XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX).

BACKGROUND: There is no consensus on whether triplet regimen is better than doublet regimen in the first-line treatment of advanced gastric cancer (AGC). We aimed to compare the efficacy and safety of oxaliplatin plus capecitabine (XELOX) and epirubicin, oxaliplatin, plus capecitabine (EOX) regimens in treating AGC. METHODS: This phase III trial enrolled previously untreated patients with AGC who were randomly assigned to receive the XELOX or EOX regimen. The primary endpoint was non-inferiority in progression-free survival (PFS) for XELOX as compared with EOX on an intention-to-treat basis. RESULTS: Between April 10, 2015 and August 20, 2020, 448 AGC patients were randomized to receive XELOX (n = 222) or EOX (n = 226). The median PFS (mPFS) was 5.0 months (95% confidence interval [CI] = 4.5-6.0 months) in the XELOX arm and 5.5 months (95% CI = 5.0-6.0 months) in the EOX arm (hazard ratio [HR] = 0.989, 95% CI = 0.812-1.203; Pnon-inferiority = 0.003). There was no significant difference in median overall survival (mOS) (12.0 vs. 12.0 months, P = 0.384) or objective response rate (37.4% vs. 45.1%, P = 0.291) between the two groups. In patients with poorly differentiated adenocarcinoma and liver metastasis, the EOX arm had a significantly longer mOS (P = 0.021) and a trend of longer mPFS (P = 0.073) than the XELOX arm. The rate of grade 3/4 adverse events (AEs) was 42.2% (90/213) in the XELOX arm and 72.5% (156/215) in the EOX arm (P = 0.001). The global health-related quality of life (QoL) score was significantly higher in the XELOX arm than in the EOX arm during chemotherapy. CONCLUSIONS: This non-inferiority trial demonstrated that the doublet regimen was as effective as the triplet regimen and had a better safety profile and QoL as a first-line treatment for AGC patients. However, the triplet regimen might have a survival advantage in patients with poorly differentiated adenocarcinoma and liver metastasis.

ENO2 Promotes Cell Proliferation, Glycolysis, and Glucocorticoid-Resistance in Acute Lymphoblastic Leukemia.

BACKGROUND/AIMS: The metabolic features of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. The expression of glycolytic enzyme enolase 2 (ENO2) was found to be closely associated with the clinical features of acute lymphoblastic leukemia (ALL) patients, but its functions remain unclear in ALL. METHODS: We evaluated the association between ENO2 mRNA expression in bone marrow mononuclear cells (BM-MNCs) and the efficacy of chemotherapy, and further explored the function of ENO2 in ALL. The molecular mechanisms of ENO2 expression and its effects on cell growth, glycolysis and glucocorticoid resistance were explored by Cell Counting Kit-8, glucose-consumption assay, Quantitative RT-PCR, Western blotting and in vivo tumorigenesis in NOD/SCID mice. RESULTS: The results showed that ENO2 mRNA expression in BM-MNCs was significantly decreased when patients completed induction chemotherapy and reached complete remission (CR). ENO2 mRNA expression was increased when patients suffered relapse. Functional studies demonstrated that ENO2 promoted cell growth, glycolysis, and glucocorticoid resistance, all of which were effectively inhibited when ENO2 was silenced with shRNAs. Further studies revealed that ENO2 up-regulated various glycolysis-related genes and enhanced Akt activity with subsequent glycogen synthase kinase3ß (GSK-3ß) phosphorylation, inducing cell proliferation and glycolysis. The combination of silencing ENO2 and 2-deoxyglucose (2-DG) synergistically inhibited leukemia cell survival. CONCLUSIONS: These results indicate that ENO2 may be a biological marker for monitoring chemotherapeutic efficacy and relapse in ALL. ENO2 may provide a potential therapeutic strategy for ALL.

High level of soluble interleukin-2 receptor in serum predicts treatment resistance and poor progression-free survival in multiple myeloma.

