What happens next? Recurrence Rates for First Unprovoked Seizures in Children

Abstract

Seizures represent approximately 1% of all ED visits in the United States. ¹ Unprovoked first seizures in children commonly present to the Emergency Department (ED), and even after the neurological exam normalizes, the prospect of recurrence can be a source of great anxiety for caregivers. ² Compared to febrile seizures, unprovoked seizures carry a higher rate of recurrence and epilepsy. Previous studies focused on long term recurrence and the cumulative risk of a second seizure was 29%, 37%, 43%, and 46% at 1, 2, 5, and 10 years, respectively. ³ There has been limited information on the short-term risk of recurrence to guide emergency physicians.

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Dr. Rodgers’ Last Lessons: reflections after the death of a mentor

Abstract

The Indiana University emergency medicine family is grieving. We, the residency program directors, are grieving. The Monday morning before Thanksgiving, Dr. Kevin Rodgers, KRodge, a lifelong educator and mentor to most of us, was killed in his home following his overnight shift. Kevin's death has shaken us deeply and we are tired from crying. As emergency physicians, we're supposed to know about death – we see it regularly; we write about it in our literature; we comfort the families of our dying patients. But when it is one of our own – a father-figure – we don't know how to react. We can't compartmentalize this. As a way to try to find meaning out of the senselessness, we've been reflecting on what it means to be an emergency medicine educator.

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Chk2 deficiency alleviates irradiation-induced taste dysfunction by inhibiting p53-dependent apoptosis

Abstract

Objective

Taste dysfunction is one of the most common complications following radiotherapy, which leads to decreased appetite and life quality of patients suffering from head and neck cancer. The aim of this study was to investigate the role of Checkpoint kinase2 (Chk2) deficiency in irradiation-induced taste dysfunction.

Materials and methods

Alterations in oxidative stress, DNA damage and potential signaling pathway were compared between Chk2-deficient (Chk2^-/-) mice and their wild-type (WT) littermates pre-irradiation, and 7 and 30 days post-irradiation by biochemistry and immunohistochemistry.

Results

Chk2^-/- mice showed less loss of type II and type III taste cells, lower expression of p53, Caspase-3 and cleaved Caspase-3, and lower apoptosis levels. However, no significant differences in H₂O₂ and MDA concentrations, T-SOD and GSH-Px activities, and expression of SOD1, SOD2 and 8-OHdG were detected in the taste buds of Chk2^-/- mice as compared to that of WT mice.

Conclusion

Chk2 deficiency down-regulated the expression of p53 and inhibited cellular apoptosis, partly contributing to the radio-protective effect on taste cells, but did not alter oxidative stress levels, antioxidant ability and oxidative DNA damage in taste buds.

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Skin cancer rates in North Rhine-Westphalia, Germany before and after the introduction of the nationwide skin cancer screening program (2000–2015)

Abstract

Germany is the first nation that implemented a nationwide skin cancer screening program in 2008. The aim is to study the effect of the program on skin cancer rates and to estimate the number needed to screen for an unselected and a hypothetical high-risk population in Germany. We used population-based data on skin cancer incidence (2000–2014), mortality, hospitalization and sick leave (2000–2015) from North Rhine-Westphalia, Germany (18 million population). We calculated annual age-standardized rates per 100,000 person years and calculated the relative change of the rates (%) including 95% confidence intervals (95% CI). Between 2007 and 2014, the estimated annual percentage change (EAPC) of the age-standardized incidence rate of skin melanoma was 3.8% among men and women. These increases were accompanied by increases of the age-standardized mortality rates (EAPC men 3.2%, women 2.0%) and age-standardized sick leave rates (EAPC men 11.0%, women 6.1%). Hospitalization rates showed barely any change. All types of rates for nonmelanoma skin cancer showed marked increases. The number needed to screen for skin melanoma death would be 34,000 if the risk reduction due to screening would be 50%. In a hypothetical high-risk approach with 10% of the population at high risk, that is, a relative risk of melanoma death of 4.0, a skin melanoma mortality risk reduction of 50% among these people due to screening would result in a reduction of the skin melanoma mortality by 15% in the total population. However, this reduction would require a number needed to screen of 11,141. Seven years after the introduction of the skin cancer screening program, there is no discernible beneficial effect at population level. The estimated number needed to screen for skin melanoma in an unselected approach is high and a realistic high-risk approach is currently not feasible.

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Hypothetical interventions to prevent stroke: an application of the parametric g-formula to a healthy middle-aged population

Abstract

The effects of interventions on multiple lifestyle and metabolic risk factors, initiated in midlife or later in a healthy population, on the long-term risk of first-ever stroke is not known. A particular methodological challenge in observational studies is to estimate the unbiased effect of a time-varying exposure in presence of time-varying confounders, if those confounders are affected by prior exposure. In such cases, the parametric g-formula can be applied to estimate an unbiased effect. We applied the parametric g-formula to estimate the 18-years (1994–2012) cumulative stroke risk under different scenarios of hypothetical interventions on levels of blood pressure, cholesterol, weight, physical activity, smoking and alcohol intake; and compared these to the observed scenario, to calculate the population risk ratios and risk differences. Among 14,796 eligible participants in the prospective, population-based Tromsø study (baseline mean age 46.1 years, 51% women), the observed 18-years stroke risk was 5.9%. A feasible joint hypothetical intervention on six lifestyle and metabolic risk factors would reduce the 18-year stroke risk by 32% (95% confidence interval 16, 44). A combination of more intensive interventions reduced the estimated 18-years stroke risk by 64% (95% confidence interval 40, 80). Blood pressure reduction and quitting smoking significantly reduced the risk when applied separately.

