Cancers, Vol. 10, Pages 150: Determining the Radiation Enhancement Effects of Gold Nanoparticles in Cells in a Combined Treatment with Cisplatin and Radiation at Therapeutic Megavoltage Energies

Cancers, Vol. 10, Pages 150: Determining the Radiation Enhancement Effects of Gold Nanoparticles in Cells in a Combined Treatment with Cisplatin and Radiation at Therapeutic Megavoltage Energies

Cancers doi: 10.3390/cancers10050150

Authors: Celina Yang Kyle Bromma Wonmo Sung Jan Schuemann Devika Chithrani

Combined use of chemotherapy and radiation therapy is commonly used in cancer treatment, but the toxic effects on normal tissue are a major limitation. This study assesses the potential to improve radiation therapy when combining gold nanoparticle (GNP) mediated radiation sensitization with chemoradiation compared to chemoradiation alone. Incorporation of GNPs with 2 Gy, 6 MV (megavoltage) radiation resulted in a 19 ± 6% decrease in survival of MDA-MB-231 cells. Monte-Carlo simulations were performed to assess dosimetric differences in the presence of GNPs in radiation. The results show that physics dosimetry represents a small fraction of the observed effect. The survival fraction of the cells exposed to GNPs, cisplatin, and radiation was 0.16 ± 0.007, while cells treated with cisplatin and radiation only was 0.23 ± 0.011. The presence of GNPs resulted in a 30 ± 6% decrease in the survival, having an additive effect. The concentration of the GNPs and free drug used for this study was 0.3 and 435 nM, respectively. These concentrations are relatively lower and achievable in an in vivo setting. Hence, the results of our study would accelerate the incorporation of GNP-mediated chemoradiation into current cancer therapeutic protocols in the near future.

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Comparison of anti-HBV regimen with or without adefovir on hepatocellular carcinoma development of Chronic hepatitis B patients with compensated cirrhosis: a retrospective cohort study

Abstract

Background

The impact of different anti-virus regimens on prognosis of Chronic hepatitis B (CHB) related cirrhosis remains to be explored. We aim to investigate whether CHB-related HCC patients receiving nucleoside analogue regimen or not have a different prognosis.

Methods

242 CHB-related compensated cirrhosis patients from 2008 June to 2011 December were included in our study and attributed into groups based on their anti-virus regimens containing adefovir (ADV) or not. The clinical parameters and virological response between ADV-containing regimen group and non-ADV containing regimen groups were reviewed and compared. The risk of hepatocellular carcinoma (HCC) development were analyzed and compared between two groups.

Results

127 patients received anti-virus regimen containing ADV and 115 patients received anti-virus regimen without ADV. The cumulative risk of HCC development among patients treated with ADV-contained therapy was significantly lower than that observed in patients with non-ADV-contained therapy (p<0.05). Multivariate analysis indicated that ADV-containing regimen treatment was significantly associated with lower probability of HCC development, (hazard ratio, 0.18; 95% confidence interval range, 0.07-0.45, p<0.05).

Conclusion

Both anti-virus regimens were effective in reducing serum HBV DNA. Regimen containing ADV decreased the incidence of HCC development in CHB patients with compensated cirrhosis.

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Taking a “Snapshot”: Evaluation of a Conversation Aid for Identifying Psychosocial Needs in Young Adults with Cancer

Journal of Adolescent and Young Adult Oncology, Ahead of Print.


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Modulation the crosstalk between tumor-associated macrophages and non-small cell lung cancer to inhibit tumor migration and invasion by ginsenoside Rh2

Abstract

Background

Tumor-associated macrophages (TAMs) play a critical role in modulating the tumor microenvironment and promote tumor metastases. Our studies have demonstrated that ginsenoside Rh2 (G-Rh2), a monomeric compound extracted from ginseng, is a promising anti-tumor agent in lung cancer cells. However, it remains unclear whetherG-Rh2 can modulate the differentiation of TAMs and its interaction with tumor microenvironment. In this study, we investigated how G-Rh2 regulates the phenotype of macrophages and affects the migration of non-small cell lung cancer (NSCLC) cells.

Methods

Murine macrophage-like RAW264.7 cells and human THP-1 monocyte were differentiated into M1 and M2 subsets of macrophages with different cytokines combination, which were further identified by flow cytometry with specific biomarkers. M2 macrophages were sorted out to co-culture with NSCLC cell lines, A549 and H1299. Wound healing assay was performed to examine the cell migration. Expression levels of matrix metalloproteinases 2 and 9 (MMP-2, − 9) and vascular endothelial growth factor-C (VEGF-C) were measured by RT-qPCR and western blot, and the release of VEGF in the supernatant was measured by a VEGF ELISA kit. Finally, modulation of TAMs phenotype and VEGF expression by G-Rh2 was examined in vivo.

Results

We demonstrated that M2 subset of macrophages alternatively differentiated from RAW264.7 or THP-1cells promote migration of NSCLC cells. Further examinations revealed that NSCLC significantly increased the release of VEGF to the media and elevated the expression levels of VEGF at mRNA and protein levels after being co-cultured with M2 macrophages. Similar alterations in MMP-2 and MMP-9 were observed in NSCLC after being co-cultured. Of note,G-Rh2 had a potential to effectively convert M2 phenotype to M1 subset of macrophages. Importantly, G-Rh2 had a preference to decrease the expression levels of VEGF, MMP2, and MMP9 in co-cultured lung cancer cells, over than those in lung cancer cells without co-culturing. Consistently, G-Rh2 reduced M2 macrophage marker CD206 and VEGF expression levels in vivo.

Conclusions

All of these results suggested that M2 subset macrophages drive lung cancer cells with more aggressive phenotypes. G-Rh2 has a potential to convert TAMs from M2 subset to M1 in the microenvironment and prevents lung cancer cell migration, suggesting the therapeutic effects of G-Rh2onlung cancer.

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Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T Cell Receptors in High-risk MYCN-not-amplified Human Neuroblastoma

Purpose: High-risk neuroblastoma is an aggressive disease. DNA sequencing studies have revealed a paucity of actionable genomic alterations and a low mutation burden, posing challenges to develop effective novel therapies. We used RNA sequencing (RNA-seq) to investigate the biology of this disease including a focus on tumor-infiltrating lymphocytes (TILs). Experimental Design: We performed deep RNA-seq on pre-treatment diagnostic tumors from 129 high-risk and 21 low- or intermediate-risk patients with neuroblastomas. We used single-sample gene set enrichment analysis to detect gene expression signatures of TILs in tumors and examined their association with clinical and molecular parameters including patient outcome. The expression profiles of 190 additional pre-treatment diagnostic neuroblastomas, a neuroblastoma tissue microarray, and T-cell receptor (TCR) sequencing were used to validate our findings. Results: We found that MYCN-not-amplified (MYCN-NA) tumors had significant higher cytotoxic TIL signatures compared to MYCN-amplified (MYCN-A) tumors. A reported MYCN-activation-signature was significantly associated with poor outcome for high-risk patients with MYCN-NA tumors; however, a subgroup of these patients who had elevated activated NK cells, CD8+ T-cells, and cytolytic signatures showed improved outcome and expansion of infiltrating T-cell receptor (TCR) clones. Furthermore, we observed up-regulation of immune exhaustion marker genes, indicating an immune suppressive microenvironment in these neuroblastomas. Conclusions: This study provides evidence that RNA signatures of cytotoxic TIL are associated with the presence of activated NK-/T-cells and improved outcomes in high-risk neuroblastoma patients harboring MYCN-NA tumors. Our findings suggest that these high-risk patients with MYCN-NA neuroblastoma may benefit from additional immunotherapies incorporated into the current therapeutic strategies.

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Radiation followed by OX40 stimulation drives local and abscopal antitumor effects in an anti-PD1-resistant lung tumor model

Purpose: Radiation is used extensively to treat localized cancer, but improved understanding of its effects on the immune system have increased interest in its potential systemic (abscopal) effects, particularly in combination with checkpoint inhibitors such as anti-PD1. The majority of patients either do not respond or develop resistance to monotherapy over time. Here, we investigated the efficacy of OX40 (CD134) stimulation as an alternative immunotherapeutic approach in combination with radiotherapy (XRT) in a murine model of anti-PD1-resistant lung tumors. Experimental Design: We established a bilateral tumor model in 129Sv/Ev mice using an anti-PD1 resistant lung tumor cell line. Primary tumors were treated with intratumoral injection of an OX40 agonist antibody, given as adjuvant therapy after XRT (36 Gy in three 12-Gy fractions), while secondary tumors were left untreated to investigate abscopal outcomes.  Results: The combination of XRT followed by OX40 stimulation effectively inhibited local and systemic antitumor growth, limited lung metastases, and improved survival rates. This treatment regimen augmented CD4⁺ and CD8⁺ T cell expansion. XRT induced the expression of OX40 on T cells in tumors and spleens and increased the percentages of splenic CD103⁺ dendritic cells. Conclusion: Our data extends the benefits of radiation to systemic disease control, especially when combined with anti-OX40 agonist to promote immunologically mediated abscopal effects. Moreover, this study provides a rational treatment approach and sequence to overcome anti-PD1 resistant poorly immunogenic tumors.