The IL-2/IL-2 receptor (IL-2R) system plays a central role in maintaining normal T cell immunity, and its disturbance is associated with several hematologic disorders. Studies have found in several types of lymphoma that abnormal amounts of soluble IL-2R (sIL-2R) may result in imbalance of the IL-2/IL-2R system and hence of the T cell immunoregulation. Whether the level of sIL-2R in blood could predict treatment outcomes or not needs to be investigated in multiple myeloma (MM) patients. The level of sIL-2R in serum was measured using enzyme-linked immunosorbent assay (ELISA) in 81 patients with newly diagnosed MM. Twenty-six patients (32.1%) were treated with bortezomib-based regimens and 55patients (67.9%) received old drugs-based regimens. The mean concentration of sIL-2R for myeloma patients was 8.51 ng/ml, significantly higher than that of healthy controls (0.56 ng/ml, p < 0.0001). The best cutoff value for sIL-2R in predicting high risk for disease progression is 6.049 ng/ml with an area under curve (AUC) of 0.665 (p = 0.013). Thirty-six patients (44.4%) were classified as higher sIL-2R level group (> 6.049 ng/ml), and 45 patients (55.6%) as lower group (≤ 6.049 ng/ml). The overall response rate (ORR) was 60.0% in lower sIL-2R level group, and 41.7% in higher level group (p = 0.156). The median progression-free survival (PFS) and overall survival (OS) was 12 months (range, 2.0-65 months) and 20 months (range, 2.0-118 months), respectively. In a multivariate survival analysis, including Eastern Cooperative Oncology Group performance status score, treatment response, and sIL-2R level, it was found that all these three parameters were significantly independent prognostic factors for PFS (p = 0.032, 0.016, and 0.043, respectively), but none factors maintained their value in predicting OS. Subgroup analysis revealed that high level of sIL-2R is correlated with significantly inferior PFS in patients treated with bortezomib-based regimens (p = 0.004). Serum sIL-2R level is an independent prognostic factor for PFS, indicating novel drugs targeting the imbalance of IL-2/IL-2R system may be a promising strategy in MM.

New risk factors and new tendency for central nervous system relapse in patients with diffuse large B-cell lymphoma: a retrospective study.

BACKGROUND: In patients with diffuse large B-cell lymphoma (DLBCL), central nervous system (CNS) relapse is uncommon but is nearly always fatal. This study aimed to determine the risk factors for CNS relapse in DLBCL patients and to evaluate the efficacy of rituximab and intrathecal chemotherapy prophylaxis for CNS relapse reduction. METHODS: A total of 511 patients with newly diagnosed DLBCL treated at the Sun Yat-sen University Cancer Center between January 2003 and December 2012 were included in the study. Among these patients, 376 received R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment, and 135 received CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) as primary treatment. Intrathecal chemotherapy prophylaxis (methotrexate plus cytarabine) was administered to those who were deemed at high risk for CNS relapse. In the entire cohort and in the R-CHOP set in particular, the Kaplan-Meier method coupled with the log-rank test was used for univariate analysis, and the Cox proportional hazards model was used for multivariate analysis. Differences were evaluated using a two-tailed test, and P < 0.05 was considered significant. RESULTS: At a median follow-up of 46 months, 25 (4.9%) patients experienced CNS relapse. There was a trend of reduced occurrence of CNS relapse in patients treated with rituximab; the 3-year cumulative CNS relapse rates were 7.1% in CHOP group and 2.7% in R-CHOP group (P = 0.045). Intrathecal chemotherapy prophylaxis did not confer much benefit in terms of preventing CNS relapse. Bone involvement [hazard ratio (HR) = 4.21, 95% confidence interval (CI) 1.38-12.77], renal involvement (HR = 3.85, 95% CI 1.05-14.19), alkaline phosphatase (ALP) >110 U/L (HR = 3.59, 95% CI 1.25-10.34), serum albumin (ALB) <35 g/L (HR = 3.63, 95% CI 1.25-10.51), treatment with rituximab (HR = 0.34, 95% CI 0.12-0.96), and a time to complete remission ≤ 108 days (HR = 0.22, 95% CI 0.06-0.78) were independent predictive factors for CNS relapse in the entire cohort. Bone involvement (HR = 4.44, 95% CI 1.08-18.35), bone marrow involvement (HR = 11.70, 95% CI 2.24-60.99), and renal involvement (HR = 10.83, 95% CI 2.27-51.65) were independent risk factors for CNS relapse in the R-CHOP set. CONCLUSIONS: In the present study, rituximab decreased the CNS relapse rate of DLBCL, whereas intrathecal chemotherapy prophylaxis alone was not sufficient for preventing CNS relapse. Serum levels of ALB and ALP, and the time to complete remission were new independent predictive factors for CNS relapse in the patients with DLBCL. In the patients received R-CHOP regimen, a trend of increased CNS relapse was found to be associated with extranodal lesions.

