Circulating tumor cells help differentiate benign ovarian lesions from cancer before surgery: A literature review and proof of concept study using flow cytometry with fluorescence imaging.

Current tools are insufficient for distinguishing patients with ovarian cancer from those with benign ovarian lesions before extensive surgery. The present study utilized a readily accessible platform employing a negative selection strategy, followed by flow cytometry, to enumerate circulating tumor cells (CTCs) in patients with ovarian cancer. These counts were compared with those from patients with benign ovarian lesions. CTC counts at baseline, before and after anticancer therapy, and across various clinical scenarios involving ovarian lesions were assessed. A negative-selection protocol we proposed was applied to patients with suspected ovarian cancer and prospectively utilized in those subsequently confirmed to have malignancy. The protocol was implemented before anticancer therapy and at months 3, 6, 9 and 12 post-treatment. A cut-off value for CTC number at 4.75 cells/ml was established to distinguish ovarian malignancy from benign lesions, with an area under the curve of 0.900 (P<0.001). In patients with ovarian cancer, multivariate Cox regression analysis revealed that baseline CTC counts and the decline in CTCs within the first three months post-therapy were significant predictors of prolonged progression-free survival. Additionally, baseline CTC counts independently prognosticated overall survival. CTC counts obtained with the proposed platform, used in the present study, suggest that pre-operative CTC testing may be able to differentiate between malignant and benign tumors. Moreover, CTC counts may indicate oncologic outcomes in patients with ovarian cancer who have undergone cancer therapies.

Nasopharyngeal carcinoma patient-derived xenograft mouse models reveal potential drugs targeting cell cycle, mTOR, and autophagy pathways.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is associated with Epstein-Barr virus (EBV) infection. To test preclinical NPC drugs, we established two patient-derived xenograft (PDX) mouse models, EBV-positive PDX-B13 and EBV-negative PDX-Li41, for drug screening. METHODS: Based on next generation sequencing (NGS) studies, PDX-B13 had CCND1 copy number (CN) gain but CDKN2A CN loss, whereas PDX-Li41 had CDKN2A and RB1 CN loss, TSC1 (negative regulator of mTOR) frameshift deletion mutation, and increased activation of mTOR, a serine/threonine kinase that governs metabolism, autophagy, and apoptosis. Increased mTOR was also associated with poor NPC prognosis. RESULTS: Everolimus, an mTOR inhibitor, suppressed tumor growth in the two PDX NPC models and had an additive antitumor effect with palbociclib, a CDK4/6 inhibitor. PDX tumors treated with various drugs or untreated were subjected to RNA sequencing, transcriptome profile analysis, and selective Western blotting to understand the interactions between these drugs and gene expression profiles. Palbociclib also suppressed EB viral nuclear antigen (EBNA1) expression in PDX-B13. Everolimus together with autophagy inhibitor, hydroxychloroquine, had additive anti-tumor effect on PDX-B13 tumor. Immunohistochemistry revealed that high mTOR levels were correlated with poor overall survival in patients with metastatic NPC (N = 90). CONCLUSIONS: High mTOR levels are a poor prognostic factor in NPC, and cell cycle, mTOR and autophagy pathways may serve as therapeutic targets in NPC. In addition, PDX models can be used for efficiently testing potential NPC drugs.

Long-term use and risk of major adverse cardiac events: Comparing enzalutamide and abiraterone in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

