OBJECTIVE: To explore the risk factors for delayed excretion in adult acute lymphoblastic leukemia (ALL) patients treated with high-dose methotrexate (HD-MTX), and construct a risk prediction model to improve the safety of clinical medication. METHODS: From March 2010 to March 2023, 39 adult ALL patients who received 74 courses of HD-MTX chemotherapy in our hospital were analyzed retrospectively. The blood concentration of MTX was monitored by high-performance liquid chromatography (HPLC) at 0, 20 and 44 h after the end of MTX infusion. According to the MTX concentration of 44 h, the patients were divided into excretion delay group (≥0.3 μmol/L) and non-excretion delay group ( < 0.3 μmol/L), and the incidences of side effects were compared between the two groups. Clinical data and the results of laboratory test were collected. The risk factors associated with delayed MTX excretion were screened, and the independent risk factors for delayed excretion were identified by logistic regression analysis. A nomogram prediction model was established by R software based on the risk factors, and the predictive value of the model was also evaluated. RESULTS: A total of 27 courses of delayed excretion occurred in 74 courses of chemotherapy. As compared with the non-excretion delay group, the incidences of mucosal injury and nephrotoxicity increased significantly in the excretion delay group (both P <0.05). The dosage of MTX, blood uric acid level, and MTX peak concentration (i.e., blood drug concentration at 0 h after the end of MTX infusion) were independent factors influencing delayed MTX excretion. Based on these three independent factors, a nomogram prediction model was established for delayed MTX excretion. Calibration curve, concordance index (C-index), area under curve (AUC), and decision curve analysis showed that the model performed well. The model had showed good consistency and discrimination. CONCLUSION The incidence of delayed MTX excretion during HD-MTX chemotherapy in adult ALL patients is relatively high. The nomogram model based on the screened independent risk factors can be used to evaluate the risk of delayed excretion, timely identify individuals with high-risk of delayed excretion and adjust rescue measures combined with detection of MTX concentration to reduce the occurrence of side effects and ensure the safety of chemotherapy.
Humans ; Methotrexate/administration & dosage* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Retrospective Studies ; Risk Factors ; Adult ; Male ; Antimetabolites, Antineoplastic/therapeutic use* ; Female ; Nomograms ; Middle Aged

PURPOSE: Decitabine, a DNA hypomethylating agent, was recently approved for use in Korea for older adults with acute myeloid leukemia (AML) who are not candidates for standard chemotherapy. This study aimed to evaluate the role of decitabine as a first-line treatment for older adults with AML. MATERIALS AND METHODS: Twenty-four patients with AML who received at least one course of decitabine (20 mg/m²/d intravenously for 5 days every 4 weeks) as a first-line therapy at Severance Hospital were evaluated retrospectively. RESULTS: The median age of the patients was 73.5 years. The longest follow-up duration was 502 days. A total of 113 cycles of treatment were given to 24 patients, and the median number of cycles was four (range, 1–14). Thirteen patients dropped out because of death, no or loss of response, patient refusal, or transfer to another hospital. Twenty-one (87.5%) and 12 (50%) patients completed the second and fourth cycles, respectively, and responses to treatment were evaluated in 17. A complete response (CR) or CR with incomplete blood-count recovery was achieved in six (35.3%) patients, and the estimated median overall survival was 502 days. Ten patients developed grade >2 hematologic or non-hematologic toxicities. In univariate analysis, bone marrow blasts, lactate dehydrogenase, serum ferritin level, and bone marrow iron were significantly associated with response to decitabine. CONCLUSION: Five-day decitabine treatment showed acceptable efficacy in older patients with AML who are unfit for conventional chemotherapy, with a CR rate 35.3% and about a median overall survival of 18 months.
Aged ; Antimetabolites, Antineoplastic/administration & dosage/*therapeutic use ; Azacitidine/*analogs & derivatives/therapeutic use ; DNA Methylation ; Female ; Humans ; Leukemia, Myeloid, Acute/*drug therapy/mortality ; Male ; Middle Aged ; Remission Induction ; Republic of Korea ; Retrospective Studies ; Treatment Outcome

OBJECTIVEThe aim of this study was to explore the effect of SPARC on the anti-cancer effect of gemcitabine and underlying mechanism in pancreatic cancer.