Serum neuron-specific enolase levels are upregulated in patients with acute lymphoblastic leukemia and are predictive of prognosis.

We explored the relationship between neuron-specific enolase (NSE) levels and the clinical features of acute lymphoblastic leukemia (ALL). Seventy ALL patients and forty-two healthy controls were enrolled in this study, and their serum NSE levels were measured using an electrochemiluminescence assay. The serum NSE concentration was higher in ALL patients than in healthy controls. In ALL patients, the mean serum NSE level declined after complete remission (CR) but increased with relapse. In addition, the mean serum NSE level was lower in the CR group than in the non-CR group. High NSE levels were associated with poorer progression-free and overall survival than low NSE levels. Serum NSE levels closely correlated with several clinical features, including the immunophenotype, risk stratification and serum lactate dehydrogenase levels. Multivariate analysis revealed that high NSE expression was an independent prognostic factor in adult ALL patients. NSE mRNA levels were also higher in ALL cell lines and bone marrow mononuclear cells from ALL patients than in control cells. These results suggested that NSE could be a clinical prognostic factor and a potential therapeutic target in ALL.

A childhood chemotherapy protocol improves overall survival among adults with T-lymphoblastic lymphoma.

A broadly accepted standard treatment for adult T-lymphoblastic lymphoma (T-LBL) has not yet been defined. To address that issue, we retrospectively compared three chemotherapy regimens used to treat 110 adult patients with newly diagnosed T-LBL. These included two adult regimens (ECOG2993 and hyper-CVAD) and a childhood regimen (BFM-90). These intensive drug regimens are mainly used to treat childhood and adult acute lymphoblastic leukemia. They included induction, consolidation, and maintenance chemotherapy protocols and were administered over the course of 2 years. Seventy-five patients (80%) achieved a complete remission (CR). Within a median follow-up time of 31 months (range: 5-152 months), the 5-year overall survival (OS) and progression-free survival (PFS) rates were 47.7% (95% CI, 35.0-69.8%) and 45.7% (95% CI, 27.6-56.6%), respectively. Shorter survival was associated with age > 40 years, poor ECOG PS and bone marrow involvement. Elevated lactic dehydrogenase (LDH) level, Ann Arbor stage and International Prognostic Index (IPI) score had no prognostic value. The childhood chemotherapy regimen improved CR and the overall survival rate more than the adult regimen in patients aged < 40 years.

High level of interleukin-10 in serum predicts poor prognosis in multiple myeloma.

