Cancer by Sfakianakis Alexandros: 03/05/16

Σάββατο 5 Μαρτίου 2016

Plexin-B1 indirectly affects glioma invasiveness and angiogenesis by regulating the RhoA/αvβ3 signaling pathway and SRPK1

Abstract

Gliomas are one of the most common primary brain tumors in adults. They display aggressive invasiveness, are highly vascular, and have a poor prognosis. Plexin-B1 is involved in numerous cellular processes, especially cellular migration and angiogenesis. However, the role and regulatory mechanisms of Plexin-B1 in gliomas are not understood and were thus investigated in this study. By using multiple and diverse experimental techniques, we investigated cell apoptosis, mitochondrial membrane potential, cell migration and invasion, angiogenesis, PI3K and Akt phosphorylation, and also the levels of SRPK1 and αvβ3 in glioma cells and animal glioma tissues. The results indicated that Plexin-B1 expression in glioma cell lines is increased compared to normal human astrocytes. Plexin-B1 mediates RhoA/integrin αvβ3 involved in the PI3K/Akt pathway and SRPK1 to influence the growth of glioma cell, angiogenesis, and motility in vitro and in vivo. Thus, Plexin-B1 signaling regulates the Rho/α_vβ₃/PI3K/Akt pathway and SRPK1, which are involved in glioma invasiveness and angiogenesis. Therefore, the new drug research should focus on Plexin-B1 as a target for the treatment of glioma invasion and angiogenesis.

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Waldenstrom Macroglobulinemia: Familial Predisposition and the Role of Genomics in Prognosis and Treatment Selection

Opinion statement

Waldenstrom macroglobulinemia (WM) is a non-Hodgkin lymphoma (NHL) characterized by the presence of a CD20 + lymphoplasmacytic bone marrow (BM) infiltrate and serum immunoglobulin M monoclonal protein. Both sporadic and familial forms exist. A remarkable improvement in outcome of nearly all age groups of WM patients may be primarily a consequence of successful integration of anti-CD20 monoclonal antibody, rituximab, to the conventional chemotherapy. However, the seminal discoveries of MYD88 ^L265P mutation, present in the vast majority (85–100 %), and CXCR4 ^WHIM mutations, identified in nearly a third of patients (who almost exclusively harbor the MYD88 ^L265P variant), have laid a solid foundation for a paradigm shift in our diagnostic and therapeutic approaches towards this rare hematologic malignancy. Given that 20–25 % of patients are asymptomatic at diagnosis and early intervention does not translate into survival benefit, we follow a risk-adapted approach and actively monitor this subset of "smoldering" patients. Those with low-grade cytopenias can generally be managed with an abbreviated course of rituximab monotherapy, while those with B symptoms, bulky lymphadenopathy, or profound disease-related cytopenias require more aggressive strategies, incorporating several courses of chemoimmunotherapy. For symptoms associated with hyperviscosity, prompt plasma exchange is warranted prior to initiation of cytoreductive therapy. Prospective data are unavailable to a support a unique approach in familial WM or initiation of rituximab maintenance post-induction. A multitude of potentially effective therapies targeting cell-survival pathways are in development and offer a more precise approach for WM patients. One such agent, ibrutinib, a Bruton's tyrosine kinase inhibitor, was recently granted approval. Off-study, we limit the use of ibrutinib to relapsed-refractory WM patients who harbor MYD88 mutations. Autologous stem-cell transplantation (ASCT) is another viable option in the relapsed setting for chemosensitive transplant-eligible patients. Unfortunately, despite substantial progress, achieving a minimal residual disease-negative state—a prerequisite for cure—is rare in WM.

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Characterization of passive permeability at the blood–tumor barrier in five preclinical models of brain metastases of breast cancer

Abstract

The blood–brain barrier (BBB) is compromised in brain metastases, allowing for enhanced drug permeation into brain. The extent and heterogeneity of BBB permeability in metastatic lesions is important when considering the administration of chemotherapeutics. Since permeability characteristics have been described in limited experimental models of brain metastases, we sought to define these changes in five brain-tropic breast cancer cell lines: MDA-MB-231BR (triple negative), MDA-MB-231BR-HER2, JIMT-1-BR3, 4T1-BR5 (murine), and SUM190 (inflammatory HER2 expressing). Permeability was assessed using quantitative autoradiography and fluorescence microscopy by co-administration of the tracers ¹⁴C-aminoisobutyric acid (AIB) and Texas red conjugated dextran prior to euthanasia. Each experimental brain metastases model produced variably increased permeability to both tracers; additionally, the magnitude of heterogeneity was different among each model with the highest ranges observed in the SUM190 (up to 45-fold increase in AIB) and MDA-MB-231BR-HER2 (up to 33-fold in AIB) models while the lowest range was observed in the JIMT-1-BR3 (up to 5.5-fold in AIB) model. There was no strong correlation observed between lesion size and permeability in any of these preclinical models of brain metastases. Interestingly, the experimental models resulting in smaller mean metastases size resulted in shorter median survival while models producing larger lesions had longer median survival. These findings strengthen the evidence of heterogeneity in brain metastases of breast cancer by utilizing five unique experimental models and simultaneously emphasize the challenges of chemotherapeutic approaches to treat brain metastases.

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Lipomatous ependymoma: report of a rare differentiation pattern with a comprehensive review of literature

Abstract

We report the case of a 13-year-old girl presenting with left-sided hemiparesis, altered sensorium and episodic headache with bouts of projectile vomiting. Imaging revealed a large heterodense intraventricular mass lesion displaying focal calcification and hyperintensity on T1- and T2- weighted fluid attenuated inversion recovery (FLAIR) magnetic resonance images suggesting the presence of intratumoral fat. Histologically, the tumour showed sheets of glial cells, focal perithelial rosettes and individual cells showing fat vacuoles. The morphological impression was of an ependymoma with lipomatous differentiation. Glial fibrillary acid protein (GFAP) immunohistochemistry revealed positivity in the cytoplasmic processes of the tumour cells as well as in the cytoplasmic rim of the cells having an adipocytic appearance. S100 and vimentin were also immunoreactive. Ultrastructural studies confirmed the ependymal differentiation of the tumour and the presence of an osmiophilic fat component confirming the diagnosis. After 1 year of follow-up, the patient presented with similar complaints and MRI evidence of recurrence of the tumour. A comprehensive literature review revealed that half of the reported cases of this pattern recurred suggesting a possibly tenacious clinical course.

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Expression and gene doses changes of the p53-regulator PPM1D in meningiomas: a role in meningioma progression?

Abstract

The aim of our study was to clarify the expression and gene copy number levels of protein phosphatase 1D magnesium-dependent, delta isoform (PPM1D), which is thought to be a regulator of the p53 protein in meningiomas of all three different WHO grades. Genomic DNA and mRNA were extracted from frozen tissues of meningiomas (WHO grade I, 20 cases; grade II, 17 cases; grade III, 20 cases). For analysis of the mRNA expression and gene dosage level of PPM1D, semiquantitative duplex RT-PCR, real-time RT-PCR, and semiquantitative duplex PCR were performed. We also analyzed several genes which locate near PPM1D in the genomic locus 17q22–24 using semiquantitative duplex RT-PCR. We found that the mean mRNA expression of PPM1D is higher in WHO grade II and III meningiomas than in grade I tumors. This finding is accompanied by moderate gene dosage increases for PPM1D in meningiomas of higher grades. Other genes located in the vicinity of PPM1D also showed mRNA overexpression in single meningioma cases. For these genes, however, no significant expression differences between meningioma grades could be observed. Thus, PPM1D in the chromosomal location 17q22–24 might be the most relevant candidate gene with respect to a potential functional implication in meningioma progression.