METHODSAfter treating with gemcitabine, the proliferation rate of MIA PaCa2, MIA PaCa2/V and MIA PaCa2/SPARC69 cells was detected by MTT assay. The cell cycle distribution and cell apoptosis in each group were examined by flow cytometry, and the capability of clone formation was tested by adhesion-dependent clone formation assay. The apoptosis-related proteins were analyzed by Western blot.

RESULTSThe growth of pancreatic cancer cells was inhibited by gemcitabine in a time-dependent and dose-dependent manner. Its IC50 at 24, 48, and 72-h was (40.1 ± 2.5) µmol/L, (15.0 ± 0.5) µmol/L and (6.6 ± 0.1) µmol/L, respectively. The overexpression of SPARC increased the inhibitory effect of gemcitabine on growth of pancreatic cancer MIA PaCa2/SPARC69 cells, presenting a dose- and time- dependent manner. Its IC50 at 24, 48, 72 h was (24.3 ± 1.5) µmol/L, (7.7 ± 0.3) µmol/L and (4.8 ± 0.2) µmol/L, respectively. The clone formation assay showed that before gemcitabine treatment, the clone numbers of MIA PaCa2, MIA PaCa2/V and MIA PaCa2/SPARC69 cells were (2350 ± 125), (2130 ± 120) and (1567 ± 11), respectively. After gemcitabine treatment, the clone numbers of MIA PaCa2, MIA PaCa2/V and MIA PaCa2/SPARC69 cells were ( 1674 ± 79) , (1587 ± 94) and (557 ± 61), respectively. The overexpression of SPARC enhanced the chemosensitivity of MIA PaCa2 cells to gemcitabine chemotherapy. After treating with 10 µmol/L gemcitabine for 48 h, the ratio of G0/G1 cells in MIA PaCa2, MIA PaCa2/V and MIA PaCa2/SPARC69 cells were (56.0 ± 5.5)%, (55.0 ± 4.5)% and (68.0 ± 7.0)%, respectively. The cells arrested at G0/G1 phase were significantly increased in the MIA PaCa2/SPARC69 cells. The apoptosis rates of MIA PaCa2, MIA PaCa2/V and MIA PaCa2/SPARC69 cells were (22.4 ± 2.5)%, (19.9 ± 2.0)% and (37.7 ± 3.9)%, respectively, indicating that overexpression of SPARC enhanced the gemcitabine-induced apoptosis in MIA PaCa2 cells. The Western blot analysis showed that, compared with MIA PaCa2 and MIA PaCa2/V cells, the expression of caspase-2, -8, -9 and cleaved PARP protein was significantly increased, while the expression of Bcl-2 was not changed significantly in the MIA PaCa2/SPARC69 cells.

CONCLUSIONSPARC can enhance the chemosensitivity of pancreatic cancer cells to gemcitabine via regulating the expression of apoptosis-related proteins.

Antimetabolites, Antineoplastic ; administration & dosage ; pharmacology ; Apoptosis ; drug effects ; Caspase 2 ; metabolism ; Caspase 8 ; metabolism ; Caspase 9 ; metabolism ; Cell Cycle ; drug effects ; Cell Cycle Checkpoints ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cysteine Endopeptidases ; metabolism ; Deoxycytidine ; administration & dosage ; analogs & derivatives ; pharmacology ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm ; Humans ; Osteonectin ; metabolism ; Pancreatic Neoplasms ; metabolism ; pathology ; Poly(ADP-ribose) Polymerases ; metabolism ; Time Factors