BACKGROUND: Interleukin-10 (IL-10) is a inhibiting inflammatory cytokine that plays an important role in immune suppressive microenvironment in multiple myeloma (MM). Whether the level of serum IL-10 could predict treatment response and survival outcomes or not needs to be investigated in MM patients. METHODS: The level of IL-10 in serum was measured using enzyme-linked immunosorbent assay in 188 patients with newly diagnosed MM. RESULTS: The best cutoff value for IL-10 in predicting survival is 169.69 pg ml(-1) with an area under the curve (AUC) value of 0.747 (P<0.001). In all, 92 patients (48.9%) were classified as high-IL-10 group (>169.96 pg ml(-1)) and 96 patients (51.1%) as low-IL-10 group (⩽169.96 pg ml(-1)). The overall response rate (ORR) was 79.2% in low-IL-10 group, significantly higher than that in high-IL-10 group (53.3%, P<0.001). Patients in low-IL-10 group had significantly better survival compared with those in high-IL-10 group (3-year PFS rate: 69.3% vs 13.3%, P<0.001; 3-year OS rate: 93.6% vs 51.9%, P<0.001). Multivariate analysis revealed that serum IL-10 level >169.96 pg ml(-1) at diagnosis and certain cytogenetic abnormalities were two adverse factors for PFS and OS. CONCLUSIONS: Our data suggest that serum IL-10 at diagnosis is a novel, powerful predictor of prognosis for MM.

Consolidation therapy of arsenic trioxide alternated with chemotherapy achieves remarkable efficacy in newly diagnosed acute promyelocytic leukemia.

BACKGROUND: Currently, all-trans retinoic acid (ATRA) combined with daunorubicin and ATRA combined with arsenic trioxide (ATO) therapies are considered the standard induction therapy regimens for adult patients newly diagnosed with acute promyelocytic leukemia (APL). However, there is no consensus concerning the optimal consolidation and maintenance therapies after induction therapy. In this study, we explored a new therapeutic strategy for APL that may be simple, effective, and safe. METHODS: The patients in our study were divided into high white blood cell (WBC) group and low WBC group according to the numeration of leukocytes at the first visit. The low WBC group received ATRA and ATO until complete remission (CR), and the high WBC group received anthracycline, ATRA, and ATO until CR. After achieving hematologic CR, ATO was alternated with chemotherapy for consolidation therapy. Three cycles were completed in the 1st year with no maintenance therapy. The patients were followed for a median of 5 years after their initial treatment. RESULTS: After induction therapy, the rate of CR for the 18 patients was 100%. The rate of negativity for the PML/RARα fusion gene following induction therapy was 100%. There was no mortality during the treatment. Both the 5-year event-free survival rate and 5-year overall survival rate were 100%. No relapses occurred during the follow-up period. CONCLUSION: This study proposes a novel treatment for APL that is efficient, well-tolerated, and very simple to perform.

Serum levels of soluble programmed death ligand 1 predict treatment response and progression free survival in multiple myeloma.

Immune checkpoint signaling plays an important role in immunosuppression in multiple myeloma (MM). Blood levels of soluble programmed death-ligand 1 (sPD-L1), a checkpoint-relevant protein, might predict treatment response and survival outcomes in MM patients. We used an enzyme-linked immunosorbent assay to measure serum sPD-L1 levels in 81 newly diagnosed MM patients. We found that myeloma patients had higher sPD-L1 concentrations than healthy controls. The best sPD-L1 cutoff value for predicting disease progression risk was 2.783 ng/mL. The overall response rate to treatment was higher in low sPD-L1 patients than in high sPD-L1 patients. The 3-year progression free survival (PFS) and overall survival (OS) rates for all patients were 16% and 64%, respectively. Multivariate survival analysis including Eastern Cooperative Oncology Group performance status score, treatment response, and sPD-L1 level showed that a less than partial treatment response (PR) and higher sPD-L1 levels (>2.783 ng/ml) were independent prognostic factors for shorter PFS; neither factor was predictive of OS. The serum sPD-L1 level is a valuable biomarker for predicting treatment response and an independent prognostic factor for PFS. PD-1/ PD-L1 blockade may be a promising novel immune-based therapeutic strategy in MM.

The prognostic nutritional index predicts survival for patients with extranodal natural killer/T cell lymphoma, nasal type.

