OBJECTIVE: To investigate the anti-tumor effects of cinobufacini (CINO) on hepatocellular carcinoma (HCC) induced by des-gamma-carboxy-prothrombin (DCP) and to uncover the underlying mechanisms. METHODS: The inhibitory effect of CINO on HCC cell proliferation was evaluated using the cell counting kit-8 method, and the apoptosis rate was quantified using flow cytometry. Immunofluorescence and Western blot analyses were used to investigate the differential expression of proteins associated with cell growth, apoptosis, migration, and invasion pathways after CINO treatment. The therapeutic potential of CINO for HCC was confirmed, and the possibility of combining cinobufacini with c-Met inhibitor for the treatment of primary HCC was further validated by in vivo experiments. RESULTS: Under the induction of DCP, CINO inhibited the activity of HCC cells, induced apoptosis, and inhibited migration and invasion. Upon the induction of DCP, CINO regulated c-Met activation and the activation of the phosphatidylinositol-3 kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathways. In a mouse model of HCC, CINO exhibited significant antitumor effects by inhibiting the phosphorylation of c-Met and the downstream PI3K/AKT and MEK/ERK pathways in tumor tissues. CONCLUSIONS CINO inhibited HCC cell growth, promoted apoptosis, and suppressed HCC cell invasion and migration by targeting c-Met and PI3K/AKT and MEK/ERK signaling pathways under DCP induction.
Carcinoma, Hepatocellular/drug therapy* ; Proto-Oncogene Proteins c-met/metabolism* ; Liver Neoplasms/drug therapy* ; Signal Transduction/drug effects* ; Animals ; Humans ; Cell Movement/drug effects* ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Amphibian Venoms/therapeutic use* ; Cell Line, Tumor ; Neoplasm Metastasis ; Cell Survival/drug effects* ; Proto-Oncogene Proteins c-akt/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Neoplasm Invasiveness ; Mice, Inbred BALB C ; Mice, Nude ; Mice ; Male ; Bufanolides/therapeutic use* ; Protein Precursors ; Prothrombin ; Biomarkers

Brain metastasis (BM) is the leading cause of mortality in lung cancer patients. The process of BM (from initial primary tumor development, migration and intravasation, dissemination and survival in the bloodstream, extravasation, to colonization and growth to metastases) is a complex process for which few tumor cells complete the entire process. Recent research on BM of lung cancer has recently stressed the essential role of tumor microenvironment (TME) in assisting tumor cells in the completion of each BM step. This review summarizes recent studies regarding the effects of TME on tumor cells in the entire process of BM derived from lung cancer. The identification of vulnerable targets in the TME and their prospects to provide novel therapeutic opportunities are also discussed.
Brain Neoplasms/pathology* ; Humans ; Lung Neoplasms/drug therapy* ; Neoplasm Metastasis ; Tumor Microenvironment

OBJECTIVE: To retrospectively evaluate the safety and efficacy of percutaneous radiofrequency ablation (RFA) in patients with metachronous hepatic metastases arising from pancreatic adenocarcinoma who had previously received curative surgery.MATERIALS AND METHODS: Between 2002 and 2017, percutaneous RFA was performed on 94 metachronous hepatic metastases (median diameter, 1.5 cm) arising from pancreatic cancer in 60 patients (mean age, 60.5 years). Patients were included if they had fewer than five metastases, a maximum tumor diameter of ≤ 5 cm, and disease confined to the liver or stable extrahepatic disease. For comparisons during the same period, we included 66 patients who received chemotherapy only and met the same eligibility criteria described.RESULTS: Technical success was achieved in all hepatic metastasis without any procedure-related mortality. During follow-up, local tumor progression of treated lesions was observed in 38.3% of the tumors. Overall median survival and 3-year survival rates were 12 months and 0%, respectively from initial RFA, and 14.7 months and 2.1%, respectively from the first diagnosis of liver metastasis. Multivariate analysis showed that a large tumor diameter of > 1.5 cm, a late TNM stage (≥ IIB) before curative surgery, a time from surgery to recurrence of < 1 year, and the presence of extrahepatic metastasis, were all prognostic of reduced overall survival after RFA. Median overall (12 months vs. 9.1 months, p = 0.094) and progression-free survival (5 months vs. 3.3 months, p = 0.068) were higher in the RFA group than in the chemotherapy group with borderline statistical difference.CONCLUSION: RFA is safe and may offer successful local tumor control in patients with metachronous hepatic metastases arising from pancreatic adenocarcinoma. Patients with a small diameter tumor, early TNM stage before curative surgery, late hepatic recurrence, and liver-only metastasis benefit most from RFA treatment. RFA provided better survival outcomes than chemotherapy for this specific group with borderline statistical difference.
Adenocarcinoma ; Catheter Ablation ; Diagnosis ; Disease-Free Survival ; Drug Therapy ; Follow-Up Studies ; Humans ; Liver ; Mortality ; Multivariate Analysis ; Neoplasm Metastasis ; Pancreatic Neoplasms ; Recurrence ; Retrospective Studies ; Survival Rate

