[Correlation between Peripheral Blood Intermediate Monocytes Increased and the Disease Progression of Patients with Diffuse Large BCell Lymphoma].

AbstractObjective: To explore the distribution characteristics and clinical significance of peripheral blood monocyte subgroups in patients with diffuse large Bcell lymphoma(DLBCL). METHODS: The percentage of peripheral blood monocyte subsets of 82 DLBCL patients (including 32 newly diagnosis, 29 remission and 21 relapse) and 30 healthy controls were detected by flow cytometry, and the correlation with the clinical characteristics and its diagnostic value of DLBCL were analyzed. RESULTS: The proportion of intermediate monocytes in patients with newly diagnosed DLBCL group was higher than that in healthy controls (t=5.888, P<0.01). The proportion in relapsed group was higher than those in newly diagnosed DLBCL group（t=2.106，P=0.04） and remission group （t=6.882， P＜0.01）, and the proportion of intermediate monocytes in newly diagnosed DLBCL group was higher than that in Remission group (t=3.969, P<0.01). With the increase of International Prognostic Index (IPI) score, the percentage of intermediate monocytes in patients with DLBCL increased (r=0.37). Furthermore, when the proportion of intermediate monocytes was 10.91% as the cutoff value, the sensitivity and specificity of the whole sample were 90.60% and 9100%, respectively. CONCLUSION: The disease progression is related to the increased intermediate monocytes, which can be used as a potential diagnostic index for DLBCL.

Trastuzumab plus docetaxel and capecitabine as a first-line treatment for HER2-positive advanced gastric or gastroesophageal junction cancer: a phase II, multicenter, open-label, single-arm study.

Gastric cancer (GC) is the second most common cancer in China. The ToGA study showed that trastuzumab in combination with fluoropyrimidine plus cisplatin prolonged overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced GC (AGC). However, some patients may not be able to receive this regimen. We conducted a clinical study to evaluate the efficacy and safety of trastuzumab in combination with docetaxel+capecitabine (DX) in patients with HER2-positive AGC. This phase II, multi-center, open-label, single arm study enrolled patients with HER2-positive AGC who had not received prior treatment for metastatic disease. Patients were treated with a regimen of trastuzumab (8 mg/kg loading dose followed by 6 mg/kg, day 1), capecitabine (1000 mg/m2 twice daily, days 1-14) and docetaxel (60 mg/m2, day 1 for 6 cycles) every 3 weeks. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), OS and safety profiles. Sixty-seven patients with AGC were enrolled from 14 centers. 64 were included in the full analysis set (FAS). The median PFS was 8.1 months (95% confidence interval [CI]: 5.6-12.8) and the median OS was 20.9 months (95% CI: 15.1-33.0). Response was evaluated in 59 patients. The ORR was 67.8%. The most common adverse events of Grade ≥3 were neutropenia, leukopenia, hand-foot syndrome, febrile neutropenia and anemia. We concluded that combination treatment with trastuzumab and DX was well-tolerated and highly effective in patients with HER2-positive AGC, and may offer an alternative to current treatments.

Combined LIM kinase 1 and p21-Activated kinase 4 inhibitor treatment exhibits potent preclinical antitumor efficacy in breast cancer.

LIM kinase 1 (LIMK1) and p21-activated kinase 4 (PAK4) are often over-expressed in breast tumors, which causes aggressive cancer phenotypes and unfavorable clinical outcomes. In addition to the well-defined role in regulating cell division, proliferation and invasion, the two kinases promote activation of the MAPK pathway and cause endocrine resistance through phosphorylating estrogen receptor alpha (ERα). PAK4 specifically phosphorylates LIMK1 and its functional partners, indicating possible value of suppressing both kinases in cancers that over-express PAK4 and/or LIMK1. Here, for the first time, we assessed the impact of combining LIMK1 inhibitor LIMKi 3 and PAK4 inhibitor PF-3758309 in preclinical breast cancer models. LIMK1 and PAK4 pharmacological inhibition synergistically reduced the survival of various cancer cell lines, exhibiting specific efficacy in luminal and HER2-enriched models, and suppressed development and ERα-driven signals in a BT474 xenograft model. In silico analysis demonstrated the cell lines with reliance on LIMK1 were the most prone to be susceptible to PAK4 inhibition. Double LIMK1 and PAK4 targeting therapy can be a successful therapeutic strategy for breast cancer, with a unique efficiency in the subtypes of luminal and HER2-enriched tumors.