This is a retrospective cohort study by analyzing a multi-institutional electronic medical records database in Taiwan to compare long-term effectiveness and risk of major adverse cardiac events (MACE) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide (ENZ) or abiraterone (AA). Patients aged 20 years and older and newly receiving androgen receptor targeted therapies ENZ or AA from September 2016 to December 2019 were included. We followed patients from initiation of therapies to the occurrence of outcomes (prostate-specific antigen (PSA) response rate, PSA progression free survival (PFS), overall survival (OS), and MACE), death, the last clinical visit, or December 31, 2020. We performed multivariable Cox proportional hazard models to compare ENZ and AA groups for the measured outcomes. A total of 363 patients treated with either ENZ (n = 157) or AA (n = 206) were identified. The analysis found a significantly higher proportion of patients with a PSA response rate higher than 50% among those receiving ENZ than among those receiving AA (ENZ vs AA: 75.80% vs 63.59%, P = .01). However, there was no significant difference in PSA PFS (adjusted hazard ratio: 0.86; 95% CI 0.63-1.17) and OS (0.68: 0.41-1.14) between the use of ENZ and AA in chemotherapy-naïve mCRPC patients. Regarding the cardiovascular (CV) safety outcome, there was a significantly lower risk of MACE in patients receiving ENZ, compared to patients receiving AA (0.20: 0.07-0.55). The findings suggest that enzalutamide may be more efficacious for PSA response and suitable for chemotherapy-naïve mCRPC patients with high CV risk profile.

Association of early changes of circulating cancer stem-like cells with survival among patients with metastatic breast cancer.

Background: This study aimed to investigate the role of circulating tumor cells (CTCs) and circulating cancer stem-like cells (cCSCs) before and after one cycle of chemotherapy and assessed the effects of early changes in CTCs and cCSCs on the outcomes of patients with metastatic breast cancer. Methods: Patients with stage IV invasive ductal carcinoma of the breast who received first-line chemotherapy between April 2014 and January 2016 were enrolled. CTCs and cCSCs were measured before the first cycle of chemotherapy (baseline) and on day 21, before the second cycle of chemotherapy commenced; a negative selection strategy and flow cytometry protocol were employed. Results: CTC and cCSC counts declined in 68.8 and 45.5% of patients, respectively. Declines in CTCs and cCSCs following the first chemotherapy cycle were associated with superior chemotherapy responses, longer progression-free survival (PFS), and longer overall survival (OS). An early decline in cCSCs remained an independent prognostic indicator for OS and PFS in multivariate analysis. Conclusions: A cCSC decline after one cycle of chemotherapy for metastatic breast cancer is predictive of a superior chemotherapy response and longer PFS and OS, implying that cCSC dynamic monitoring may be helpful in early prediction of treatment response and prognosis.

Circulating p16-Positive and p16-Negative Tumor Cells Serve as Independent Prognostic Indicators of Survival in Patients with Head and Neck Squamous Cell Carcinomas.

BACKGROUND: Decisions regarding the staging, prognosis, and treatment of patients with head and neck squamous cell carcinomas (HNSCCs) are made after determining their p16 expression levels and human papillomavirus (HPV) infection status. METHODS: We investigated the prognostic roles of p16-positive and p16-negative circulating tumor cells (CTCs) and their cell counts in HNSCC patients. We enrolled patients with locally advanced HNSCCs who received definitive concurrent chemoradiotherapy for final analysis. We performed CTC testing and p16 expression analysis before chemoradiotherapy. We analyzed the correlation between p16-positive and p16-negative CTCs and HPV genotyping, tissue p16 expression status, response to chemoradiotherapy, disease-free survival, and overall survival. RESULTS: Forty-one patients who fulfilled the study criteria were prospectively enrolled for final analysis. The detection rates of p16-positive (>0 cells/mL blood) and p16-negative (≥3 cells/mL blood) CTCs were 51.2% (n = 21/41) and 70.7%, respectively. The best responses of chemoradiotherapy and the p16 positivity of CTCs are independent prognostic factors of disease progression, with hazard ratios of 1.738 (95% confidence interval (CI): 1.031-2.927), 5.497 (95% CI: 1.818-16.615), and 0.176 (95% CI: 0.056-0.554), respectively. The p16 positivity of CTCs was a prognostic factor for cancer death, with a hazard ratio of 0.294 (95% CI: 0.102-0.852). CONCLUSIONS: The p16-positive and p16-negative CTCs could predict outcomes in HNSCC patients receiving definitive chemoradiotherapy. This non-invasive CTC test could help stratify the risk and prognosis before chemoradiotherapy in clinical practice and enable us to perform de-intensifying therapies.

