Targeted Doxorubicin-loaded Bacterially Derived Nano-cells for the Treatment of Neuroblastoma

Advanced stage neuroblastoma is an aggressive disease with limited treatment options for patients with drug resistant tumors. Targeted delivery of chemotherapy for pediatric cancers offers promise to improve treatment efficacy and reduce toxicity associated with systemic chemotherapy. The EnGeneIC delivery vehicle (EDVTM) is a nanocell which can package chemotherapeutic drugs and target tumors via attachment of bispecific proteins to the surface of the nanocell. Phase 1 trials in adults with refractory tumors have shown an acceptable safety profile. Herein we investigated the activity of EGFR-targeted and doxorubicin-loaded EDVTM (EGFREDVTMDox) for the treatment of neuroblastoma. Two independent neuroblastoma cell lines with variable expression of EGFR protein (SK-N-BE(2), high; SH-SY-5Y, low) were used. EGFREDVTMDox induced apoptosis in these cells compared to control, doxorubicin or non-doxorubicin loaded EGFREDVTM. In 3D-tumor spheroids, imaging and Fluorescence Life-time Microscopy revealed that EGFREDVTMDox had a marked enhancement of doxorubicin penetration compared to doxorubicin alone, and improved penetration compared to non-EGFR-targeted EDVTMDox, with enhanced spheroid penetration leading to increased apoptosis. In two independent orthotopic human neuroblastoma xenograft models, short term studies (28 days) of tumor-bearing mice led to a significant decrease in tumor size in EGFREDVTMDox treated animals compared to control, doxorubicin or non-EGFR EDVTMDox. There was increased TUNEL staining of tumors at day 28 compared to control, doxorubicin or non-EGFR EDVTMDox. Moreover, overall survival was increased in neuroblastoma mice treated with EGFREDVTMDox (P < 0007) compared to control. Drug-loaded bispecific-antibody targeted EDVsTM offer a highly promising approach for the treatment of aggressive pediatric malignancies such as neuroblastoma.

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Anodal transcranial direct current stimulation (tDCS) boosts dominant brain oscillations

Publication date: Available online 28 February 2018
Source:Brain Stimulation
Author(s): Caroline Di Bernardi Luft, Ioanna Zioga, Joydeep Bhattacharya




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Long-lasting effects of transcranial static magnetic field stimulation on motor cortex excitability

Publication date: Available online 7 February 2018
Source:Brain Stimulation
Author(s): Michele Dileone, Laura Mordillo-Mateos, Antonio Oliviero, Guglielmo Foffani
BackgroundTranscranial static magnetic field stimulation (tSMS) was recently added to the family of inhibitory non-invasive brain stimulation techniques. However, the application of tSMS for 10–20 min over the motor cortex (M1) induces only short-lasting effects that revert within few minutes.ObjectiveWe examined whether increasing the duration of tSMS to 30 min leads to long-lasting changes in cortical excitability, which is critical for translating tSMS toward clinical applications.MethodsThe study comprised 5 experiments in 45 healthy subjects. We assessed the impact of 30-min-tSMS over M1 on corticospinal excitability, as measured by the amplitude of motor evoked potentials (MEPs) and resting motor thresholds (RMTs) to single-pulse transcranial magnetic stimulation (TMS) (experiments 1–2). We then assessed the impact of 30-min-tSMS on intracortical excitability, as measured by short-interval intracortical facilitation (SICF) and short-interval intracortical inhibition (SICI) using paired-pulse TMS protocols (experiments 2–4). We finally assessed the impact of 10-min-tSMS on SICF and SICI (experiment 5).Results30-min-tSMS decreased MEP amplitude compared to sham for at least 30 min after the end of the stimulation. This long-lasting effect was associated with increased SICF and reduced SICI. 10-min-tSMS –previously reported to induce a short-lasting decrease in MEP amplitude– produced the opposite changes in intracortical excitability, decreasing SICF while increasing SICI.ConclusionsThese results suggest a dissociation of intracortical changes in the consolidation from short-lasting to long-lasting decrease of corticospinal excitability induced by tSMS. The long-lasting effects of 30-min-tSMS open the way to the translation of this simple, portable and low-cost technique toward clinical trials.