PURPOSE: For locally unresectable hepatocellular carcinoma (HCC) patients, concurrent chemoradiotherapy (CCRT) has been applied as a loco-regional treatment. After shrinkage of tumors in selected patients, surgical resection is performed. The aim of this study was to evaluate prognostic factors and long-term survivors in such patients. MATERIALS AND METHODS: From January 2000 to January 2009, 264 patients with HCC were treated with CCRT (45 Gy with fractional dose of 1.8 Gy), and intra-arterial chemotherapy was administered during radiotherapy. Eighteen of these patients (6.8%) underwent hepatic resection after showing a response to CCRT. Cases were considered resectable when tumor-free margins and sufficient remnant volumes were obtained without extrahepatic metastasis. Prior to operation, there were six patients with complete remission, 11 with partial remission, and six with stable disease according to modified Response Evaluation Criteria in Solid Tumors. RESULTS: In pathologic review, four patients (22.2%) showed total necrosis and seven patients (38.9%) showed 70-99% necrosis. A high level of necrosis (> or =80%) was correlated with low risk for extrahepatic metastasis and long-term survival. In univariate analyses, vessel invasion and capsular infiltration were significantly correlated with disease free survival (DFS) (p=0.017 and 0.013, respectively), and vessel invasion was significantly correlated with overall survival (OS) (p=0.013). In multivariate analyses, capsule infiltration was a significant factor for DFS (p=0.016) and vessel invasion was significant for OS (p=0.015). CONCLUSION: CCRT showed favorable responses and locally advanced HCC converted into resectable tumor after CCRT in selected patients. Long-term survivors showed the pathological features of near total necrosis, as well as negative capsule and vessel invasion.
Adult ; Aged ; Antimetabolites, Antineoplastic/administration & dosage ; Antineoplastic Agents/administration & dosage ; Carcinoma, Hepatocellular/mortality/pathology/*therapy ; Chemoradiotherapy/*methods ; Cisplatin/administration & dosage ; Disease-Free Survival ; Female ; Fluorouracil/administration & dosage ; Humans ; Liver Neoplasms/mortality/pathology/*therapy ; Male ; Middle Aged ; Prognosis ; Radiotherapy, Conformal ; Remission Induction ; Republic of Korea/epidemiology ; *Salvage Therapy ; Survival Rate ; Treatment Outcome ; Tumor Burden

This study was aimed to investigate the effects of the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-Aza-CdR) and histone deacetylase inhibitor trichostatin A (TSA) on DLC-1 gene transcription regulation and molecular biological behaviours in the human multiple myeloma RPMI-8226 cells. The cells were treated respectively with 5-Aza-CdR and TSA alone, or the both combination; the cell proliferation and apoptosis, DLC-1 expression, the protein expression of Ras homolog family member A (RhoA) and Ras-related C3 botulinum toxin substrate 1 (Rac1) were examined by CCK-8 method, RT-PCR and ELISA, respectively. The results showed that the 5-Aza-CdR and TSA had cell growth inhibitory and apoptosis-inducing effects in dose-dependent manner (P < 0.05). Compared with a single drug (5-Aza-CdR or TSA alone), the effects were significantly enhanced after treatment with the combination of 5-Aza-CdR and TSA (P < 0.05). DLC-1 was weakly expressed in the control group; the treatment with 5-Aza-CdR alone enhanced its re-expression dose-dependently (P < 0.05). Compared with 5-Aza-CdR alone, 5-Aza-CdR plus TSA enhanced DLC-1 re-expression significantly.Compared with the control, 5-Aza-CdR and TSA significantly decreased RhoA and Rac1 protein expression (P < 0.05). It is concluded that 5-Aza-CdR and TSA can effectively reverse DLC-1 expression of RPMI-8226 cells; TSA has a synergistic effect on its re-expression. 5-Aza-CdR and TSA have significant cell growth inhibitory and apoptosis-inducing effects on RPMI-8226 cells. These effects may be related to the inhibition of Rho/Rho kinase signalling pathway.
Antimetabolites, Antineoplastic ; pharmacology ; Apoptosis ; drug effects ; Azacitidine ; administration & dosage ; analogs & derivatives ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; GTPase-Activating Proteins ; metabolism ; Gene Expression ; drug effects ; Humans ; Hydroxamic Acids ; administration & dosage ; pharmacology ; Multiple Myeloma ; genetics ; pathology ; Tumor Suppressor Proteins ; metabolism

OBJECTIVETo evaluate the efficacy and safety of fixed dose rate (FDR) gemcitabine infusion in combination with docetaxel in patients with relapsed/refractory soft tissue sarcoma.

METHODSClinicopathological data of 28 patients with relapsed/refractory soft tissue sarcoma treated in our hospital from April 2008 to August 2013 were reviewed in this study. The patients received 900 mg/m² gemcitabine with a FDR infusion (10 mg/m²/min) in a total dose of 900 mg/m² on days 1 and 8, and 75 mg/m² docetaxel intravenously over 60 min on day 8 of a 21-day cycle. When irradiation was conducted before drug therapy, the dose of gemcitabine was reduced to 675 mg/m² on days 1 and 8. The clinicopathological characteristics, short-term response, long-term survival status and toxicity were analyzed retrospectively.