Definitive concurrent chemoradiotherapy with paclitaxel plus carboplatin is superior to cisplatin plus 5-fluorouracil in patients with inoperable esophageal squamous cell carcinoma using retrospective, real-world evidence.

BACKGROUND: The optimal definitive chemotherapy regimen during concurrent chemoradiotherapy (CRT) for patients with advanced esophageal squamous cell carcinoma (ESCC) remains unclear because of conflicting evidence. This study aimed to compare the effectiveness of taxane-based chemotherapy with that of conventional cisplatin plus 5-fluorouracil (PF) as the chemotherapy regimen in definitive CRT for ESCC. PATIENTS AND METHODS: This retrospective study included patients with ESCC who received paclitaxel plus carboplatin (PC) or PF during definitive CRT between May 2012 and February 2015 in a medical center in Taiwan. Survival outcomes were compared after adjustment for risk factors. RESULTS: Overall, 229 patients were evaluated. Patients in the PC group had an objective response rate of 71.1% compared with the 51.4% of the PF group (p = 0.016). The PC group showed a significantly longer progression-free survival (PFS, p = 0.002) and overall survival (OS, p = 0.019) than the PF group. Salvage surgery also helped prolong both the PFS and OS (p < 0001). Sex (male vs. female, HR, 1.831; 95% CI, 1.016-3.303), clinical stage (HR, 1.282; 95% CI, 1.069-1.537), accumulative radiation dose (≥41.4 Gy vs. <41.4 Gy; HR, 0.640; 95% CI, 0.413-0.993), salvage surgery (yes vs. no, HR: 0.412, 95% CI: 0.298-0.570), and regimen (PF vs. PC; HR, 1.514; 95% CI, 1.109-2.067) were independent prognostic factors for cancer mortality. CONCLUSION: Compared with the PF regimen, the PC regimen for definitive CRT yielded significantly increased response rates and longer survival times; therefore, the PC regimen may be preferable for chemotherapy for definitive CRT in patients with advanced ESCC.

Combination of Epithelial Growth Factor Receptor Blockers and CDK4/6 Inhibitor for Nasopharyngeal Carcinoma Treatment.

BACKGROUND: Nasopharyngeal carcinoma (NPC) involves host genetics, environmental and viral factors. In clinical observations, patients of young and old ages were found to have higher recurrence and metastatic rates. METHODS: Cytokine array was employed to screen druggable target(s). The candidate target(s) were confirmed through patient-derived xenografts (PDXs) and a new EBV-positive cell line, NPC-B13. RESULTS: Overexpression of epithelial growth factor (EGF) and EGF receptor (EGFR) was detected in young patients than in older patients. The growth of NPC PDX tumors and cell lines was inhibited by EGFR inhibitors (EGFRi) cetuximab and afatinib when used separately or in combination with the cell cycle blocker palbociclib. Western blot analysis of these drug-treated PDXs demonstrated that the blockade of the EGF signaling pathway was associated with a decrease in the p-EGFR level and reduction in PDX tumor size. RNA sequencing results of PDX tumors elucidated that cell cycle-related pathways were suppressed in response to drug treatments. High EGFR expression (IHC score ≥ grade 3) was correlated with poor survival in metastatic patients (p = 0.008). CONCLUSIONS: Our results provide encouraging preliminary data related to the combination treatment of EGFRi and palbociclib in patients with NPC.

Purely laparoscopic feeding jejunostomy: a procedure which deserves more attention.

