Microbiota Manipulation With Prebiotics and Probiotics in Patients Undergoing Stem Cell Transplantation

Abstract

Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy that often comes at the cost of complications such as graft-versus-host disease and post-transplant infections. With improved technology to understand the ecosystem of microorganisms (viruses, bacteria, fungi, and microeukaryotes) that make up the gut microbiota, there is increasing evidence of the microbiota's contribution to the development of post-transplant complications. Antibiotics have traditionally been the mainstay of microbiota-altering therapies available to physicians. Recently, interest is increasing in the use of prebiotics and probiotics to support the development and sustainability of a healthier microbiota. In this review, we will describe the evidence for the use of prebiotics and probiotics in combating microbiota dysbiosis and explore the ways in which they may be used in future research to potentially improve clinical outcomes and decrease rates of graft-versus-host disease (GVHD) and post-transplant infection.

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Radiographic patterns and survival of patients with early and late brain metastases in EGFR wild type and mutant non small cell lung cancer

Abstract

Brain metastasis (BM) in NSCLC is a negative prognostic indicator. In the era of EGFR mutations we evaluated the difference between early (≤6 months from diagnosis) versus late BM (>6 months), in EGFR wild type (WT) and mutant (MT) NSCLC patients with respect to radiographic patterns and overall survival (OS). A retrospective study was conducted of referred patients with non-squamous NSCLC with known EGFR mutation status treated for BM from Mar 2010–Dec 2012. Radiographic patterns, treatment and survival were collected. 430 patients were identified: 327 WT (207 early vs. 120 late) and 103 MT (65 early vs. 38 late). Early and late BM radiographic patterns were similar in EGFR WT patients. In EGFR MT there was a trend towards multiple lesions in the late compared to early BM group. OS from initial diagnosis early BM: WT 7.1 months versus MT 19.9 months (p < 0.001). OS from initial diagnosis late BM: WT 24.9 months versus MT 25.6 months (p = 0.51). In multivariate analysis chemotherapy, single lesion and late BM were associated with better survival in WT patients whereas age, and systemic treatment but not BM timing or single lesion were predictive of better outcomes in MT patients. In early BM, EGFR MT have an OS comparable to late BM. In contrast, early BM EGFR WT have a significantly reduced survival compared to late BM. The positive outcome in EGFR MT may be secondary to systemic control and EGFR TKI penetrance across the blood brain barrier.

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IDH mutation is associated with higher risk of malignant transformation in low-grade glioma

Abstract

Acquisition of IDH1 or IDH2 mutation (IDHmut) is among the earliest genetic events that take place in the development of most low-grade glioma (LGG). IDHmut has been associated with longer overall patient survival. However, its impact on malignant transformation (MT) remains to be defined. A collection of 210 archived adult LGG previously stratified by IDHmut, MGMT methylation (MGMTmet), 1p/19q combined loss of heterozygosity (1p19qloh) and TP53 immunopositivity (TP53pos) status was analyzed. We used multistate models to assess MT-free survival, considering one initial, one transient (MT), and one absorbing state (death). Missing explanatory variables were multiply imputed. Overall, although associated with a lower risk of death (HR_DEATH = 0.35, P = 0.0023), IDHmut had a non-significantly higher risk of MT (HR_MT = 1.84; P = 0.1683) compared to IDH wild type (IDHwt). The double combination of IDHmut and MGMTmet and the triple combination of IDHmut, MGMTmet and 1p/19qloh, despite significantly lower hazards for death (HR_DEATH versus IDHwt: 0.35, P = 0.0194 and 0.15, P = 0.0008, respectively), had non-significantly different hazards for MT. Conversely, the triple combination of IDHmut/MGMTmet/TP53pos, with a non-significantly different hazard for death, had a significantly higher hazard for MT than IDHwt (HR_MT versus IDHwt: 2.83; P = 0.0452). Although IDHmut status is associated with longer overall patient survival, all IDHmut/MGMTmet subsets consistently showed higher risks of MT than of death, compared to IDHwt LGG. This supports the findings that molecular events relevant to IDH mutations impact early glioma development prior to malignant transformation.

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Radiographic patterns and survival of patients with early and late brain metastases in EGFR wild type and mutant non small cell lung cancer

Abstract

Brain metastasis (BM) in NSCLC is a negative prognostic indicator. In the era of EGFR mutations we evaluated the difference between early (≤6 months from diagnosis) versus late BM (>6 months), in EGFR wild type (WT) and mutant (MT) NSCLC patients with respect to radiographic patterns and overall survival (OS). A retrospective study was conducted of referred patients with non-squamous NSCLC with known EGFR mutation status treated for BM from Mar 2010–Dec 2012. Radiographic patterns, treatment and survival were collected. 430 patients were identified: 327 WT (207 early vs. 120 late) and 103 MT (65 early vs. 38 late). Early and late BM radiographic patterns were similar in EGFR WT patients. In EGFR MT there was a trend towards multiple lesions in the late compared to early BM group. OS from initial diagnosis early BM: WT 7.1 months versus MT 19.9 months (p < 0.001). OS from initial diagnosis late BM: WT 24.9 months versus MT 25.6 months (p = 0.51). In multivariate analysis chemotherapy, single lesion and late BM were associated with better survival in WT patients whereas age, and systemic treatment but not BM timing or single lesion were predictive of better outcomes in MT patients. In early BM, EGFR MT have an OS comparable to late BM. In contrast, early BM EGFR WT have a significantly reduced survival compared to late BM. The positive outcome in EGFR MT may be secondary to systemic control and EGFR TKI penetrance across the blood brain barrier.