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Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma lung cancer patients harboring EGFR-sensitizing mutations in China

Abstract

Purpose

EGFR tyrosine kinase inhibitors (TKIs) have been established as standard therapy for EGFR-mutated adenocarcinomas; for non-adenocarcinoma non-small cell lung cancer (NSCLC) patients, this therapy remains debatable.

Methods

Stage IIIB/IV patients with non-adenocarcinoma NSCLC who underwent EGFR testing were identified at the Shanghai Chest Hospital from January 2009 to September 2014.

Results

A total of 51 patients with EGFR-sensitizing mutations [26 patients with squamous cell carcinoma (SCC), 15 patients with adenosquamous cell carcinoma (ASC), and 10 patients with large cell lung carcinoma (LCLC)] were available for analysis of EGFR TKI treatment efficacy. The progression-free survival (PFS) for the 51 patients harboring EGFR-sensitizing mutations was 4.93 months (95 % CI 3.93–5.93). The PFS for the SCC, ASC, and LCLC patients was 3.98 months (95 % CI 3.32–4.63), 8.08 months (95 % CI 4.17–12.00), and 4.40 months (95 % CI 1.56–7.24), respectively. Among the 51 non-adenocarcinoma NSCLC patients, the PFS of the non-smokers and smokers was 5.49 months (95 % CI 3.28–7.70) and 3.78 months (95 % CI 2.61–4.95), respectively (P = 0.036). The PFS for the patients with a deletion in exon 19 and for those with an exon 21 L858R mutation was 5.16 months (95 % CI 4.21–6.11) and 4.04 months (95 % CI 2.35–5.73), respectively (P = 0.414).

Conclusions

EGFR TKIs could be an option for the treatment of EGFR-mutated non-adenocarcinoma NSCLC, especially for patients with adenosquamous histology and non-smokers.

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JMJD1A promotes tumorigenesis and forms a feedback loop with EZH2/let-7c in NSCLC cells

Abstract

Lung cancer is the most common cause of cancer-related deaths worldwide, and non-small cell lung cancer (NSCLC) accounts for 80 to 85 % of all lung cancer. Although the standard treatment regimen has been established, long-term survival for NSCLC patients is still generally poor. The histone demethylase Jumonji domain containing 1A (JMJD1A) has been proposed as an oncogene in several types of human cancer, but its clinical significance and functional roles in NSCLC remain largely unclear. In the present study, JMJD1A was frequently upregulated in NSCLC compared with para-carcinoma tissues. JMJD1A knockdown significantly inhibited NSCLC cell growth, migration, and invasion in vitro and tumorigenesis in vivo. Further experiments demonstrated that JMJD1A knockdown could decrease the expression of EZH2, which has been shown to play a crucial role in the carcinogenesis of NSCLC and, in turn, increase the expression of anti-tumor microRNA let-7c. Also, let-7c directly targeted the 3′-untranslated regions of JMJD1A and EZH2. Taken together, JMJD1A could promote NSCLC tumorigenesis. JMJD1A/EZH2/let-7c constituted a feedback loop and might represent a promising therapeutic target for NSCLC.

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DPPIV/CD26: a tumor suppressor or a marker of malignancy?

Abstract

Dipeptidyl peptidase IV (DPPIV/CD26) is a multifunctional protein with intrinsic peptidase activity that inactivates or degrades some bioactive peptides. It is the main cellular binding protein for ecto-adenosine deaminase and interacts with extracellular matrix proteins, besides participating in different signaling pathways. Due to these multiple functions, DPPIV/CD26 has been shown to be closely related to the tumor process. It has been reported that the progression of certain types of cancer is accompanied by a decrease in DPPIV/CD26 expression, and studies have shown that the malignant phenotype can be reverted when DPPIV/CD26 expression is induced in these cancer cells, characterizing this protein as a tumor suppressor. On the other hand, DPPIV/CD26 was described as a protein associated with invasion and metastatic spread, characterizing it as a marker of malignancy. Thus, this review explores the roles of DPPIV/CD26 expression in tumor progression in different types of cancer and demonstrates the importance of this protein as a promising therapeutic target and tumor biomarker.

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Armc8 regulates the invasive ability of hepatocellular carcinoma through E-cadherin/catenin complex

Abstract

Armc8 (armadillo-repeat-containing protein 8) was proved to promote disruption of E-cadherin complex through regulating α-catenin degradation. In this study, we investigated Armc8 expression in hepatocellular carcinoma using immunohistochemistry (IHC). The positive rate of Armc8 expression in hepatocellular carcinoma was 53.9 % and higher than that in normal hepatic tissues (9.2 %) (p < 0.05). Clinicopathological analysis shows that Armc8 expression in hepatocellular carcinoma was significantly associated with larger tumor size (≥5 cm), multiple tumor numbers, higher pathological grade (media and poor), advanced TNM stages (II/III), and advanced BCLC stages (B/C). Western blot study also detected higher Armc8 expression in hepatocellular carcinoma cells including HepG2, HCC97L, and SMMC-7721 than in human hepatic cell Bel-7402. We further use specific small interfering RNAs (siRNAs) to knock down Armc8 expression in HepG2 cells and found that knockdown of Armc8 expression significantly inhibited the invasive ability of HepG2 cells. Downregulation of Armc8 expression significantly upregulated α-catenin, β-catenin, and E-cadherin expression in HepG2 cells. Immunofluorescent study shows that knockdown of Armc8 expression restored E-cadherin expression in membrane of HepG2 cells. These results indicate that Armc8 may be a potential cancer marker in hepatocellular carcinoma and may regulate cancer invasion through E-cadherin/catenin complex.

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Plexin-B1 indirectly affects glioma invasiveness and angiogenesis by regulating the RhoA/αvβ3 signaling pathway and SRPK1

Abstract

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Notch-1 signaling activates NF-κB in human breast carcinoma MDA-MB-231 cells via PP2A-dependent AKT pathway

Abstract

Breast cancer has a high incidence in the world and is becoming a leading cause of death in female patients due to its high metastatic ability. High expression of Notch-1 and its ligand Jagged-1 correlates with poor prognosis in breast cancer. Our previous work has shown that Notch-1 signaling pathway upregulates NF-κB transcriptional activity and induces the adhesion, migration and invasion of human breast cancer cell line MDA-MB-231. However, the role of Notch-1 in NF-κB activation is still poorly understood. Here, we aim to understand the exact mechanism that Notch-1 regulates NF-κB activity. In MDA-MB-231 cells where Notch-1 is constitutively activated, the phosphorylation of p85 and AKT (Tyr308/Ser473) is upregulated, indicating PI3K/AKT pathway is activated. Notch-1 activation caused the increase of PP2A phosphorylation at Tyr307, indicating Notch-1 inhibits PP2A activity. NF-κB transcriptional activity was evaluated by dual-luciferase reporter assay, and the results showed that, while silencing of Notch-1, PP2A activity was upregulated and NF-κB activity was downregulated, whereas PP2A inhibitor okadaic acid (OA) restored NF-κB activity. Immunofluorescence and Western blots showed that OA treatment antagonized the decrease of p65 nuclear translocation caused by Notch-1 silencing. Moreover, OA treatment also upregulated MMP-2, MMP-9 and VEGF mRNA expression levels, indicating OA rescues Notch-1 silencing that caused low cell invasion. Taken together, our results suggest that Notch-1-activating PI3K/AKT/NF-κB pathway is PP2A dependent; PP2A may be a potential therapeutic target in breast cancer.