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Glutathione system in animal model of solid tumors: From regulation to therapeutic target

Publication date: Available online 21 May 2018
Source:Critical Reviews in Oncology/Hematology
Author(s): Claudia Rita Corso, Alexandra Acco
Glutathione (GSH) is one of the most important defenses against oxidative stress through the fine-tuned regulation of redox homeostasis. Glutathione is also involved in many metabolic processes and is important for the regulation of cell survival, proliferation, and death. Furthermore, GSH and the enzymes that are involved in its biosynthesis, catabolism, and detoxification (e.g., disulfide-oxidized glutathione, glutathione S-transferase, glutathione peroxidase, glutathione reductase, and γ-glutamyltranspetidase) play an important role in several diseases, including cancer. In cancer cells, these enzymes protect the tumor microenvironment against oxidative stress and cell death and are important for tumor growth and development. Thus, the GSH system is an important tool for investigating new pharmacological approaches for cancer treatment. Several preclinical models of solid tumors are available for this purpose. This review summarizes and discusses the regulation and dysregulation of GSH and its related enzymes in different models of solid tumors, and potential treatments that target the GSH system.



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Molecular subtype-specific immunocompetent models of high-grade urothelial carcinoma reveal differential neoantigen expression and response to immunotherapy

High-grade urothelial cancer contains intrinsic molecular subtypes that exhibit differences in underlying tumor biology and can be divided into luminal-like and basal-like subtypes. We describe here the first subtype-specific murine models of bladder cancer and show that Upk3a-CreERT2; Trp53L/L; PtenL/L; Rosa26LSL-Luc (UPPL: luminal-like) and BBN (basal-like) tumors are more faithful to human bladder cancer than the widely-used MB49 cells. Following engraftment into immunocompetent C57BL/6 mice, BBN tumors were more responsive to PD-1 inhibition than UPPL tumors. Responding tumors within the BBN model showed differences in immune microenvironment composition, including increased ratios of CD8+:CD4+ and memory:regulatory T cells. Finally, we predicted and confirmed immunogenicity of tumor neoantigens in each model. These UPPL and BBN models will be a valuable resource for future studies examining bladder cancer biology and immunotherapy.

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Childbirth after adolescent and young adult cancer: a population-based study

Abstract

Purpose

Annually, > 45,000 US women are diagnosed with cancer during adolescence and young adulthood (AYA). Since 2006, national guidelines have recommended fertility counseling for cancer patients. We examined childbirth after AYA cancer by calendar period, cancer diagnosis, and maternal characteristics.

Methods

We identified a cohort of women with an incident invasive AYA cancer diagnosis at ages 15–39 during 2000–2013 in North Carolina. Cancer records were linked with statewide birth certificates through 2014. Hazard ratios (HR) and 95% confidence intervals (CI) for first post-diagnosis live birth were calculated using Cox proportional hazards regression.

Results

Among 17,564 AYA cancer survivors, 1989 had ≥ 1 birth after diagnosis during 98,397 person-years. The 5- and 10-year cumulative incidence of live birth after cancer was 10 and 15%, respectively. AYA survivors with a post-diagnosis birth were younger at diagnosis, had lower stage disease, and had less often received chemotherapy than those without a birth. The 5-year cumulative incidence of post-diagnosis birth was 10.0% for women diagnosed during 2007–2012, compared to 9.4% during 2000–2005 (HR = 1.01; 0.91, 1.12), corresponding to periods before and after publication of American Society of Clinical Oncology fertility counseling guidelines in 2006.

Conclusions

Despite advances in fertility preservation options and recognition of fertility counseling as a part of high-quality cancer care, the incidence of post-diagnosis childbirth has remained stable over the last 15 years.

Implications for Cancer Survivors

Our study uses statewide data to provide recent, population-based estimates of how often AYA women have biological children after a cancer diagnosis.

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A back-to-back tumor composed of papillary renal cell carcinoma and oncocytoma treated by laparoscopic partial nephrectomy: a case report

Renal oncocytoma is the most common benign renal tumor, and papillary renal cell carcinoma is the second most common histologic subtype of renal cell carcinoma. Renal tumors containing different components suc...

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Molar pregnancy with normal viable fetus presenting with severe pre-eclampsia: a case report

While gestational trophoblastic disease is not rare, hydatidiform mole with a coexistent live fetus is a very rare condition occurring in 0.005 to 0.01% of all pregnancies. As a result of the rarity of this co...

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Antibodies Against Chlamydia trachomatis and Ovarian Cancer Risk in Two Independent Populations

Abstract

Background

Pelvic inflammatory disease (PID) has been associated with ovarian cancer risk. To clarify the role of Chlamydia trachomatis and other infectious agents in the development of ovarian cancer, we evaluated the association of serologic markers with incident ovarian cancer using a staged approach in two independent populations.

Methods

Studies included: 1) a case–control study in Poland (244 ovarian cancers/556 control subjects) and 2) a prospective nested case–control study in the PLCO Cancer Screening Trial (160 ovarian cancers/159 control subjects). Associations of serologic marker levels with ovarian cancer risk at diagnostic as well as higher thresholds, identified in Poland and independently evaluated in PLCO, were estimated using multivariable adjusted logistic regression.

Results

In the Polish study, antibodies (based on laboratory cut-point) against the chlamydia plasmid-encoded Pgp3 protein (serological gold standard) were associated with increased ovarian cancer risk (adjusted odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.20 to 2.22); when a positive result was redefined at higher levels, ovarian cancer risk was increased (cut-point 2: OR = 2.00, 95% CI = 1.38 to 2.89; cut-point 3 [max OR]: OR = 2.19, 95% CI = 1.29 to 3.73). In the prospective PLCO study, Pgp3 antibodies were associated with elevated risk at the laboratory cut-point (OR = 1.43, 95% CI = 0.78 to 2.63) and more stringent cut-points (cut-point 2: OR = 2.25, 95% CI = 1.07 to 4.71); cut-point 3: OR = 2.53, 95% CI = 0.63 to 10.08). In both studies, antibodies against other infectious agents measured were not associated with risk.

Conclusions

In two independent populations, antibodies against prior/current C. trachomatis (Pgp3) were associated with a doubling in ovarian cancer risk, whereas markers of other infectious agents were unrelated. These findings lend support for an association between PID and ovarian cancer.

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Brain Activity Associated With Attention Deficits Following Chemotherapy for Childhood Acute Lymphoblastic Leukemia

Abstract

Background

The impact of contemporary chemotherapy treatment for childhood acute lymphoblastic leukemia on central nervous system activity is not fully appreciated.

Methods

Neurocognitive testing and functional magnetic resonance imaging (fMRI) were obtained in 165 survivors five or more years postdiagnosis (average age = 14.4 years, 7.7 years from diagnosis, 51.5% males). Chemotherapy exposure was measured as serum concentration of methotrexate following high-dose intravenous injection. Neurocognitive testing included measures of attention and executive function. fMRI was obtained during completion of two tasks, the continuous performance task (CPT) and the attention network task (ANT). Image analysis was performed using Statistical Parametric Mapping software, with contrasts targeting sustained attention, alerting, orienting, and conflict. All statistical tests were two-sided.

Results

Compared with population norms, survivors demonstrated impairment on number-letter switching (P < .001, a measure of cognitive flexibility), which was associated with treatment intensity (P = .048). Task performance during fMRI was associated with neurocognitive dysfunction across multiple tasks. Regional brain activation was lower in survivors diagnosed at younger ages for the CPT (bilateral parietal and temporal lobes) and the ANT (left parietal and right hippocampus). With higher serum methotrexate exposure, CPT activation decreased in the right temporal and bilateral frontal and parietal lobes, but ANT alerting activation increased in the ventral frontal, insula, caudate, and anterior cingulate.

Conclusions

Brain activation during attention and executive function tasks was associated with serum methotrexate exposure and age at diagnosis. These findings provide evidence for compromised and compensatory changes in regional brain function that may help clarify the neural substrates of cognitive deficits in acute lymphoblastic leukemia survivors.