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IDH mutation is associated with higher risk of malignant transformation in low-grade glioma

Abstract

Acquisition of IDH1 or IDH2 mutation (IDHmut) is among the earliest genetic events that take place in the development of most low-grade glioma (LGG). IDHmut has been associated with longer overall patient survival. However, its impact on malignant transformation (MT) remains to be defined. A collection of 210 archived adult LGG previously stratified by IDHmut, MGMT methylation (MGMTmet), 1p/19q combined loss of heterozygosity (1p19qloh) and TP53 immunopositivity (TP53pos) status was analyzed. We used multistate models to assess MT-free survival, considering one initial, one transient (MT), and one absorbing state (death). Missing explanatory variables were multiply imputed. Overall, although associated with a lower risk of death (HR_DEATH = 0.35, P = 0.0023), IDHmut had a non-significantly higher risk of MT (HR_MT = 1.84; P = 0.1683) compared to IDH wild type (IDHwt). The double combination of IDHmut and MGMTmet and the triple combination of IDHmut, MGMTmet and 1p/19qloh, despite significantly lower hazards for death (HR_DEATH versus IDHwt: 0.35, P = 0.0194 and 0.15, P = 0.0008, respectively), had non-significantly different hazards for MT. Conversely, the triple combination of IDHmut/MGMTmet/TP53pos, with a non-significantly different hazard for death, had a significantly higher hazard for MT than IDHwt (HR_MT versus IDHwt: 2.83; P = 0.0452). Although IDHmut status is associated with longer overall patient survival, all IDHmut/MGMTmet subsets consistently showed higher risks of MT than of death, compared to IDHwt LGG. This supports the findings that molecular events relevant to IDH mutations impact early glioma development prior to malignant transformation.

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Lycopene acts through inhibition of IκB kinase to suppress NF-κB signaling in human prostate and breast cancer cells

Abstract

We studied the effect of the potent dietary antioxidant lycopene on multiple points along the nuclear factor kappa B (NF-κB) signaling pathway in prostate and breast cancer cells. Lycopene significantly inhibited prostate and breast cancer cell growth at physiologically relevant concentrations of ≥1.25 μM. Similar concentrations also caused a 30–40 % reduction in inhibitor of kappa B (IκB) phosphorylation in the cells, as determined by western blotting. Furthermore, the same degree of inhibition by lycopene was observed for NF-κB transcriptional activity, as determined by reporter gene assay. Concomitant with this, immunofluorescence staining of lycopene-treated cells showed a significant suppression (≥25 %) of TNF-induced NF-κB p65 subunit nuclear translocation. Further probing of lycopene's effects on upstream elements of the NF-κB pathway showed a 25 % inhibition of both activity of recombinant IκB kinase β (IKKβ) kinase in a cell-free in vitro assay, as well as activity of IKKβ immunoprecipitated from MDA-MB-231 cells treated with lycopene. In conclusion, the anticancer properties of lycopene may occur through inhibition of the NF-κB signaling pathway, beginning at the early stage of cytoplasmic IKK kinase activity, which then leads to reduced NF-κB-responsive gene regulation. Furthermore, these effects in cancer cells were observed at concentrations of lycopene that are relevant and achievable in vivo.

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Monitoring the treatment outcome in endometrial cancer patients by CEA and TATI

Abstract

An attempt was made to compare the usefulness of determining markers carcinoembryonic antigen (CEA) and tumor-associated trypsin inhibitor (TATI) in endometrial cancer patients in whom recurrence or distant metastasis was diagnosed in observation after treatment. The study included 316 patients aged 32–81, average age of 61 years, SD = 8.72, with diagnosed endometrial cancer, treated between 1994 and 1995 at the Oncology Center in Warsaw and then under observation from 4 months to 17 years after completion of treatment. The levels of the markers TATI and CEA were assessed from the first five serum samples taken during postoperative radiotherapy and in the initial period of observation after completed treatment. Receiver operating characteristic (ROC) curves were generated, determining the sensitivity and specificity of both CEA and TATI in patients who experienced treatment failure, i.e., recurrence and distant metastasis. Assessing the sensitivity of the marker CEA, it was found that if in the third sample, i.e., during radiation therapy, the marker level increased by more than 20 % compared with the first sample, then recurrence of cancer occurred during the observation period in 75.9 % of patients and metastatic occurred in 69.7 % of patients. In the evaluation of the marker TATI, it was found that if the level of TATI between the first and the third sample increases by 10.6 % from the initial level, then in 84.4 % (sensitivity) of cases, this means the occurrence of cancer recurrence and in 75.7 % (sensitivity) of cases, the occurrence of metastasis. The specificity of both markers is low and not useful diagnostically.

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Combination of platelet count and mean platelet volume (COP-MPV) predicts postoperative prognosis in both resectable early and advanced stage esophageal squamous cell cancer patients

Abstract

The aim of this study is to search the most powerful prognostic factor from routine blood test for esophageal squamous cell cancer (ESCC) patients. Multiple laboratory tests were evaluated including those reflecting red blood cell parameters (hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and red blood cell distribution width (RDW)), platelet morphological parameters (mean platelet volume (MPV) and platelet count (PLT)), blood coagulation status (D-dimer), and tumor biomarker (CA19-9). Known inflammatory indices (NLR and PLR) were also calculated. A total of 468 patients who were diagnosed with ESCC between December 2005 and December 2008 were retrospectively analyzed in this study. By utilizing univariate and multivariate Cox proportional hazard analyses, we found that PLT and MPV were significantly associated with overall survival (OS) and disease-free survival (DFS) of ESCC patients, with optimal cutoff values of 212 and 10.6, respectively. Moreover, the combination of the preoperative PLT and MPV (COP-MPV) was calculated as follows: patients with both PLT (≥212 × 10⁹ L⁻¹) and MPV (≥10.6 fL) elevation were assigned a score of 2, and patients with one or neither were assigned a score of 1 and 0. The COP-MPV was an independent prognostic factor for OS (hazard ratio (HR) 0.378, 95 % confidence interval (CI) 0.241 to 0.593, P < 0.001, 0/2) and DFS (HR 0.341, 95 % CI 0.218 to 0.534, P < 0.001, 0/2) in multivariate analyses. In subgroup analyses for early (stages I and II) and locally (stage III) advanced stage patients, COP-MPV was found significantly associated with OS and DFS in each group (P = 0.025 and P = 0.018 for OS and P = 0.029 and P = 0.002 for DFS). In conclusion, we considered that COP-MPV is a promising predictor for postoperative survival in ESCC patients.