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Body mass index and treatment outcomes following neoadjuvant therapy in women aged 45 years or younger: evidence from a historic cohort.

Body mass index and treatment outcomes following neoadjuvant therapy in women aged 45 years or younger: evidence from a historic cohort.

Cancer Biol Ther. 2016 Mar 2;:0

Authors: D'Aiuto M, Chirico A, De Riggi MA, Frasci G, De Laurentiis M, Di Bonito M, Vici P, Pizzuti L, Sergi D, Marcello MS, Barba M, Giordano A

Abstract
PURPOSE: Large and consistent evidence supports the role of body mass index (BMI) as a prognostic and predictive indicator in breast cancer. However, there is paucity of data specifically referred to women diagnosed at a young age across the different disease settings. We investigated the impact of BMI on treatment outcomes in 86 breast cancer patients aged 45 years or less treated with neoadjuvant chemotherapy (CT) followed by surgery.
METHODS: Pathologic complete response (pCR) was defined as the eradication of cancer from both breast and lymph nodes. Overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier product-limit method. Curves were compared by long rank test for significance. Potential predictors of survival were tested in Cox models.
RESULTS: We observed a pCR in 19 patients (22%). Lower values of BMI were more commonly associated with pCR (p=0.05). Results from univariate, but not multivariate, models were somewhat supportive of higher pCR rates in leaner women (p=0.06). None of the variables impacted DFS. OS was longer in leaner patients (medians and 95%CI: 74.6 months, 66.2-82.9 and 58.5 months, 49.6-67.4, p=0.009). Longer OS was also related to lower T-stage, adjuvant radiotherapy (RT), and non triple negative (TN) subtype (p=0.046, p=0.024, and p=0.015, respectively). Cox models confirmed the protective role of lower BMI (Hazard Ratios: 0.30, 95%CI: 0.12-0.71, p=0.007), non TN subtype and adjuvant RT (p=0.008 and p=0.024).
CONCLUSIONS: In young breast cancer patients treated with neoadjuvant CT followed by surgery, lower values of BMI are associated with longer OS. Our data also showed longer OS in association with a non TN molecular subtype and adjuvant RT. The modifiable nature of BMI and aggressive biologic behavior of the disease diagnosed at a young age encourage further studies to corroborate our findings.

PMID: 26934127 [PubMed - as supplied by publisher]

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Waldenstrom Macroglobulinemia: Familial Predisposition and the Role of Genomics in Prognosis and Treatment Selection

Opinion statement

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Genome-wide analysis of abdominal and pleural malignant mesothelioma with DNA arrays reveals both common and distinct regions of copy number alteration

10.1080/15384047.2016.1145850<br/>Alain C. Borczuk

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p.(L576P) -KIT mutation in GIST: favourable prognosis and sensitive to imatinib?

p.(L576P) -KIT mutation in GIST: favourable prognosis and sensitive to imatinib?

Cancer Biol Ther. 2016 Mar 4;:0

Authors: Noujaim J, Gonzalez D, Thway K, Jones RL, Judson I

Abstract
Exon 11 KIT mutations are found in a majority of gastrointestinal stromal tumours (GIST) and are usually predictive of response to imatinib, a KIT, PDGFRA and ABL inhibitor. Exon 11 mutations with poor sensitivity to imatinib and poor outcome can be observed on rare occasions, including p.(L576P). In silico and in vitro studies suggested a decreased binding affinity for imatinib in p.(L576P) KIT mutations, thereby offering an explanation for their poor outcome and poor response to standard therapy. These observations were further corroborated with anecdotal case reports of refractoriness or non-durable response to imatinib therapy. However, we describe the favourable response to imatinib and outcome in five p.(L576P)-KIT mutant GIST patients treated at a tertiary sarcoma referral center. The sensitivity of p.(L576P)-KIT mutations to imatinib, and the prognostic impact of this mutation need to be further evaluated in a larger cohort. Based on our observations, p.(L576P) mutated GISTs should be treated with standard first line imatinib therapy.

PMID: 26942271 [PubMed - as supplied by publisher]

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EDAG-1 promotes proliferation and invasion of human thyroid cancer cells by activating MAPK/Erk and AKT signal pathways.

EDAG-1 promotes proliferation and invasion of human thyroid cancer cells by activating MAPK/Erk and AKT signal pathways.

Cancer Biol Ther. 2016 Mar 2;:0

Authors: Chen DL, Hu ZQ, Zheng XF, Wang XY, Xu YZ, Li WQ, Fang HS, Kan L, Wang SY

Abstract
Erythroid differentiation-associated gene (EDAG) is differentially expressed in normal hematopoietic progenitor/stem cells and a variety of embryonic tissues. High EDAG-1 expression is also found in human thyroid cancer cells and peripheral blood of patients with leukemia, but its functional significance was unclear. Current study aims to further clarify the expression pattern of EDAG-1 and tests its roles in proliferation and invasion of human thyroid cancer cells in vitro and in vivo. To this end, we have performed gain-of-function and loss-of-function studies to clarify how EDAG-1 regulates the proliferation, invasion, and adhesion ability of human thyroid cancer cells SW579cells. We found that overexpression of EDAG-1 promoted the proliferation, invasion, and adhesion of human thyroid cancer cells, whereas silencing of EDAG-1 reversed all these changes and reduced the tumorigenesis risk of nude mice. Mechanistically, we found that overexpression of EDAG-1 activated the MAPK/Erk and AKT signal pathways. These findings provide novel insights of the role of EDAG-1 in thyroid tumors, and may have direct clinical implication.

PMID: 26934676 [PubMed - as supplied by publisher]

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KLF4 is downregulated but not mutated during human esophageal squamous cell carcinogenesis and has tumor stage-specific functions.

KLF4 is downregulated but not mutated during human esophageal squamous cell carcinogenesis and has tumor stage-specific functions.

Cancer Biol Ther. 2016 Mar 2;:0

Authors: Yang Y, Katz JP

Abstract
The transcriptional regulator Krüppel-like factor 4 (KLF4) is decreased in human esophageal squamous cell cancer (ESCC), and Klf4 deletion in mice produces squamous cell dysplasia. Nonetheless the mechanisms of KLF4 downregulation in ESCC and the functions of KLF4 during ESCC development and progression are not well understood. Here, we sought to define the regulation of KLF4 and delineate the stage-specific effects of KLF4 in ESCC. We found that KLF4 expression was decreased in human ESCC and in 8 of 9 human ESCC cell lines. However, by genomic sequencing, we observed no KLF4 mutations or copy number changes in any of 52 human ESCC, suggesting other mechanisms for KLF4 silencing. In fact, KLF4 expression in human ESCC cell lines was increased by the DNA methylation inhibitor 5-azacytidine, suggesting an epigenetic mechanism for KLF4 silencing. Surprisingly, while KLF4 decreased in high-grade dysplasia and early stage tumors, KLF4 increased with advanced cancer stage, and KLF4 expression in ESCC was inversely correlated with survival. Interestingly, KLF4 promoted invasion of human ESCC cells, providing a functional link to the stage-specific expression of KLF4. Taken together, these findings suggest that KLF4 loss is necessary for esophageal tumorigenesis but that restored KLF4 expression in ESCC promotes tumor spread. Thus, the use of KLF4 as a diagnostic and therapeutic target in cancer requires careful consideration of context.

PMID: 26934576 [PubMed - as supplied by publisher]

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Targeting Blockage of STAT3 Inhibits Hepatitis B Virus-related Hepatocellular Carcinoma.

Targeting Blockage of STAT3 Inhibits Hepatitis B Virus-related Hepatocellular Carcinoma.