OBJECTIVE: Pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising antitumor activity and acceptable tolerability in phase II and phase III randomized clinical trials. We assessed the activity and safety of oral pyrotinib for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer patients in the real world. METHODS: We retrospectively analyzed 72 HER2 positive metastatic breast cancer (MBC) patients who received oral pyrotinib based regimens at Beijing Cancer Hospital and other four hospitals (Peking University First Hospital, China-Japan Friendship Hospital, General Hospital of PLA, Peking University Third Hospital) from August 2018 to September 2019. Progression free survival (PFS), objective response rate (ORR), adverse events (AE) of pyrotinib were investigated. RESULTS: Seventy-two patients with HER2 positive MBC were enrolled. The median age of the patients was 55 years (range: 32-79 years). Sixty-nine (95.8%) patients had received anti-HER2 treatment in the metastatic and/or (neo) adjuvant settings; 61 (84.7%) patients had received anti-HER2 treatments in the metastatic setting in terms of trastuzumab 56 (77.8%) patients, lapatinib 36 (50.0%) patients, and T-DM1 4 (5.6%) patients. Among these 72 patients who received oral pyrotinib based regimens, 62 (86.1%) patients received pyrotinib (±trastuzumab) in combination with chemotherapy, 6 (8.3%) patients received pyrotinib (± trastuzumab) in combination with endocrine therapy and 4 (5.6%) patients received pyrotinib (±trastuzumab). Sixty-five (90.3%) patients received 400 mg pyrotinib once daily as initial dose, and 7 (9.7%) patients received 320 mg. OBJECTIVE response and safety to pyrotinib based therapy were evaluable in all the 72 patients. One (1.4%) patient achieved complete response (CR), 18 (25.0%) patients achieved partial response (PR), 41 (56.9%) patients had stable disease (SD), and 12 (16.7%) patients had progressive disease (PD). The ORR (CR+PR) was 26.4% and the median PFS was 7.6 months (95%CI: 5.5-9.7 months). Among the 36 patients with prior lapatinib therapy, the median PFS was 7.9 months (95%CI: 4.1-11.7 months). Among the 15 patients with brain metastasis, the median PFS was 6.0 months (95%CI: 2.2-9.8 months). The main toxicities related to pyrotinib were diarrhea in 57 (79.2%) cases, and 48 (66.7%) cases with grade 1-2 as well as 9 (12.5%) cases with grade 3. CONCLUSION Pyrotinib based therapy is an effective treatment for patients with HER2 positive MBC, including patients with lapatinib treatment failure and brain metastasis, and the toxicities can be tolerated.
Acrylamides/therapeutic use* ; Adult ; Aged ; Aminoquinolines/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols ; Breast Neoplasms/drug therapy* ; China ; Humans ; Middle Aged ; Neoplasm Metastasis ; Receptor, ErbB-2 ; Retrospective Studies ; Trastuzumab ; Treatment Outcome

metastasis stage, differentiation, invasion depth, and lymph node metastasis (p< 0.005). ProGRP levels were significantly decreased after chemotherapy (p<0.001). Receiver operating characteristic curves revealed a sensitivity and specificity for serum ProGRP in GC of 85.9% and 81.2%, respectively. ProGRP levels were positively correlated with CA72-4 and CEA (r=0.792 and 0.688, p<0.05, respectively). Combined detection of ProGRP, CEA, and CA72-4 showed the best diagnostic power for GC.CONCLUSION: ProGRP may be useful as a potential biomarker for GC diagnosis and therapy.]]>
Carcinoembryonic Antigen ; Diagnosis ; Drug Therapy ; Humans ; Lymph Nodes ; Male ; Neoplasm Metastasis ; ROC Curve ; Sensitivity and Specificity ; Stomach Diseases ; Stomach Neoplasms

