The risks and trends of cardiac-specific mortality associated with chemotherapy or radiotherapy in a large cohort of non-elderly patients with non-small cell lung cancer.

BACKGROUND: Anticancer treatment-related heart events is a major concern. However, the frequent occurrence time of cardiac death and the association between cardiac-specific mortality (CSM) and various lung lobes among non-elderly non-small cell lung cancer (NSCLC) patients after chemotherapy or radiotherapy (RT) are uncertain. METHODS: Data of patients aged 20-59 years and diagnosed with NSCLC during 1975-2014 were extracted from the Surveillance, Epidemiology and End Results (SEER) database. We divided them into four groups: no chemotherapy or RT, chemotherapy-only, RT-only and chemoradiation therapy (CRT). The Fine and Gray model was applied to evaluate the risks; the cumulative curves of CSM were established by Gray's test. Furthermore, the forest graphs delineated the hazards of different tumor subsites to CSM as the survival time prolonged. Eventually, we analyzed and elucidated the tendency of CSM decade by decade. RESULTS: We identified 121,302 patients and 3,423 died of heart diseases. In chemotherapy-only group, age, sex, race, marital status and surgery were significantly correlated to CSM while the subsite location of tumor was the key risk among RT-only patients. The hazard ratio (HR) of CSM was greatest in 2-5 years after RT (P=0.008, HR =2.30). CSMs of chemotherapy (P=0.130, HR =2.480) and CRT (P=0.028, HR =2.600) peaked in 1985-1994 and decreased sharply hereafter, whereas the CSMs of RT-only declined over time. CONCLUSIONS: The risks of CSM after chemotherapy were similar to the common hazards of heart diseases; tumor in the left-lower lobe was a remarkable risk for patients receiving RT-only and the frequent occurrence of cardiac death was from the second year after RT. The CSMs of chemotherapy and CRT culminated in 1985-1994 and then descended; it declined all the time in RT-only group.

Tumor microenvironment interruption: a novel anti-cancer mechanism of Proton-pump inhibitor in gastric cancer by suppressing the release of microRNA-carrying exosomes.

Poor prognosis of gastric cancer is related to not only malignancy of gastric cancer cells, but also the tumor microenvironment. Thus drugs, which can inhibit both of them, are urgently needed to be explored. Studies on effect of Proton-pump inhibitors (PPIs) in anti-neoplasms are increasing, but is rare in gastric in gastric cancer. Here we investigated how the gastric cancer microenvironment is regulated by PPIs. The objective response rate of gastric cancer patients in our hospital treated by PPIs is investigated. PPIs' effects were further explored by observing the change of microRNAs, cytokines, cellular apoptosis. Bioinformatic pathway analysis of microarray was used to discover the pathway involved in PPIs' regulation of gastric cancer microenvironments. Immunoblotting assays and qRT-PCR were used to define molecular events with PPIs treatment. We report here that PPIs can improve the prognosis of advanced gastric cancer patients; and inhibit the progress of gastric cancer both in vivo and in vitro. Moreover, high dose of PPIs can regulate the pathway associated with tumor malignancy and microenvironment via inhibiting the release of exosomes, which packed microRNAs. PPIs can inhibit the transformation of CAFs (cancer associated fibroblasts) and cytokines released from CAFs. In addition, PPIs inhibit the malignancy of gastric cancer through regulating HIF-1α-FOXO1 axis. High dose of PPIs can inhibit malignancy of gastric cancer and regulate its surrounding tumor microenvironment. This finding suggests that PPIs maybe of potential value as a therapeutic tool for treatment of gastric cancer.

Change of SPARC expression after chemotherapy in gastric cancer.