Cancer Biol Ther. 2016 Mar 2;:0

Authors: Yang Y, Zheng B, Han Q, Zhang C, Tian Z, Zhang J

Abstract
Hepatitis B virus (HBV) infection is a significant cause of liver disease pathogenesis, which results in the development of hepatic dysfunction, cirrhosis and hepatocellular carcinoma (HCC). Our previous studies showed that oncogene STAT3 might be an ideal target for HCC therapy. Here, we investigated whether targeting blockage of STAT3 signaling is efficient for HBV-related HCC. Based on the refractory of HCC and the persistence of HBV, in this study, we designed shRNAs targeting STAT3. The results showed that blocking STAT3 signaling by shRNAs could promote HBV positive HCC cell apoptosis and induce cell cycle arrest, resulting in HCC cell growth inhibition in vitro. Importantly, STAT3-shRNAs efficiently suppressed HBV replication, which would reduce HBV-derived stimulation to STAT3 signaling and augment STAT3-shRNAs-mediated anti-HCC effect. Finally, STAT3-shRNAs-mediated anti-HBV positive HCC effect was confirmed in xenograft nude mice. This study suggested that targeting STAT3 therapies such as STAT3-shRNAs may be an efficacious strategy for HBV-related HCC.

PMID: 26934469 [PubMed - as supplied by publisher]

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Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment.

Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment.

Cancer Biol Ther. 2016 Mar 2;:0

Authors: Pisklakova A, Grigson E, Ozerova M, Chen F, Sullivan DM, Nefedova Y

Abstract
Multiple myeloma (MM), a blood cancer characterized by the uncontrolled proliferation of plasma cells, remains incurable by current therapy. Notch signaling has been implicated in the growth and chemoresistance of various cancer types including MM, and therefore we hypothesized that targeting the Notch pathway could be beneficial for the treatment of this disease. Here, we report an anti-tumor effect of Notch/γ-secretase inhibitor RO4929097 in a pre-clinical model of MM. We demonstrate that this effect was associated with decreased angiogenesis and significant down-regulation of TGF-β1. In addition, we also show that treatment with RO4929097 results in decreased number and functional activity of osteoclasts. Taken together, our data indicate that targeting Notch may be considered as a new strategy to be tested for MM therapy.

PMID: 26934342 [PubMed - as supplied by publisher]

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Body mass index and treatment outcomes following neoadjuvant therapy in women aged 45 years or younger: evidence from a historic cohort.

Body mass index and treatment outcomes following neoadjuvant therapy in women aged 45 years or younger: evidence from a historic cohort.

Cancer Biol Ther. 2016 Mar 2;:0

Authors: D'Aiuto M, Chirico A, De Riggi MA, Frasci G, De Laurentiis M, Di Bonito M, Vici P, Pizzuti L, Sergi D, Marcello MS, Barba M, Giordano A

PMID: 26934127 [PubMed - as supplied by publisher]

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Resveratrol potentiates growth inhibitory effects of rapamycin in PTEN-deficient lipoma cells by suppressing p70S6 kinase activity.

Resveratrol potentiates growth inhibitory effects of rapamycin in PTEN-deficient lipoma cells by suppressing p70S6 kinase activity.

Nutr Cancer. 2016 Mar 4;:1-8

Authors: Leipert J, Kässner F, Schuster S, Händel N, Körner A, Kiess W, Garten A

Abstract
Patients with phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome and germline mutations in PTEN frequently develop lipomatosis, for which there is no standard treatment. Rapamycin was shown to reduce the growth of lipoma cells with heterozygous PTEN deficiency in vitro, but concomitantly induced an upregulation of AKT phosphorylation. Since it was shown that resveratrol stabilizes PTEN, we asked whether co-incubation with resveratrol could suppress the rapamycin-induced AKT phosphorylation in PTEN-deficient lipoma cells. Resveratrol incubation resulted in decreased lipoma cell viability by inducing G1-phase cell cycle arrest and apoptosis. PTEN expression and AKT phosphorylation were not significantly changed, whereas p70S6 kinase (p70S6K) phosphorylation was reduced in PTEN-deficient lipoma cells after resveratrol incubation. Rapamycin/resveratrol co-incubation significantly decreased viability further at lower doses of resveratrol and resulted in decreased p70S6K phosphorylation compared to rapamycin incubation alone, suggesting that resveratrol potentiated the growth inhibitory effects of rapamycin by reducing p70S6K activation. Both viability and p70S6K phosphorylation of primary PTEN wild-type preadipocytes were less affected compared to PTEN-deficient lipoma cells by equimolar concentrations of resveratrol. These results support the concept of combining chemopreventive natural compounds with mammalian target of rapamycin (mTOR) inhibitors to increase the efficacy of chemotherapeutic drugs for patients suffering from overgrowth syndromes.

PMID: 26943752 [PubMed - as supplied by publisher]

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The effect of preoperative oral immunonutrition on complications and length of hospital stay after elective surgery for pancreatic cancer-a randomized controlled trial.

The effect of preoperative oral immunonutrition on complications and length of hospital stay after elective surgery for pancreatic cancer-a randomized controlled trial.

Nutr Cancer. 2016 Mar 4;:1-9

Authors: Gade J, Levring T, Hillingsø J, Hansen CP, Andersen JR

Abstract
Major gastrointestinal surgery is associated with immune suppression and a high risk of postoperative complications. The aim of this open, randomized controlled trial was to examine the effect of supplementary per oral immunonutrition (IN) seven days before surgery for pancreatic cancer (PC) on postoperative complications and length of hospital stay (LOS). Secondary outcomes were the changes in functional capability and body weight (BW). Consecutive patients referred for surgery for diagnosed or plausible PC were included. The patients in the intervention group received supplementary IN (Oral Impact®, Nestlé) to reach a goal of 1.5 g protein/kg BW. The control group continued their habitual diet. Complications and LOS were independently assessed by the surgical staff. Secondary outcomes were measured 10, 20, and 30 days postoperatively. Thirty-five patients were included, of whom 19 (54%) were allocated to the intervention group. The doses of IN ranged from 250 to 1000 ml per day and the median compliance was 100 (0-100%). Based on the principle of intention-to-treat, no significant differences were found between the groups. We conclude that the lack of effect could be due to the limited dosage of IN, and/or because only 40% of the patients were at nutritional risk.

PMID: 26943500 [PubMed - as supplied by publisher]

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Changes in the detection and recognition thresholds of three basic tastes in lung cancer patients receiving cisplatin and paclitaxel and its association with nutritional and quality of life parameters.

Changes in the detection and recognition thresholds of three basic tastes in lung cancer patients receiving cisplatin and paclitaxel and its association with nutritional and quality of life parameters.

Nutr Cancer. 2016 Mar 4;:1-9

Authors: Turcott JG, Juárez-Hernández E, De la Torre-Vallejo M, Sánchez-Lara K, Luvian-Morales J, Arrieta O

Abstract
We evaluated the effects of cisplatin and paclitaxel on taste acuity and their associations with nutritional and health-related quality of life (HRQL) in patients with advanced non-small-cell lung cancer (NSCLC). Forty chemotherapy (CT)-naïve patients were assessed at baseline and after two cycles of paclitaxel and cisplatin. The taste evaluation was performed using a rinsing technique to identify detection and recognition thresholds (DT and RT) of bitter, sweet, and umami tastes. At baseline, 37.5% of the patients reported dysgeusia. After CT, the patients showed lower medians DT (p = 0.017) and RT (p = 0.028) for umami taste. These decreases were associated with clinical neuropathy, worse HRQL, and a tendency toward increased appetite loss. Additionally, CT did not significantly reduce the median DT for sweet (p = 0.09), which is associated with lower intake of protein (p = 0.015), animal protein (p = 0.010), fat (p = 0.004), and iron (p = 0.047). CT decreased the median DT for bitter (p = 0.035); however, this decrease was not associated with nutritional parameters or with HRQL. Sensitivity to taste increased with paclitaxel and cisplatin CT, making foods more unpleasant, and it was associated with neuropathy, worse HRQL, and reduced nutrient intake in advanced NSCLC patients. The protocol was registered at clinicaltrials.gov (NCT01540045).