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Reply to: Comments on “Breast augmentation together with intraoperative glandular transposition flap for prevention and correction of lower pole deformities”

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Targeting liver sinusoidal endothelial cells with miR-20a-loaded nanoparticles reduces murine colon cancer metastasis to the liver

Abstract

Phenotypic transformation of liver sinusoidal endothelial cells is one of the most important stages of liver metastasis progression. The miRNA effects on liver sinusoidal endothelial cells during liver metastasis have not yet been studied. Herein, whole genome analysis of miRNA expression in these cells during colorectal liver metastasis revealed repressed expression of microRNA-20a. Importantly, downregulation of miR-20a occurs in parallel with upregulation of its known protein targets. To restore normal miR-20a levels in liver sinusoidal endothelial cells, we developed chondroitin sulfate-sorbitan ester nanoparticles conjugated with miR-20a in a delivery system that specifically targets liver sinusoidal endothelial cells. The restoration of normal mir-20a levels in these cells induced downregulation of the expression of its protein targets, and this also resulted in a reduction of in vitro LSEC migration and a reduction of in vivo activation and tumor-infiltrating capacity and ability of the tumor decreased by approximately 80% in a murine liver metastasis model. This article is protected by copyright. All rights reserved.

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Leveraging the success of HIV drug development paradigms for cancer

In the 1980s, infection by the human immunodeficiency virus (HIV) was a devastating condition, signifying near-certain lethality; however, people infected by HIV today may have life expectancies typical of the general population. A major driver of this progress was the introduction of combination antiretroviral therapy (cART) into clinical practice. In contrast, progress for people with cancer has been incremental over the past few decades, although we have recently witnessed improved outcomes in some cancers, owing in part to the development of new therapies. Gains in our fundamental understanding of disease biology, coupled with careful clinical investigations, led to remarkable success in HIV and for certain cancers. Perhaps the development of effective therapies for HIV in the past three decades can provide further insights for continued progress in oncology.

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Combinations of Bevacizumab and Erlotinib show activity in colorectal cancer independent of RAS status

Purpose: There is extensive cross-talk between VEGF- and EGFRpathway signaling in colorectal cancer (CRC). However, combinations of VEGF- and EGFR-targeted monoclonal antibodies (mAbs) show disappointing activity, in particular for patients with mutant RAS. Previous results show that tyrosine kinase inhibitors (TKIs) can be active in CRC models resistant to mAbs. This promoted us to examine whether the activity of bevacizumab can be increased by combination with erlotinib. Experimental design: The antitumor activity of bevacizumab, erlotinib and their combination was determined in CRC models with different RAS status and bevacizumab sensitivity. EGFR/VEGF pathway activation was characterized by immunohistochemistry, Western blot and ELISA assays. The influence of cetuximab and erlotinib on EGFmediated migration and the EGFR-EGF ligand feed-back loop was established in CRC cell lines with different RAS status. Results: The addition of erlotinib increased bevacizumab activity in all models independent of RAS status. Bevacizumab exposure was accompanied by marked EGFR activation in tumor cells as well as in tumor-associated endothelial cells (TECs) and resulted in strong accumulation of intracellular EGFR, which could be attenuated by erlotinib. In cellular models, erlotinib was able to attenuate EGFmediated functions in all cell lines independent of RAS status while cetuximab only showed activity in RAS wt cells. Conclusions: These results should provide a molecular framework to better understand the increased activity of the bevacizumab-erlotinib combination, compared to bevacizumab alone, in the GERCOR DREAM phase III clinical trial. Differential activity of mAbs and TKIs targeting the same signaling pathway is likely applicable for other tumor types.

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Discovery and validation of circulating biomarkers of colorectal adenoma by high-depth small RNA sequencing

Purpose: Colorectal cancer (CRC) is the third most common cancer worldwide, causing ~700,000 deaths each year. The majority of CRCs begin as adenomas. Definitive screening for colorectal adenomas is currently accomplished through colonoscopy but, owing largely to costs and invasiveness, is typically limited to patient groups at higher risk by virtue of age or family history. We sought to determine if blood-based small RNA markers could detect colorectal adenoma. Experimental Design: We applied high-depth small RNA sequencing to plasma from a large (n=189) cohort of patients, balanced for age, sex, and ancestry. Our analytical methodology allowed for the detection of both microRNAs and other small RNA species. We replicated sequencing results by qPCR on plasma samples from an independent cohort (n=140). Results: We found several small RNA species with significant associations to colorectal adenoma, including both microRNAs and non-microRNA small RNAs. These associations were robust to correction for patient covariates, including age. Among the adenoma-associated small RNAs, two, a miR-335-5p isoform and an un-annotated small RNA, validated by qPCR in an independent cohort. A classifier trained on measures of these two RNAs in the discovery cohort yields an AUC of 0.755 (0.775 with age) for adenoma detection in the independent cohort. This classifier accurately detects adenomas in patients under 50 and is robust to sex or ancestry. Conclusions: Circulating small RNAs (including but not limited to miRNAs) discovered by sequencing and validated by qPCR identify patients with colorectal adenomas effectively.