BACKGROUND: Laparoscopic procedure has inherent merits of smaller incisions, better cosmesis, less postoperative pain, and earlier recovery. In the current study, we presented our method of purely laparoscopic feeding jejunostomy and compared its results with that of conventional open approach. METHODS: We retrospectively reviewed our patients from 2012 to 2019 who had received either laparoscopic jejunostomy (LJ, n = 29) or open ones (OJ, n = 94) in Chang Gung Memorial Hospital, Linkou. Peri-operative data and postoperative outcomes were analyzed. RESULTS: In the current study, we employed 3-0 Vicryl, instead of V-loc barbed sutures, for laparoscopic jejunostomy. The mean operative duration of LJ group was about 30 min longer than the OJ group (159 ± 57.2 mins vs 128 ± 34.6 mins; P = 0.001). There were no intraoperative complications reported in both groups. The patients in the LJ group suffered significantly less postoperative pain than in the OJ group (mean NRS 2.03 ± 0.9 vs. 2.79 ± 1.2; P = 0.002). The majority of patients in both groups received early enteral nutrition (< 48 h) after the operation (86.2% vs. 74.5%; P = 0.143). CONCLUSIONS: Our study demonstrated that purely laparoscopic feeding jejunostomy is a safe and feasible procedure with less postoperative pain and excellent postoperative outcome. It also provides surgeons opportunities to enhance intracorporeal suture techniques.

Significance of the Glasgow Prognostic Score in Predicting the Postoperative Outcome of Patients with Stage III Gastric Cancer.

This study aimed at investigating the ability of a preoperative Glasgow prognostic score (GPS) to predict postoperative complications and survival outcomes in patients with stage III gastric cancer undergoing D2 gastrectomy. We retrospectively reviewed data from 272 such patients, treated between 2010 and 2016, at a Taiwanese medical center. The patients were categorized according to their GPS. In total, 36.8%, 48.5%, and 14.7% of the patients were assigned to groups with a GPS of 0, 1, and 2, respectively. Overall surgical complication rates in these groups were 30%, 45.5%, and 52.5% (p = 0.016); postoperative intensive care unit admission rates were 10%, 14.4%, and 22.5% (p = 0.15); postoperative 30-day re-admission rates were 6%, 15.2%, and 20% (p = 0.034); and the in-hospital mortality rates were 1.0%, 1.5%, and 10.0%, respectively (p = 0.006). The median survival times of the patients were 42.9 months (95% confidence interval [CI], 29.1-56.6), 22.6 months (95% CI, 19.3-25.8), and 16.6 months (95% CI, 7.8-25.4), respectively (p< 0.001). A significant correlation was observed between the preoperative GPS, short-term postoperative complications, and long-term survival outcomes in patients with gastric cancer undergoing D2 gastrectomy. These findings recommend the usage of the GPS as a predictive and prognostic factor in patients with gastric cancer considering surgical resection.

Effect of S-1 on survival outcomes in 838 patients with advanced pancreatic cancer: A 7-year multicenter observational cohort study in Taiwan.

OBJECTIVE: Studies have rarely explored the efficacy of S-1 in treating advanced pancreatic cancer outside Japan. This study compared the survival outcomes of patients with advanced pancreatic cancer treated with S-1 with the survival outcomes of those without S-1 treatment before and after S-1 reimbursement was introduced in Taiwan in June of 2014. METHOD: We retrospectively analyzed 838 patients with locally advanced or metastatic pancreatic cancer who underwent palliative chemotherapy from 2010 to 2016 at 4 institutes in Taiwan. For survival analysis, patients were categorized into two groups according to whether they received S-1 treatment as palliative chemotherapy after diagnosis: (a) S-1-treated (n = 335) and (b) non-S-1-treated (n = 503) groups. RESULTS: The median overall survival was longer in the S-1-treated group than in the non-S-1-treated group (10.7 vs 6.0 mo, P < 0.001). Subgroup survival analyses showed that the S-1-treated group had more favorable outcomes than the non-S-1-treated group in terms of stage III (19.6 vs 10.1 mo, P < 0.001) and stage IV (8.5 vs 5.3 mo, P < 0.001) disease. The disease control rates were 43.6% and 32.8% (P < 0.001) in patients treated with and without S-1 in the first-line setting, respectively. In multivariate analysis, exposure to S-1 treatment was an independent prognosticator for survival. CONCLUSION: Our results support the clinical use of S-1 as the treatment of choice for patients with locally advanced or metastatic pancreatic cancer, particularly in resource-limited situations.

Hepatic resection for hepatocellular carcinoma in the octogenarian: is it justified?