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A xenograft model for venous malformation

Abstract

Vascular malformations are defects caused by the abnormal growth of the vasculature. Among them, venous malformation (VM) is an anomaly characterized by slow-flow vascular lesions with abnormally shaped veins, typically in sponge-like configuration. VMs can expand over years causing disfigurement, obstruction of vital structures, thrombosis, bleeding, and pain. Treatments have been very limited and primarily based on supportive care, compression garments, sclerotherapy, and/or surgical resection. Sirolimus treatment has recently shown efficacy in some patients with complicated vascular anomalies, including VMs. Activating somatic TIE2 gene mutations have been identified in up to 60% of VMs and PIK3CA mutations have been found in another 25%. Here, we report a xenograft model of VM that reflects the patients' mutation heterogeneity. First, we established a protocol to isolate and expand in culture endothelial cells (VM–EC) from VM tissue or VM blood of nine patients. In these cells, we identified somatic mutations of TIE2, PIK3CA, or a combination of both. Both TIE2 and PIK3CA mutations induced constitutive AKT activation, while TIE2 mutations also showed high MAPK–ERK signaling. Finally, VM–EC implanted into immune-deficient mice generated lesions with ectatic blood-filled channels with scarce smooth muscle cell coverage, similar to patients' VM. This VM xenograft model could be instrumental to test the therapeutic efficacy of Sirolimus in the presence of the different TIE2 or PIK3CA mutations or to test for efficacy of additional compounds in targeting the specific mutated protein(s), thus enabling development of personalized treatment options for VM patients.

https://ift.tt/2KKkMzB

The upper limit for TSH during pregnancy: why we should stop using fixed limits of 2.5 or 3.0 mU/l

Abstract

Physiological changes necessitate the use of pregnancy-specific reference ranges for TSH and FT4 to diagnose thyroid dysfunction during pregnancy. Although many centers use fixed upper limits for TSH of 2.5 or 3.0 mU/L, this comment describeds new data which indicate that such cut-offs are too low and may lead to overdiagnosis or even overtreatment. The new guidelines of the American Thyroid Association have considerably changed recommendations regarding thyroid function reference ranges in pregnancy accordingly. Also a stepwise approach to interpreting these guidelines is discussed as well as the relevant role of FT4 in diagnosis.

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Novel non-invasive early detection of lung cancer using liquid immunobiopsy metabolic activity profiles

Abstract

Lung cancer is the leading cause of cancer death worldwide. Survival is largely dependent on the stage of diagnosis: the localized disease has a 5-year survival greater than 55%, whereas, for spread tumors, this rate is only 4%. Therefore, the early detection of lung cancer is key for improving prognosis. In this study, we present an innovative, non-invasive, cancer detection approach based on measurements of the metabolic activity profiles of immune system cells. For each Liquid ImmunoBiopsy test, a 384 multi-well plate is loaded with freshly separated PBMCs, and each well contains 1 of the 16 selected stimulants in several increasing concentrations. The extracellular acidity is measured in both air-open and hermetically-sealed states, using a commercial fluorescence plate reader, for approximately 1.5 h. Both states enable the measurement of real-time accumulation of 'soluble' versus 'volatile' metabolic products, thereby differentiating between oxidative phosphorylation and aerobic glycolysis. The metabolic activity profiles are analyzed for cancer diagnosis by machine-learning tools. We present a diagnostic accuracy study, using a multivariable prediction model to differentiate between lung cancer and control blood samples. The model was developed and tested using a cohort of 200 subjects (100 lung cancer and 100 control subjects), yielding 91% sensitivity and 80% specificity in a 20-fold cross-validation. Our results clearly indicate that the proposed clinical model is suitable for non-invasive early lung cancer diagnosis, and is indifferent to lung cancer stage and histological type.

https://ift.tt/2rX1qA1

Novel non-invasive early detection of lung cancer using liquid immunobiopsy metabolic activity profiles

Abstract

Lung cancer is the leading cause of cancer death worldwide. Survival is largely dependent on the stage of diagnosis: the localized disease has a 5-year survival greater than 55%, whereas, for spread tumors, this rate is only 4%. Therefore, the early detection of lung cancer is key for improving prognosis. In this study, we present an innovative, non-invasive, cancer detection approach based on measurements of the metabolic activity profiles of immune system cells. For each Liquid ImmunoBiopsy test, a 384 multi-well plate is loaded with freshly separated PBMCs, and each well contains 1 of the 16 selected stimulants in several increasing concentrations. The extracellular acidity is measured in both air-open and hermetically-sealed states, using a commercial fluorescence plate reader, for approximately 1.5 h. Both states enable the measurement of real-time accumulation of 'soluble' versus 'volatile' metabolic products, thereby differentiating between oxidative phosphorylation and aerobic glycolysis. The metabolic activity profiles are analyzed for cancer diagnosis by machine-learning tools. We present a diagnostic accuracy study, using a multivariable prediction model to differentiate between lung cancer and control blood samples. The model was developed and tested using a cohort of 200 subjects (100 lung cancer and 100 control subjects), yielding 91% sensitivity and 80% specificity in a 20-fold cross-validation. Our results clearly indicate that the proposed clinical model is suitable for non-invasive early lung cancer diagnosis, and is indifferent to lung cancer stage and histological type.

https://ift.tt/2rX1qA1

The impact of pharmacokinetic gene profiles across human cancers

Abstract

Background

The right drug to the right patient at the right time is one of the ideals of Individualized Medicine (IM) and remains one of the most compelling promises of the post-genomic age. The addition of genomic information is expected to increase the precision of an individual patient's treatment, resulting in improved outcomes. While pilot studies have been encouraging, key aspects of interpreting tumor genomics information, such as somatic activation of drug transport or metabolism, have not been systematically evaluated.

Methods

In this work, we developed a simple rule-based approach to classify the therapies administered to each patient from The Cancer Genome Atlas PanCancer dataset (n = 2858) as effective or ineffective. Our Therapy Efficacy model used each patient's drug target and pharmacokinetic (PK) gene expression profile; the specific genes considered for each patient depended on the therapies they received. Patients who received predictably ineffective therapies were considered at high-risk of cancer-related mortality and those who did not receive ineffective therapies were considered at low-risk. The utility of our Therapy Efficacy model was assessed using per-cancer and pan-cancer differential survival.

Results

Our simple rule-based Therapy Efficacy model classified 143 (5%) patients as high-risk. High-risk patients had age ranges comparable to low-risk patients of the same cancer type and tended to be later stage and higher grade (odds ratios of 1.6 and 1.4, respectively). A significant pan-cancer association was identified between predictions of our Therapy Efficacy model and poorer overall survival (hazard ratio, HR = 1.47, p = 6.3 × 10^− 3). Individually, drug export (HR = 1.49, p = 4.70 × 10^− 3) and drug metabolism (HR = 1.73, p = 9.30 × 10^− 5) genes demonstrated significant survival associations. Survival associations for target gene expression are mechanism-dependent. Similar results were observed for event-free survival.

Conclusions

While the resolution of clinical information within the dataset is not ideal, and modeling the relative contribution of each gene to the activity of each therapy remains a challenge, our approach demonstrates that somatic PK alterations should be integrated into the interpretation of somatic transcriptomic profiles as they likely have a significant impact on the survival of specific patients. We believe that this approach will aid the prospective design of personalized therapeutic strategies.

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Sanguinarine triggers intrinsic apoptosis to suppress colorectal cancer growth through disassociation between STRAP and MELK

Abstract

Background

Previous studies showed sanguinarine induced apoptosis in CRC cells but did not define the underlying mechanisms. The purpose of this work was to determine the in vivo and in vitro effects of sanguinarine on CRC tumors and to elucidate the mechanism in regulating the intrinsic apoptosis.

Methods

Cell viability of CRC cell lines treated with sanguinarine was measured by MTT assay. Apoptotic cells stained with Annexin V and 7-AAD were detected by flow cytometry. Mitochondrial membrane potential and reactive oxygen species (ROS) were analyzed by JC-1 and DCFH-DA staining, respectively. The in vitro kinase activity of MELK was analyzed by using HTRF^® KinEASE™-STK kit. The expression of proteins were determined using Western blotting and immunohistochemistry. Co-immunoprecipitation and immunofluorecence were used to study the interaction between STRAP and MELK. The anti-neoplastic effect of sanguinarine was observed in vivo in an orthotopic CRC model.

Results

Sanguinarine decreased the tumor size in a dose-dependent manner in orthotopical colorectal carcinomas through intrinsic apoptosis pathway in BALB/c-nu mice. It significantly increased cleavage of caspase 3 and PARP in implanted colorectal tissues. Sanguinarine increased mitochondrial ROS and triggered mitochondrial outer membrane permeabilization in multiple colorectal cancer (CRC) cell lines. NAC pretreatment lowered ROS level and downregulated apoptosis induced by sanguinarine. The intrinsic apoptosis induced by sanguinarine was Bax-dependent. The elevated expression and association between serine-threonine kinase receptor-associated protein (STRAP) and maternal embryonic leucine zipper kinase (MELK) were observed in Bax positive cells but not in Bax negative cells. Sanguinarine dephosphorylated STRAP and MELK and disrupted the association between them in HCT116 and SW480 cells. The expression and association between STRAP and MELK were also attenuated by sanguinarine in the tumor tissues. Importantly, we found that STRAP and MELK were overexpressed and highly phosphorylated in colorectal adenocarcinomas and their expression were significantly correlated with tumor stages. Furthermore, the expression of MELK, but not STRAP, was associated with lymph node metastasis.