The prognostic nutritional index (PNI), an indicator of nutritional status and systemic inflammation, is associated with survival in several types of tumors. The prognostic value of the PNI in lymphoma remains unclear. The present study aimed to evaluate the prognostic significance of the PNI in patients with extranodal natural killer/T cell lymphoma, nasal type (ENKTL). This retrospective study in two institutions was comprised of 177 patients with newly diagnosed ENKTL. Patients with a combined albumin (g/L) + 5 × total lymphocyte count × 10(9)/l ≥ 45 were allocated a PNI score of 0. Patients in whom this total was <45 were allocated a score of 1. Patients with a pretreatment PNI score of 1 had more adverse clinical features, lower complete remission rates (p = 0.005), and worse overall survival (OS, p < 0.001) and progression-free survival (p = 0.004) compared with those with a PNI score of 0. Multivariate analysis showed that the PNI (p < 0.001) and tumor mass ≥5 cm (p < 0.001) were independent predictors of worse OS. The PNI was predictive in extranasal disease and nasal disease (both p < 0.05). The PNI could differentiate low-risk patients as classified according to the International Prognostic Index and Prognosis Index for peripheral T cell lymphoma scoring, as well as patients in a different category using the Korean Prognostic Index scores with different survival outcomes (all p < 0.05). The PNI is a powerful predictor of survival in ENKTL. Nutritional status and inflammatory responses at diagnosis might play an important role in survival in patients with ENKTL.

Increased serum levels of interleukin-15 correlate with negative prognostic factors in extranodal NK/T cell lymphoma.

Interleukin-15 (IL-15) is a proinflammatory cytokine involved in the proliferation, survival, and activation of multiple lymphocyte lineages. However, the prognostic significance of IL-15 for extranodal NK/T cell lymphoma (ENKTL) has not been well established. We retrospectively analyzed 112 patients with newly diagnosed ENKTL. Baseline serum IL-15 levels were determined using sandwich enzyme-linked immunosorbent assays. Patients with high IL-15 (>3.94 mg/L) at diagnosis tended to have more adverse clinical features. Patients with low IL-15 (≤3.94 mg/L) at diagnosis had better progression-free survival (PFS; P < 0.001) and overall survival (OS; P < 0.001) and achieved higher complete remission rates (P = 0.001). Multivariate analysis revealed independent prognostic factors for PFS. Similarly, high IL-15 levels (P = 0.009), no CR after chemotherapy (P = 0.001), Stage III/IV (P = 0.048), and elevated serum EBV-DNA (P = 0.038) were independently predictive of shorter OS. Using the International Prognostic Index or Korean Prognostic Index for nasal NK/T cell lymphoma, the majority of patients were in the low-risk category (with no or one adverse factor). Serum IL-15 was helpful to differentiate the low-risk patients with different survival outcomes (P < 0.001).Our data suggest that serum IL-15 at diagnosis is a novel, powerful predictor of prognosis for ENKTL, which suggests a role for IL-15 in the pathogenesis of this disease and offers new insight into potential therapeutic strategies.

Serum levels of interleukin-9 correlate with negative prognostic factors in extranodal NK/T-cell lymphoma.

Interleukin-9 (IL-9) is more functionally diverse than previously expected, especially with regards to lymphomagenesis. However, the relationship between IL-9 and the clinicopathological features of extranodal NK/T-cell lymphoma is less well established. Patients with this lymphoma in Sun Yat-Sen University Cancer Center between January 2003 and March 2013 were systematically reviewed in an intention-to-treat analysis. Baseline serum IL-9 levels were determined using sandwich enzyme-linked immunosorbent assays. A total of seventy-four patients were enrolled in this study. The mean concentration of serum IL-9 for all patients was 6.48 pg/mL (range: 1.38-51.87 pg/mL). Age, B symptoms and local lymph node involvement were found to be related to high serum IL-9 levels. Patients with low IL-9 levels tended to have higher rates of complete remission. Notably, the median progression-free survival (PFS) and overall survival (OS) were longer in the low IL-9 level group than in the high IL-9 level group (PFS: 68.7 months vs. 28.3 months, P<0.001; OS: 86 months vs. 42.8 months, P = 0.001). Multivariate analysis revealed independent prognostic factors for PFS. Similarly, high IL-9 levels (P = 0.003) and old age (P = 0.007) were independently predictive of shorter OS. Serum IL-9 is closely related to several clinical features, such as age, B symptoms and local lymph node involvement. It can also be a significant independent prognostic factor for extranodal NK/T-cell lymphoma, which suggests a role for IL-9 in the pathogenesis of this disease and offers new insight into potential therapeutic strategies.