Liver resection is a standard treatment for hepatocellular carcinoma (HCC). The purpose of this study was to investigate the clinicopathological characteristics and long-term outcomes of octogenarians with HCC treated with liver resection. Records of patients who underwent liver resection for HCC were reviewed, and patients older and younger than 80 years were compared. There were 77 patients 80 years of age or older and 3,309 younger than 80 years. Hepatitis C virus infection was the most common etiology among the octogenarians (43.1%), followed by non-viral causes (37.5%). The older group had more co-morbidity but less hepatitis B virus infection and cirrhosis. More than 70% of the non-viral older group had diabetes mellitus, as compared to only 21.6% in the viral older group. The older group had rates of perioperative morbidity, mortality, disease-free survival, and overall survival comparable to the younger group (all p>0.1). Multivariate analysis revealed that α-fetoprotein ≥400 ng/mL, tumor size ≥10 cm, and vascular invasion were independent prognostic factors for overall survival in the older patients. These findings demonstrate that liver resection is a justified treatment for HCC in octogenarians, and it can achieve surgical outcomes comparable to those in younger populations.

A prognostic model based on lymph node metastatic ratio for predicting survival outcome in gastric cancer patients with N3b subclassification.

BACKGROUND: Determining the survival outcome for gastric cancer patients with metastases to more than 15 regional lymph nodes is difficult. This study aims to develop a lymph node metastatic ratio (LNR)-based prognostic model to predict the survival outcome after D2 surgery in such patient groups. METHODS: Our study retrospectively enrolled 139 gastric cancer patients with metastases to more than 15 regional lymph nodes who underwent D2 surgery between 2007 and 2014. Clinicopathologic variables to predict overall survival (OS) using multivariate Cox regression were selected to create a prognostic model. RESULTS: The prognostic model for predicting OS was developed based on five independent factors, namely, T-classification (T2 or T3 vs. T4), LNR (<0.80 vs. ≥0.80), carcinoembryonic antigen level (<5 vs. ≥5 ng/ml), Eastern Cooperative Oncology Group performance scale (scale 0-1 vs. ≥2), and adjuvant chemotherapy (yes vs. no). Using the prognostic score, patients were stratified into good, intermediate, and poor prognostic groups. The median OS in the good, intermediate, and poor prognostic risk groups was 32.0 months (95% confidence interval [CI]: 22.3-41.7), 12.4 months (95% CI: 8.5-16.3), and 5.4 months (95% CI: 2.1-8.7), respectively. The c-index of the prognostic model was 0.79 (95% CI: 0.71-0.87). CONCLUSION: This study developed an accurate LNR-based prognostic model for predicting the survival outcome after D2 surgery in gastric cancer patients with metastasis to more than 15 regional lymph nodes. This model might assist clinicians in prognostic stratification of such patients and convince eligible patients to receive adjuvant chemotherapy.

Factors related to patient propensity to receive adjuvant chemotherapy and outcomes in stage III gastric cancer cases after D2 surgery.

BACKGROUND: Radical gastrectomy and extended lymph node (D2) dissection followed by adjuvant chemotherapy is the optimal treatment for patients with stage III gastric cancer in Asian population. The clinical factors associated with patient propensity to receive adjuvant chemotherapy and outcomes were analyzed. METHODS: In total, 509 patients with stage III gastric cancer who had undergone D2 surgery between 2007 and 2017 at a single medical center in Taiwan were analyzed. The patients' preoperative clinical characteristics relevant to adjuvant chemotherapy adherence were analyzed using multivariate regression. Significant variables were analyzed using recursive partitioning analysis (RPA) for identifying specific patient groups with the lowest and highest probabilities of adjuvant chemotherapy adherence. RESULTS: After surgery, 361 (70.9%) patients in the cohort had received adjuvant chemotherapy. All patients were categorized into five probability groups with adherence to adjuvant chemotherapy according to age, Eastern Cooperative Oncology Group (ECOG) performance status grade, and American Society of Anesthesiologists (ASA) class, which were discovered to be independent factors in the RPA-based probability prediction. In general, adjuvant chemotherapy improved survival across broad categories of stage III gastric cancer patients (overall survival hazard ratio: 0.53-0.75 and disease-free survival hazard ratio: 0.47-0.76). CONCLUSIONS: Our study identified that age, ECOG grade, and ASA class were independent clinical factors associated with patient propensity to receive adjuvant chemotherapy in stage III gastric cancer. Knowledge of the clinical factors of patients may help clinicians identify and encourage specific patients to receive the adjuvant chemotherapy.