Conclusions

Sanguinarine dephosphorelates STRAP and MELK and disassociates the interaction between them to trigger intrinsic apoptosis. Overexpression of STRAP and MELK may be markers of CRC and their disassociation may be a determinant of therapeutic efficacy.

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Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review

Abstract

Background

Lynch syndrome is an autosomal dominant inherited disease caused by germline mutations in mismatch repair genes. Analysis for microsatellite instability (MSI) and immunohistochemistry (IHC) of protein expressions of disease-associated genes is used to screen for Lynch syndrome in endometrial cancer patients. When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer.

Case presentation

Here we report a woman who developed endometrial cancer at the age of 49 years. She had a family history of colorectal cancer (first-degree relative aged 52 years) and stomach cancer (second-degree relative with the age of onset unknown). No other family history was present, and she failed to meet the Amsterdam II criteria for the diagnosis of Lynch syndrome. Losses of MLH1 and PMS2, but not MSH2 and MSH6, proteins were observed by IHC in endometrial cancer tissues. Because MLH1 promoter hypermethylation was detected in endometrial cancer tissue samples, the epigenetic silencing of MLH1 was suspected as the cause of the protein loss. However, because of the early onset of endometrial cancer and the positive family history, a diagnosis of Lynch syndrome was also suspected. Therefore, we provided her with genetic counseling. After obtaining her consent, MLH1 promoter methylation testing and genetic testing of peripheral blood were performed. MLH1 promoter methylation was not observed in peripheral blood. However, genetic testing revealed a large deletion of exon 5 in MLH1; thus, we diagnosed the presence of Lynch syndrome.

Conclusions

Both MLH1 germline mutation and MLH1 promoter hypermethylation may be observed in endometrial cancer. Therefore, even if MLH1 promoter hypermethylation is detected, a diagnosis of Lynch syndrome cannot be excluded.

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Fat-suppressed gadolinium-enhanced isotropic high-resolution 3D-GRE-T1WI for predicting small node metastases in patients with rectal cancer

Abstract

Background

To investigate the application value of fat-suppressed gadolinium-enhanced isotropic high-resolution 3D-GRE-T1WI in regional nodes with different short-axis diameter ranges in rectal cancer, especially in nodes ≤5 mm.

Methods

Patients with rectal adenocarcinoma confirmed by postoperative histopathology were included, and all the patients underwent preoperative 3.0 T rectal magnetic resonance imaging (MRI) and total mesorectal excision (TME) within 2 weeks after an MR scan. The harvested nodes from specimens were matched with nodes in the field of view (FOV) of images for a node-by-node evaluation. The maximum short-axis diameters of all the visible nodes in the FOV of images were measured by a radiologist; the morphological and enhancement characteristics of these nodes were also independently evaluated by two radiologists. The χ² test was used to evaluate differences in morphological and enhancement characteristics between benign and malignant nodes. The enhancement characteristics were further compared between benign and malignant nodes with different short-axis diameter ranges using the χ² test. Kappa statistics were used to describe interobserver agreement.

Results

A total of 441 nodes from 70 enrolled patients were included in the evaluation, of which 111 nodes were metastatic. Approximately 85.5 and 95.6% of benign nodes were found to have obvious enhancement and homogeneous or mild-heterogeneous enhancement, respectively, whereas approximately 89.2 and 85.1% of malignant nodes showed moderate or mild enhancement and obvious-heterogeneous or rim-like enhancement, respectively. The area under the receiver operating characteristic (ROC) curve (AUC) values of the enhancement degree for identifying the overall nodal status, nodes ≤5 mm and nodes > 5 mm and ≤ 10 mm were 0.887, 0.859 and 0.766 for radiologist 1 and 0.892, 0.823 and 0.774 for radiologist 2, respectively. The AUCs of enhancement homogeneity were 0.940, 0.928 and 0.864 for radiologist 1 and 0.944, 0.938 and 0.842 for radiologist 2, respectively. Nodal border and signal homogeneity were also of certain value in distinguishing metastatic nodes.

Conclusions

Enhancement characteristics based on fat-suppressed gadolinium-enhanced isotropic high-resolution 3D-GRE-T1WI were helpful for diagnosing metastatic nodes in rectal cancer and were a reliable indicator for nodes ≤5 mm.

https://ift.tt/2IWjJ24

Hepatocellular Carcinoma: Updates to Screening and Diagnosis

In what is considered to be "a global problem," liver cancer has tripled in incidence in the United States over the past 20 to 30 years, and is now present in 7 per 100,000 Americans. Thus, screening for disease should be at the forefront to effectively treat high-risk populations. At the 2018 NCCN 23rd Annual Conference, Dr. Anne M. Covey discussed the updated NCCN Guidelines for the screening and diagnosis of hepatocellular carcinoma, which place ultrasound as the most cost-effective and least toxic primary screening option, with a screening interval of approximately 6 months for individuals considered to be at high risk.

https://ift.tt/2IC5xIi

NCCN Frameworks for Resource Stratification of NCCN Guidelines: Adult Cancer Pain and Palliative Care

The NCCN Framework aims to provide adapted guidelines for low- and middle-resource countries to improve the experience of patients with cancer. In particular, the NCCN Frameworks for Adult Cancer Pain and Palliative Care and were designed to help expand access to pain management and palliative care for patients in low-resource countries. The NCCN Framework is one of several tools that can improve cancer care in the developing world. The NCCN Harmonized Guidelines for Sub-Saharan Africa, a collaborative effort between NCCN, American Cancer Society, Clinton Health Access Initiative, and African Cancer Coalition, was developed to harmonize NCCN recommendations with local guidelines across Africa and to make best use of available services and resources.

https://ift.tt/2Llo25g

New Therapies for Ovarian Cancer

In the latest NCCN Guidelines for Ovarian Cancer, the histologic subtypes of ovarian cancer are described in more depth as they vary by frequency, typical age and disease stage at presentation, treatment recommendations, and survival probabilities. The less common subtypes are also discussed. The update with the greatest impact on the treatment of ovarian cancer, however, is probably the use of maintenance therapy with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors, and 3 PARP inhibitors are now included in the guidelines. These drugs have made a large difference in outcome, both for patients with BRCA mutations and in unselected patients.

https://ift.tt/2KEawJ1

Head and Neck Cancers: Advantages of Advanced Radiation Therapy and Importance of Supportive Care

For more than a decade, the incidence of head and neck cancers has been increasing in the United States. Worldwide, they are the ninth most common cancer. Today, newer advances in radiotherapy (RT), such as fractionation, 4-dimensional cone-beam CT, and intensity-modulated RT, have provided clinicians with the opportunity for improved patient outcomes. At the NCCN 23rd Annual Conference, Sharon Spencer, MD, described the advantages of advances in RT and the means to mitigate untoward side effects.

https://ift.tt/2LkAWAK

Use of Direct Oral Anticoagulants for Treating Venous Thromboembolism in Patients With Cancer

For patients with cancer who experience venous thromboembolism (VTE), low-molecular-weight heparin (LMWH) remains the standard of care in the NCCN Guidelines for VTE, but under certain conditions direct oral anticoagulants (DOACs) are acceptable alternatives. A growing body of literature suggests that DOACs may more effective than LMWHs in preventing recurrences, but they do carry some increased risk of bleeding. Most of this risk is seen in patients with gastrointestinal or urinary pathology or implanted devices. DOACs are also acceptable when the pain, cost, and inconvenience of LMWHs are expected to be obstacles to compliance. Through careful patient selection, most patients can be treated successfully with a DOAC, although for most patients with gastrointestinal or urinary pathology, LMWH remains the safer choice.