Tumor-associated macrophages predict prognosis in diffuse large B-cell lymphoma and correlation with peripheral absolute monocyte count.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is characterized by its clinical and biological heterogeneity. The clinical prognostic implications of tumor-associated macrophages (TAMs) in DLBCL remain controversial and the correlation between TAMs and peripheral absolute monocyte count (AMC) has not yet been elucidated. METHODS: In 221 untreated, newly diagnosed patients with DLBCL, we evaluated the prognostic value of TAMs using immunohistochemical analysis, as well as the association of TAMs and AMC. RESULTS: We found that high CD68 or high CD163 expression was correlated with clinicopathological characteristics, high CD163 expression was an adverse predictor for both overall survival (OS) [hazard ratio (HR) = 2.265, P = 0.005] and progression- free survival (PFS) (HR = 1.925, P = 0.017) in patients with DLBCL. Patients with high CD68 or high CD163 expression had significantly poorer OS and PFS than those with low CD68 or low CD163 expression, respectively (CD68: OS: P<0.001, PFS: P<0.001; CD163: OS: P<0.001, PFS: P<0.001), even in the rituximab era. Moreover, high-risk patients could be further identified by the expression of CD68 or CD163, especially in those classified as low/intermediate risk by International Prognostic Index (IPI). Furthermore, the significant positive correlation was also detected between CD68 expression or CD163 expression and AMC (r = 0.256, P<0.001; r = 0.303, P<0.001). CONCLUSIONS: Patients with high expression of TAMs tend to have poorer OS and PFS, even in the rituximab era, and have positive correlation with AMC. Therefore, the peripheral AMC is a useful prognostic marker reflecting the status of the tumor microenvironment (TME) in DLBCL.

Expression of ALDH1A1 and CD133 is associated with the prognosis and effect of different chemotherapeutic regimens in gastric cancer.

Gastric cancer (GC) is one of the most common malignant tumors worldwide. Previous studies have reported that aldehyde dehydrogenase-1A1 (ALDH1A1) and cluster of differentiation (CD)-133 are considered to be cancer stem cell markers in GCs. The present study immunohistochemically examined the distribution and expression of two tumor stem cell markers, CD133 and ALDH1A1, in both primary tumors and para-tumor tissues. In 91 cases with stage III, 57 (62%) were positive for ALDH1A1 and 60 (66%) were positive for CD133. ALDH1A1 was detected in para-tumors and cancerous tissues of the stomach, and the immunoreactivity of the tumors was stronger than that in para-tumor tissues. CD133 was only detected in tumors. The expression of ALDH1A1 was significantly associated with advanced T/N stage (T stage, P=0.012; N stage, P=0.023) and poor differentiation (P=0.020), while CD133 was associated with advanced T stage (P=0.007). Univariate and multivariate Cox proportional hazards analysis revealed that tumor stage, CD133 expression, vascular invasion and sex were independent predictors of disease-free survival (DFS) time, and tumor size, vascular invasion and sex were independent predictors of overall survival (OS) time in patients with GC. Patients with CD133+ GC had poorer DFS (P=0.042), while ALDH1A1+ GC was not associated with poorer DFS. In regard to chemotherapy, improvements in survival were not observed after the addition of taxane compared with two-drug therapy. However, the subgroup analysis indicated that in the ALDH1A1- subgroup, and CD133+ and ALDH1A1- subgroups, an increased OS was observed in two-drug therapy (P=0.043). The results of the present study indicate that ALDH1A1 and CD133 may play an important role in tumor invasion, metastasis and prognosis, and ALDH1A1- expression does not benefit the taxane-based triple chemotherapeutic regimen in patients with GC.