Adenovirus-mediated delivery of the human IFN-γ gene potentiates the cytotoxicity of daunorubicin against leukemic cells through downregulation of the α4ß1 integrin/ILK/apoptosis pathway.

The recurrence of acute myeloid leukemia (AML) is primarily attributed to drug resistance and minimal residual disease. In addition, adhesion of hematopoietic tumor cells to bone marrow extracellular matrix via ß1 integrins (α4ß1 and α5ß1) is crucial in this process. In the current study, the viability and antiapoptotic ability of U937 cells exposed to daunorubicin (DNR) were shown to be enhanced when cocultured with the mesenchymal stem cells (MSCs) or MSCs transduced with a recombinant adeno-LacZ vector (MSCs-LacZ), followed by upregulation of the adhesion rate of leukemic cells. Notably, cell viability, antiapoptotic and adhesive ability were reversed when U937 cells were cocultured with the MSCs transduced with a recombinant adeno-IFN-γ vector (MSCs-IFN-γ). Transwell assay showed that cell-cell contact is essential for the protective effects of unmodified MSC and the antitumor effects of IFN-γ-expressing MSCs. Western blot analysis and caspase activity assay results indicated that the α4ß1 integrin/ILK/apoptosis pathway contributes to the combination effects of DNR and MSCs-IFN-γ, which was further confirmed by the results of the α4ß1 integrin siRNA experiments. Thus, gene-modified MSCs expressing IFN-γ may enhance the cytotoxicity of DNR against leukemic cells through downregulation of the α4ß1 pathway and may present a novel promising therapeutic strategy for AML.

"Sandwich" Chemotherapy (CT) with Radiotherapy (RT) improves outcomes in patients with stage IE/IIE extranodal natural killer (NK)/T-cell Lymphomas.

The extranodal natural killer/T-cell lymphoma (ENKTL) shows high local or systemic failure rates when radiotherapy (RT) is taken as the primary treatment, suggesting a role for chemotherapy (CT) added to RT for this disease. However, the appropriate mode of combined modality therapy (CMT) has not been fully defined. A total of one hundred and twenty-one patients with ENKTL receiving sandwich CT with RT were reviewed between January 2003 and August 2012. The primary endpoints were the response rate, progression-free survival (PFS), overall survival (OS), and the relapse rate. After the initial CT, there were 84 (69.4%) patients in CR, 22 (18.2%) patients in PR, 9 (7.4%) patients in SD, and 6 (5%) patients in PD, respectively. At the end of RT, the CR, PR, SD, and PD rates for all patients were 90.9% (n=110), 1.7% (n=2), 4.1% (n=5), and 3.3% (n=4), respectively. After a median follow-up of 42.3 months (3.5~112.3 months), the 5-year PFS was 74.7% (95% CI 70.4%~79.0%), and 5-year OS was 77.3% (95% CI 67.9%~86.7%). Disease progression was documented in 25 (20.7%) patients. The rates of systemic failure, local failure, and regional failure were 18.2%, 5.8%, 1.7%, respectively. Twenty death events (16.5%) were observed for the entire group of patients (18 deaths related to PD). Furthermore, CR to the initial CT and low Korean Prognostic Index (KPI) can independently predict long PFS and OS. The sandwich CMT achieved an excellent outcome for localized ENKTL with acceptable toxicity. We recommend it can be applied as the optimal choice for localized ENKTL.

Beclin-1 expression is a significant predictor of survival in patients with lymph node-positive gastric cancer.