PURPOSE: The purpose of this study was to evaluate the risk of central nervous system (CNS) failure in Korean patients with human epidermal growth factor receptor 2 (HER2)-enriched breast cancer treated with surgery followed by postoperative radiotherapy (RT). METHODS: A total of 749 patients from eight institutions were enrolled in this study. All of them underwent surgery followed by postoperative RT from 2003 to 2011; 246 (32.8%) received neoadjuvant chemotherapy and 649 (81.7%) received adjuvant chemotherapy. Adjuvant trastuzumab was administered to 386 patients (48.6%). RESULTS: The median follow-up duration was 84 (range, 8–171) months. The 7-year disease-free and overall survival rates were 79.0% and 84.2%, respectively. On multivariate analysis, mastectomy, nodal involvement, and presence of lymphatic invasion were correlated with poor overall survival (p = 0.004, 0.022, and 0.011, respectively), whereas T stage and lymphatic invasion were associated with disease-free survival (p = 0.018 and 0.005, respectively). Regarding CNS failures, 30 brain metastases, 2 leptomeningeal metastases, and 8 brain and leptomeningeal metastases were noted. The 7-year CNS relapse-free survival rates in patients receiving and not receiving trastuzumab were 91.2% and 96.9%, respectively (p = 0.005). On multivariate analysis, the administration of adjuvant trastuzumab was the only prognostic factor in predicting a higher CNS failure rate (hazard ratio, 2.260; 95% confidence interval, 1.076–4.746; p = 0.031). CONCLUSION: Adjuvant trastuzumab was associated with higher CNS failure rate in Korean patients with HER2-enriched breast cancer. Close monitoring and reasonable approaches such as CNS penetrating HER2 blockades combined with the current standard therapy could contribute to improving intracranial tumor control and quality of life in patients with CNS metastasis from HER2-enriched breast cancer.
Brain ; Breast Neoplasms ; Breast ; Central Nervous System Neoplasms ; Central Nervous System ; Chemotherapy, Adjuvant ; Disease-Free Survival ; Drug Therapy ; Follow-Up Studies ; Humans ; Mastectomy ; Multivariate Analysis ; Neoplasm Metastasis ; Quality of Life ; Radiation Oncology ; Radiotherapy ; Receptor, Epidermal Growth Factor ; Retrospective Studies ; Survival Rate ; Trastuzumab

PURPOSE: Many patients with cytology proven node-positive breast cancer receive a neoadjuvant chemotherapy (NAC) treatment. We developed a nomogram to predict the breast and axillary pathologic complete responses (pCR) in patients with a cytologically proven axillary node positive breast cancer with NAC. METHODS: We selected 995 patients who were diagnosed with an invasive breast cancer and axillary lymph nodes metastasis, and who were treated with NAC followed by a curative surgery at the Samsung Medical Center between January 2007 and December 2014. The baseline patient and tumor characteristics, chemotherapy regimen, and tumor and nodal responses were thoroughly analyzed and reviewed. A nomogram was developed using a binary logistic regression model with a cross validation. RESULTS: Axillary pCR was achieved in 47.3% and breast pCR was achieved in 24.3% of the patients after NAC. In this case, the both pCR was associated with an initial clinical tumor stage, negative progesterone receptor status, positive human epidermal growth factor receptor 2 status, and clinical radiologic nodal responses. A nomogram was developed based on the clinical and statistically significant predictors. It had good discrimination performance (area under the curve [AUC], 0.868; 95% confidence interval, 0.84–0.89) and calibration fit as noted in that case. The cross validation had an average AUC 0.853 (0.837–0.869). CONCLUSION: Our nomogram might help to predict breast and axillary pCRs after NAC in patients with an initially node-positive breast cancer. Minimal surgery might be acceptable in patients for whom the nomogram indicates a high probability of achieving pCRs.
Area Under Curve ; Breast Neoplasms ; Breast ; Calibration ; Discrimination (Psychology) ; Drug Therapy ; Humans ; Logistic Models ; Lymph Nodes ; Neoadjuvant Therapy ; Neoplasm Metastasis ; Nomograms ; Polymerase Chain Reaction ; Receptor, Epidermal Growth Factor ; Receptors, Progesterone