Prognostic significance of monocyte chemoattractant protein-1 and CC chemokine receptor 2 in diffuse large B cell lymphoma.

Aberrant monocyte chemoattractant protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2) expression in malignant tissues have been reported; however, their role in hematological malignancies prognosis remains little known. The aim of this study was to investigate the prognostic value of MCP-1 and CCR2 expression in patients with diffuse large B cell lymphoma (DLBCL). The study included 221 patients with DLBCL. MCP-1 and CCR2 expression was analyzed by immunohistochemical staining and its correlations with clinicopathologic features and prognosis were evaluated. High expression of MCP-1 or CCR2 was correlated with clinicopathological characteristics, and an adverse prognostic factor for overall survival (OS) and progression-free survival (PFS) of DLBCL patients. Also, significant positive correlation between MCP-1 and CCR2 expression was revealed (r = 0.545, P < 0.001). Patients with high MCP-1 or high CCR2 expression had significantly poorer OS and PFS than those with low MCP-1 or low CCR2 expression (OS: P < 0.001, P < 0.001; PFS: P < 0.001, P < 0.001), respectively, even in the rituximab era, and MCP-1 or CCR2 expression could further identify high-risk patients otherwise classified as low/intermediate risk by the International Prognostic Index (IPI) alone. Furthermore, incorporation of MCP-1 or CCR2 expression into the IPI score could improve prognostic value for OS. This is the first report describing the clinicopathological features and survival outcome according to expression of MCP-1 and CCR2 in DLBCL.

The PD-1 rs36084323 A > G polymorphism decrease cancer risk in Asian: A meta-analysis.

The rs36084323 A > G polymorphism in programmed cell death-1(PD-1) gene has been reported to be associated with cancer risk. However, the results of previous studies were inconsistent. Therefore, we performed a meta-analysis to identify the potential association, by searching the PubMed, EMBASE, Cochrane Library, and the Chinese CNKI, WANFANG and CBM databases. Data were extracted and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the strength of the association. A total of 10 relevant studies involving 4445 cancer cases and 5126 controls were recruited. Overall, the results indicated that the PD-1 rs36084323 A > G polymorphism was not statistically associated with cancer risk. However, stratified analysis revealed that there was a statistically reduced cancer risk in Asians(G vs. A, OR = 0.89, 95%CI:0.81-0.97, P = 0.008, I2 = 48.8%; GG vs. AA, OR = 0.79, 95% CI:0.66-0.94, P = 0.008, I2 = 48.7%; GG/AG vs. AA, OR = 0.87, 95%CI:0.76-0.98, P = 0.017, I2 = 34.9%; GG vs. AG/AA, OR = 0.85, 95%CI:0.75-0.97, P = 0.027, I2 = 40%) and in the patients with EOC(AG vs. AA, OR = 0.69, 95%CI:0.54-0.90, P = 0.005, I2 = 0%; GG/AG vs. AA, OR = 0.67, 95%CI:0.52-0.85, P = 0.001, I2 = 0). Meta-regression showed that ethnicity (P = 0.029) but not cancer types (P = 0.792), source of controls (P = 0.207) or ample size (P = 0.585) were the sources of heterogeneity. This meta-analysis demonstrates the PD-1 rs36084323 A > G polymorphism is associated with decreased cancer risk in Asian, and suggests it could potentially serve as a biomarker to screen high-risk individuals. Large-scale and well-designed case-control studies are needed to enrich the evidence of this result.

Dysregulation of mRNA profile in cisplatin-resistant gastric cancer cell line SGC7901.