PMID: 26943275 [PubMed - as supplied by publisher]

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Macranthoside B induces apoptosis and autophagy via reactive oxygen species accumulation in human ovarian cancer A2780 cells.

Macranthoside B induces apoptosis and autophagy via reactive oxygen species accumulation in human ovarian cancer A2780 cells.

Nutr Cancer. 2016 Mar 4;:1-10

Authors: Shan Y, Guan F, Zhao X, Wang M, Chen Y, Wang Q, Feng X

Abstract
Macranthoside B (MB), a saponin compound in Lonicera macranthoides, can block cell proliferation and induce cell death in several types of cancer cells; however, the precise mechanisms by which MB exerts its anticancer effects remain poorly understood. MB blocked A2780 human ovarian carcinoma cell proliferation both dose- and time-dependently. MB induced apoptosis, with increased poly (ADP-ribose) polymerase (PARP) and caspase-3/9 cleavage. MB also caused autophagy in A2780 cells, with light chain 3 (LC3)-II elevation. Inhibiting MB-induced autophagy with the autophagy inhibitor 3-methyladenine (3-MA) significantly decreased apoptosis, with a reduction of growth inhibition; inhibiting MB-induced apoptosis with the pan-caspase inhibitor Z-VAD-FMK did not decrease autophagy but elevated LC3-II levels, indicating that MB-induced autophagy is cytotoxic and may be upstream of apoptosis. Furthermore, MB increased intracellular reactive oxygen species (ROS) levels, with activated 5' adenosine monophosphate-activated protein kinase (AMPK), decreased mammalian target of rapamycin (mTOR) and P70S6 kinase phosphorylation, and increased PARP and caspase-3/9 cleavage, and LC3-II elevation; treatment with the ROS scavenger N-acetyl cysteine and the AMPK inhibitor Compound C diminished this effect. Therefore, the ROS/AMPK/mTOR pathway mediates the effect of MB on induction of apoptosis via autophagy in human ovarian carcinoma cells.

PMID: 26943028 [PubMed - as supplied by publisher]

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Docosahexaenoic acid induces growth suppression on epithelial ovarian cancer cells more effectively than eicosapentaenoic acid.

Docosahexaenoic acid induces growth suppression on epithelial ovarian cancer cells more effectively than eicosapentaenoic acid.

Nutr Cancer. 2016 Mar 4;:1-8

Authors: Wan XH, Fu X, Ababaikeli G

Abstract
Omega-3 fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to possess definitively suppressive effects on the growth of epithelial ovarian cancer cells. This study investigated the differential effects of pure EPA and DHA on the growth of epithelial ovarian cancer cells and the potential molecular mechanisms that may be involved. There were significant time- and dose-dependent inhibitory effects of both EPA and DHA on cellular proliferation of the epithelial ovarian cancer cell line TOV-21G (P < 0.05). TOV-21G cells pretreated with peroxisome proliferator receptor activator gamma (PPARγ) antagonist, GW9662, markedly suppressed EPA/DHA-induced apoptosis as determined by TUNEL assay, Annexin V-FITC/PI staining, and caspase-3 activity. EPA/DHA significantly induced PPARγ and p53 overexpression as observed in immunoblotting assay and the induction of p53 by EPA/DHA was abolished by GW9662. In all cases, the effect of DHA was significantly more potent than that of EPA (P < 0.05). Our findings suggested that DHA may be more effective than EPA in growth suppression of TOV-21G cells and the biologic effects may be partly mediated by PPARγ and p53 activation. Further research is required to elucidate additional divergent mechanisms to account for apparent differences between EPA and DHA.

PMID: 26942868 [PubMed - as supplied by publisher]

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Cancers, Vol. 8, Pages 32: South Asian Medicinal Compounds as Modulators of Resistance to Chemotherapy and Radiotherapy

Cancer is a hyperproliferative disorder that involves transformation, dysregulation of apoptosis, proliferation, invasion, angiogenesis and metastasis. During the last 30 years, extensive research has revealed much about the biology of cancer. Chemotherapy and radiotherapy are the mainstays of cancer treatment, particularly for patients who do not respond to surgical resection. However, cancer treatment with drugs or radiation is seriously limited by chemoresistance and radioresistance. Various approaches and strategies are employed to overcome resistance to chemotherapy and radiation treatment. Many plant-derived phytochemicals have been investigated for their chemo- and radio-sensitizing properties. The peoples of South Asian countries such as India, Pakistan, Sri Lanka, Nepal, Bangladesh and Bhutan have a large number of medicinal plants from which they produce various pharmacologically potent secondary metabolites. The medicinal properties of these compounds have been extensively investigated and many of them have been found to sensitize cancer cells to chemo- and radio-therapy. This review focuses on the role of South Asian medicinal compounds in chemo- and radio-sensitizing properties in drug- and radio-resistant cancer cells. Also discussed is the role of South Asian medicinal plants in protecting normal cells from radiation, which may be useful during radiotherapy of tumors to spare surrounding normal cells.

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p.(L576P) -KIT mutation in GIST: favourable prognosis and sensitive to imatinib?

p.(L576P) -KIT mutation in GIST: favourable prognosis and sensitive to imatinib?

Cancer Biol Ther. 2016 Mar 4;:0

Authors: Noujaim J, Gonzalez D, Thway K, Jones RL, Judson I

PMID: 26942271 [PubMed - as supplied by publisher]

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EDAG-1 promotes proliferation and invasion of human thyroid cancer cells by activating MAPK/Erk and AKT signal pathways.

EDAG-1 promotes proliferation and invasion of human thyroid cancer cells by activating MAPK/Erk and AKT signal pathways.

Cancer Biol Ther. 2016 Mar 2;:0

Authors: Chen DL, Hu ZQ, Zheng XF, Wang XY, Xu YZ, Li WQ, Fang HS, Kan L, Wang SY

PMID: 26934676 [PubMed - as supplied by publisher]

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KLF4 is downregulated but not mutated during human esophageal squamous cell carcinogenesis and has tumor stage-specific functions.

KLF4 is downregulated but not mutated during human esophageal squamous cell carcinogenesis and has tumor stage-specific functions.

Cancer Biol Ther. 2016 Mar 2;:0

Authors: Yang Y, Katz JP

PMID: 26934576 [PubMed - as supplied by publisher]

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Targeting Blockage of STAT3 Inhibits Hepatitis B Virus-related Hepatocellular Carcinoma.

Targeting Blockage of STAT3 Inhibits Hepatitis B Virus-related Hepatocellular Carcinoma.

Cancer Biol Ther. 2016 Mar 2;:0

Authors: Yang Y, Zheng B, Han Q, Zhang C, Tian Z, Zhang J

PMID: 26934469 [PubMed - as supplied by publisher]

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Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment.

Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment.

Cancer Biol Ther. 2016 Mar 2;:0

Authors: Pisklakova A, Grigson E, Ozerova M, Chen F, Sullivan DM, Nefedova Y

PMID: 26934342 [PubMed - as supplied by publisher]

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Body mass index and treatment outcomes following neoadjuvant therapy in women aged 45 years or younger: evidence from a historic cohort.