BACKGROUND: Beclin 1 is a main actor of autophagy. The expression of Beclin 1 and its prognostic role in gastric cancer is largely unexplored. The purpose of the present study is to investigate the expression of beclin 1 in gastric cancer cells, tissues and its relationship with prognosis. METHODS: The expression of Beclin 1 was detected in 271 specimens of lymph-node positive gastric cancer patients by immunohistochemistry. The correlation of Beclin 1 expression to clinicopathologic features and survival of gastric cancer was studied. Beclin-1 expression in gastric cancer cell lines and clinical specimens is also detected using reverse transcription-PCR and Western blotting. RESULTS: Beclin 1 is up-regulated at both mRNA and protein levels in six gastric cancer cell lines compared with those in normal gastric mucosa cell line (GES-1). The expression of Beclin-1 in gastric clinical specimens is also higher than those in the adjacent noncancerous tissues. Of the 271 patients, 229 (84.5%) were Beclin 1 high expression tumors by immunohistochemistry. Beclin 1 expression is closely associated with intravascular embolus. Kaplan-Meier analysis showed high beclin 1 expression was associated with longer overall survival. Both univariate analysis and multivariate analysis revealed that Beclin 1 expression were independent prognostic factors in the patients with node-positive gastric cancer. CONCLUSIONS: Our findings strongly suggest that Beclin 1 has a potential role in tumorigenesis of gastric cancer and could be a promising biomarker for predicting the prognosis of patients with lymph node-positive gastric cancer. It might also serve as a novel therapeutic target for gastric cancer treatment.

Curcumin potentiates antitumor activity of L-asparaginase via inhibition of the AKT signaling pathway in acute lymphoblastic leukemia.

L-asparaginase (L-ASP) is a universal component of therapy for acute lymphoblastic leukemia (ALL). Curcumin is a naturally occurring yellow pigment that is derived from the rhizome of Curcuma longa. In this study, we evaluated the cytotoxicity of the combined treatment of L-ASP and curcumin in three ALL cell lines. Synergistic cytotoxicity was observed in all three cell lines following the combined treatment of curcumin and L-ASP. Our results revealed that curcumin significantly enhanced the antitumor effect of L-ASP in the three ALL cell lines compared to that for L-ASP alone ( p < 0.05). Curcumin and L-ASP co-treatments induced apoptosis, via activation and cleavage of caspase-8 and BID cleavage accompanied by release of cytochrome c and activation of caspase-9/3, compared to the group treated with only L-ASP and the control group. Furthermore, the combination of curcumin and L-ASP led to significant reductions in phosphorylated AKT and expression of AKT-regulated gene products (FoxO1, GSK3ß, IKKα, NF-κB, XIAP) compared with the group treated with only L-ASP and the control group. Overall, our findings suggest that curcumin potentiates the antitumor effects of L-ASP in acute lymphoblastic leukemia by constitutively inhibiting AKT and AKT-regulated gene products.

Induction therapy using the MRC UKALLXII/ECOG E2993 protocol in Chinese adults with acute lymphoblastic leukemia.

Patients with newly diagnosed acute lymphoblastic leukemia (ALL) at a single institution were analyzed retrospectively. From 2006 to 2010, 47 patients were treated using the MRC UKALLXII/ECOG E2993 protocol. Prior to July 2005, 40 patients had been treated with the JALSG ALL 87 protocol. A complete remission (CR) rate of 91.5% was achieved with the E2993 protocol, which was not significantly higher than the 80% achieved using JALSG (P > 0.05). The median duration of CR in months was 19 for all patients treated with the MRC UKALLXII/ECOG E2993 protocol. Ph+ patients showed a median CR duration of 11.5 months, while Ph- patients had a significantly longer CR duration of 19 months (P = 0.019). Further, Ph- patients at standard risk (stratified on the basis of age and white blood cell count at diagnosis) had a CR duration of 21 months, which was significantly longer than the 12-month CR duration for the ten Ph- patients at high risk (P = 0.001). Significant differences were found in the 2-year event-free survival and overall survival rates between the MRC UKALLXII/ECOG E2993 and JALSG ALL 87 groups in the following three cohorts: all patients (P = 0.009 and 0.022, respectively), Ph- patients (P = 0.009 and 0.018, respectively), and standard-risk patients (P = 0.014 and 0.007, respectively). The overall mortality rate for induction therapy in the MRC UKALLXII/ECOG E2993 group was 2.1% (1 of 47 patients). One or more instances of grade IV myelosuppression occurred during induction therapy. Among the non-hematological toxicities, alopecia and elevated ALT and AST levels were the most common. The levels of ALT and AST could be reduced to less than twofold the normal values within 1-2 weeks. The data indicate that the MRC UKALLXII/ECOG E2993 regimen is well tolerated in Chinese adults with ALL and can improve survival compared with the JALSG ALL 87 protocol. Risk stratification at diagnosis based on age and WBC count is suitable for adults with ALL, and it is necessary to adopt different strategies as determined by diagnostic results. Lastly, Ph+ patients have an extremely poor prognosis.