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Low expression of fibulin-1 correlates with unfavorable prognosis in gastric cancer

Abstract

The tumor-suppressing role of fibulin-1 has been described in several types of cancers. However, the expression and role of fibulin-1 in the development and progression of gastric cancer (GC) remain largely unknown. In this study, RT-PCR and immunochemistry were used to detect the fibulin-1 expression in GC samples. We have found that the fibulin-1 protein and mRNA levels were downregulated in GC. When investigating the correlation between fibulin-1 expression and clinicopathological characteristics, we have found that low fibulin-1 protein expression was associated with poor tumor differentiation and advanced N stage. Low fibulin-1 protein expression was also an independent prognostic factor for patient survival. To clarify the reason of fibulin-1 downregulation in GC, the mRNA expression and methylation status of fibulin-1 were examined in GC fresh tissue samples (n = 36). We found that the transcriptional expression of fibulin-1 was negatively associated with fibulin-1 promoter hypermethylation, and fibulin-1 hypermethylation was associated with Helicobacter pylori infection. Finally, the effects of fibulin-1 overexpression on cell proliferation and apoptosis were examined. We have found that fibulin-1 overexpression suppressed the growth of GC both in vitro and in vivo and induced apoptosis by increasing cleaved caspase-3 expression. In conclusion, fibulin-1 acts as a tumor suppressor gene, is frequently hypermethylated in GC, and can potentially serve as a useful biomarker for patient prognosis.

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Influence of XPC , XPD , XPF , and XPG gene polymorphisms on the risk and the outcome of acute myeloid leukemia in a Romanian population

Abstract

XPC, XPD, XPF, and XPG genes are implicated in the nucleotide excision repair (NER) system. Gene polymorphisms in NER repair system may influence the individual's capacity to recognize and repair DNA lesions, thus increasing the cancer risk. We hypothesized that these gene polymorphisms might influence the probability of developing acute myeloid leukemia (AML). We investigated the XPC, XPD, XPF, and XPG gene polymorphisms in 108 AML cases and 163 healthy controls. Also cytogenetic analyses besides FLT3 and DNMT3A mutations status were investigated. We found that variant genotypes (heterozygous and homozygous) of XPD 2251A > C and 22541A > C and the heterozygous genotype of XPG 3507G > C were associated with the risk of developing AML (OR = 2.55; 95% CI = 1.53–4.25; p value <0.001; OR = 1.66, 95 % CI = 1.02–2.72; p value = 0.047, and OR = 2.36; 95 % CI = 1.32–4.21; p value = 0.004, respectively). No association was found between white blood cell counts, FLT3, DNMT3A mutations, cytogenetic risk group, and variant genotypes of none of the analyzed polymorphisms. Variant homozygous XPF 673C > T genotype was associated with higher dose of cytosine arabinoside treatment administrated to AML patients (p value = 0.04). No differences were found regarding survival time and variant genotype in the investigated gene polymorphisms with the exception of XPD 2251A > C. In conclusion, XPD 22541A > C, XPD 2251A > C, and XPG 3507G > C gene polymorphisms confer susceptibility to AML, while XPC 2920A > C, XPF-673C > T, XPF 11985A > G are not associated with AML.

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MicroRNA-21 promotes proliferation, invasion and suppresses apoptosis in human osteosarcoma line MG63 through PTEN/Akt pathway

Abstract

Osteosarcoma, which accounts for 5 % of pediatric tumor, remains the major cause of death among orthopedic malignancies. However, the factors associated with its malignant biological behavior are still poorly understood. MicroRNAs are a class of small noncoding RNAs, which have been considered to associate with malignant progression including cell differentiation, proliferation, apoptosis, invasion, and distant metastasis. In our research, we found that microRNA-21 (miR-21) was significantly overexpressed in human osteosarcoma cell line MG63 compared to human fetal osteoblastic cell line hFOB1.19 by using quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, miR-21 overexpression in MG63 caused a significant raise in cell proliferation and invasion and a significant reduction in cell apoptosis. However, miR-21 underexpression in MG63 caused an opposite result. Western blotting displayed that proteins related with proliferation, apoptosis, and invasion were significantly changed in different groups, respectively. Furthermore, we demonstrated that PTEN may be a potential target of miR-21 in MG63 cells and miR-21 could activate PI3K/Akt pathway by suppressing PTEN expression. In summary, our findings suggested that miR-21 played an active role in osteosarcoma and it could predict the occurrence and development of osteosarcoma.

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Are SMAD7 rs4939827 and CHI3L1 rs4950928 polymorphisms associated with colorectal cancer in Egyptian patients?

Abstract

A wide variety of genes have been associated with colorectal cancer (CRC) development and progression. The SMAD7 gene encodes an intracellular protein, which inhibits the transforming growth factor beta (TGF-β) signaling pathway, thereby having a key role in the control of neoplastic processes in various organs. The CHI3L1 gene encodes glycoprotein YKL-40, which plays a role in cell proliferation, anti-apoptosis, and angiogenesis. The present study aimed to evaluate the association of single nucleotide polymorphisms (SNPs) SMAD7 rs4939827 and CHI3L1 rs4950928, as well as circulating TGFβ-1 and YKL-40 levels with CRC in an Egyptian population of 77 CRC patients and 36 healthy controls. Polymorphisms in the SMAD7 rs4939827 and the CHI3L1 rs4950928 genes were determined using the real-time polymerase chain reaction (RT-PCR). Both the SMAD7 rs4939827 TT genotype and the CHI3L1 rs4950928 C allele were associated with the rectal but not the colon cancer. In addition, the C allele of both SMAD7 rs4939827 and CHI3L1 rs4950928 was associated with increased serum levels of TGF-β1 and YKL-40, respectively. In conclusion, our data suggest that SMAD7 rs4939827 and CHI3L1 rs4950928 SNPs have no significant association with CRC. A significant association of SNP in SMAD7 rs4939827 and CHI3L1 rs4950928 was revealed between the rectal cancer and colon cancer patients.