Predictive factors of postoperative complications in single-port video-assisted thoracoscopic anatomical resection: Two center experience.

The purpose of this study was to identify the risk factors for adverse events during single-port video-assisted thoracoscopic (SPVATS) anatomical resections.We retrospectively reviewed patients who had undergone SPVATS anatomic resections between January 2014 and February 2017 in Coruña University Hospital's Minimally Invasive Thoracic Surgery Unit (CHUAC, Spain) and Chang Gung Memorial Hospital (CGMH, Taiwan). Four hundred forty-two patients (male: 306, female: 136) were enrolled in this study. Logistic regression analysis was performed on variables for postoperative complications.Postoperative complications with a 30-day mortality occurred in 94 patients (21.3%) and with a 90-day mortality in 3 patients (0.7%) while the major complication rate was 3.9%. Prolonged air leak (PAL > 5 days) was the most common complication and came by postoperative arrhythmia. Logistic regression indicated that pleural symphysis (odds ratio (OR), 1.91; 95% confidence interval (CI), 1.14-3.18; P = .014), computed tomography (CT) pulmonary emphysema (OR, 2.63; 95% CI, 1.41-4.76; P = .002), well-developed pulmonary CT fissure line (OR, 0.49; 95% CI, 0.29-0.84; P = .009), and tumor size (≥3 cm) (OR, 2.15; 95% CI, 1.30-3.57; P = .003) were predictors of postoperative complications.Our preliminary results revealed that SPVATS anatomic resection achieves acceptable 30- and 90-day surgery related mortality (0.7%) and major complications rate (3.9%). Prolonged Air leak (PAL > 5 days) was the most common postoperative complication. Pleural symphysis, pulmonary emphysema, well-developed pulmonary CT fissure line and tumor size (≥3 cm) were predictors of adverse events during SPVATS anatomic resection.

Integrated genomic analyses in PDX model reveal a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for nasopharyngeal carcinoma.

BACKGROUND: Patient-derived xenograft (PDX) tumor model has become a new approach in identifying druggable tumor mutations, screening and evaluating personalized cancer drugs based on the mutated targets. METHODS: We established five nasopharyngeal carcinoma (NPC) PDXs in mouse model. Subsequently, whole-exome sequencing (WES) and genomic mutation analyses were performed to search for genetic alterations for new drug targets. Potential drugs were applied in two NPC PDX mice model to assess their anti-cancer activities. RNA sequencing and transcriptomic analysis were performed in one NPC PDX mice to correlate with the efficacy of the anti-cancer drugs. RESULTS: A relative high incident rate of copy number variations (CNVs) of cell cycle-associated genes. Among the five NPC-PDXs, three had cyclin D1 (CCND1) amplification while four had cyclin-dependent kinase inhibitor CDKN2A deletion. Furthermore, CCND1 overexpression was observed in > 90% FFPE clinical metastatic NPC tumors (87/91) and was associated with poor outcomes. CNV analysis disclosed that plasma CCND1/CDKN2A ratio is correlated with EBV DNA load in NPC patients' plasma and could serve as a screening test to select potential CDK4/6 inhibitor treatment candidates. Based on our NPC PDX model and RNA sequencing, Palbociclib, a cyclin-dependent kinase inhibitor, proved to have anti-tumor effects by inducing G1 arrest. One NPC patient with liver metastatic was treated with Palbociclib, had stable disease response and a drop in Epstein Barr virus (EBV) EBV titer. CONCLUSIONS: Our integrated information of sequencing-based genomic studies and tumor transcriptomes with drug treatment in NPC-PDX models provided guidelines for personalized precision treatments and revealed a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for NPC.