OBJECTIVE: To examine outcomes of patients having treatments for newly diagnosed advanced stage low-grade serous ovarian cancer (LGSC). METHODS: We conducted a retrospective case series of women affected by advanced stage (stage IIIB or more) LGSC undergoing surgery in a single oncologic center between January 2000 and December 2017. Survival outcomes were assessed using Kaplan-Meier and Cox models. RESULTS: Data of 72 patients were retrieved. Primary cytoreductive surgery was attempted in 68 (94.4%) patients: 19 (27.9%) had residual disease (RD) >1 cm after primary surgery. Interval debulking surgery (IDS) was attempted in 15 of these 19 (78.9%) patients and the remaining 4 patients having not primary debulking surgery. Twelve out of 19 (63.1%) patients having IDS had RD. After a mean (±standard deviation) follow-up was 61.6 (±37.2) months, 50 (69.4%) and 22 (30.5%) patients recurred and died of disease, respectively. Via multivariate analysis, non-optimal cytoreduction (hazard ratio [HR]=2.79; 95% confidence interval [CI]=1.16–6.70; p=0.021) and International Federation of Obstetrics and Gynecologists (FIGO) stage IV (HR=3.15; 95% CI=1.29–7.66; p=0.011) were associated with worse disease-free survival. Via multivariate analysis, absence of significant comorbidities (HR=0.56; 95% CI=0.29–1.10; p=0.093) and primary instead of IDS (HR=2.95; 95% CI=1.12–7.74; p=0.027) were independently associated with an improved overall survival. CONCLUSION: LGSC is at high risk of early recurrence. However, owing to the indolent nature of the disease, the majority of patients are long-term survivors. Further prospective studies and innovative treatment modalities are warranted to improve patients care.
Comorbidity ; Cytoreduction Surgical Procedures ; Disease-Free Survival ; Drug Therapy ; Female ; Follow-Up Studies ; Gynecologic Surgical Procedures ; Humans ; Multivariate Analysis ; Neoplasm Metastasis ; Obstetrics ; Ovarian Neoplasms* ; Proportional Hazards Models ; Prospective Studies ; Recurrence ; Retrospective Studies ; Survivors

BACKGROUND/AIMS: This study was conducted to identify risk factors that predict vulnerability to cancer therapy on the basis of the clinical, geriatric, and quality of life assessment before starting treatment in elderly patients. METHODS: Seventy-five patients aged 65 years and over with newly diagnosed stage IV solid cancer receiving chemotherapy were analyzed. Clinical and laboratory data were collected. The geriatric assessment was performed using the Korean versions of the Modified Barthel Index, Instrumental Activities of Daily Living, Mini-Mental State Examination, and Geriatric Depression Scale. The European Organisation for Research and Treatment of Cancer Quality-of-Life Core Questionnaire (EORTC-QLQ-C30) was also performed. RESULTS: Forty-one patients stopped cancer treatment during or after the end of first-line therapy and were classified as the treatment interruption group. By univariate analysis, treatment interruption was associated with metastases to ≥ 2 distant sites, lower albumin level, lower EORTC-QLQ-C30 physical and role functioning scores, and higher EORTC-QLQ-C30 fatigue and appetite loss symptom scores. By multivariate analysis, treatment interruption was significantly associated with low score for the EORTC-QLQ-C30 physical functioning scale (odds ratio [OR], 1.020; 95% confidence interval [CI], 1.002 to 1.039; p = 0.030), and ≥ 2 sites of distant metastases (OR, 2.965; 95% CI, 1.012 to 8.681; p = 0.047). CONCLUSIONS: The EORTC-QLQ-C30 physical functioning score and metastases to ≥ 2 organs, which indicate a poor physical functional status and metastatic high tumor burden, were significantly associated with interruption of first-line treatment in elderly patients with cancer.
Activities of Daily Living ; Aged* ; Appetite ; Depression ; Drug Therapy ; Fatigue ; Geriatric Assessment ; Humans ; Multivariate Analysis ; Neoplasm Metastasis ; Quality of Life ; Risk Factors ; Tumor Burden

OBJECTIVES: We conducted a protocol-based cohort study to evaluate the outcomes of interval debulking surgery (IDS) followed by paclitaxel-based hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of advanced-stage ovarian cancer. METHODS: From October 2015 to May 2018, 65 patients with stages IIIC–IV ovarian cancer were treated according to the study protocol. HIPEC was performed with paclitaxel (175 mg/m2) for 90 minutes, only in cases of optimal cytoreduction. RESULTS: Of 65 patients, 40 (61.5%) patients underwent neoadjuvant chemotherapy (NAC), 34 (52.3%) patients had a high tumor burden with a Fagotti score ≥8 at diagnostic laparoscopy, and 6 (9.2%) had definite stage IV metastasis and/or poor performance status before NAC. Twenty-seven (41.5%) patients underwent IDS followed by HIPEC. The mean duration of IDS with HIPEC was 543.8 (range, 277.0–915.0) minutes. Grade III/IV perioperative complications occurred in 7.4% (n=2)/3.7% (n=1) of patients and no cases of mortality were reported within 30 days postoperatively. The median progression-free survival was 21.3 months, and the median overall survival was not reached for those who received HIPEC. CONCLUSIONS: According to our study protocol, IDS followed by paclitaxel-based HIPEC as a first-line treatment appears to be feasible and safe for the treatment of advanced-stage ovarian cancer. Further evaluations of this procedure are required to assess its survival benefits.
Cohort Studies ; Disease-Free Survival ; Drug Therapy* ; Humans ; Laparoscopy ; Mortality ; Neoplasm Metastasis ; Ovarian Neoplasms* ; Paclitaxel ; Pilot Projects* ; Tumor Burden