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Prognostic Significance of Molecular Markers and Targeted Regimens in the Management of Acute Myeloid Leukemia

The diagnosis, staging, and treatment of acute myeloid leukemia (AML) has evolved based on identification of important genetic alterations and drugs to target those genes. Cytogenetic abnormalities play a major role in managing AML. Achieving minimal residual disease is an increasingly important milestone. Four new targeted therapies are now available for the treatment of AML.

https://ift.tt/2IDiOAj

Management of Multiple Myeloma

The most recent NCCN Guidelines for Multiple Myeloma include a ranking of the many treatment options for various settings as "preferred," "other," and "useful in certain circumstances." For patients eligible for autologous stem cell transplant (ASCT), the preferred regimen remains bortezomib/lenalidomide/dexamethasone (category 1) or bortezomib/cyclophosphamide/dexamethasone. Upfront ASCT also remains a preferred strategy for patients who are transplant-eligible, despite highly effective newer agents such as induction therapy. Double (tandem) ASCT may benefit patients with high-risk cytogenetics, such as 17p deletion. Lenalidomide maintenance is the standard posttransplant approach and results in improved progression-free and overall survivals. For relapsed disease, a host of new agents have been shown to improve outcomes, mostly in combination with bortezomib or lenalidomide, but their selection depends largely on response and tolerability to prior therapies.

https://ift.tt/2Li3WJl

Management of Locoregional Rectal Cancer

The NCCN Guidelines for Rectal Cancer are now more closely aligned with those for colon cancer. A new MRI-based definition of the rectum has been included and the use of MRI in staging has been elevated in importance. There is a new emphasis on neoadjuvant therapy, especially the concurrent use of chemotherapy and radiotherapy. One of the biggest changes is more acceptance of an observational approach—"watch and wait, nonoperative management"—for select patients experiencing a complete clinical response with no evidence of residual disease after neoadjuvant therapy.

https://ift.tt/2KHdPPv

NCCN Guidelines Updates: Prostate Cancer and Prostate Cancer Early Detection

Peter H. Carroll, MD, MPH, and James L. Mohler, MD, updated attendees on what is new in the 2018 NCCN Guidelines for Prostate Cancer Early Detection and for Prostate Cancer, respectively. Their presentations touched on new screening recommendations, shared decision-making, risk stratification, the role of genomic and molecular testing, active surveillance, and newer systemic treatments.

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Emerging Treatment Options for Acute Lymphoblastic Leukemia: Focus on CAR T-Cell Therapy

Acute lymphoblastic leukemia (ALL) comprises a heterogeneous group of diseases with different morphologic, cytogenetic, and molecular subgroups, some of which have significant therapeutic implications. It typically presents with an aggressive clinical course, and among adults, responds poorly to standard chemotherapy, and carries a high risk for relapse. Despite the significant progress made in inducing remission, frequent relapses remain a challenge. Novel drugs, such as potent later-generation tyrosine kinase inhibitors, antibody-drug conjugates, bispecific monoclonal antibodies, and chimeric antigen receptor (CAR) T-cell therapies, are being investigated in patients with ALL. This summary describes therapies currently approved for the treatment of patients with ALL, identifies emerging targeted immunotherapies for patients with ALL, and discusses adverse events and mechanisms of resistance.

https://ift.tt/2IBi9ze

Pregnancy in Patients With Chronic Myeloid Leukemia

Estimates suggest that nearly 30% of patients diagnosed with chronic myeloid leukemia (CML) are aged <49 years, with approximately half being women. For many of these women, childbearing concerns are a major factor as they initiate treatment with tyrosine kinase inhibitors, which are known to be teratogenic. During her presentation at the NCCN 23rd Annual Conference, Dr. Berman identified the challenges in helping women undergoing treatment for CML who want to have children, and emphasized the importance of an individualized and multidisciplinary approach to management. In addition, she encouraged NCCN to create a pregnancy registry of this patient population to enable clinicians to collect firm data to guide clinical decision-making.

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The Changing Treatment Landscape for Metastatic Urothelial Carcinoma

Urothelial carcinoma is the predominant histologic type of bladder cancer. After 30 years of minimal progress in the treatment of advanced-stage disease, recent advances in the genomic characterization of urothelial cancer and breakthroughs in bladder cancer therapeutics have rejuvenated the field. Nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab are among the exciting recent novel therapeutic advances gaining approvals by the FDA for treatment of advanced-stage urothelial carcinoma. Yet the challenge for clinicians is to determine the optimal choice of agents as first-line or second-line therapy and which offers the best chance for overall survival for the individual patient in this rapidly changing field.

https://ift.tt/2IBi2Uk

Updates to the Management of Kidney Cancer

Several updates were made to the 2018 NCCN Guidelines for Kidney Cancer. Adjuvant sunitinib is the first adjuvant therapy to be endorsed by the panel for patients with stage II and III clear cell histology renal cell carcinoma (RCC; category 2B). A promising new treatment—ipilimumab plus nivolumab for patients at intermediate and poor risk in the frontline setting—was added to the guidelines as well. Cabozantinib was added as a first-line option for poor- and intermediate-risk patients with advanced RCC.

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Role of Molecular Pathology in the Treatment of Anaplastic Gliomas and Glioblastomas

The 2016 WHO Classification of Tumors of the Central Nervous System integrated molecular biomarkers into the classifications of malignant gliomas. Several markers now play a key role in our understanding of these tumors and are integral for clinical decision-making; these include codeletion of 1p and 19q and IDH1 and IDH2 mutations. The presentation by Matthias Holdhoff, MD, PhD, at the NCCN 23rd Annual Conference discussed the current understanding of anaplastic gliomas (WHO grade III) in the context of the new classification and its implications on clinical practice. The 2018 NCCN Guidelines for Central Nervous System Cancers incorporate molecular and histologic characteristics in the staging and treatment of both low- and high-grade gliomas (WHO grades II–IV).

https://ift.tt/2KHDRCx

New NCCN Guidelines for Uveal Melanoma and Treatment of Recurrent or Progressive Distant Metastatic Melanoma

The NCCN Guidelines Panel for Melanoma debuted new guidelines for uveal melanoma at the NCCN 23rd Annual Conference. Although uveal melanoma and cutaneous melanoma share the same name, they do have different characteristics and treatments. The NCCN Guidelines describe how tumor size guides therapeutic options, which for most tumors is radiotherapy. Predictors of melanoma-related mortality include advanced age, larger tumor size, and histopathologic and molecular features. The NCCN Guidelines for Cutaneous Melanoma have not changed notably, but adjuvant therapy with immunotherapies is now recommended. The best second-line treatment in the metastatic setting remains unclear.

https://ift.tt/2LjVQ32

Optimizing Adjuvant Therapy for Localized Colon Cancer and Treatment Selection in Advanced Colorectal Cancer

Results from the pivotal IDEA trial, which evaluated 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy, are incorporated into the NCCN Guidelines for Colon Cancer. The guidelines recommend that for patients with low-risk stage III disease, the preferred regimen is CAPEOX for 3 months or FOLFOX for 3 to 6 months. For patients with high-risk stage III disease, the preferred regimen is CAPEOX for 3 to 6 months or FOLFOX for 6 months. In metastatic disease, tumor sidedness should be a consideration when choosing a biologic. For BRAF-mutated disease, several triplets are now recommended options. Importantly, for a subset of patients with metastatic disease, new to the NCCN Guidelines is the incorporation of nivolumab and pembrolizumab as subsequent therapy for those with microsatellite instability–high or mismatch repair–deficient tumors.

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New NCCN Guidelines: Cancer Management in People Living With HIV

Since the emergence of HIV in the United States in the 1980s, cancer has been a part of the story. The good news is that antiretroviral therapy has improved survival for those living with HIV infection, with life expectancy now approaching that of uninfected people. Consequently, this patient population is living long enough to develop different types of cancer. At the 23rd NCCN Annual Conference, Gita Suneja, MD, MSHP, presented the debut of the new NCCN Guidelines for Cancer in People Living With HIV, discussing the intersection between cancer and HIV infection, the cancers most likely to develop in this group of patients, and the importance of oncologists working in conjunction with HIV specialists to render the most appropriate and individualized care.

https://ift.tt/2Li3laz

NCCN Guidelines Updates: Breast Cancer

The emergence of CDK4/6 inhibitors has changed the treatment algorithm for advanced/metastatic estrogen receptor–positive breast cancer. In pivotal trials of palbociclib, ribociclib, and abemaciclib, doubling in progression-free survival has been seen. All 3 agents in this class are now included in the NCCN Guidelines for Breast Cancer, and clinicians should be incorporating these agents into their treatment algorithms. The other important issue in this breast cancer setting is extended duration of endocrine therapy. Most of the benefit is modest and toxicity is an issue; therefore, extended-duration endocrine therapy should be highly individualized. For triple-negative disease, platinum agents and PARP inhibitors are helping some patients, but immunotherapies and other novel classes of drugs now in development hold the promise of even better outcomes. In HER2-positive early-stage disease, dual HER2 blockade is of modest benefit, and extended treatment with neratinib may be a good option for some high-risk patients.

https://ift.tt/2KIbYdl

Targeted Therapy for Patients With Metastatic Non-Small Cell Lung Cancer

Molecular testing is recommended for initial diagnosis in patients with non–small cell lung cancer (NSCLC), according to the updated NCCN Guidelines, because targeted therapies are available that can improve patient outcomes. Targeted therapies are currently approved for EGFR mutations, ALK and ROS1 gene rearrangements, and BRAF mutations, with the list of emerging "actionable" targets growing. The 2018 NCCN Guidelines for NSCLC incorporate new therapies, including the EGFR tyrosine kinase inhibitor osimertinib and the ALK inhibitor alectinib, as first-line preferences.

https://ift.tt/2Lk4eiL

The NCCN 23rd Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care

https://ift.tt/2KI70xj

The PARP inhibitor olaparib potentiates the effect of the DNA damaging agent doxorubicin in osteosarcoma

Abstract

Background

PARP1 facilitates the recovery of DNA-damaged cells by recruiting DNA damage response molecules such as γH2AX and BRCA1/2, and plays a role in resistance to antitumor therapies. Therefore, PARP inhibition being evaluated as an anti-cancer therapy. However, there are limited studies regrading PARP inhibition in osteosarcoma.