Activated mammalian target of rapamycin is a potential therapeutic target in gastric cancer.

BACKGROUND: The mammalian target of rapamycin (mTOR) plays a key role in cellular growth and homeostasis. The purpose of our present study is to investigate the expression of activated mTOR (p-mTOR) in gastric cancer patients, their prognostic significance and the inhibition effect of RAD001 on tumor growth and to determine whether targeted inhibition of mTOR could be a potential therapeutic strategy for gastric cancer. METHODS: The expression of p-mTOR was detected in specimens of 181 gastric cancers who underwent radical resection (R0) by immunohistochemistry. The correlation of p-mTOR expression to clinicopathologic features and survival of gastric cancer was studied. We also determined the inhibition effect of RAD001 on tumor growth using BGC823 and AGS human gastric cancer cell lines. RESULTS: Immunostaining for p-mTOR was positive in 93 of 181 (51.4%) gastric cancers, closely correlated with lymph node status and pTNM stage. Patients with p-mTOR positive showed significantly shorter disease-free survival (DFS) and overall survival (OS) rates than those with p-mTOR-negative tumors in univariable analyses, and there was a trend toward a correlation between p-mTOR expression and survival in multivariable analyses. RAD001 markedly inhibited dose-dependently proliferation of human gastric carcinoma cells by down-regulating expression of p70s6k, p-p70s6k, C-myc, CyclinD1 and Bcl-2, up-regulating expression of P53. CONCLUSIONS: In gastric cancer, p-mTOR is a potential therapeutic target and RAD001 was a promising treatment agent with inducing cell cycle arrest and apoptosis by down-regulating expression of C-myc, CyclinD1 and Bcl-2, up-regulating expression of P53.

Positive lymph node ratio is an independent prognostic factor in gastric cancer after d2 resection regardless of the examined number of lymph nodes.

The purpose of this study was to clarify the outcome of the ratio between metastatic and examined lymph nodes (N ratio) in gastric cancer patients with < or =15 examined lymph nodes after D2 lymphadenectomy. A retrospective study was performed in 906 patients with gastric cancer who had undergone D2 resection. Patients with < or =15 examined lymph nodes (group 1, n = 729) and those with >15 lymph nodes (group 2, n = 177) were analyzed separately. N ratio categories were identified as follows: N ratio 0, 0%; N ratio 1, 1% to 9%; N ratio 2, 10% to 25%; N ratio 3, >25%. Univariate analysis found that both the tumor, node, metastasis system (N staging system) and N ratio system well classified patients with significantly different prognosis. By multivariate analysis, only the N ratio classification was retained as an independent prognostic factor in both group 1 and 2 compared with the N stage system. Furthermore, when patients were divided into four groups according to the number of lymph nodes examined (1 to 3, 4 to 7, 8 to 11, and 12 to 15), the 5-year survival rates remained similar between groups according to the same N ratio (p > .05). Positive N ratio classification is a better prognostic tool compared with N staging system after D2 resection in patients with gastric cancer. It can prevent stage migration and can be used regardless of the examined number of lymph nodes.