RESULTSThe 28 patients received a total of 118 cycles of therapy (range 1-8 cycles, median 4 cycles per patient). No patient achieved complete response (CR), 4 partial responses (PR) and 11 stable diseases (SD), with an overall response rate (ORR) of 14.3% and clinical benefit rate (CBR) of 53.6%. The median progression-free survival (PFS) was 3.2 months and the median overall survival (OS) was 8.5 months. PFS and OS were correlated with the response to this treatment regimen (P < 0.0001). Patients with clinical benefit had significantly better PFS and OS than the patients with progressive disease (P < 0.05 for all). The ORR, CBR, PFS and OS were better in patients with leiomyosarcoma than in patients with other histological subtypes in this study, but the differences were not significant (P > 0.05 for all). Grade 3-4 neutropenia, anemia and thrombocytopenia were 50.0%, 17.9% and 14.3%, respectively. Only one patient (3.6%) had febrile neutropenia. Grade 3 non-hematologic toxicities were nausea/vomiting (3.6%) and mucositis (3.6%). No grade 4 non-hematologic toxicities were observed. Almost all non-hematologic toxicities were grade 1-2 and manageable.

CONCLUSIONSThe fixed dose rate (FDR) gemcitabine infusion in combination with docetaxel is an effective treatment regimen for patients with relapsed/refractory soft tissue sarcoma, and with tolerable adverse reactions.

Antimetabolites, Antineoplastic ; administration & dosage ; therapeutic use ; Antineoplastic Agents ; administration & dosage ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Deoxycytidine ; administration & dosage ; analogs & derivatives ; therapeutic use ; Disease-Free Survival ; Humans ; Leiomyosarcoma ; drug therapy ; Neoplasm Recurrence, Local ; drug therapy ; Neutropenia ; Retrospective Studies ; Sarcoma ; drug therapy ; Taxoids ; administration & dosage ; therapeutic use ; Treatment Outcome

OBJECTIVETo investigate the postoperative adverse events and survival of patients with sustained-released fluorouracil implanted during operation.

METHODSData of 124 patients with advanced gastric cancer undergoing radical operation in Tianjin Medical University Cancer Institute and Hospital from January 2007 to January 2009 were analyzed retrospectively. All the patients were divided into two groups according to whether intra-operative fluorouracil was implanted or not. The treatment group(n=64) was implanted with fluorouracil in abdominal cavity after radical resection. The control group(n=60) did not receive fluorouracil implant in abdominal cavity after radical resection. Abdominal drainage fluid, temperature and adverse events within 15 postoperative days and 3-year survival were observed and compared between the two groups.

RESULTSPathological findings of the two groups were similar. No statistical significances existed in abdominal drainage fluid, temperature and adverse events within 15 postoperative days(P>0.05). The 3-year survival rate was higher in treatment group(64.3% vs. 42.4%, P=0.018).

CONCLUSIONIntra-operative sustained-released fluorouracil implants are safe and tolerable, and can improve the survival rate of patients with advanced gastric cancer.

Abdominal Cavity ; Antimetabolites, Antineoplastic ; administration & dosage ; therapeutic use ; Fluorouracil ; administration & dosage ; therapeutic use ; Humans ; Retrospective Studies ; Stomach Neoplasms ; drug therapy ; surgery ; Survival Rate

BACKGROUND: Aggressive fibromatosis is a rare but invasive tumor infiltrating widely between fascia and muscle fibers. It has a high tendency to be locally recurrent despite complete resection. Effectiveness of adjuvant treatment for aggressive fibromatosis including radiotherapy, pharmacological agents, hormonal treatments, and chemotherapy have been previously reported. The purpose of this article was to collect and analyze all information regarding the effectiveness and side effects of oral methotrexate in aggressive fibromatosis. METHODS: From 2005 to 2011, eleven patients with aggressive fibromatosis treated with oral methotrexate at our institution were analyzed in this study. Oral methotrexate was administered once per week at 10 mg per week. Authors collected information about effectiveness concerning cases of local recurrence and metastasis. RESULTS: Eleven patients had remission, two patients had local recurrence. Fatal complications or toxicity were not observed. CONCLUSIONS: Oral methotrexate given at this dose and schedule was considered as a useful treatment in primary inoperable fibromatosis and recurrent fibromatosis.
Administration, Oral ; Adolescent ; Adult ; Aged ; Antimetabolites, Antineoplastic/*administration & dosage ; Child ; Female ; Fibromatosis, Aggressive/*drug therapy/surgery ; Humans ; Male ; Methotrexate/*administration & dosage ; Middle Aged ; Neoplasm Recurrence, Local/*drug therapy/surgery ; Retrospective Studies ; Young Adult