AIM: To explore novel therapeutic target of cisplatin resistance in human gastric cancer. METHODS: The sensitivity of SGC7901 cells and cisplatin-resistant SGC7901 cells (SGC7901/DDP) for cisplatin were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. High-quality total RNA which isolated from SGC7901/DDP cells and SGC7901 cells were used for mRNA microarray analysis. Results were analyzed bioinformatically to predict their roles in the development of cisplatin resistance and the expression of 13 dysregulated mRNAs we selected were validated by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: SGC7901/DDP cells highly resistant to cisplatin demonstrated by MTT assay. A total of 1308 mRNAs (578 upregulated and 730 downregulated) were differentially expressed (fold change ≥ 2 and P-value < 0.05) in the SGC7901/DDP cells compared with SGC7901 cells. The expression of mRNAs detected by qRT-PCR were consistent with the microarray results. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway and protein-protein interaction analysis demonstrated that the differentially expressed mRNAs were enriched in PI3K-Akt, Notch, MAPK, ErbB, Jak-STAT, NF-kappaB signaling pathways which may be involved in cisplatin resistance. Several genes such as PDE3B, VEGFC, IGFBP3, TLR4, HIPK2 and EGF may associated with drug resistance of gastric cancer cells to cisplatin. CONCLUSION: Exploration of those altered mRNAs may provide more promising strategy in diagnosis and therapy for gastric cancer with cisplatin resistance.

Guggulsterone-induced apoptosis in cholangiocarcinoma cells through ROS/JNK signaling pathway.

Cholangiocarcinoma (CCA), the most common biliary tract malignancy, is arising from the bile duct epithelium with the global significantly increased morbidity and mortality. Here, we showed the effect of guggulsterone, a steroid found in the resin of the guggul plant, on human HuCC-T1 and RBE CCA cells. Exposure to various concentrations of guggulsterone for multiple action time resulted in significant apoptosis in the CCA cells via activating both extrinsic and intrinsic pathways. Furthermore, we demonstrated that the apoptosis of CCA cells was induced by Reactive oxygen species (ROS) mediated JNK signaling pathway. Consistently, inhibition of JNK activity, overexpression of JBD, its binding protein or reduction of ROS by overexpression of catalase, all decreased apoptotic cells. Our results also revealed that guggulsterone-induced apoptosis was coupled with endoplasmic reticulum stress (ERS) in CHOP-dependent pathway. Downregulation of CHOP instead of other ERS markers could inhibit CCA cell apoptosis. Taken together, our results showed that guggulsterone could induce apoptosis of human CCA cells through ROS/JNK signaling pathway, indicating that guggulsterone could be important for the clinical therapy of CCA.

Sarcoidosis in gastric cancer at the time of diagnosis: A case report.

Sarcoidosis is a multisystemic inflammatory disease that commonly affects the lungs and lymphatic system and is characterized by the formation of non-caseating granulomas. Although the association between sarcoidosis and malignant diseases has been well described, it remains controversial whether this association is merely a coincidence or the consequence of a common pathophysiological mechanism. The present study reports a rare case of sarcoidosis that was present in a patient with gastric cancer at the time of diagnosis. A 64-year-old female diagnosed with stage I gastric cancer underwent curative surgery, and the postoperative pathology of the lymph nodes revealed non-caseating granulomas. At the 4-year follow-up, the sarcoidosis remained stable, and no recurrence of cancer was identified. The present case revealed that sarcoidosis and gastric cancer may coexist simultaneously and focused on the potential advantages of histological confirmation in patients with cancer and sarcoidosis.

Peripheral blood lymphocyte/monocyte ratio at the time of first relapse predicts outcome for patients with relapsed or primary refractory diffuse large B-cell lymphoma.