OBJECTIVE: The expression of tumor biomarkers may change after chemotherapy. However, whether secreted protein acidic and rich in cysteine (SPARC) expression changes after chemotherapy in gastric cancer (GC) is unclear. This study investigated the influence of chemotherapy on SPARC expression in GC. METHODS: Immunohistochemistry was used to analyze SPARC expression in 132 GC cases (including 54 cases with preoperative chemotherapy and 78 cases without preoperative chemotherapy). SPARC expression of postoperative specimens with and without preoperative chemotherapy was assessed to analyze the influence of chemotherapy on SPARC expression. RESULTS: SPARC was highly expressed in GC compared with the desmoplastic stroma surrounding tumor cells and noncancerous tissues. High SPARC expression was correlated with invasion depth, lymph node, and TNM stage. After chemotherapy, a lower proportion of high SPARC expression was observed in patients with preoperative chemotherapy than in the controls. For 54 patients with preoperative chemotherapy, gross type, histology, depth of invasion, lymph node, TNM stage, and SPARC expression were related to overall survival. Further multivariate analysis showed that lymph node, histology, and SPARC expression after chemotherapy were independent prognostic factors. CONCLUSION: SPARC expression may change after chemotherapy in GC. SPARC expression should be reassessed for patients with GC after chemotherapy.

Safety analysis of weekly paclitaxel plus S-1 versus paclitaxel plus 5-fluorouracil/calcium folinate as first-line therapy in advanced gastric cancer: a multicenter open random phase II trial.

PURPOSE: To report the results of a safety analysis from a phase II trial comparing administration of weekly paclitaxel plus S-1 (TS) versus paclitaxel plus 5-fluorouracil (5-FU)/calcium folinate (LV) (TLF) as first-line therapy for advanced gastric cancer. METHODS: Patients (n = 240) with previously untreated advanced gastric cancer were randomly assigned to receive either TS or TLF in a 28-day cycle for six cycles. RESULTS: The clinical features of both sets of patients were similar, with the exception of the incidence of prior chemotherapy (P>0·05). Most treatment-related adverse events occurred at similar rates in both treatment arms. However, patients receiving TS experienced an increase in all-grade especially grade 3/4 neutropenia, with an incidence of 43·7% in the TS arm and 16·3% in the TLF arm, respectively (P<0·05). Other severe adverse events were infrequent and not significantly different between the groups. CONCLUSION: The safety and tolerance of weekly paclitaxel plus S-1 or 5-FU/LV is well in untreated advanced gastric cancer patients.

Overexpression of cyclin L2 inhibits growth and enhances chemosensitivity in human gastric cancer cells.

Cyclin L2 is a novel member of the cyclin family, recently implicated in the regulation of cell cycle progression and/or transcriptional regulation. The present study was undertaken to investigate the effects of overexpression on tumor cell growth and chemosensitivity in human gastric cells in vitro. Cyclin L2 was transfected into human gastric cancer cell line BCG823 and expressed with a mammalian expression vector pcDNA3.1. The effects and mechanisms of cyclin L2 on cell growth, cell cycling and apoptosis were studied. Compared to control vectors, overexpression of cyclin L2 inhibited the growth of BCG823 cells and enhance their chemosensitivity to fluorouracil, docetaxel and cisplatin. The anti-proliferative effects of cyclin L2 could be due to G0/G1 arrest and apoptosis. Cyclin L2 induced G0/G1 arrest and apoptosis involved upregulation of caspase-3 and down regulation Bcl-2 and survivin. The results indicated that overexpression of cyclin L2 protein may promote efficient growth inhibition and enhance chemosensitivity to chemotherapeutic agents in human gastric cancer cells by inducing G0/G1 cell cycle arrest and apoptosis.

[A phase II prospective randomized controlled trial of weekly paclitaxel combined with S-1 or fluorouracil for advanced gastric carcinoma].