Body mass index and treatment outcomes following neoadjuvant therapy in women aged 45 years or younger: evidence from a historic cohort.

Cancer Biol Ther. 2016 Mar 2;:0

Authors: D'Aiuto M, Chirico A, De Riggi MA, Frasci G, De Laurentiis M, Di Bonito M, Vici P, Pizzuti L, Sergi D, Marcello MS, Barba M, Giordano A

PMID: 26934127 [PubMed - as supplied by publisher]

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Healthcare Cost of Over-Diagnosis of Low-Grade Dysplasia in Barrett’s Esophagus

Abstract

Introduction

Published reports have demonstrated that many Barrett's esophagus patients are over-diagnosed as low-grade dysplasia (BE-LGD). We performed an analysis of the surveillance and treatment costs associated with the over-diagnosis of BE-LGD.

Methods

As the principal cost variables, we used endoscopic and histologic procedures performed during the recommended surveillance intervals for patients with BE-LGD, the national average Medicare reimbursement for the Current Procedural Terminology codes of the procedures performed, and a spreadsheet-based tool we created to determine the overall healthcare cost associated with the over-diagnosis of BE-LGD in the US population.

Results

The average excess cost (range) for every patient in the US who is over-diagnosed with BE-LGD is estimated to be $5557 ($3115 to $8072). The principal contributors to the excess cost of over-diagnosis of BE-LGD in these patients are: endoscopy ($2626 to $4639), pathologist biopsy review ($275 to $2185), and esophagogastroduodenoscopy-guided endoscopic ablation ($214 to $1249).

Conclusions

The healthcare cost of over-diagnosis of BE-LGD is significant. To reduce the overall healthcare cost impact of over-diagnosis of BE-LGD, strict adherence to the recommendations of the American Gastroenterological Association, American College of Gastroenterology, and American Society for Gastrointestinal Endoscopy that pathology review of all BE biopsy specimens be performed by a gastrointestinal pathologist is warranted.

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New Methodologies in the Molecular Monitoring of CML

Abstract

In chronic myeloid leukemia (CML), the BCR-ABL fusion gene is both the therapeutic target of tyrosine kinase inhibitors and the indisputable direct marker of disease burden. Thus, sensitive assays for BCR-ABL now drive therapeutic options and are good surrogates for short- and long-term outcomes. Because CML is such an ideal model, new methods are arising that should make testing in CML faster, more reliable, and reach a greater sensitivity. These methods should be able to be transferred to other hematological malignancies that have mutation markers.

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Pencil beam scanning proton therapy for pediatric intracranial ependymoma

Abstract

To assess the clinical outcome and late side effect profile of pencil beam scanning proton therapy (PT) delivered to children with intracranial ependymoma. Between July-2004 and March-2013, 50 patients with intracranial ependymoma (n = 46, grade 3) received involved-field PT at Paul Scherrer Institute (PSI). Median age at time of PT was 2.6 years (range 1.1–15.2). Thirty-six patients had infratentorial and 14 supratentorial ependymomas. Seventeen patients presented with macroscopic residual disease after subtotal resection before starting PT (8 with ≤1.5 cc and 9 with >1.5 cc residual tumor respectively). Forty-three (86 %) patients received post-operative chemotherapy before PT according to protocols; 44 (88 %) patients younger than 5 years required general anesthesia. Median prescribed dose was 59.4 Gy (RBE) (range 54–60) delivered in 1.8–2 Gy (RBE) per fraction. Late toxicity was assessed according to CTCAE v4.0. With a mean follow-up time of 43.4 months (range 8.5–113.7) seven patients experienced local failure (6 with infratentorial tumors and 1 with supratentorial tumor); four of the local failures were in patients with residual disease ≥1.5 cc at the time of PT and 3 without residual macroscopic disease. Five patients died from tumor progression. Actuarial 5-year Local Control rates were 78 ± 7.5 % and 5-year OS rates were 84 ± 6.8 %. Three patients developed grade ≥3 toxicity: 2 developed unilateral deafness (infratentorial tumors infiltrating into the internal acoustic canal), one patient developed a fatal brainstem necrosis. Repeated general anesthesia in children younger than 5 years was delivered without complications. Our data indicate the safety and the effectiveness of PT for pediatric ependymomas. Local control and survival rates are encouraging considering the high grade histology in 92 % of the patients and the number of patients with residual tumor ≥1.5 cc. The rates of late effects compare favorably with published photon-treated cohorts.

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Superselective intraarterial cerebral infusion of cetuximab after osmotic blood/brain barrier disruption for recurrent malignant glioma: phase I study

Abstract

Objective To establish a maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of Cetuximab after osmotic disruption of the blood–brain barrier (BBB) with mannitol, and examine safety of the procedure in patients with recurrent malignant glioma.

Methods A total of 15 patients with recurrent malignant glioma were included in the current study. The starting dose of Cetuximab was 100 mg/m² and dose escalation was done to 250 mg/m². All patients were observed for 28 days post-infusion for any side effects.

Results There was no dose-limiting toxicity from a single dose of SIACI of Cetuximab up to 250 mg/m² after osmotic BBB disruption with mannitol. A tolerable rash was seen in 2 patients, anaphylaxis in 1 patient, isolated seizure in 1 patient, and seizure and cerebral edema in 1 patient.

Discussion SIACI of mannitol followed by Cetuximab (up to 250 mg/m²) for recurrent malignant glioma is safe and well tolerated. A Phase I/II trial is currently underway to determine the efficacy of SIACI of cetuximab in patients with high-grade glioma.

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The Synergistic Effect of Serine with Selenocompounds on the Expression of SelP and GPx in HepG2 Cells

Abstract

We explored the synergistic effect of serine combined with several selenocompounds or used alone on the expression of selenoprotein P (SelP) and glutathione peroxidase (GPx) in this study. We first compared the SelP and GPx expression difference between HepG2 and Hela cells treated with serine and finally chose HepG2 as experimental cell. In the serine-used-alone experiment, three kinds of selenium nutritional models (low-, adequate-, and high-selenium) were established and serine was 10 times gradient diluted (0.01 to 100 μmol/L). In the combined experiment, the selenocompound doses were set as 0.01, 0.1, and 1 μmol Se/L and serine was set according to its molar ratio with the selenocompounds. We found that SelP and GPx concentrations in the low-, adequate-, and high-selenium models increased following with serine dose. When the concentration of sodium selenite and SeMet was 1 μmol Se/L while MeSeCys was 0.1 and 1 μmol Se/L, SelP concentrations for serine combined with selenocompounds groups were significantly higher than that of selenocompounds used alone. When the concentration of sodium selenite was 0.1 μmol Se/L, SeMet was 0.1 and 1 μmol Se/L while MeSeCys was 0.01 and 1 μmol Se/L, GPx concentrations for serine combined with selenocompounds groups were significantly higher than that of selenocompounds used alone. Our preliminary result indicated the beneficial effect of serine on the expression of SelP and GPx, which suggested that it might be a candidate for combined selenium supplement.

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Valproic acid inhibits the angiogenic potential of cervical cancer cells via HIF-1α/VEGF signals

Abstract

Purpose

Cervical cancer is one of the most prevalent malignancies in women worldwide. Therefore, the investigation about the molecular pathogenesis and related therapy targets of cervical cancer is an emergency. The objective of the present study is to investigate the effects of valproic acid (VPA), a histone deacetylase inhibitor, on the angiogenesis of cervical cancer.

Methods

The effects and mechanisms of VPA on in vitro angiogenesis and vascular endothelial growth factor (VEGF) expression of human cervical cancer HeLa and SiHa cells were investigated.