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Overexpression of annexin A4 indicates poor prognosis and promotes tumor metastasis of hepatocellular carcinoma

Abstract

The prognosis of hepatocellular carcinoma (HCC) after surgical resection remains unsatisfactory for the majority of HCC patients who developed early recurrence or metastasis. There is still a lack of reliable biomarkers that can be used to predict the possibility of recurrence/metastasis in HCC patients after operation. In the current study, annexin A4, a calcium-dependent phospholipid-binding protein, has been found to be significantly elevated in HCC patients with early recurrence/metastasis, and had a strong correlation with portal vein tumor thrombosis (p = 0.03) and advanced BCLC stage (p = 0.002). Cox proportional hazards regression analysis revealed that annexin A4 was an independent prognostic predictor for both early recurrence/metastasis (HR = 1.519, p = 0.032) and overall survival (HR = 1.827, p = 0.009) after surgical resection. Meanwhile, Kaplan–Meier analysis showed that Patients with high-expression levels of annexin A4 had higher recurrence rate and shorter overall survival than those with low expression (log-rank test, p < 0.001). Furthermore, in vitro studies have demonstrated that overexpression of annexin A4 facilitated HCC cell migration and invasion via regulating epithelial–mesenchymal transition (EMT). In conclusion, annexin A4 has played important roles in the progression of HCC, and might act as a potential prognostic biomarker for HCC.

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Correlation of Cyfra 21-1 levels in saliva and serum with CK19 mRNA expression in oral squamous cell carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) accounts for 90 % of malignant lesions of oral cavity. The study assessed the potential of Cyfra 21-1 as a tumor marker in OSCC. The study included 50 patients of OSCC to evaluate levels of Cyfra 21-1 in serum and saliva by electrochemiluminescent immunoassay (ECLIA) and CK19 messenger RNA (mRNA) expression in tissue by florescent quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) along with healthy individuals as control. The salivary and serum Cyfra 21-1 levels in patients of OSCC were significantly higher compared to controls (p value < 0.01). There was a 2.75-fold increase in CK19 mRNA expression in OSCC cases compared to controls. A significant positive correlation was found between serum and salivary Cyfra 21-1, serum Cyfra 21-1, and CK19 mRNA expression and between salivary Cyfra 21-1 and CK19 mRNA expression. Among these, correlation between serum and salivary Cyfra 21-1 was highly significant. Salivary and serum Cyfra 21-1 showed significantly elevated levels in grade II OSCC compared to grade I histopathologically. Elevated levels of salivary Cyfra 21-1 were associated with recurrence in OSCC patients. Reverse operating curve constructed using 3 ng/ml as a cutoff for serum Cyfra 21-1 revealed the sensitivity and specificity to be 88 and 78.2 %, respectively. Using a cutoff value of 8.5 ng/ml for salivary Cyfra 21-1, the sensitivity was found to be 93.8 % and specificity 84.3 %. We advocate salivary Cyfra 21-1 as a better diagnostic marker over serum Cyfra 21-1 as well as a potential marker in the prognosis of OSCC.

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Reduced platelet transfusions and earlier platelet engraftment using alemtuzumab-based conditioning regimen in allogeneic stem cell transplantation

Abstract

Purpose

In patients undergoing allogeneic stem cell transplantation, conditioning regimens containing alemtuzumab instead of anti-thymocyte globulin (ATG) may result in an earlier platelet engraftment and a reduced number of platelet transfusions.

Methods

We performed a retrospective, single-center, case–control study analyzing time to engraftment and transfusion needs using alemtuzumab in comparison with ATG as part of conditioning protocol.

Results

Median values for time to platelet engraftment, number of transfused platelet concentrates and number of transfused red cell concentrates were 12 versus 19.5 days (p < 0.001), 2 versus 14 (p < 0.001) and 6 versus 14.5 (p = 0.003) in the alemtuzumab and ATG group. Time to leukocyte engraftment did not differ with median 15 days in both groups. Patients in the ATG group showed a significant higher decrease in platelet count during conditioning (68 vs. 29 %, p = 0.001), leading to significant lower median platelet counts at the day of stem cell infusion (38 vs. 95.5 Gpt/l, p = 0.008), and higher values for median C-reactive protein after first antibody infusion (69.0 vs. 43.6 mg/l, p = 0.001) compared with alemtuzumab group. Test for significance was done by using Wilcoxon rank-sum test. Subgroup analysis considering the type of ATG used (Thymoglobulin vs. ATG Fresenius) revealed that differences between alemtuzumab and ATG group were more due to effects of ATG Fresenius than Thymoglobulin.

Conclusions

The use of alemtuzumab in comparison with ATG as part of the conditioning regimen may be an approach to reduce the number of transfused platelet and red cell concentrates after allogeneic stem cell transplantation.

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Pharmacokinetic interaction between pazopanib and cisplatin regimen

Abstract

Purpose

A phase I study combining daily oral pazopanib and cisplatin (given iv every 3 weeks) was performed in order to determine the maximum tolerated dose of both drugs in combination. Pharmacokinetic interactions were evaluated.

Methods

Plasma pazopanib and ultrafilterable cisplatin concentrations were obtained in 32 patients treated according to four levels of dose corresponding to 200, 400 or 600 mg daily dose of pazopanib and 60 or 75 mg/m² of cisplatin. Two sequences of treatment were performed in order to explore any interaction of cisplatin on pazopanib pharmacokinetics and inversely. Data were analyzed using the NONMEM program.

Results

Maximum tolerated dose was 400 mg of pazopanib and 75 mg/m² of cisplatin. Mean (CV % for inter-individual variability) cisplatin clearance was 10.3 L/h (33.2 %) and appeared not to be influenced by pazopanib. However, pazopanib pharmacokinetics was significantly modified by the cisplatin regimen. Mean (CV %) of oral pazopanib clearance was 0.66 L/h (55 %) at Day 0 (before cisplatin administration), 24.8 % lower at Day 1 and 32.9 % lower at Day 2. The interaction is less likely to be due to cisplatin than to a competitive inhibition of pazopanib metabolism and efflux by aprepitant, an antiemetic drug systematically administered with cisplatin. The plasma pazopanib exposures observed at Day 0 with a 400 mg dose were similar to those observed at the recommended dose of pazopanib in monochemotherapy (800 mg) during the first-in-man phase 1 study.

Conclusion

The observed pazopanib plasma overexposure probably contributed to the poor tolerance encountered during this phase 1 study.

