rectal mesentery showing sarcomatosis about 4 years after previous tumor resection. This 69-year-old male had no clinical symptoms but was transferred to our hospital because of a suspected tumor recurrence from follow-up abdominal computed tomography. Tumor markers (CEA, CA 19-9 and CA 125) were within the normal range. Open laparotomy showed sarcomatosis, and pathology confirmed its mesenchymal origin and diagnosis as the solitary fibrous tumor. Our case may be the second recurrent mesentery solitary fibrous tumor reported to date, and the only one with progression to sarcomatosis. There has been no evidence of recurrence in follow-up at the 28th mo after extensive intra-operative peritoneal lavage and cytoreductive surgery. CONCLUSION: Although there are few risk factors of cancer recurrence in this patient, careful long-term follow-up after cytoreductive surgery is necessary.

6M50LSG Scoring System Increased the Proportion of Adequate Excess Body Weight Loss for Suspected Poor Responders After Laparoscopic Sleeve Gastrectomy in Asian Population.

PURPOSE: We aimed to evaluate the efficacy of the predictive tool, 6M50LSG scoring system, to identify suspected poor responders after laparoscopic sleeve gastrectomy (LSG). METHODS: The 6M50LSG scoring system has been applied since 2019. Suspected poor responders are defined by EBWL at 1 month < 19.5% or EBWL at 3 months < 37.7% based on the 6M50LSG scoring system. Our analysis included 109 suspected poor responders. Based on the date of LSG, the patients were separated into two groups: the 2016-2018 group (before group, BG, with regular care) and the 2019-2020 group (after group, AG, with upgrade medical nutrition therapy). RESULTS: At the end of the study, the AG group had a significantly higher proportion of adequate weight loss, which was defined as EBWL ≥ 50% at 6 months after LSG, than that in the BG group (18.92% in BG vs. 48.57% in AG, p = 0.003). The AG group demonstrated significantly more 3-months-TWL (BG: 15.22% vs. AG: 17.54%, p < 0.001) and 6-months-TWL (BG: 21.08% vs. AG: 25.65%, p < 0.001). In multivariate analyses and adjustments, the scoring system (AG) resulted in significantly higher chances of adequate weight loss in suspected poor responders (adjusted OR 3.392, 95% CI = 1.345-8.5564, p = 0.010). One year after LSG, suspected poor responders in AG had a significantly higher weight loss than those in BG (BG vs. AG: TWL 27.17% vs. 32.20%, p = 0.014) . CONCLUSION: This study confirmed that the 6M50LSG scoring system with upgraded medical nutrition therapy increased the proportion of suspected poor responders with adequate weight loss after LSG.

Correlation of Body Mass Index with Oncologic Outcomes in Colorectal Cancer Patients: A Large Population-Based Study.

It has been acknowledged that excess body weight increases the risk of colorectal cancer (CRC); however, there is little evidence on the impact of body mass index (BMI) on CRC patients' long-term oncologic results in Asian populations. We studied the influence of BMI on overall survival (OS), disease-free survival (DFS), and CRC-specific survival rates in CRC patients from the administrative claims datasets of Taiwan using the Kaplan-Meier survival curves and the log-rank test to estimate the statistical differences among BMI groups. Underweight patients (<18.50 kg/m2) presented higher mortality (56.40%) and recurrence (5.34%) rates. Besides this, they had worse OS (aHR:1.61; 95% CI: 1.53-1.70; p-value: < 0.0001) and CRC-specific survival (aHR:1.52; 95% CI: 1.43-1.62; p-value: < 0.0001) rates compared with those of normal weight patients (18.50-24.99 kg/m2). On the contrary, CRC patients belonging to the overweight (25.00-29.99 kg/m2), class I obesity (30.00-34.99 kg/m2), and class II obesity (≥35.00 kg/m2) categories had better OS, DFS, and CRC-specific survival rates in the analysis than the patients in the normal weight category. Overweight patients consistently had the lowest mortality rate after a CRC diagnosis. The associations with being underweight may reflect a reverse causation. CRC patients should maintain a long-term healthy body weight.

Gastrointestinal cytomegalovirus disease secondary to measles in an immunocompetent infant.

Yang et al reported an immunocompetent infant with gastrointestinal cytomegalovirus disease secondary to measles infection. We express our opinion about the diagnosis and treatment of this rare disease.

Synergistic Antiproliferative Effect of Ribociclib (LEE011) and 5-Fluorouracil on Human Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. This study aimed to investigate the anticancer effect of the combination treatment of Ribociclib (LEE011) and 5-Fluorouracil (5-FU) on CRC cells. MATERIALS AND METHODS: HT-29 and SW480 cells were treated with LEE011, 5-FU, or the combination of LEE011 and 5-FU. Cell viability and cycle were investigated through 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and flow cytometry. The expression of cell cycle-related proteins was determined through western blot. RESULTS: The combined treatment of LEE011 with 5-FU synergistically reduced cell viability in HT-29 and SW480 cells. Specifically, it induced cell cycle arrest at the G1 phase, down-regulated the phosphorylation of retinoblastoma protein and the expression of p53. CONCLUSION: LEE011 exhibited potential as an effective therapeutic inhibitor for the combination treatment of CRC patients.

Check point to get adequate weight loss within 6-months after laparoscopic sleeve gastrectomy for morbid obesity in Asian population.