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Targeting tumor vasculature with TNF leads effector T cells to the tumor and enhances therapeutic efficacy of immune checkpoint blockers in combination with ACT

Purpose: Irregular blood flow and endothelial cell anergy, which characterize many solid tumors, hinder tumor infiltration by cytotoxic T lymphocytes (CTLs). This confers resistance to cancer immunotherapy with monoclonal antibodies directed against regulatory pathways in T lymphocytes (i.e., immune checkpoint blockade, ICB). We investigated whether NGR-TNF, a TNF derivative capable of targeting the tumor vasculature, and improving intra-tumor infiltration by activated CTLs, could sensitize tumors to ICB with antibodies specific for the PD-1 and CTLA-4 receptors. Experimental Design: Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with autochthonous prostate cancer, and C57BL/6 mice with orthotopic B16 melanoma were treated with NGR-TNF, adoptive T cell therapy (ACT), and ICB, and monitored for immune surveillance and disease progression. Results: The combination of ACT, NGR-TNF and ICB was the most effective in delaying disease progression, and in improving overall survival of mice bearing ICB-resistant prostate cancer or melanoma. Mechanistically, the therapeutic effects associated with potent tumor infiltration especially by endogenous but also by adoptively transferred PD-1+, granzyme B+, and interferon-+ CTLs. The therapeutic effects also associated with favorable T-effector/Treg ratios. Conclusions:Targeting the tumor vasculature with low-dose TNF in association with ACT may represent a novel strategy for enhancing T-cell infiltration in tumors and overcoming resistance to immune checkpoint blockers.

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A genetic polymorphism in CTLA-4 is associated with overall survival in sunitinib-treated patients with clear cell metastatic renal cell carcinoma

Purpose: The survival of patients with clear cell metastatic renal cell carcinoma (cc-mRCC) has improved substantially since the introduction of tyrosine kinase inhibitors (TKIs). With the fact that TKIs interact with immune responses, we investigated whether polymorphisms of genes involved in immune checkpoints are related to the clinical outcome of cc-mRCC patients treated with sunitinib as first TKI. Experimental Design: 27 single nucleotide polymorphisms (SNPs) in CD274 (PD-L1), PDCD1 (PD-1) and CTLA-4 were tested for a possible association with progression-free survival (PFS) and overall survival (OS) in a discovery cohort of 550 sunitinib-treated cc-mRCC patients. SNPs with a significant association (p<0.05) were tested in an independent validation cohort of 138 sunitinib-treated cc-mRCC patients. Finally, data of the discovery and validation cohort were pooled for meta-analysis. Results: CTLA-4 rs231775 and CD274 rs7866740 showed significant associations with OS in the discovery cohort after correction for age, gender and Heng prognostic risk group (HR=0.84, 95%CI: 0.72-0.98, p=0.028 and HR=0.73, 95%CI: 0.54-0.99, p=0.047, respectively). In the validation cohort, the associations of both SNPs with OS did not meet the significance threshold of p<0.05. After meta-analysis, CTLA-4 rs231775 showed a significant association with OS (HR=0.83, 95%CI: 0.72-0.95, p=0.008). Patients with the GG-genotype had longer OS (35.1 months) compared to patients with an AG (30.3 months) or AA genotype (24.3 months). No significant associations with PFS were found. Conclusions:The G-allele of rs231775 in the CTLA-4 gene is associated with improved OS in sunitinib-treated cc-mRCC patients and could potentially be used as a prognostic biomarker.

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Molecular Alterations and Buparlisib Efficacy in Patients With Squamous Cell Carcinoma of the Head and Neck: Biomarker Analysis From BERIL-1