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Radionuclide Therapies in Prostate Cancer: Integrating Radium-223 in the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) frequently metastasizes to the bone, often resulting in painful skeletal events, reduced quality of life, and reduced survival. The beta-emitting radiopharmaceuticals strontium-89 and samarium-153 alleviated pain in mCRPC patients with widespread skeletal metastases and have been associated with myelotoxicity. Radium-223, a first-in-class alpha-emitting radiopharmaceutical, prolonged overall survival, delayed symptomatic skeletal events, and improved quality of life, versus placebo, in patients with CRPC and symptomatic bone metastases and no visceral metastases. Radium-223 provided survival benefit to patients with CRPC and symptomatic bone metastases, regardless of prior docetaxel use. Importantly, prostate-specific antigen level and pain palliation were not a measure of radium-223 treatment response and should not alter the decision to administer all six radium-223 injections, the recommended regimen for survival benefit. Radium-223 was generally well tolerated, leading to ongoing clinical trials in combination with other therapeutics. Thus, radium-223 is a valuable addition to the mCRPC treatment armamentarium.

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Effect of Spirulina maxima Supplementation on Calcium, Magnesium, Iron, and Zinc Status in Obese Patients with Treated Hypertension

Abstract

The effects of Spirulina maxima supplementation on calcium, magnesium, iron, and zinc status were studied in a double-blind placebo-controlled trial of 50 obese subjects with treated hypertension, each randomized to receive 2 g of spirulina or a placebo daily for 3 months. At baseline and after treatment, the calcium, magnesium, iron, and zinc concentration in plasma was assessed. It was found that 3 months of S. maxima supplementation resulted in a significant decrease in the iron level in the plasma of obese patients. In conclusion, this is the first clinical study on the influence of spirulina supplementation on mineral status in obese patients with hypertension. Spirulina supplementation affects the iron status of obese Caucasians with well-treated hypertension.

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Effect of regulation reform on clinical trials for registering novel therapeutic agents in Taiwan: a chronological analysis

Summary

The registration process for new drugs is crucial in the clinical application of medicines. Previously, the registration of imported novel therapeutic agents in Taiwan depended considerably on their approvals in developed countries. The Taiwanese government enacted Article 38–1 of the Regulations for Registration of Medicinal Products in September 2009. According to the new submission criteria, approvals may be exempted if the number of Taiwanese participants in the clinical trials fulfills the required threshold. The present study compared the profiles of clinical trials of novel therapeutic agents before and after the enactment of this regulation in terms of over-threshold trials, structural types, and therapeutic areas across phases. The outcome—whether the liberalization of the submission criteria functioned as an incentive to launch clinical trials in Taiwan—was also evaluated. The results revealed that the number of clinical trial applications increased after the reformed regulation was enacted, even after the over-threshold criteria were considered; however, the increase disappeared for phase III trials. Most clinical trials were for chemical products and antineoplastic agents across all phases and study periods before and after the enactment of Article 38–1. Furthermore, the increase in the number of international clinical trials conducted in Taiwan was not directly caused by the regulation reform because the percentage of investigational products fulfilling the exemption criteria did not increase. These paradoxical results were interpreted in several aspects, referring particularly to the well-established infrastructure for launching clinical trials as well as the integral environment of medical services in Taiwan.

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Monitoring the treatment outcome in endometrial cancer patients by CEA and TATI

Abstract

An attempt was made to compare the usefulness of determining markers carcinoembryonic antigen (CEA) and tumor-associated trypsin inhibitor (TATI) in endometrial cancer patients in whom recurrence or distant metastasis was diagnosed in observation after treatment. The study included 316 patients aged 32–81, average age of 61 years, SD = 8.72, with diagnosed endometrial cancer, treated between 1994 and 1995 at the Oncology Center in Warsaw and then under observation from 4 months to 17 years after completion of treatment. The levels of the markers TATI and CEA were assessed from the first five serum samples taken during postoperative radiotherapy and in the initial period of observation after completed treatment. Receiver operating characteristic (ROC) curves were generated, determining the sensitivity and specificity of both CEA and TATI in patients who experienced treatment failure, i.e., recurrence and distant metastasis. Assessing the sensitivity of the marker CEA, it was found that if in the third sample, i.e., during radiation therapy, the marker level increased by more than 20 % compared with the first sample, then recurrence of cancer occurred during the observation period in 75.9 % of patients and metastatic occurred in 69.7 % of patients. In the evaluation of the marker TATI, it was found that if the level of TATI between the first and the third sample increases by 10.6 % from the initial level, then in 84.4 % (sensitivity) of cases, this means the occurrence of cancer recurrence and in 75.7 % (sensitivity) of cases, the occurrence of metastasis. The specificity of both markers is low and not useful diagnostically.

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Combination of platelet count and mean platelet volume (COP-MPV) predicts postoperative prognosis in both resectable early and advanced stage esophageal squamous cell cancer patients

Abstract

The aim of this study is to search the most powerful prognostic factor from routine blood test for esophageal squamous cell cancer (ESCC) patients. Multiple laboratory tests were evaluated including those reflecting red blood cell parameters (hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and red blood cell distribution width (RDW)), platelet morphological parameters (mean platelet volume (MPV) and platelet count (PLT)), blood coagulation status (D-dimer), and tumor biomarker (CA19-9). Known inflammatory indices (NLR and PLR) were also calculated. A total of 468 patients who were diagnosed with ESCC between December 2005 and December 2008 were retrospectively analyzed in this study. By utilizing univariate and multivariate Cox proportional hazard analyses, we found that PLT and MPV were significantly associated with overall survival (OS) and disease-free survival (DFS) of ESCC patients, with optimal cutoff values of 212 and 10.6, respectively. Moreover, the combination of the preoperative PLT and MPV (COP-MPV) was calculated as follows: patients with both PLT (≥212 × 10⁹ L⁻¹) and MPV (≥10.6 fL) elevation were assigned a score of 2, and patients with one or neither were assigned a score of 1 and 0. The COP-MPV was an independent prognostic factor for OS (hazard ratio (HR) 0.378, 95 % confidence interval (CI) 0.241 to 0.593, P < 0.001, 0/2) and DFS (HR 0.341, 95 % CI 0.218 to 0.534, P < 0.001, 0/2) in multivariate analyses. In subgroup analyses for early (stages I and II) and locally (stage III) advanced stage patients, COP-MPV was found significantly associated with OS and DFS in each group (P = 0.025 and P = 0.018 for OS and P = 0.029 and P = 0.002 for DFS). In conclusion, we considered that COP-MPV is a promising predictor for postoperative survival in ESCC patients.