Results

Our present study reveals that 1 mM VPA can significantly inhibit the in vitro angiogenic potential and VEGF expression of human cervical cancer HeLa and SiHa cells. Further, the transcription and protein levels of hypoxia inducible factor-1α (HIF-1α), and not HIF-1β, are significantly inhibited in VPA-treated cervical cancer cells. Over expression of HIF-1α can obviously reverse VPA-induced VEGF down regulation. VPA-treatment decreases the activation of Akt and ERK1/2 in both HeLa and SiHa cells in a time-dependent manner. The inhibitor of Akt (LY 294002) or ERK1/2 (PD98059) can inhibit VEGF alone and cooperatively reinforce the suppression effects of VPA on HIF-1α and VEGF expression.

Conclusion

Collectively, our data reveal that the inhibition of PI3K/Akt and ERK1/2 signals are involved in VPA-induced HIF-1α and VEGF suppression of cervical cancer cells.

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Local iron homeostasis in the breast ductal carcinoma microenvironment

Abstract

Background

While the deregulation of iron homeostasis in breast epithelial cells is acknowledged, iron-related alterations in stromal inflammatory cells from the tumor microenvironment have not been explored.

Methods

Immunohistochemistry for hepcidin, ferroportin 1 (FPN1), transferrin receptor 1 (TFR1) and ferritin (FT) was performed in primary breast tissues and axillary lymph nodes in order to dissect the iron-profiles of epithelial cells, lymphocytes and macrophages. Furthermore, breast carcinoma core biopsies frozen in optimum cutting temperature (OCT) compound were subjected to imaging flow cytometry to confirm FPN1 expression in the cell types previously evaluated and determine its cellular localization.

Results

We confirm previous results by showing that breast cancer epithelial cells present an 'iron-utilization phenotype' with an increased expression of hepcidin and TFR1, and decreased expression of FT. On the other hand, lymphocytes and macrophages infiltrating primary tumors and from metastized lymph nodes display an 'iron-donor' phenotype, with increased expression of FPN1 and FT, concomitant with an activation profile reflected by a higher expression of TFR1 and hepcidin. A higher percentage of breast carcinomas, compared to control mastectomy samples, present iron accumulation in stromal inflammatory cells, suggesting that these cells may constitute an effective tissue iron reservoir. Additionally, not only the deregulated expression of iron-related proteins in epithelial cells, but also on lymphocytes and macrophages, are associated with clinicopathological markers of breast cancer poor prognosis, such as negative hormone receptor status and tumor size.

Conclusions

The present results reinforce the importance of analyzing the tumor microenvironment in breast cancer, extending the contribution of immune cells to local iron homeostasis in the tumor microenvironment context.

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Neutrophil-to-lymphocyte ratio is a prognostic marker in bladder cancer patients after radical cystectomy

Abstract

Background

There is no reliable biomarker for predicting the prognosis of patients who undergo radical cystectomy for bladder cancer. Recent studies have shown that the neutrophil-to-lymphocyte ratio (NLR) could function as a useful prognostic factor in several types of malignancies. This study aimed to assess the usefulness of NLR in bladder cancer.

Methods

A total of 74 patients who underwent radical cystectomy in our institutions from 1999 to 2014 were analyzed. The NLR was calculated using the patients' neutrophil and lymphocyte counts before radical cystectomy. An immunohistochemical analysis was also performed to detect tumor infiltrating neutrophils (CD66b) and lymphocytes (CD8) in bladder cancer specimens.

Results

A univariate analysis showed that the patients with a high NLR (≥2.38; HR = 4.84; p = 0.007), high C-reactive protein level (>0.08; HR = 10.06; p = 0.030), or pathological lymph node metastasis (HR = 4.73; p = 0.030) had a significantly higher risk of cancer-specific mortality. Kaplan-Meier and log-rank tests further revealed that NLR was strongly correlated with overall survival (p = 0.018), but not progression-free survival (p = 0.137). In a multivariate analysis, all of these were found to be independent risk factors (HR = 4.62, 10.8, and 12.35, respectively). The number of CD8-positive lymphocytes was significantly increased in high-grade (p = 0.001) and muscle-invasive (p = 0.012) tumors, in comparison to low-grade and non-muscle-invasive tumors, respectively.

Conclusions

The NLR predicted the prognosis of patients who underwent radical cystectomy and might therefore function as a reliable biomarker in cases of invasive bladder cancer.

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Mitogen-activated protein kinase signaling causes malignant melanoma cells to differentially alter extracellular matrix biosynthesis to promote cell survival

Abstract

Background

Intrinsic and acquired resistance to drug therapies remains a challenge for malignant melanoma patients. Intratumoral heterogeneities within the tumor microenvironment contribute additional complexity to the determinants of drug efficacy and acquired resistance.

Methods

We use 3D biomimetic platforms to understand dynamics in extracellular matrix (ECM) biogenesis following pharmaceutical intervention against mitogen-activated protein kinases (MAPK) signaling. We further determined temporal evolution of secreted ECM components by isogenic melanoma cell clones.

Results

We found that the cell clones differentially secrete and assemble a myriad of ECM molecules into dense fibrillar and globular networks. We show that cells can modulate their ECM biosynthesis in response to external insults. Fibronectin (FN) is one of the key architectural components, modulating the efficacy of a broad spectrum of drug therapies. Stable cell lines engineered to secrete minimal levels of FN showed a concomitant increase in secretion of Tenascin-C and became sensitive to BRAF^V600E and ERK inhibition as clonally- derived 3D tumor aggregates. These cells failed to assemble exogenous FN despite maintaining the integrin machinery to facilitate cell- ECM cross-talk. We determined that only clones that increased FN production via p38 MAPK and β1 integrin survived drug treatment.

Conclusions

These data suggest that tumor cells engineer drug resistance by altering their ECM biosynthesis. Therefore, drug treatment may induce ECM biosynthesis, contributing to de novo resistance.

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Intensive care unit prognostic factors in critically ill patients with advanced solid tumors: a 3-year retrospective study

Abstract

Background

The objective of this study was to identify risk factors predicting prognosis of critically ill medical patients with advanced solid tumors in the intensive care unit (ICU).

Methods

We retrospectively analyzed all ICU unplanned medical admissions to the ICU of patients with advanced solid cancer in Tianjin Medical University Cancer Institute and Hospital between October 1, 2012 and March 1, 2015. Approval was obtained from the Ethical Commission of Tianjin Medical University Cancer Institute and Hospital to review and publish information from patients' records.

Results

One hundred and forty-one patients with full code status met the criteria for inclusion from among 813 ICU admissions. ICU mortality was 14.9 % and in-hospital mortality was 29.8 %. The major reasons for unplanned ICU admission were respiratory failure (38.3 %) and severe sepsis or septic shock (27.7 %). The ICU mortality in patients who required vasopressors, mechanical ventilation or renal replacement therapy for >24 h was 25, 25.9 and 40 %, respectively. The mean overall survival was 28.6 months. After adjusting for hypertension, type of solid cancer, intervention time, need for mechanical ventilation and Acute Physiology and Chronic Health Evaluation II score, only Sepsis-related Organ Failure Assessment (SOFA) score on day 7 of ICU treatment remained a significant predictor of ICU mortality (adjusted odds ratio 1.612, 95 % confidence interval 1.137–2.285, P = 0.007).

Conclusions

We suggest broadening the criteria for ICU admission. The patients should be allowed an ICU trial consisting of unlimited ICU support, including invasive hemodynamic monitoring, mechanical ventilation and renal replacement therapy. An interdisciplinary meeting, including an ethics consultation, should be held to make end-of-life decisions if the SOFA score on day 7 shows clinical deterioration with no available therapeutic options.