Methods

We evaluated the expression of DNA damage response molecules in 35 human osteosarcomas and investigated the effects of co-treatment of the PARP inhibitor, olaparib, and doxorubicin in osteosarcoma cells.

Results

The expression patterns of PARP1, γH2AX, BRCA1, and BRCA2 were significantly associated with shorter survival of osteosarcoma patients. In osteosarcoma cells, knock-down of PARP1 and treatment of olaparib significantly inhibited proliferation of cells and induced apoptosis. Moreover, the anti-tumor effect was more significant with co-treatment of olaparib and doxorubicin in vitro and in vivo.

Conclusions

This study suggests that combined use of a PARP inhibitor with doxorubicin, a DNA damaging agent, might be effective in the treatment of osteosarcoma patients, especially in the poor-prognostic subgroups of osteosarcoma expressing PARP1, γH2AX, or BRCA1/2.

https://ift.tt/2LkTSiH

How to measure the immunosuppressive activity of MDSC: assays, problems and potential solutions

Abstract

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of mononuclear and polymorphonuclear myeloid cells, which are present at very low numbers in healthy subjects, but can expand substantially under disease conditions. Depending on disease type and stage, MDSC comprise varying amounts of immature and mature differentiation stages of myeloid cells. Validated unique phenotypic markers for MDSC are still lacking. Therefore, the functional analysis of these cells is of central importance for their identification and characterization. Various disease-promoting and immunosuppressive functions of MDSC are reported in the literature. Among those, the capacity to modulate the activity of T cells is by far the most often used and best-established read-out system. In this review, we critically evaluate the assays available for the functional analysis of human and murine MDSC under in vitro and in vivo conditions. We also discuss critical issues and controls associated with those assays. We aim at providing suggestions and recommendations useful for the contemporary biological characterization of MDSC.

https://ift.tt/2GDUuMK

Neoadjuvant oxaliplatin and capecitabine combined with bevacizumab plus radiotherapy for locally advanced rectal cancer: results of a single-institute phase II study

Abstract

Background

Neoadjuvant chemoradiotherapy followed by surgery is recommended as the standard of care for locally advanced rectal cancer, reducing local recurrence but not distant metastasis. Intensified systemic therapy is warranted to reduce the risk of distant metastasis. The present study aimed to evaluate the safety and efficacy of neoadjuvant oxaliplatin and capecitabine (XELOX) combined with bevacizumab plus radiotherapy for locally advanced rectal cancer.

Methods

Patients with stages II to III rectal cancer received one cycle of induction chemotherapy and concurrent chemoradiotherapy with XELOX plus bevacizumab. Surgery was performed 6–8 weeks after completion of radiotherapy, and postoperative chemotherapy with three cycles of XELOX and two cycles of capecitabine were given. The primary endpoints were pathologic complete response (pCR) rate and safety, and the secondary endpoints were 3-year overall survival and progression-free survival.

Results

Forty-five patients were enrolled between February 2013 and April 2015. All completed the neoadjuvant therapy. Seven patients (15.6%) refused subsequent surgical therapy for personal reasons, and the other 38 patients received radical resection, with a sphincter preservation rate of 84.2% and a pCR rate of 39.5%. Toxicity was acceptable, with grades 3–4 hematological toxicity and diarrhea observed in six and two patients, respectively. Incidence of anastomotic leak that required surgical intervention was 13.3%. After a median follow-up period of 37 months, five patients developed disease progression and two died of cancer. The 3-year overall survival rate and 3-year progression-free survival rate were 95.3% and 88.6%, respectively.

Conclusions

The addition of bevacizumab to neoadjuvant chemoradiotherapy resulted in a satisfying pCR rate and 3-year survival, but also may increase the risk of anastomotic leak, thus this regimen is not suitable to be considered for regular recommendation for locally advanced rectal cancer.

Trial registration Clinicaltrials.govidentifierNCT01818973

https://ift.tt/2GDAFVR

Long- versus short-interval follow-up after resection of hepatocellular carcinoma: a retrospective cohort study

Abstract

Background

Average postoperative follow-up intervals vary in patients undergoing hepatocellular carcinoma (HCC) resection because of limited evidence regarding the optimal interval. We aimed to compare the associations of long-versus short-interval follow-up with survival and recurrence in risk-stratified HCC patients.

Methods

We performed a retrospective cohort study between 2007 and 2014. In total, 1227 patients treated by curative resection of Barcelona Clinic Liver Cancer stage A or B HCC were stratified as having a low (n = 865) or high (n = 362) risk of early recurrence (within the first 2 years after resection) based on prognostic factors identified by the least absolute shrinkage and selection operation algorithm. Patients were further classified into long-interval (every 4–6 months) and short-interval (every 2–4 months) follow-up subgroups based on follow-up within 2 years after resection (low risk, long vs. short: n = 390 vs. n = 475; high-risk, long vs. short: n = 149 vs. n = 213).

Results

The short-interval follow-up did not prolong overall survival in either the low-risk (hazard ratio [HR] = 1.152; 95% confidence interval [CI] 0.720–1.843) or high-risk (HR = 1.213; 95% CI 0.702–2.094) patients. Early recurrence occurred in 401 patients. For high-risk patients, the short-interval follow-up subgroup exhibited smaller intrahepatic recurrence than did the long-interval group (2.6 vs. 3.5 cm, respectively, P = 0.045). However, no significant difference in the rate of Barcelona Clinic Liver Cancer stage 0/A recurrence was found between the long- and short-interval follow-up groups in either low- or high-risk patients (63.1% vs. 68.2%, respectively, P = 0.580; 31.3% vs. 41.5%, respectively, P = 0.280). The rate of curative intent treatment for recurrence (34.5% vs. 39.7%, respectively, P = 0.430; 14.6% vs. 20.3%, respectively, P = 0.388) was also similar between the follow-up groups for low- and high-risk patients.

Conclusions

Shortening the postoperative follow-up interval from every 4–6 months to every 2–4 months within the first 2 years after resection did not increase the rate of curative intent treatment or prolong the overall survival of patients with Barcelona Clinic Liver Cancer stage A or B HCC.

https://ift.tt/2IXtT2t

Metabolic recoding of epigenetics in cancer

Abstract

Dysregulation of metabolism allows tumor cells to generate needed building blocks as well as to modulate epigenetic marks to support cancer initiation and progression. Cancer-induced metabolic changes alter the epigenetic landscape, especially modifications on histones and DNA, thereby promoting malignant transformation, adaptation to inadequate nutrition, and metastasis. Recent advances in cancer metabolism shed light on how aberrations in metabolites and metabolic enzymes modify epigenetic programs. The metabolism-induced recoding of epigenetics in cancer depends strongly on nutrient availability for tumor cells. In this review, we focus on metabolic remodeling of epigenetics in cancer and examine potential mechanisms by which cancer cells integrate nutritional inputs into epigenetic modification.

https://ift.tt/2IzkDhD

Lipid metabolism reprogramming and its potential targets in cancer

Abstract

Reprogramming of lipid metabolism is a newly recognized hallmark of malignancy. Increased lipid uptake, storage and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth. Lipids constitute the basic structure of membranes and also function as signaling molecules and energy sources. Sterol regulatory element-binding proteins (SREBPs), a family of membrane-bound transcription factors in the endoplasmic reticulum, play a central role in the regulation of lipid metabolism. Recent studies have revealed that SREBPs are highly up-regulated in various cancers and promote tumor growth. SREBP cleavage-activating protein is a key transporter in the trafficking and activation of SREBPs as well as a critical glucose sensor, thus linking glucose metabolism and de novo lipid synthesis. Targeting altered lipid metabolic pathways has become a promising anti-cancer strategy. This review summarizes recent progress in our understanding of lipid metabolism regulation in malignancy, and highlights potential molecular targets and their inhibitors for cancer treatment.