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Influence of XPC , XPD , XPF , and XPG gene polymorphisms on the risk and the outcome of acute myeloid leukemia in a Romanian population

Abstract

XPC, XPD, XPF, and XPG genes are implicated in the nucleotide excision repair (NER) system. Gene polymorphisms in NER repair system may influence the individual's capacity to recognize and repair DNA lesions, thus increasing the cancer risk. We hypothesized that these gene polymorphisms might influence the probability of developing acute myeloid leukemia (AML). We investigated the XPC, XPD, XPF, and XPG gene polymorphisms in 108 AML cases and 163 healthy controls. Also cytogenetic analyses besides FLT3 and DNMT3A mutations status were investigated. We found that variant genotypes (heterozygous and homozygous) of XPD 2251A > C and 22541A > C and the heterozygous genotype of XPG 3507G > C were associated with the risk of developing AML (OR = 2.55; 95% CI = 1.53–4.25; p value <0.001; OR = 1.66, 95 % CI = 1.02–2.72; p value = 0.047, and OR = 2.36; 95 % CI = 1.32–4.21; p value = 0.004, respectively). No association was found between white blood cell counts, FLT3, DNMT3A mutations, cytogenetic risk group, and variant genotypes of none of the analyzed polymorphisms. Variant homozygous XPF 673C > T genotype was associated with higher dose of cytosine arabinoside treatment administrated to AML patients (p value = 0.04). No differences were found regarding survival time and variant genotype in the investigated gene polymorphisms with the exception of XPD 2251A > C. In conclusion, XPD 22541A > C, XPD 2251A > C, and XPG 3507G > C gene polymorphisms confer susceptibility to AML, while XPC 2920A > C, XPF-673C > T, XPF 11985A > G are not associated with AML.

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Overexpression of annexin A4 indicates poor prognosis and promotes tumor metastasis of hepatocellular carcinoma

Abstract

The prognosis of hepatocellular carcinoma (HCC) after surgical resection remains unsatisfactory for the majority of HCC patients who developed early recurrence or metastasis. There is still a lack of reliable biomarkers that can be used to predict the possibility of recurrence/metastasis in HCC patients after operation. In the current study, annexin A4, a calcium-dependent phospholipid-binding protein, has been found to be significantly elevated in HCC patients with early recurrence/metastasis, and had a strong correlation with portal vein tumor thrombosis (p = 0.03) and advanced BCLC stage (p = 0.002). Cox proportional hazards regression analysis revealed that annexin A4 was an independent prognostic predictor for both early recurrence/metastasis (HR = 1.519, p = 0.032) and overall survival (HR = 1.827, p = 0.009) after surgical resection. Meanwhile, Kaplan–Meier analysis showed that Patients with high-expression levels of annexin A4 had higher recurrence rate and shorter overall survival than those with low expression (log-rank test, p < 0.001). Furthermore, in vitro studies have demonstrated that overexpression of annexin A4 facilitated HCC cell migration and invasion via regulating epithelial–mesenchymal transition (EMT). In conclusion, annexin A4 has played important roles in the progression of HCC, and might act as a potential prognostic biomarker for HCC.

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MicroRNA-21 promotes proliferation, invasion and suppresses apoptosis in human osteosarcoma line MG63 through PTEN/Akt pathway

Abstract

Osteosarcoma, which accounts for 5 % of pediatric tumor, remains the major cause of death among orthopedic malignancies. However, the factors associated with its malignant biological behavior are still poorly understood. MicroRNAs are a class of small noncoding RNAs, which have been considered to associate with malignant progression including cell differentiation, proliferation, apoptosis, invasion, and distant metastasis. In our research, we found that microRNA-21 (miR-21) was significantly overexpressed in human osteosarcoma cell line MG63 compared to human fetal osteoblastic cell line hFOB1.19 by using quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, miR-21 overexpression in MG63 caused a significant raise in cell proliferation and invasion and a significant reduction in cell apoptosis. However, miR-21 underexpression in MG63 caused an opposite result. Western blotting displayed that proteins related with proliferation, apoptosis, and invasion were significantly changed in different groups, respectively. Furthermore, we demonstrated that PTEN may be a potential target of miR-21 in MG63 cells and miR-21 could activate PI3K/Akt pathway by suppressing PTEN expression. In summary, our findings suggested that miR-21 played an active role in osteosarcoma and it could predict the occurrence and development of osteosarcoma.

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Correlation of Cyfra 21-1 levels in saliva and serum with CK19 mRNA expression in oral squamous cell carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) accounts for 90 % of malignant lesions of oral cavity. The study assessed the potential of Cyfra 21-1 as a tumor marker in OSCC. The study included 50 patients of OSCC to evaluate levels of Cyfra 21-1 in serum and saliva by electrochemiluminescent immunoassay (ECLIA) and CK19 messenger RNA (mRNA) expression in tissue by florescent quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) along with healthy individuals as control. The salivary and serum Cyfra 21-1 levels in patients of OSCC were significantly higher compared to controls (p value < 0.01). There was a 2.75-fold increase in CK19 mRNA expression in OSCC cases compared to controls. A significant positive correlation was found between serum and salivary Cyfra 21-1, serum Cyfra 21-1, and CK19 mRNA expression and between salivary Cyfra 21-1 and CK19 mRNA expression. Among these, correlation between serum and salivary Cyfra 21-1 was highly significant. Salivary and serum Cyfra 21-1 showed significantly elevated levels in grade II OSCC compared to grade I histopathologically. Elevated levels of salivary Cyfra 21-1 were associated with recurrence in OSCC patients. Reverse operating curve constructed using 3 ng/ml as a cutoff for serum Cyfra 21-1 revealed the sensitivity and specificity to be 88 and 78.2 %, respectively. Using a cutoff value of 8.5 ng/ml for salivary Cyfra 21-1, the sensitivity was found to be 93.8 % and specificity 84.3 %. We advocate salivary Cyfra 21-1 as a better diagnostic marker over serum Cyfra 21-1 as well as a potential marker in the prognosis of OSCC.

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Pharmacokinetic interaction between pazopanib and cisplatin regimen

Abstract

Purpose

A phase I study combining daily oral pazopanib and cisplatin (given iv every 3 weeks) was performed in order to determine the maximum tolerated dose of both drugs in combination. Pharmacokinetic interactions were evaluated.