Cadherin 17 is related to recurrence and poor prognosis of cytokeratin 19-positive hepatocellular carcinoma.

A previous study demonstrated that cytokeratin 19 (CK19) expression in hepatocellular carcinoma (HCC) is an indicator of HCC invasiveness, including lymph node metastasis (LNM), tumor infiltration/non-encapsulation and poor prognosis. The exact mechanism by which CK19 expression results in poor prognosis remains unclear. Through the use of an Affymetrix U133A oligonucleotide microarray [20 patients with hepatitis B virus (HBV)-HCC], it was demonstrated that cadherin 17 (CDH17) significantly correlated with CK19 expression (R2, 0.867; P<0.001) in HBV-HCC. Immunohistochemical analysis (114 patients with HBV-HCC) also demonstrated a significant correlation between CK19 and CDH17 expressions in primary tumor tissue (R2, 0.414; P<0.001). In addition, CK19 and CDH17 expressions levels revealed a significant association with LNM (P<0.001). Cox regression multivariate analysis demonstrated that indocyanine green retention at 15 min >10% and CDH17 expression were independent prognostic factors for disease free survival (P=0.010 and 0.002, respectively). In vitro studies showed that epidermal growth factor can induce the expression of both CK19 and CDH17, and CDH17 in turn can enhance the expression of CK19 in HCC. In summary, this study demonstrated that the early recurrence and poor prognosis of CK19(+) HCC may be due to the expression of CDH17, a gene known to be associated with vascular invasion, tumor metastasis, and advanced tumor stage of HCC. Thus, novel therapeutics by targeting CDH17 may be beneficial for CK19(+) HCC.

Adjuvant Chemotherapy Improves Survival in Stage III Gastric Cancer after D2 Surgery.

Background: Stage III gastric cancer is characterized by locally advanced disease with varying anatomic extent as measured by the 7th edition of the American Joint Committee on Cancer (AJCC) staging system. There are no prognostic factors specifically identified in patients with stage III gastric cancer following extended lymph node dissection (D2) surgery. Materials and Methods: From 2007 to 2014, 534 patients with stage III gastric cancer underwent radical gastrectomy and D2 dissection at the Chang Gung Memorial Hospital. Patients' characteristics and the impact of adjuvant chemotherapy were analyzed using univariate and multivariate analyses to identify variables associated with overall survival (OS) and disease-free survival (DFS). Results: There were 320 deaths (60.0%) and 284 recurrences (53.2%) by the end of the study. The median OS and DFS were 30.7 months (95% confidence interval [CI]: 27.5-33.9) and 26.4 months (95% CI: 21.2-31.6), respectively. The multivariate analysis identified 7 variables that were independent prognostic factors both for OS and DFS including ratio of metastatic lymph nodes to total resection lymph nodes, carcinoembryonic antigen level, Eastern Cooperative Oncology Group performance status, gastrectomy method, vascular invasion, surgical margin, and adjuvant chemotherapy. Patients with stage IIIA-IIIC disease who received adjuvant chemotherapy had better OS and DFS outcomes than those who did not. Conclusions: Our study identified several independent prognostic factors that might help determine the appropriate counseling patients following surgical treatment. D2 surgery alone was inadequate to achieve long-term survival. As the only correctable independent prognostic factor, postoperative adjuvant chemotherapy should be recommended for eligible patients with stage III gastric cancer.

Clinical Factors Associated With Adherence to the Premedication Protocol for Withdrawal of Mechanical Ventilation in Terminally Ill Patients: A 4-Year Experience at a Single Medical Center in Asia.