https://ift.tt/2IVdKdX

How to measure the immunosuppressive activity of MDSC: assays, problems and potential solutions

Abstract

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of mononuclear and polymorphonuclear myeloid cells, which are present at very low numbers in healthy subjects, but can expand substantially under disease conditions. Depending on disease type and stage, MDSC comprise varying amounts of immature and mature differentiation stages of myeloid cells. Validated unique phenotypic markers for MDSC are still lacking. Therefore, the functional analysis of these cells is of central importance for their identification and characterization. Various disease-promoting and immunosuppressive functions of MDSC are reported in the literature. Among those, the capacity to modulate the activity of T cells is by far the most often used and best-established read-out system. In this review, we critically evaluate the assays available for the functional analysis of human and murine MDSC under in vitro and in vivo conditions. We also discuss critical issues and controls associated with those assays. We aim at providing suggestions and recommendations useful for the contemporary biological characterization of MDSC.

https://ift.tt/2GDUuMK

Determining the impact of a pre-radiation treatment verification simulation/“dry run” by analyzing intradepartmental reported incidents and surveying staff and patients

Publication date: Available online 21 May 2018
Source:Practical Radiation Oncology
Author(s): Steven Gresswell, Paul Renz, Shaakir Hasan, Margaret Werts, Missy Fortunato, Day Werts
BackgroundError identification in radiation therapy is critical to maintaining a safe and efficient therapeutic environment. A verification simulation, also called a "dry run" for patient information, provides a dedicated time prior to treatment to duplicate steps of patient setup, imaging, and treatment process as a final quality assurance step. Through the use of surveys and analysis of reported incidents, we sought to determine the value of a verification simulation before initiating patient treatment.Methods and Materials.In November 2014, a verification simulation (VS) was instituted across our network of 11 radiation oncology clinics. A comparison of the incident rate reported through our departmental incident learning system (ILS) was made between a non-VS group, comprised of 965 patients treated in the 18-months prior to instituting the verification simulation, and a VS group, consisting of 984 patients treated over 18-months with the verification simulation policy in place. From August–December 2016 surveys were completed by 211 patients and 55 physicians, nurses, and therapists detailing perspectives on the verification simulation.ResultsThere were 28 incidents (2.9%) in the non-VS group compared to 18 incidents (1.8%) in the VS group (p=0.03). In the VS group there were more incidents detected before the day of treatment (P=0.03) and less incidents detected on the day of treatment (P=0.02). Additionally, there was a trend toward fewer incidents reported after treatment started (P=0.09). Patient surveys indicated 99.5% of patients were informed of the verification simulation, 83% reported decreased anxiety during treatment, and 5% indicated concern about delaying treatment. The majority of staff members (67%) were satisfied with the verification simulation.ConclusionA verification simulation helps identify and correct incidents before administration of radiotherapy and reduces patient anxiety.



https://ift.tt/2KJZDFp

Cancers, Vol. 10, Pages 152: 40 Years of Research Put p53 in Translation

Cancers, Vol. 10, Pages 152: 40 Years of Research Put p53 in Translation

Cancers doi: 10.3390/cancers10050152

Authors: Virginie Marcel Flora Nguyen Van Long Jean-Jacques Diaz

Since its discovery in 1979, p53 has shown multiple facets. Initially the tumor suppressor p53 protein was considered as a stress sensor able to maintain the genome integrity by regulating transcription of genes involved in cell cycle arrest, apoptosis and DNA repair. However, it rapidly came into light that p53 regulates gene expression to control a wider range of biological processes allowing rapid cell adaptation to environmental context. Among them, those related to cancer have been extensively documented. In addition to its role as transcription factor, scattered studies reported that p53 regulates miRNA processing, modulates protein activity by direct interaction or exhibits RNA-binding activity, thus suggesting a role of p53 in regulating several layers of gene expression not restricted to transcription. After 40 years of research, it appears more and more clearly that p53 is strongly implicated in translational regulation as well as in the control of the production and activity of the translational machinery. Translation control of specific mRNAs could provide yet unsuspected capabilities to this well-known guardian of the genome.

https://ift.tt/2KIvnL4

Upstaging to invasive ductal carcinoma after mastectomy for ductal carcinoma in situ: predictive factors and role of sentinel lymph node biopsy

Abstract

Background

The aim of this study was to investigate preoperative factors associated with ductal carcinoma in situ (DCIS) upstaged to invasive ductal carcinoma (IDC) and sentinel lymph node (SLN) status in patients who underwent mastectomy for a preoperative diagnosis of DCIS.

Methods

The medical records of 220 patients who underwent mastectomy for a preoperative diagnosis of DCIS were retrospectively reviewed.

Results

Fifty-one (22.6%) of 226 lesions were upgraded to IDC after mastectomy. Preoperative factors associated with upstaging to IDC included patient-reported signs and symptoms, a clinically palpable mass, ultrasound findings classified as category 4 or 5, the ultrasound appearance of a mass or widely distributed non-mass abnormality (NMA), and a high Ki67 index. The prevalence of SLN macrometastasis was 0.9%. IDC was diagnosed for 10.9% of lesions of a preoperative ultrasound category of 0–3, 13.0% of those with no mass or NMA detected by ultrasonography, and 14.1% of lesions preoperatively diagnosed by methods other than core needle biopsy (CNB). Of those lesions, none was associated with SLN metastasis.

Conclusions

Routinely performing SLN biopsy for patients undergoing mastectomy for a preoperative diagnosis of DCIS is overtreatment, because the prevalence of SLN metastasis was low. SLN biopsy can be omitted for most patients. In particular, we suggest omitting SLN biopsy for patients who have lesions of ultrasound category 0–3, who have neither a mass nor NMA detected by ultrasound, or whose initial diagnosis was made based on a specimen obtained by methods other than CNB.

https://ift.tt/2wXG7Dv

Survival analysis according to period and analysis of the factors influencing changes in survival in patients with recurrent breast cancer: a large-scale, single-center study

Abstract

Background

We performed this study to analyze changing survival patterns regarding recurrent breast cancer in Korea during the last 16 years (1993–2008). We also sought to determine factors possibly influencing outcomes and changes over time in the duration of survival after recurrence.

Methods

We retrospectively analyzed 9671 patients with breast cancer treated between January 1993 and December 2008, comparing the periods 1993–2002 and 2003–2008.We retrospectively reviewed the collected database including the age at diagnosis, clinical manifestations, pathology report, surgical methods, types of adjuvant treatment modalities, type of recurrence, and follow-up period.

Results

There were 1944 cases (20.1%) of recurrence. Median age at the first recurrence was 49.5 years (range 21.8–92.9). Median follow-up was 28.8 months (range 0–228.0) from the time of relapse. Median survival time was 35.0 months. Survival after recurrence (SAR) significantly improved in 2003–2008 compared to that in 1993–2002. Median survival time increased from 27.6 months in the period I to 42.3 months in period II (p = 0.001). Independent prognostic factors after the first recurrence by multivariate analysis were age at diagnosis, tumor size, nodal status, tumor grade, subtype, anti-hormonal therapy, time at diagnosis, and disease-free interval.

Conclusions

Outcomes of breast cancer have been improving recently, and survival time after the first recurrence of breast cancer has steadily increased in recent decades. We confirmed that advances in treatments have contributed to this improvement in survival after the first recurrence.

https://ift.tt/2IxLWwO

Prognostic Impact of the Components of Progressive Disease on Survival After First-Line Tyrosine Kinase Inhibitor Therapy for Metastatic Renal Cell Carcinoma

Abstract

Background

According to the Response Evaluation Criteria in Solid Tumors (RECIST) classification, progressive disease (PD) is defined as target lesion growth (TLG), unequivocal non-target lesion growth (NTLG), or new lesion appearance (NLA). The prognostic impact of the components of PD in tyrosine kinase inhibitor (TKI) therapy for metastatic renal cell carcinoma (mRCC) remains unknown.

Objective

We retrospectively evaluated the prognostic impact of these PD components on survival in patients with mRCC after first-line TKI therapy.

Patients and Methods

Patients were divided into three groups (TLG, NTLG, and NLA) based on the components of PD. Progression-free survival (PFS) and overall survival (OS) after first-line TKI therapy were compared between groups using the Kaplan-Meier method and log-rank test. The predictive impact of the PD components was evaluated using multivariate analyses.

Results

Among the 116 patients included, 80 (69.0%) had TLG, 18 (15.5%) NTLG, and 69 (58.6%) NLA. The mean PFS and OS were shorter for patients with TLG than those without TLG (PFS, 7.1 vs. 11.6 months, p = 0.0071; OS, 18.2 vs. 25.5 months, p = 0.0091). TLG was an independent predictor of PFS (hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.02–2.51; p = 0.0395) and OS (HR, 1.67; 95% CI, 1.02–2.83; p = 0.040). NTLG and NLA were not associated with survival.