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A randomised phase II trial of Stereotactic Ablative Fractionated radiotherapy versus Radiosurgery for Oligometastatic Neoplasia to the lung (TROG 13.01 SAFRON II)

Abstract

Background

Stereotactic ablative body radiotherapy (SABR) is emerging as a non-invasive method for precision irradiation of lung tumours. However, the ideal dose/fractionation schedule is not yet known. The primary purpose of this study is to assess safety and efficacy profile of single and multi-fraction SABR in the context of pulmonary oligometastases.

Methods/Design

The TROG 13.01/ALTG 13.001 clinical trial is a multicentre unblinded randomised phase II study. Eligible patients have up to three metastases to the lung from any non-haematological malignancy, each < 5 cm in size, non-central targets, and have all primary and extrathoracic disease controlled with local therapies. Patients are randomised 1:1 to a single fraction of 28Gy versus 48Gy in four fractions of SABR. The primary objective is to assess the safety of each treatment arm, with secondary objectives including assessment of quality of life, local efficacy, resource use and costs, overall and disease free survival and time to distant failure. Outcomes will be stratified by number of metastases and origin of the primary disease (colorectal versus non-colorectal primary). Planned substudies include an assessment of the impact of online e-Learning platforms for lung SABR and assessment of the effect of SABR fractionation on the immune responses. A total of 84 patients are required to complete the study.

Discussion

Fractionation schedules have not yet been investigated in a randomised fashion in the setting of oligometastatic disease. Assuming the likelihood of similar clinical efficacy in both arms, the present study design allows for exploration of the hypothesis that cost implications of managing potentially increased toxicities from single fraction SABR will be outweighed by costs associated with delivering multiple-fraction SABR.

Trials registration

ACTRN12613001157763, registered 17th October 2013

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Primary diffuse leptomeningeal gliomatosis as a rare cause of pain in cervical spine

Abstract

Background

Primary diffuse leptomeningeal gliomatosis (PDLG) is a very rare neuro-oncological disease, with only 90 cases of PDLG described in medical literature so far.

Case presentation

We present a case report of a 56-years-old female patient, who was originally hospitalized due to cervical spine pain lasting several months. Despite complex diagnostics and treatment, the neurological state of the patient progressively deteriorated. Patient died 10 months after the first reported symptom. Postmortem pathological findings resulted in the diagnosis of PDLG.

Conclusions

Affection of the cervical spine in early stages of PDLG is rare and has been described in only six patients so far. PDLG is a fatal neuro-oncological disease and it must be kept in mind in the differential diagnosis of persistent back pain syndromes.

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On Predicting lung cancer subtypes using ‘omic’ data from tumor and tumor-adjacent histologically-normal tissue

Abstract

Background

Adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are the most prevalent histological types among lung cancers. Distinguishing between these subtypes is critically important because they have different implications for prognosis and treatment. Normally, histopathological analyses are used to distinguish between the two, where the tissue samples are collected based on small endoscopic samples or needle aspirations. However, the lack of cell architecture in these small tissue samples hampers the process of distinguishing between the two subtypes.

Molecular profiling can also be used to discriminate between the two lung cancer subtypes, on condition that the biopsy is composed of at least 50 % of tumor cells. However, for some cases, the tissue composition of a biopsy might be a mix of tumor and tumor-adjacent histologically normal tissue (TAHN). When this happens, a new biopsy is required, with associated cost, risks and discomfort to the patient. To avoid this problem, we hypothesize that a computational method can distinguish between lung cancer subtypes given tumor and TAHN tissue.

Methods

Using publicly available datasets for gene expression and DNA methylation, we applied four classification tasks, depending on the possible combinations of tumor and TAHN tissue. First, we used a feature selector (ReliefF/Limma) to select relevant variables, which were then used to build a simple naïve Bayes classification model. Then, we evaluated the classification performance of our models by measuring the area under the receiver operating characteristic curve (AUC). Finally, we analyzed the relevance of the selected genes using hierarchical clustering and IPA® software for gene functional analysis.

Results

All Bayesian models achieved high classification performance (AUC > 0.94), which were confirmed by hierarchical cluster analysis. From the genes selected, 25 (93 %) were found to be related to cancer (19 were associated with ADC or SCC), confirming the biological relevance of our method.

Conclusions

The results from this study confirm that computational methods using tumor and TAHN tissue can serve as a prognostic tool for lung cancer subtype classification. Our study complements results from other studies where TAHN tissue has been used as prognostic tool for prostate cancer. The clinical implications of this finding could greatly benefit lung cancer patients.

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Erratum to: Population attributable risks of modifiable reproductive factors for breast and ovarian cancers in Korea

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Piperine potentiates the effects of trans -resveratrol on stress-induced depressive-like behavior: involvement of monoaminergic system and cAMP-dependent pathway

Abstract

Stress can act as a precipitation factor in the onset of emotional disorders, particularly depression. Trans-resveratrol is a polyphenolic compound enriched in polygonum cuspidatum and has been found to exert antidepressant-like effects in our previous studies. In present study, we assessed the effects of trans-resveratrol used in combination with piperine, commonly known as a bioavailability enhancer, on chronic unpredictable mild stress-induced depressive-like behaviors and relevant molecular targets. Trans-resveratrol used alone reduced the immobility time of rats in the forced swimming test, with the maximal effects of trans-resveratrol around 60 % inhibition at the highest dose tested, 40 mg/kg. However, when a subthreshold dose of piperine, 2.5 mg/kg was used in combination with trans-resveratrol, the minimum effective dose of trans-resveratrol in reducing the immobility time was reduced to 20 mg/kg. Further evidence from neurochemical (monoamines in the frontal cortex and the hippocampus), biochemical (monoamine oxidase, MAO activities) and molecular biological (cAMP, PKA, CREB and BDNF) assays supported the findings in the behavioral studies. These results suggest that the co-treatment strategy with trans-resveratrol and piperine might be an alternative therapy that provides efficacious protection against chronic stress.

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Pencil beam scanning proton therapy for pediatric intracranial ependymoma

Abstract

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Superselective intraarterial cerebral infusion of cetuximab after osmotic blood/brain barrier disruption for recurrent malignant glioma: phase I study

Abstract

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The Effects of an Educational Intervention on Preventing Cervical Cancer Among Vietnamese Women in Southern Taiwan

Abstract

This paper aims to conduct and evaluate an educational intervention on preventing cervical cancer among married immigrant women of Vietnamese origin. The study design was a quasi-experimental method with two groups. In total, 260 married immigrant women of Vietnamese origin with national health insurance at least 30 years of age were recruited from November 2013 to January 2015 in southern Taiwan. The effects of the educational intervention, including cervical cancer and Papanicolaou test knowledge, attitudes towards cervical cancer, fatalism, barriers to receiving Papanicolaou tests, intention for receiving Papanicolaou tests within the next year, and intention for receiving Papanicolaou tests within the next 3 years, were evaluated. Repeated measures analyses of variance showed significant interactions between the intervention group and time for cervical cancer knowledge, knowledge of Papanicolaou test, attitudes towards cervical cancer, and intention for receiving a Papanicolaou test within the next 3 years; in addition, 71.4 % reported being satisfied or very satisfied with the intervention. The results of this study can provide information for governments to make appropriate health policies for screening behavior of cervical cancer, increase healthcare professionals' competencies towards Vietnamese women, and increase Papanicolaou test screening rates to decrease cervical cancer mortality. Effective interventions may require particular consideration of married immigrant women.

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