PURPOSE: Data on end-of-life care practices in Asia are scarce. This study aimed to analyze the clinical factors associated with the recommended premedication protocol for mechanical ventilation withdrawal, in Taiwan. METHODS: A total of 135 terminally ill patients who had mechanical ventilation withdrawn between 2013 and 2016 from a single medical center in Taiwan were enrolled. A premedication protocol of morphine and midazolam intravenous bolus was routinely recommended for the patients before mechanical ventilation withdrawal. Receipt of opioids and/or benzodiazepines during the withdrawal process was defined as full (both), partial (1 drug), and no (none) adherence. The clinical factors relevant to the adherence of recommended premedication protocol for mechanical ventilation withdrawal were analyzed. RESULTS: Overall, 126 (93.3%) patients died, 8 (5.9%) patients were transferred to other institutions for further care, and 1 (0.7%) patient was discharged to home after mechanical ventilation withdrawal. The median survival time was 45 minutes, and 102 (75.6%) patients died within 1 day after the withdrawal process. The full, partial, and no adherence rates for premedication guideline were 17.8%, 40.0%, and 42.2%, respectively. The main diagnosis of cancer, receipt of hospice care, and preservation of spontaneous respiration were independent variables associated with the partial or full adherence to the premedication protocol. CONCLUSION: Our data show that adherence to the premedication protocol for mechanical ventilation withdrawal in terminally ill patients was inadequate in Taiwan. Promoting hospice care and educating medical personnel in the compassionate withdrawal of mechanical ventilation, especially in patients with noncancer disease, are warranted.

Characterization of a novel androgen receptor (AR) coregulator RIPK1 and related chemicals that suppress AR-mediated prostate cancer growth via peptide and chemical screening.

Using bicalutamide-androgen receptor (AR) DNA binding domain-ligand binding domain as bait, we observed enrichment of FxxFY motif-containing peptides. Protein database searches revealed the presence of receptor-interacting protein kinase 1 (RIPK1) harboring one FxxFY motif. RIPK1 interacted directly with AR and suppressed AR transactivation in a dose-dependent manner. Domain mapping experiments showed that the FxxFY motif in RIPK1 is critical for interactions with AR and the death domain of RIPK1 plays a crucial role in its inhibitory effect on transactivation. In terms of tissue expression, RIPK1 levels were markedly higher in benign prostate hyperplasia and non-cancerous tissue regions relative to the tumor area. With the aid of computer modeling for screening of chemicals targeting activation function 2 (AF-2) of AR, we identified oxadiazole derivatives as good candidates and subsequently generated a small library of these compounds. A number of candidates could effectively suppress AR transactivation and AR-related functions in vitro and in vivo with tolerable toxicity via inhibiting AR-peptide, AR-coregulator and AR N-C interactions. Combination of these chemicals with antiandrogen had an additive suppressive effect on AR transcriptional activity. Our collective findings may pave the way in creating new strategies for the development and design of anti-AR drugs.

Progesterone analogues reduce plasma Epstein-Barr virus DNA load and improve pain control in recurrent/metastatic nasopharyngeal carcinoma patients under supportive care.

BACKGROUND: Progesterone analogues, such as megestrol acetate (MA) and medroxyprogesterone (MPA), have been used for the palliative care of cancer cachexia for decades and have proven to increase body weight and improve quality of life and performance status. The objective of this study was to determine the effect of progesterone analogue use on quality of life in terms of pain control, performance status, body weight gain, and Epstein-Barr virus (EBV) DNA load in recurrent/metastatic nasopharyngeal carcinoma (NPC) patients. METHODS: We retrospectively enrolled 41 patients with locally recurrent or metastatic NPC who received MA or MPA for cachexia management between January 2007 and February 2014. Patients who underwent aggressive treatment with intravenous chemotherapy were excluded. Body weight, performance status, pain score, and plasma EBV DNA load were used to assess quality of life before and after MA/MPA treatment. RESULTS: Of the 41 patients, 33 patients (80.5%) experienced body weight gain after progesterone analogue intervention. A significant reduction in plasma EBV DNA load was noted after progesterone analogue use (p < 0.001). In addition, median pain and Karnofsky performance scores were also significantly improved in progesterone analogue responders compared with non-responders (4 vs. 1 and 70 vs. 80, respectively; p = 0.004 and p < 0.001, respectively). CONCLUSION: Progesterone analogues improve quality of life in terms of performance status, pain control, and plasma EBV DNA load in patients with locally recurrent/metastatic NPC under palliative care.