Conclusions

In this retrospective single-center study, patients with TLG had poor survival after first-line TKI therapy for mRCC. Thus, individual components of PD influence patient prognosis.

https://ift.tt/2wXFSs5

Atezolizumab: A Review in Previously Treated Advanced Non-Small Cell Lung Cancer

Abstract

Atezolizumab (TECENTRIQ™), an immune checkpoint inhibitor, is an immunoglobulin G1 monoclonal antibody that binds to programmed death ligand 1 (PD-L1) and blocks its interactions with programmed death 1 and B7.1 receptors. Atezolizumab is approved as monotherapy in several countries worldwide for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who have previously received chemotherapy. Approval was based on its clinical benefit in this setting in the phase II POPLAR and phase III OAK trials. In these studies, atezolizumab significantly prolonged overall survival (OS) relative to docetaxel, regardless of PD-L1 status. Increasing PD-L1 expression was associated with OS improvements. Atezolizumab also demonstrated efficacy in the phase II FIR and BIRCH trials, as assessed by objective response rates (ORRs) in patients with tumours expressing PD-L1. Higher ORRs were seen in patients with high PD-L1 expression. Atezolizumab had an acceptable, manageable tolerability profile, with a low incidence of immune-related adverse events. Therefore, atezolizumab is a valuable treatment option for patients with advanced NSCLC that has progressed during or after chemotherapy.

https://ift.tt/2wXFKZD

Managing Synchronous Liver Metastases in Colorectal Cancer

Abstract

The most common site of blood-borne metastases from colorectal cancers (CRC) is the liver. Resection of (liver) metastases is a part of standard treatment of metastatic colorectal cancer. Hepatic resection is the first-line treatment of liver metastases, with 5-year survival rates between 25 and 58%. The enhanced efficacy of systemic chemotherapeutic regimens has increased tumor response rates and improved the progression-free and overall survival of patients with these malignancies. In approximately 20% of patients with initially unresectable liver metastases, the metastases may become resectable after administration of neoadjuvant chemotherapy. Unresectable liver metastases can be managed with systemic therapy and/or a variety of liver-directed techniques such as radiofrequency ablation, hepatic artery infusion, or yttrium-90 radioembolization. Our examination of the literature led us to propose a new patient-oriented algorithm to guide clinicians' decisions on the best choice of upfront therapy for CRC and synchronous liver metastases. The need for multidisciplinary consensus has become especially important for metastatic CRC.

https://ift.tt/2GzYyxN

Triclosan treatment decreased the antitumor effect of sorafenib on hepatocellular carcinoma cells

https://ift.tt/2KxXH2N

Indirubin inhibits cell proliferation, migration, invasion and angiogenesis in tumor-derived endothelial cells

https://ift.tt/2k4ufGr

Cancers, Vol. 10, Pages 151: Organoids Provide an Important Window on Inflammation in Cancer

Cancers, Vol. 10, Pages 151: Organoids Provide an Important Window on Inflammation in Cancer

Cancers doi: 10.3390/cancers10050151

Authors: Kristi Baker

Inflammation is a primary driver of cancer initiation and progression. However, the complex and dynamic nature of an inflammatory response make this a very difficult process to study. Organoids are a new model system where complex multicellular structures of primary cells can be grown in a 3D matrix to recapitulate the biology of the parent tissue. This experimental model offers several distinct advantages over alternatives including the ability to be genetically engineered, implanted in vivo and reliably derived from a wide variety of normal and cancerous tissue from patients. Furthermore, long-term organoid cultures reproduce many features of their source tissue, including genetic and epigenetic alterations and drug sensitivity. Perhaps most significantly, cancer organoids can be cocultured in a variety of different systems with a patients&rsquo; own immune cells, uniquely permitting the study of autologous cancer-immune cell interactions. Experiments with such systems promise to shed light on the mechanisms governing inflammation-associated cancer while also providing prognostic information on an individual patient&rsquo;s responsiveness to immunotherapeutic anti-cancer drugs. Thanks to their ability to capture important features of the complex relationship between a cancer and its microenvironment, organoids are poised to become an essential tool for unraveling the mechanisms by which inflammation promotes cancer.

https://ift.tt/2KGofyV

Effects of cardiac output on the onset of rocuronium-induced neuromuscular block in elderly patients

Abstract

Purpose

The aim of this study was to elucidate the relationship between the onset of rocuronium-induced neuromuscular block and arterial pressure-based cardiac output (CO) in elderly patients.

Methods

Forty elderly patients aged 65–83 years were enrolled in this study. After induction of anesthesia, contractions of the adductor pollicis muscle to ulnar nerve train-of-four stimulation were acceleromyographically evaluated and 1 mg/kg rocuronium was administered following CO measurement. The correlation between onset of rocuronium action and CO was analyzed.

Results

The mean [SD] CO reduced after induction of anesthesia from 5.1 [1.8] L/min to 3.8 [1.1] L/min. The onset time of rocuronium-induced neuromuscular block was 110.3 [23.9] s (range 60–165). There was a statistically significant inverse correlation between the onset time of rocuronium and CO [onset time (s) = − 13.2·CO + 159.7, R² = 0.376].

Conclusions

In the elderly, CO influences the onset of action of rocuronium.

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Endothelium-dependent vasodilation in the cerebral arterioles of rats deteriorates during acute hyperglycemia and then is restored by reducing the glucose level

Abstract

Purpose

Acute hyperglycemia in patients with traumatic brain injury correlates with a poor neurological outcome. We investigated the endothelium function of rat cerebral arterioles during acute hyperglycemia and after reducing the glucose levels using insulin. We also examined whether or not oxidative stress was involved in the cerebral arteriole response to acute hyperglycemia.

Methods

In isoflurane-anesthetized, mechanically ventilated rats, we used closed cranial window preparation to measure the changes in the pial arteriolar diameter following the topical application of acetylcholine (ACh) or adenosine. We examined the pial arteriolar vasodilator response before hyperglycemia, during hyperglycemia, and after reducing the glucose level using insulin. After intravenous pretreatment with an NADPH oxidase inhibitor (apocynin or diphenylene iodonium), we reexamined the pial arteriolar vasodilator response following the topical application of ACh.

Results

Under control conditions, the topical application of ACh dose-dependently dilated the cerebral arterioles. The vasodilatory responses to topical ACh were impaired during hyperglycemia and improved after the administration of insulin. The vasodilatory responses to topical adenosine were not affected by the glucose levels. In the apocynin or diphenylene iodonium pretreatment group, the topical application of ACh dilated the cerebral arterioles during hyperglycemia.

Conclusion

Acute hyperglycemia induces a dysfunction of the endothelium-dependent vasodilation of rat cerebral arterioles. The dysfunction can be reversed by improving the acute hyperglycemia and it can be prevented entirely by the administration of NADPH oxidase inhibitors. These results could suggest that controlling the glucose levels works protectivity to endothelium function of cerebral arterioles.

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Preclinical impact of high dose intermittent antiangiogenic tyrosine kinase inhibitor pazopanib in intrinsically resistant tumor models

Abstract

Antiangiogenic tyrosine kinase inhibitors (TKIs) target vascular endothelial growth factor receptors and other receptor tyrosine kinases. As a result of toxicity, the clinical failures or the modest benefits associated with antiangiogenic TKI therapy may be related in some cases to suboptimal drug dosing and scheduling, thereby facilitating resistance. Most antiangiogenic TKIs, including pazopanib, are administered on a continuous daily basis. Here, instead, we evaluated the impact of increasing the dose and administering the drug intermittently. The rationale is that using such protocols, antitumor efficacy could be enhanced by direct tumor cell targeting effects in addition to inhibiting tumor angiogenesis. To test this, we employed two human tumor xenograft models, both of which manifest intrinsic resistance to pazopanib when it is administered continuously: the VHL-wildtype SN12-PM6-1 renal cell carcinoma (RCC) and the metastatic MDA-MB-231/LM2-4 variant breast cancer cell line, when treated as distant metastases. We evaluated four different doses and schedules of pazopanib in the context of primary tumors and advanced metastatic disease, in both models. The RCC model was not converted to drug sensitivity using the intermittent protocol. Using these protocols did not enhance the efficacy when treating primary LM2-4 tumors. However, one of the high-dose intermittent pazopanib protocols increased median survival when treating advanced metastatic disease. In conclusion, these results overall suggest that primary tumors showing sensitivity to continuous pazopanib treatment may predict response to this drug when given at high doses intermittently in the context of advanced metastatic disease, that are otherwise resistant to the conventional protocol.

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