Purpose of this study is to develope a scoring system to predict the likelihood of excess body weight loss (EBWL) ≥ 50% 6-months after laparoscopic sleeve gastrectomy (LSG). From April 2016 to September 2018, data was collected from 160 patients (BMI ≥ 32) who underwent primary LSG with at least 6-months follow-up. They were separated into score generation (operated by one surgeon, n = 122) and validation groups (operated by 3 different surgeons, n = 38). EBWL at 6-months ≥ 50% was considered adequate weight loss. Independent variables including age, gender, initial body mass index (BMI), comorbidities, life-style habits, percentage of EBWL and percentage of total body weight loss at 1-week, 1-month, and 3-months were analyzed with mutivariate logistic regression to generate the scoring system. The system was applied to internal and external validation groups to determine efficacy. As results, between the score generation and internal validation groups, the only significant difference in patient characteristics was in exercise participation. EBWL at 1-month > 19.5% (1 point) and EBWL at 3-months > 37.7% (2 points) were identified as independent factors to predict EBWL at 6-months ≥ 50%. When scores were > 1, the system had 94.03% positive predictive value (PPV) and 81.82% negative predictive value (NPV) (AUC: 0.923). Internal validation scores > 1 had a 95.83% PPV and 85.71% NPV (AUC: 0.975). External validation results showed 88.59% PPV and 72.00% NPV (AUC: 0.802). We concluded that this scoring system provides a reliable, objective prediction of EBWL at 6-months ≥ 50%. Patients requiring more aggressive clinical follow-up and intervention can be detected as early as 1- to 3-months after LSG.

Nerve growth factor induced farnesoid X receptor upregulation modulates autophagy flux and protects hepatocytes in cholestatic livers.

Upregulation of nerve growth factor (NGF) in parenchymal hepatocytes has been shown to exert hepatoprotective function during cholestatic liver injury. However, the modulatory role of NGF in regulation of liver autophagy remains unclear. This study aimed to scrutinize the regulatory role of NGF in hepatic expression of farnesoid X receptor (FXR), a bile acid (BA)-activated nuclear receptor, and to determine its cytoprotective effect on BA-induced autophagy and cytotoxicity. Livers of human hepatolithiasis and bile duct ligation (BDL)-induced mouse cholestasis were used for histopathological and molecular detection. The regulatory roles of NGF in autophagy flux and FXR expression, as well as its hepatoprotection against BA cytotoxicity were examined in cultured hepatocytes. FXR downregulation in human hepatolithiasis livers showed positive correlation with hepatic NGF levels. NGF administration upregulated hepatic FXR levels, while neutralization of NGF decreased FXR expression in BDL-induced cholestatic mouse livers. In vitro studies demonstrated that NGF upregulated FXR expression, increased cellular LC3 levels, and exerted hepatoprotective effect in cultured primary rat hepatocytes. Conversely, autophagy inhibition abrogated NGF-driven cytoprotection under BA exposure, suggesting involvement of NGF-modulated auophagy flux. Although FXR agonistic GW4064 stimulation did not affect auophagic LC3 levels, FXR activity inhibition significantly potentiated BA-induced cytotoxicity and increased cellular p62/SQSTM1 and Rab7 protein in SK-Hep1 hepatocytes. Moreover, FXR gene silencing abolished the protective effect of NGF under BA exposure. These findings support that NGF modulates autophagy flux via FXR upregulation and protects hepatocytes against BA-induced cytotoxicity. NGF/FXR axis is a novel therapeutic target for treatment of cholestatic liver diseases.

Correction to: Bariatric Surgery Did Not Increase the Risk of Gallstone Disease in Obese Patients: a Comprehensive Cohort Study.

In the section "Method" the first sentence should read as follows: This retrospective study was fully evaluated and approved by the Institutional Review Board of Buddhist Dalin Tzu Chi Hospital (approval B10603004) and was conducted in accordance with the principles of the Helsinki Declaration.

Bariatric Surgery Did Not Increase the Risk of Gallstone Disease in Obese Patients: a Comprehensive Cohort Study.

PURPOSE: The aim of this study was to evaluate the influence of bariatric surgery on gallstone disease in obese patients. MATERIALS AND METHODS: This large cohort retrospective study was conducted based on the Taiwan National Health Insurance Research Database. All patients 18-55 years of age with a diagnosis code for obesity (ICD-9-CM codes 278.00-278.02 or 278.1) between 2003 and 2010 were included. Patients with a history of gallstone disease and hepatic malignancies were excluded. The patients were divided into non-surgical and bariatric surgery groups. Obesity surgery was defined by ICD-9-OP codes. We also enrolled healthy civilians as the general population. The primary end point was defined as re-hospitalization with a diagnosis of gallstone disease after the index hospitalization. All patients were followed until the end of 2013, a biliary complication occurred, or death. RESULTS: Two thousand three hundred seventeen patients in the bariatric surgery group, 2331 patients in the non-surgical group, and 8162 patients in the general population were included. Compared to the non-surgery group (2.79%), bariatric surgery (2.89%) did not elevate the risk of subsequent biliary events (HR = 1.075, p = 0.679). Compared to the general population (1.15%), bariatric surgery group had a significantly higher risk (HR = 4.996, p < 0.001). In the bariatric surgery group, female gender (HR = 1.774, p = 0.032) and a restrictive procedure (HR = 1.624, p = 0.048) were risk factors for gallstone disease. CONCLUSION: The risk for gallstone disease did not increase after bariatric surgery, although the risk was still higher than the general population. The benefit of concomitant cholecystectomy during bariatric surgery should be carefully evaluated.