OBJECTIVE: To evaluate the efficacy and safety of weekly paclitaxel combined with S-1 or fluorouracil in the first line treatment of advanced gastric carcinoma. METHODS: Two hundred and forty patients with untreated advanced gastric carcinoma were randomized into two arms, patients in the experimental arm were given paclitaxel and S-1, while those in the control arm received paclitaxel and fluorouracil. The regimen of experimental arm was paclitaxel 60 mg/m(2) by intravenous infusion, day 1, 8, 15; S-1 80 - 120 mg/day given by oral administration, day 1 - 14. The regimen of control arm was fluorouracil 500 mg/m(2) by intravenous infusion continuously, day 1 - 5; CF 20 mg/m(2) by intravenous infusion, day 1 - 5. The regimens in both arms were repeated every 28 days. The efficacy and safety of both arms were assessed. RESULTS: Two hundred and twenty-eight patients were analyzed in the full analysis set, and 192 patients were analyzed in per-protocol set (experimental arm 100 patients, control arm 92 patients). The overall response rates of experimental and control arms were 50.0% and 28.3% (P = 0.002), and the disease control rates were 82.0% and 70.7% (P = 0.064), respectively. The primary endpoints of experimental arm were non-inferior to that of the control arm. The secondary endpoint of experimental arm in terms of median progression free survival was significantly better than that of control arm (5 months versus 4 months, P = 0.006). The experimental arm had a higher incidence of grade III-IV bone marrow suppression than the control arm, but the incidence of fever in both arms was not significantly different. CONCLUSIONS: Oral administration of S-1 is an alternative option of venous infusional fluorouracil. Weekly paclitaxel combined with S-1 is a safe regimen and has a promising efficacy.

Overexpression of cyclin L2 induces apoptosis and cell-cycle arrest in human lung cancer cells.

BACKGROUND: Uncontrolled cell division is one of the hallmarks of tumor growth. Researches have been focused on numerous molecules involved in this process. Cyclins are critical regulatory proteins of cell cycle progression and/or transcription. The present study aimed to investigate the anti-proliferative effect of cyclin L2, and to define its growth regulatory mechanisms using human lung adenocarcinoma cell line A549. METHODS: Human cyclin L2 was transfected into human lung adenocarcinoma cells (A549 cell), and was expressed in a mammalian expression vector pcDNA3.1. The effects and mechanisms of the cyclin L2 in cell growth, cell cycle analysis and apoptosis were studied by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), flow cytometry or Western blot, respectively. RESULTS: Overexpression of cyclin L2 inhibited the growth of A549 cells. Cell cycle analysis in cells transfected with pCCNL2 revealed an increment in proportion in G0/G1 phase ((68.07 +/- 4.2)%) in contrast to (60.39 +/- 2.82)% of the cells transfected with mock vector. Apoptosis occurred in (7.25 +/- 0.98)% cells transfected with pCCNL2, as compared with (1.25 +/- 0.21)% of the mock vector control group. Cyclin L2-induced-G0/G1 arrest and apoptosis involved upregulation of caspase-3 and downregulation of Bcl-2 and survivin. CONCLUSION: The results indicate that overexpression of cyclin L2 protein may promote efficient growth inhibition of human lung adenocarcinoma cells by inducing G0/G1 cell cycle arrest and apoptosis.

[Phase I clinical trail of intravenous pegylated recombinant human granulocyte colony-stimulating factor].

BACKGROUND & OBJECTIVE: Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is effective in the prophylaxis and management of chemotherapy-induced neutropenia, but requires daily administration because of its short half-life. Pegylated rhG-CSF (PEG-rhG-CSF) is a long-acting reagent that permits less frequent injection. This study was to evaluate the safety and tolerance of PEG-rhG-CSF in Chinese patients, and to explore its efficacy of enhancing absolute neutrophil count (ANC) and CD34+ cell count in peripheral blood. METHODS: Naïve non-small lung cancer or breast cancer patients with normal bone marrow function were eligible for this open-labeled, dose-escalation trial. All patients received 2 cycles of chemotherapy of identical regimen. In cycle 1, rhG-CSF (150 microg/day) was administrated in case of febrile neutropenia or grade 4 neutropenia; in cycle 2, patients received a single injection of PEG-rhG-CSF (30 microg/kg, 60 microg/kg, 100 microg/kg, or 200 microg/kg) 48 h after administration of paclitaxel and carboplatin. RESULTS: All the 16 patients enrolled (4 in each dose group) were evaluable for safety and efficacy of PEG-rhG-CSF. Main adverse events related to PEG-rhG-CSF were musculoskeletal pain or arthralgia (13/16), fatigue (10/16), dizziness (2/16), and injection-site pain (1/16). All adverse events were mild to moderate, and most of them were reversible without treatment. PEG-rhG-CSF enhanced ANC in a dose-dependent manner to some extent, and PEG-rhG-CSF at 60 microg/kg or higher doses prevented chemotherapy-induced neutropenia with sustained effect; CD34+ cells in peripheral blood were also increased. CONCLUSIONS: PEG-rhG-CSF is well tolerated, with no serious adverse event in this trial. The recommended dose of PEG-rhG-CSF for phase II trial is 100 microg/kg because of its adequate efficacy and less adverse events than those of 200 microg/kg.