Methods

Plasma pazopanib and ultrafilterable cisplatin concentrations were obtained in 32 patients treated according to four levels of dose corresponding to 200, 400 or 600 mg daily dose of pazopanib and 60 or 75 mg/m² of cisplatin. Two sequences of treatment were performed in order to explore any interaction of cisplatin on pazopanib pharmacokinetics and inversely. Data were analyzed using the NONMEM program.

Results

Maximum tolerated dose was 400 mg of pazopanib and 75 mg/m² of cisplatin. Mean (CV % for inter-individual variability) cisplatin clearance was 10.3 L/h (33.2 %) and appeared not to be influenced by pazopanib. However, pazopanib pharmacokinetics was significantly modified by the cisplatin regimen. Mean (CV %) of oral pazopanib clearance was 0.66 L/h (55 %) at Day 0 (before cisplatin administration), 24.8 % lower at Day 1 and 32.9 % lower at Day 2. The interaction is less likely to be due to cisplatin than to a competitive inhibition of pazopanib metabolism and efflux by aprepitant, an antiemetic drug systematically administered with cisplatin. The plasma pazopanib exposures observed at Day 0 with a 400 mg dose were similar to those observed at the recommended dose of pazopanib in monochemotherapy (800 mg) during the first-in-man phase 1 study.

Conclusion

The observed pazopanib plasma overexposure probably contributed to the poor tolerance encountered during this phase 1 study.

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Involvement of CASP3 promoter polymorphism (−1337 C > G) in the development and progression of non-small cell lung cancer

Abstract

Downregulation of CASP3 gene expression has been observed to be associated with various malignancies, and promoter polymorphisms in the CASP3 gene may have a great impact on the CASP3 transcriptional activity. The present study aimed to analyze the possible impact of the CASP3 (−1337 C > G, rs1405937) polymorphism on the expression profile of CASP3 gene and ultimately its association in the development of non-small cell lung cancer. A case–control study of 100 non-small cell lung cancer patients and 100 cancer free healthy controls was conducted, wherein genotype and expression profile of CASP3 gene were evaluated using serum DNA and serum RNA, respectively, by primer-introduced restriction fragment analysis and real-time PCR techniques. Compared to the CASP3 CC genotype, odds ratio of 11.1 was found to be associated to the homozygous GG genotype with more than sixfold decrease of CASP3 gene expression in non-small cell lung cancer patients. Significant trend of decrease in caspase 3 expression was observed with the increase in severity of the disease. Patients with CASP3 (−1337GG) genotype had significantly shorter overall survival compared to CASP3 (−1337CC) genotype carriers. In addition, significantly poor overall survival was also reflected by patients with higher fold decrease in CASP3 gene expression. CASP3 (−1337 GG) genotype was found to be associated with significantly lower CASP3 gene expression especially among patients with advanced status of the disease, suggesting that CASP3 (−1337C > G) polymorphism may be involved in the development and progression of non-small cell lung cancer.

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Cyfip1 is downregulated in acute lymphoblastic leukemia and may be a potential biomarker in acute lymphoblastic leukemia

Abstract

The aim of the present study was to analyze the expression of Cyfip1 in acute lymphoblastic leukemia (ALL) and its correlations with clinical pathologic features. A total of 86 ALL samples and 32 normal peripheral blood lymphocyte (PBL) samples were enrolled in our study. mRNA expression of the Cyfip1 was assessed by real-time fluorescent relatively quantitative PCR, and Cyfip1 protein expression was evaluated by Western blot analysis. As a result, both mRNA and protein expression levels of Cyfip1 were significantly lower in ALL patients than those in the control samples (P = 0.025 and 0.000, respectively). Moreover, both mRNA and protein expression of both had an inverse relation with lymph node metastasis (P = 0.015 and 0.007, respectively), In conclusion, detecting mRNA and protein expression of Cyfip1 could provide clinically significant information relevant to diagnosis, progression, and treatment modalities for ALL, and Cyfip1 may serve as a potential biomarker for diagnosis and prognosis in ALL.

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Total tumor volume predicts survival following liver resection in patients with hepatocellular carcinoma

Abstract

Assessing the prognosis of patients with hepatocellular carcinoma (HCC) by the number and size of tumors is sometimes difficult. The main purpose of the study was to evaluate the prognostic value of total tumor volume (TTV), which combines the two factors, in patients with HCC who underwent liver resection. We retrospectively reviewed 521 HCC patients from January 2001 to December 2008 in our center. Patients were categorized using the tertiles of TTV. The prognostic value of TTV was assessed. With a median follow-up of 116 months, the 1-, 3-, and 5-year overall survival (OS) rates of the patients were 93.1 , 69.9, and 46.3 %, respectively. OS was significantly differed by TTV tertile groups, and higher TTV was associated with shorter OS (P < 0.001). Multivariate analysis revealed that TTV was an independent prognostic factor for OS. Larger TTV was significantly associated with higher alpha-fetoprotein level, presence of macrovascular invasion, multiple tumor lesions, larger tumor size, and advanced tumor stages (all P < 0.05). Within the first and second tertiles of TTV (TTV ≤ 73.5 cm³), no significant differences in OS were detected in patients within and beyond Milan criteria (P = 0.183). TTV-based Cancer of the Liver Italian Program (CLIP) score gained the lowest Akaike information criterion value, the highest χ ² value of likelihood ratio test, and the highest C-index among the tested staging systems. Our results suggested that TTV is a good indicator of tumor burden in patients with HCC. Further studies are warranted to validate the prognostic value of TTV.

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Alpinetin targets glioma stem cells by suppressing Notch pathway

Abstract

Glioma is among the most common human malignancies with poor prognosis. Glioma stem cells (GSCs) are the culprit of glioma, suggesting that GSCs are potential therapeutic targets. Notch signaling pathway plays a pivotal role for the function of GSCs, implying that suppression of Notch pathway may be an effective strategy for GSC-targeting therapy. In this study, we found that alpinetin, a natural compound, can suppress the proliferation and invasiveness of GSCs and induce apoptosis in GSCs. Immunoblot analysis and luciferase assay revealed that Notch signaling was suppressed by alpinetin. Furthermore, restoration of Notch signaling activity rescued the effect of alpinetin on GSC's function. The anti-tumor activity of alpinetin was further confirmed in an animal model. Collectively, targeting of GSC by alpinetin is an effective strategy for glioma therapy.