For patients with unresectable pancreatic cancer, current chemotherapies have negligible survival benefits. Thus, developing effective minimally invasive therapies is currently underway. This study was conducted to evaluate the efficacy of transarterial chemoembolization plus radiofrequency ablation and/or 125I radioactive seed implantation on unresectable pancreatic cancer. We analyzed the outcome of 71 patients with unresectable pancreatic carcinoma who underwent chemoembolization plus radiofrequency ablation and/or radioactive seed implantation. Of the 71 patients, the median survival was 11 months, and the 1-, 2-, and 3-year overall survival rates were 32.4%, 9.9%, and 6.6%, respectively. Patients who had no metastasis, who had oligonodular liver metastases (≤3 lesions), and who had multinodular liver metastases (>3 lesions) had median survival of 12, 18, and 8 months, respectively, and 1-year overall survival rates of 50.0%, 68.8%, and 5.7%, respectively. Although the survival of patients without liver metastases was worse than that of patients with oligonodular liver metastasis, the result was not significant (P = 0.239). In contrast, the metastasis-negative patients had significantly better survival than did patients with multinodular liver metastases (P < 0.001). Patients with oligonodular liver lesions had a significant longer median survival than did patients with multinodular lesions (P < 0.001). In conclusion, combined minimally invasive therapies had good efficacy on unresectable pancreatic cancer and resulted in a good control of liver metastases. In addition, the number of liver metastases was a significant factor in predicting prognosis and response to treatment.
Antimetabolites, Antineoplastic ; administration & dosage ; Brachytherapy ; methods ; Catheter Ablation ; methods ; Chemoembolization, Therapeutic ; methods ; Deoxycytidine ; administration & dosage ; analogs & derivatives ; Female ; Follow-Up Studies ; Humans ; Iodine Radioisotopes ; Liver Neoplasms ; radiotherapy ; secondary ; surgery ; therapy ; Lymphatic Metastasis ; Male ; Middle Aged ; Pancreatic Neoplasms ; pathology ; radiotherapy ; surgery ; therapy ; Remission Induction ; Survival Rate

Phosphatidylinositide 3-kinase (PI3K)/protein kinase B (PKB, Akt) pathway plays a major role in proliferation and survival of many types of cells. The inhibitory effect of LY294002, widely applied as an inhibitor of PI3K, in combination with gemcitabine on proliferation of PANC-1 cells was investigated. The expression of PI3K, phosphorylated Akt (p-Akt) and multidrug-resistance like protein (MRP) in normal pancreas tissues, chronic pancreatitis tissues and pancreatic carcinoma tissues was detected. The effects of LY294002 combined with gemcitabine on proliferation of PANC-1 cells and protein levels of p-Akt and MRP were detected. The results showed that the positive expression rate of PI3K, p-Akt and MRP in pancreatic carcinoma tissues was significantly higher than that in normal pancreas tissues and chronic pancreatitis tissues (P<0.01 and P<0.05 respectively). LY294002 could effectively enhance the inhibitory effect of gemcitabine on proliferation of PANC-1 cells. Furthermore, Western blotting revealed that LY294002 combined with gemcitabine reduced the protein levels of p-Akt and MRP, which contributed to the inhibition of proliferation. It is concluded that LY294002 in combination with gemcitabine may represent an alternative therapy for pancreatic carcinoma.
Adult ; Antimetabolites, Antineoplastic ; administration & dosage ; Cell Proliferation ; drug effects ; Chromones ; administration & dosage ; Deoxycytidine ; administration & dosage ; analogs & derivatives ; Dose-Response Relationship, Drug ; Drug Synergism ; Drug Therapy, Combination ; methods ; Enzyme Inhibitors ; administration & dosage ; Female ; Humans ; Male ; Middle Aged ; Morpholines ; administration & dosage ; Pancreatic Neoplasms ; drug therapy ; pathology ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; Treatment Outcome ; Tumor Cells, Cultured