[Quality of life of malignant patients after autologous stem cell transplantation].

OBJECTIVE: To investigate the quality of life of Chinese malignant patients who treated with the high dose chemoradiotherapy combined with autologous stem cell transplantation (ASCT). METHODS: The data of 89 patients who answer the EORTC QLQ-C30 Chinese version 3.0 after finished ASCT and disease free were analyzed using SPSS 10.0. RESULTS: The score of global health status and functional assessment were near or over 80, more than 80 percent of patient had good or very good global health status or function, the patients who were experiencing moderate or severe financial dysfunction, fatigue, dyspnea, sleeping disturbance and diarrhea were in 72.5% (65/89), 50.6% (45/89), 42.7% (38/89), 33.7% (30/89) and 32.5% (29/89) respectively. The score of dyspnea in female patients was significant higher than male patients (P = 0.024). The score of global health status (P = 0.000), physical function (P = 0.000), role function (P = 0.031) and social function (P = 0.029) became higher significantly with time from transplantation and the score of fatigue became lower (P = 0.020). The Hodgkin's lymphoma patients had higher score significantly in nausea & vomiting (P = 0.002) and dyspnea (P = 0.006) than NHL. The age at transplantation and evaluation took none effect on the score. CONCLUSION: Most patient have good global health status and function after autologous stem cell transplantation, they are more suffered from financial dysfunction, fatigue, dyspnea, sleeping disturbance and diarrhea. Females have more dyspnea symptoms, the quality of life of patient will improve gradually with the time from transplantation, the Hodgkin's lymphoma patients have more symptoms than non-Hodgkin's lymphoma patients, we do not find any effect of age at transplantation and assessment on the quality of life.

[Treatment effect of DICE regimen on patients with relapsed or refractory intermediate and high grade non-Hodgkin's lymphoma].

BACKGROUND & OBJECTIVE: So far, there is still no standard salvage regimen for relapsed or refractory non-Hodgkin's lymphoma (NHL). The response rates (RR) of NHL patients received common salvage regimens, such as DICE, ESHAP, MINE, and EPOCH, are only 30%-70%. This study was to evaluate the efficacy and safety of DICE regimen, as a salvage regimen, in treating patients with relapsed or refractory intermediate and high grade NHL. METHODS: Thirty-five patients with relapsed or refractory intermediate and high grade NHL, who had been pretreated with chemotherapy dominated by CHOP or CHOP-like regimen with a median of 6 cycles (ranged 2-12 cycles), were salvaged by DICE regimen from Jun. 1999 to Jan. 2004. Of the 35 patients, 14 were T-cell original, and 21 were B-cell original. RESULTS: The 35 patients received DICE regimen with a median of 4 cycles (ranged 2-7 cycles). All patients were assessable in the efficacy and adverse events. The total RR was 74.3% with complete response (CR) rate of 31.4%, median response time (MST) of 4 months (ranged 1-30 months), median time to failure (TTF) of 7 months (ranged 2-34 months),median survival time (MST) of 14 months (ranged 3-51 months), and 2-year survival rate of 33.3%. The RRs of T-cell and B-cell NHL were 85.7% and 66.7%. The CR rate was higher in T-cells NHL than in B-cell NHL (50.0% vs. 19.0%, P=0.073). Elevated serum lactate dehydrogenase (LDH) and bulky disease were high risk factors of the efficacy of DICE regimen (P < 0.05). The response to DICE reginmen was an independent prognostic factor of patients with relapsed or refractory NHL (P = 0.001). The major toxicity was myelosuppression. Incidences of neutropenia and thrombocytopenia of grade III-IV were 71.4% and 8.6%. CONCLUSIONS: DICE regimen is a safe and effective salvage regimen for the patients with relapsed or refractory intermediate and high grade advanced NHL. Elevated serum LDH and bulky disease are the adverse prognostic factors. The response to DICE regimen may directly influence survival time of patients with relapsed or refractory NHL.