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Macrophages and endothelial cells orchestrate tumor-associated angiogenesis in oral cancer via hedgehog pathway activation

Abstract

The present study aimed to evaluate the role of Hedgehog (Hh) molecule expression in association with the clinical aspects of oral squamous cell carcinoma (OSCC), as well as angiogenesis and CD163+ macrophages. Twenty-eight cases of OSCC, nine cases of tumor-free resection margins (TM), and four cases of non-neoplastic oral mucosa (NNM) were submitted to immunohistochemistry to detect proteins Sonic Hedgehog (SHH), Indian Hedgehog (IHH), GLI1, CD163, and CD105. Protein colocalization with respect to SHH/CD163, IHH/CD163, GLI1/CD163, and GLI1/CD105 was assessed by immunohistochemical double staining. In tumor parenchyma, SHH and IHH were present in the cytoplasm of neoplastic cells, while GLI1 was observed in cytoplasm and nucleus. Endothelial cells were found to express SHH, IHH, and GLI1 within CD105+ vessels, and a positive correlation between infiltrating macrophage density (IMD) and microvascular density (MVD) was observed in cases of OSCC and TM. When compared to TM and NNM, the OSCC cases demonstrated higher immunoreactivity for SHH (p = 0.01), IHH (p = 0.39), GLI1 (p = 0.03), IMD (p = 0.0002), and MVD (p = 0.0002). Our results suggest the participation of the Hh pathway in OSCC by way of autocrine and paracrine signaling, in addition to the participation of both SHH and IHH ligands. Endothelial cells were also found to exhibit positivity with respect to Hh pathway components and we surmise that these molecules may play a role in tumor angiogenesis. CD163+ macrophages were also observed to express IHH, a ligand of this pathway, in addition to being associated with tumor neovascularization.

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MicroRNA-155 promotes apoptosis in SKOV3, A2780, and primary cultured ovarian cancer cells

Abstract

MicroRNAs (miRNAs) are a large group of small non-coding RNAs that can negatively regulate gene expression at the post-transcriptional level. The deregulation of miRNAs has been associated with tumorigenesis, drug resistance, and prognosis in cancers. Deregulated miR-155 has been reported in numerous cancers; however, its function remains unclear. 4′,6-Diamidino-2-phenylindole (DAPI) staining and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) techniques were used to determine the effects of a miR-155 mimic or inhibitor on the apoptotic ratio of ovarian cancer cells induced by cisplatin. Bioinformatic predictions, the dual-luciferase reporter assay, and western blot analysis were used to detect how miR-155 regulates X-linked inhibitor of apoptosis protein (XIAP). We demonstrated that a miR-155 mimic could decrease the IC50 value of cisplatin in SKOV3 ovarian cancer cells. Subsequently, gain- and loss-of-function analyses with a miR-155 mimic and inhibitor showed that miR-155 sensitizes ovarian cancer cells to cisplatin. Furthermore, the results from the luciferase assays and western blot analysis identified XIAP as the direct target of miR-155. In addition, introducing XIAP cDNA without a three prime untranslated region (3′-UTR) rescued the miR-155 promotion of apoptosis. These results indicate that miR-155 mediates cisplatin-induced apoptosis by targeting XIAP in ovarian cancer cells and that miR-155 could be a potential therapeutic target to increase the efficiency of ovarian cancer interventions.

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DCT015, a new sorafenib derivate, inhibits tumor growth and angiogenesis in gastric cancer models

Abstract

The objective of this study is to investigate antiproliferative activities against gastric cancer and anti-angiogenesis of DCT015, a novel sorafenib derivate, and potential mechanisms. The effects of DCT015 on proliferation and apoptosis in gastric cancer cells were evaluated by cytotoxicity assays, apoptosis analysis, flow cytometry analysis, and Western blotting assays. The in vivo antitumor effects were carried out in nude mice bearing gastric cancer. On the other hand, the anti-angiogenesis effects of DCT015 were measured by human umbilical vein endothelial cell (HUVEC) proliferation, migration, tube formation, and Western blotting analysis. The results showed that DCT015 inhibited the proliferation, induced the morphological changes of apoptosis, and increased the apoptosis percentage, as well as increased the "sub-G1" population in gastric cancer cells. DCT015 also significantly decreased the tumor volumes and tumor weights in vivo by oral administration. Immunohistochemistry assay demonstrated that DCT015 inhibited tumor growth and neovascularization. In vitro studies found that DCT015 inhibited both MEK/ERK and PI3K/Akt signaling pathways by Western blotting assays. Moreover, DCT015 significantly inhibited VEGF-induced migration and tube formation in HUVECs. Western blotting analysis showed that DCT015 downregulated VEGF-induced VEGFR2 phosphorylation with the decreased phosphorylation of the downstream key proteins. Taken together, our findings highlight that DCT015 is a promising orally anticancer drug for treating gastric cancer.

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Inhibition of proliferation and induction of apoptosis in RB116 retinoblastoma cells by afatinib treatment

Abstract

The present study investigates the effect of afatinib on the growth, induction of apoptosis in RB116 cells, and reduction of carcinoma growth in the mice transplanted with RB116 cells. The results from MTT assay revealed that afatinib inhibited the growth of RB116 cells in a dose-dependent manner. Proliferation of RB116 cells was reduced to 64 % on treatment with 200 μM concentration of afatinib after 48 h. Afatinib treatment of RB116 cells at 200 μM concentration induced apoptosis and necrosis in 49.7 and 9.4 %, respectively, after 48 h. In the RB116-transplanted mice, treatment with afatinib at 10-mg/kg doses for 45 days caused a significant (p < 0.005) reduction in the tumor volume compared to the control group. The tissue lysates of the mice containing RB116 transplant showed a significant decrease in the expressions of Ki67 and p53 in the afatinib treatment group after 45 days. However, the expression of caspase-3 was increased and of Bcl-2 remained unaltered on treatment with afatinib. Measurement of the body weight of afatinib-treated animals showed no reduction during the study. Thus, afatinib can be of therapeutic value for the treatment of retinoblastoma.

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