BACKGROUND: Despite the use of modern immunochemotherapy regimens, a significant proportion of diffuse large B-cell lymphoma (DLBCL) patients will relapse. We proposed absolute lymphocyte count/absolute monocyte count ratio (ALC/AMC ratio) as a new prognostic factor in relapsed or primary refractory DLBCL. METHODS: We retrospectively analyzed 163 patients who have been diagnosed with relapsed or primary refractory DLBCL. The overall survival (OS) and progression-free survival (PFS) were measured from the time of first relapse. The Cox proportional hazards model was used to evaluate ALC/AMC ratio as prognostic factors for OS and PFS. RESULTS: On univariate and multivariate analysis performed with factors included in the saaIPI, early relapse, prior exposure to rituximab and autologous stem-cell transplantation (ASCT), the ALC/AMC ratio at the time of first relapse remained an independent predictor of PFS and OS (PFS: P < 0.001; OS: P < 0.001). Patients with lower ALC/AMC ratio (<2.0) had lower overall response rate, 1-year PFS and 2-year OS rate compared with those with higher ALC/AMC ratio (≥2.0). Moreover, the ALC/AMC ratio can provide additional prognostic information when superimposed on the saaIPI. CONCLUSIONS: Lower ALC/AMC ratio at the time of first relapse is a adverse prognostic factor for OS and PFS in relapsed or primary refractory DLBCL, and leads to the identification of high-risk patients otherwise classified as low/intermediate risk by the saaIPI alone.

DNA repair capacity in peripheral blood lymphocytes predicts efficacy of platinum-based chemotherapy in patients with gastric cancer.

OBJECTIVE: To investigate the correlation between ERCC1 expression levels in tumor tissue and peripheral blood lymphocytes (PBL) from patients with gastric cancer and assess the relationship between PBL DNA repair rate (DRR) and the efficacy of platinum chemotherapy. METHODS: A total of 53 patients with gastric cancer receiving surgery and 20 controls were studied. ERCC1 protein expression in tumour tissue and PBL were determined by immunohistochemical staining. The PBL DRRs of 47 advanced patients and 20 controls were estimated by comet assay. RESULTS: The positive expression rates of ERCC1 were 67. 9%, 56. 6% and 10.0% in tumour tissues, PBLs of gastric cancer patients, and PBLs of the control group. PBL ERCC1 expression correlated with that in tissue (χ(2) = 15. 463, p=0.000). Pearson contingency coefficient=0.475). DRRs of cancer patients by tail length (TL) (Z=4. 662, p=0.000) and tail moment (TM) (Z=3. 827, p=0.000) were significantly lower than that of control group. When TL was applied as an indicator, the correlation between DRR and chemotherapy efficacy was significant (Spearman rank correlation r=0.327, p=0.032). Patients with low levels of DRR in PBL presented better short-term efficacy of chemotherapy than those with high levels of DRR. CONCLUSIONS: The ERCC1 expression in PBLs may indirectly reflect ERCC1 expression in gastric cancer tissues. Compared with non-cancer populations, patients with gastric cancer may have lower DNA repair capacity. DRR in PBL may predict the short-term efficacy of platinum-based chemotherapy for patients with advanced gastric cancer.

Mechanism of P-glycoprotein expression in the SGC7901 human gastric adenocarcinoma cell line induced by cyclooxygenase-2.

OBJECTIVE: To investigate possible signal pathway involvement in multi-drug resistant P-glycoprotein (P-gp) expression induced by cyclooxygenase-2 (COX-2) in a human gastric adenocarcinoma cell line stimulated with pacliaxel (TAX). METHODS: The effects of TAX on SGC7901 cell growth with different doses was assessed by MTT assay, along with the effects of the COX-2 selective inhibitor NS-398 and the nuclear factor-KB (NF-KB) pathway inhibitor pyrrolidine dithiocarbamate (PDTC). Influence on COX-2, NF-KB p65 and P-gp expression was determined by Western blotting. RESULTS: TAX, NS-398 and PDTC all reduced SGC7901 growth, with dose- dependence. With increasing dose of TAX, the expression of COX-2, p65 and P-gp showed rising trends, this being reversed by NS-398. PDTC also caused decrease in expression of p65 and P-gp over time. CONCLUSION: COX-2 may induce the expression of P-gp in SGC7901 cell line via the NF-kappa B pathway with pacliaxel stimulation.

Oral fludarabine in combination with doxorubicin and dexamethasone as first-line therapy for nodal peripheral T-cell lymphomas: early results of a prospective multicenter study.