[Clinicopathologic features of primary thyroid lymphoma].

BACKGROUND & OBJECTIVE: Primary thyroid lymphoma (PTL) is a rare disease. It is likely to be misdiagnosed, and its treatment remains controversy. This study was to investigate clinicopathologic features of PTL, and explore proper treatments. METHODS: Records of 22 patients with PTL treated in Cancer Hospital, Chinese Academy of Medical Sciences from Jan.1990 to Jan. 2004 were retrospectively analyzed. RESULTS: Of the 22 patients, 18 were women, 4 were men. The median age is 55 (33-80) years. All patients were B-cell original; according to WHO classification, 16 (72.7%) were diffuse large B-cell lymphoma (DLBCL), and 6 (27.3%) were mucosa associated lymphoid tissue (MALT) lymphoma. Five patients received surgery alone; 7 received radiotherapy after surgery, 6 received chemotherapy after surgery, 4 received chemotherapy and radiotherapy after surgery. With a median follow-up of 42 (1-168) months, 5-year relapse-free survival rate was 34.78%, and 5-year overall survival rate was 37.36%. CONCLUSIONS: PTL typically occurs in women. The majority of PTL is B-cell original; DLBCL, and MALT lymphoma were the most common histological subtypes. Patients with PTL of stage IE or IIE should be treated with surgery-based combined modality.

[Clinical and pathological analysis of 15 cases with primary breast lymphoma].

BACKGROUND & OBJECTIVE: Primary breast lymphoma (PBL), a rare disease, is likely to be misdiagnosed, and its treatment still remains controversial. This study was to investigate the clinical and pathological features of PBL, summarize the treatment experience, and obtain a better profile of the disease. METHODS: The clinical and pathological records of 15 PBL patients admitted in the Cancer Hospital, Chinese Academy of Medical Science from January 1986 to December 2003 were analyzed. RESULTS: The median age of the 15 patients was 39 years. Of all cases, 93.3%(14/15) were B-cell origin, 6.7% (1/15) were T-cell origin, 40% (6/15) were diffuse large B-cell lymphoma, and 26.6% (4/15) were mucosa associated lymphoid tissue lymphoma. No local relapse occurred in the 8 patients who were given local mastectomy combined with chemoradiotherapy, with a median follow-up of 34.5 months (ranging from 4 to 214 months). Two of the 6 patients with low grade PBL, who did not receive chemotherapy, relapsed after a short remission; 2 of the remaining 4 patients who received chemotherapy gained a constant remission, while after salvage chemoradiotherapy the other 2 gained a second remission up to now. The overall 3-, and 5-year survival rates were 88.9%, and 66.7%. CONCLUSION: The majority of PBL was B-cell origin, diffuse large B-cell lymphoma and mucosa associated lymphoid tissue lymphoma were the most frequent entities. Radical mastectomy was not necessary for good local control of combination of local mastectomy and chemoradiotherapy. PBL must be regarded as a kind of systemic disease in spite of its pathologic type. Chemotherapy should be included in the multi-modality treatment of PBL.