Purpose: The preplanned exploratory analysis of the BERIL-1 trial presented here aimed to identify biomarkers of response to the combination of buparlisib and paclitaxel. Patients and methods: BERIL-1 was a multicenter, randomized, double-blind, placebo-controlled phase 2 study. Patients with recurrent or metastatic SCCHN progressing on/after one previous platinum-based chemotherapy regimen in the recurrent or metastatic setting were treated with either buparlisib plus paclitaxel or placebo plus paclitaxel. Archival tumor tissue and ctDNA samples were analyzed for molecular alterations and immune infiltration using next generation sequencing or immunohistochemistry.  Results: Biomarker analyses were performed in randomized patients (n=158) with available biomarker data. The most frequently (>5%) mutated genes were TP53, FAT1, TET2, KMT2D, PIK3CA, NOTCH1, NFE2L2, NOTCH2, CCND1 and CDKN2A. Patients with SCCHN tumors (from various primary sites) having HPV negative status (HR=0.51), TP53 (HR=0.55) alterations or low mutational load (HR=0.57) derived overall survival (OS) benefit with the combination of buparlisib and paclitaxel. OS benefit with this combination was also increased in patients with presence of intratumoral TILs ≥10% (HR=0.51), stromal TILs ≥15% (HR=0.53), intratumoral CD8 positive cells ≥5% (HR=0.45), stromal CD8 positive cells ≥10% (HR=0.47) or CD8 positive cells in invasive margins >25% (HR=0.37). A trend for improved progression free survival with the combination of buparlisib and paclitaxel was also observed in these patients. Conclusions: The BERIL-1 biomarker analyses showed that patients with TP53 alterations, HPV-negative status, low mutational load or high infiltration of TILs or CD8-positive cells derived survival benefit with the combination of buparlisib and paclitaxel.

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Immunotherapy in Lung Cancer and the Role of Imaging

Lung cancer is the leading cause of cancer-related mortality and accounts for more deaths than breast, prostate, and colon cancers combined. Traditionally, treatment options have included surgery, chemotherapy, and radiation therapy. Continual advances in the characterization of lung cancer have resulted in the development of effective immunotherapies. These agents help the immune system recognize tumors as foreign, stimulate the immune system, and relieve the inhibition that allows the growth and spread of cancer.

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Imaging on lung cancer and treatment with targeted therapy

The identification of genetic mutations known as oncogenic driver mutations that lead to the growth and survival of cancer cells has been an important advance in the field of oncology. Treatment in advanced non-small cell lung cancer (NSCLC) has transitioned from a more general approach to a more personalized approach based on genetic mutations of the cancer itself. Common mutations detected in patients with advanced NSCLC include mutations of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK).

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Imaging of radiation treatment of lung cancer

Radiation therapy is an important modality in the treatment of patients with lung cancer. Recent advances in delivering radiotherapy were designed to improve loco-regional tumor control by focusing higher doses on the tumor. More sophisticated techniques in treatment planning include three dimensional conformal radiation therapy (3D CRT), intensity-modulated radiotherapy (IMRT), stereotactic body radiotherapy (SBRT), and proton therapy. These methods may result in non-traditional patterns of radiation injury and various radiologic appearances that can be mistaken for recurrence, infection and other lung diseases.

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ABSTRACTS OF THE 5TH INTERNATIONAL CONFERENCE ON ADVANCES IN HEMATOLOGY AND ONCOLOGY (ICAHO2017)

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Clinical Burden of Modified Glasgow Prognostic Scale in Colorectal Cancer

Background/Aim: This study aimed to clarify the potential of modified Glasgow Prognostic Score (mGPS) as a prognostic biomarker and reveal the significance of fish oil (FO)-enriched nutrition in colorectal cancer (CRC). Patients and Methods: A total of 738 CRC patients from three different patient cohorts, including 670 patients in the biomarker study and 68 patients in the nutrition-intervention study, were analyzed. Results: High preoperative mGPS was significantly correlated with well-recognized disease progression factors and advanced UICC stage classification. In addition, high mGPS was an independent prognostic factor in both cohorts, especially in stage III and IV patients. These statuses were maintained in postoperative course and correlated with sarcopenia. Furthermore, FO-enriched nutrition suppressed systemic inflammatory reaction and improved skeletal muscle mass and prognosis, especially in CRC patients with mGPS 1 or 2. Conclusion: Assessment of mGPS could identify patients with high-risk CRC, who might be candidates for FO-enriched nutrition.