PURPOSE: Nodal peripheral T-cell lymphomas (PTCLs) have particularly poor prognoses. Few data enabling establishment of an accepted standard treatment modality for PTCLs are available. We hypothesized that fludarabine-based regimens are tolerable and effective in treatment for nodal PTCLs. Therefore, this study was to analyze the toxicity of, response rate for, and outcome of treatment for nodal PTCLs with oral fludarabine, doxorubicin, and dexamethasone (FAD). METHODS: Patients with PTCLs received FAD every 28 days, consisting of oral fludarabine at 40 mg/m(2) on days 1-3, doxorubicin at 50 mg/m(2) on day 1, and oral dexamethasone at 20 mg/day on days 1-5. Patients who did not exhibit disease progression received at least four courses of treatment. RESULTS: Thirty-one of 35 patients with previously untreated nodal PTCLs enrolled in the study from 2007 to 2008 were evaluable. The incidence of grade 3-4 neutropenia was 55%. Nine patients had to have dose reductions of fludarabine and doxorubicin, none of whom had grade 3 or 4 toxic effects at the lower dose. Five of 31 patients had pneumonitis. No treatment-related mortality occurred. The response rate for the entire patient population was 71%, and the complete remission rate was 48%. The PFS and OS rates at 2 years were 54.2 and 77.1%, respectively. Four patients had died of cancer progression at the time of this analysis. The serum lactate dehydrogenase level had a significant effect on PFS and OS. CONCLUSION: The FAD regimen had encouraging efficacy with an acceptable toxicity profile in patients with nodal PTCLs.

The screening of volatile markers for hepatocellular carcinoma.

BACKGROUND: Breath analysis became promising for noninvasive diagnoses of cancer with sophisticated spectrometry technology introduced. This study aimed to screen volatile markers for hepatocellular carcinoma (HCC). METHODS: Breath samples were collected from 30 HCC patients who were comorbid with type B hepatitis and cirrhosis and from 27 hepatocirrhosis patients and 36 healthy persons, both taken as controls. The volatile organic compounds in the samples were analyzed with gas chromatography/mass spectrometry and the markers were selected by comparing their levels between groups. Each of the markers was evaluated by receiver operating characteristic (ROC) curves and a discriminant function using the markers was established. The relationships of alpha-fetoprotein (AFP) levels and clinical stages with the concentrations of the markers were also investigated. RESULTS: 3-Hydroxy-2-butanone, styrene, and decane were screened as potential markers, among which 3-hydroxy-2-butanone was found to have the best diagnostic value. The diagnostic function using these markers had a sensitivity of 86.7% and a specificity of 91.7% between HCC patients and normal controls and a sensitivity of 83.3% and a specificity of 91.7% by cross-validation. No statistically significance (P > 0.05) was found for the concentration differences of these markers between HCC patients with AFP >400 or <400 microg/L or between stage I-II and stage III-IV patients. CONCLUSION: These volatile organic compounds could be useful as breath markers of HCC patients, independent of AFP levels or clinical stages. IMPACT: Breath analysis could be useful for early diagnosis of HCC, especially for AFP-negative HCC.

Quantitative breath analysis of volatile organic compounds of lung cancer patients.

Due to state-of-art analytical techniques, non-invasive exhaled volatile organic compounds (VOCs) analysis has become a potential method for early diagnosis of lung cancer. We collected breath samples from 43 patients with non-small cell lung cancer (NSCLC) and 41 normal controls using Tedlar gas bags. The VOCs were extracted with solid phase micro-extraction (SPME) and analyzed by gas chromatography (GC)/mass spectrometry (MS). The number of VOCs detected in each breath sample ranged from 68 to 114. Among the VOCs 1-butanol and 3-hydroxy-2-butanone were found at significantly higher concentrations in breath of the lung cancer patients compared to the controls. VOCs levels were not significantly different between early stage lung cancer patients and late stage lung cancer patients. Lung adenocarcinoma was significantly related to higher VOCs concentrations in the breath. Our data showed that 1-butanol and 3-hydroxy-2-butanone in breath could possibly be taken as useful breath biomarkers for discerning potential lung cancer patients and VOCs analysis could be used as a complementary test for the diagnosis of lung cancer.