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Stereotactic Body Radiation Therapy for Patients with Early-stage Prostate Cancer

Aim: Stereotactic body radiation therapy (SBRT) is emerging as a new treatment option for early-stage prostate cancer, theoretically providing clinical and economic benefits compared to conventionally fractionated external-beam radiation therapy (CF-EBRT). This review aimed to evaluate available published data to determine if the proposed theoretical benefits translate clinically. Materials and Methods: A systematic search strategy was employed across three databases using predefined search terms, inclusion and exclusion criteria to identify relevant articles. Results: Sixteen articles were included. Biochemical progression-free survival rates of 77.1-100% were reported in SBRT studies compared to 55-98% in CF-EBRT studies. Incidence of acute grade 1, 2, and 3 genitourinary toxicities were reported in the range of 13.3-71%, 12-25% and 0-3%, respectively, in the SBRT cohort in comparison to 28.7-51.9%, 15.6-41.4%. and 1.1-8.1%, respectively, in the CF-EBRT cohort. Incidence of acute grade 1, 2, and 3 gastrointestinal toxicities were reported in the range of 13-67%, 1-27% and 0-9%, respectively, of the SBRT cohort compared to 16.1- 51.1%, 6.3-20.7% and 0-3%, respectively, of the CF-EBRT cohort. Mean treatment costs estimates associated with SBRT ranged from $22,152 to $24,873 and $33,068 to $35,431 for CF-EBRT. Conclusion: Available data support the hypothesis of lower rates of acute toxicity and reduced economic burden associated with SBRT compared to CF-EBRT, however, randomised data with longer follow-up are needed to determine whether SBRT is clinically more effective than CF-EBRT.

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Safety of Simultaneous Bilateral Pulmonary Resection for Metastatic Lung Tumors

Aim: We investigated the safety of simultaneous bilateral lung resection for lung metastases. Patients and Methods: We retrospectively analyzed 185 patients with pulmonary metastases who underwent unilateral or bilateral pulmonary resection from August 2009 to December 2016 at a single institution. Results: Single-stage bilateral lung resection was undertaken in 19 patients, and the other 166 patients underwent unilateral pulmonary resection, including 20 patients who underwent repeated resections for synchronous or metachronous metastases. Operative time and drainage days in the bilateral group were significantly longer than those in the unilateral group (220±20 vs. 152±6.9 min: p<0.01, and 2.79±0.3 vs. 2.08±0.1 days: p<0.01). Incidence of postoperative complications and postoperative in-hospital days did not differ between the two groups (p=0.33 and 0.66, respectively). The bilateral group was further divided into two groups, namely, those who underwent wedge resection on both sides (WW) and those who underwent wedge resection on one side and segmentectomy or lobectomy on an opposite side (WSL). Operative time in the WSL group was significantly longer than that in the WW group (260±19 vs. 201±18 min: p=0.03). However, there was no significant difference in duration of chest tube use and postoperative hospital days between the two groups (p=0.26 and p=0.89). No severe postoperative complications occurred in either group. Conclusion: One-stage bilateral pulmonary metastasectomy appears to be safe as long as only wedge resection is performed on at least one side.

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Centrosomal Abnormalities in Pancreatic Cancer: Molecular Mechanisms and Clinical Implications

The centrosome is the main microtubule-organizing center in human cells. It regulates normal cell-cycle progression and cell division. Aberrations in the number, structure and function of centrosomes have been found to drive genomic instability and tumorigenesis. Pancreatic cancer frequently displays centrosomal aberrations. Supernumerary and abnormal centrosomes are observed in the earliest stages of pancreatic tumor development, and the p53 pathway acts as an initial barrier to the proliferation of cells with extra centrosomes. In this review, we summarize recent advances in the understanding of centrosomal aberrations in pancreatic cancer, focusing on regulatory mechanisms and prospects for future anticancer treatment.

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Radiation Therapy for Angiosarcoma of the Scalp: Total Scalp Irradiation and Local Irradiation

Angiosarcoma, a rare cutaneous malignancy, frequently arises in the scalp of older individuals. Because it characteristically initially mimics benign disease, such as a bruise, definitive diagnosis in the early stages is difficult. Angiosarcoma of the scalp is highly malignant and often accompanied by lung metastases that cause hemopneumothorax. Although surgery has been the standard and most reliable curative treatment for angiosarcoma of the scalp, there is a high probability of local recurrence, even after wide surgical excision. Therefore, postoperative radiation therapy has been administered in an attempt to minimize local recurrence. However, surgery is contraindicated in many older patients because of severe comorbidities or age. Definitive radiation therapy has been administered to such patients and has achieved good local control. In particular, total scalp irradiation may be a promising option for curative treatment of angiosarcoma of the scalp. Recent reports suggest that chemotherapy, particularly with taxanes, can prolong survival by reducing the rate of distant failure after radiation therapy. Thus, radiation therapy along with chemotherapy is now recommended for curative treatment of patients with inoperable disease and even some patients with operable disease. Technological developments in radiation therapy, such as intensity-modulated radiation therapy, will contribute to enhanced efficacy and reduced toxicities in the treatment of patients with angiosarcoma of the scalp.

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