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Skin cancer rates in North Rhine-Westphalia, Germany before and after the introduction of the nationwide skin cancer screening program (2000–2015)

Abstract

Germany is the first nation that implemented a nationwide skin cancer screening program in 2008. The aim is to study the effect of the program on skin cancer rates and to estimate the number needed to screen for an unselected and a hypothetical high-risk population in Germany. We used population-based data on skin cancer incidence (2000–2014), mortality, hospitalization and sick leave (2000–2015) from North Rhine-Westphalia, Germany (18 million population). We calculated annual age-standardized rates per 100,000 person years and calculated the relative change of the rates (%) including 95% confidence intervals (95% CI). Between 2007 and 2014, the estimated annual percentage change (EAPC) of the age-standardized incidence rate of skin melanoma was 3.8% among men and women. These increases were accompanied by increases of the age-standardized mortality rates (EAPC men 3.2%, women 2.0%) and age-standardized sick leave rates (EAPC men 11.0%, women 6.1%). Hospitalization rates showed barely any change. All types of rates for nonmelanoma skin cancer showed marked increases. The number needed to screen for skin melanoma death would be 34,000 if the risk reduction due to screening would be 50%. In a hypothetical high-risk approach with 10% of the population at high risk, that is, a relative risk of melanoma death of 4.0, a skin melanoma mortality risk reduction of 50% among these people due to screening would result in a reduction of the skin melanoma mortality by 15% in the total population. However, this reduction would require a number needed to screen of 11,141. Seven years after the introduction of the skin cancer screening program, there is no discernible beneficial effect at population level. The estimated number needed to screen for skin melanoma in an unselected approach is high and a realistic high-risk approach is currently not feasible.

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Hypothetical interventions to prevent stroke: an application of the parametric g-formula to a healthy middle-aged population

Abstract

The effects of interventions on multiple lifestyle and metabolic risk factors, initiated in midlife or later in a healthy population, on the long-term risk of first-ever stroke is not known. A particular methodological challenge in observational studies is to estimate the unbiased effect of a time-varying exposure in presence of time-varying confounders, if those confounders are affected by prior exposure. In such cases, the parametric g-formula can be applied to estimate an unbiased effect. We applied the parametric g-formula to estimate the 18-years (1994–2012) cumulative stroke risk under different scenarios of hypothetical interventions on levels of blood pressure, cholesterol, weight, physical activity, smoking and alcohol intake; and compared these to the observed scenario, to calculate the population risk ratios and risk differences. Among 14,796 eligible participants in the prospective, population-based Tromsø study (baseline mean age 46.1 years, 51% women), the observed 18-years stroke risk was 5.9%. A feasible joint hypothetical intervention on six lifestyle and metabolic risk factors would reduce the 18-year stroke risk by 32% (95% confidence interval 16, 44). A combination of more intensive interventions reduced the estimated 18-years stroke risk by 64% (95% confidence interval 40, 80). Blood pressure reduction and quitting smoking significantly reduced the risk when applied separately.

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Issue Information

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Gastrointestinal follicular lymphoma: Current knowledge and future challenges

The gastrointestinal (GI) tract is the most commonly involved site of extranodal follicular lymphoma (FL). GI-FL shows very indolent clinical behavior and localized at GI tract without any progression or transformation compared to nodal FL. The most frequently involved site of the GI tract was the duodenum followed by the jejunum and ileum, and only 15% of FL arising in the second part of the duodenum were localized there without scattered very small daughter lesions in other GI tract examined by double-balloon endoscopy. The typical macroscopic appearance of GI-FL was multiple white nodules. Microscopically, neoplastic cells were small- to medium-sized lymphoid cells and formed neoplastic follicles. Most of the cases (>95%) were histologically Grade 1 to 2 (low grade). Several pathological and molecular characteristics were seen in GI-FL (especially duodenal FL) compared with nodal FL: immunoglobulin heavy chain deviation to VH4 and VH5; memory B-cell immunophenotype; and molecular features shared by mucosa-associated lymphoid tissue lymphoma. Considering the pathological and molecular uniqueness of this disease, GI-FL should be separately managed from nodal FL.

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Notice to Contributors

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Comparative Oncology Evaluation of Intravenous Recombinant Oncolytic Vesicular Stomatitis Virus Therapy in Spontaneous Canine Cancer

Clinical translation of intravenous therapies to treat disseminated or metastatic cancer is imperative. Comparative oncology, the evaluation of novel cancer therapies in animals with spontaneous cancer, can be utilized to inform and accelerate clinical translation. Preclinical murine studies demonstrate that single-shot systemic therapy with a vesicular stomatitis virus (VSV)-IFNβ-NIS, a novel recombinant oncolytic VSV, can induce curative remission in tumor-bearing mice. Clinical translation of VSV-IFNβ-NIS therapy is dependent on comprehensive assessment of clinical toxicities, virus shedding, pharmacokinetics, and efficacy in clinically relevant models. Dogs spontaneously develop cancer with comparable etiology, clinical progression, and response to therapy as human malignancies. A comparative oncology study was carried out to investigate feasibility and tolerability of intravenous oncolytic VSV-IFNβ-NIS therapy in pet dogs with spontaneous cancer. Nine dogs with various malignancies were treated with a single intravenous dose of VSV-IFNβ-NIS. Two dogs with high-grade peripheral T-cell lymphoma had rapid but transient remission of disseminated disease and transient hepatotoxicity that resolved spontaneously. There was no shedding of infectious virus. Correlative pharmacokinetic studies revealed elevated levels of VSV RNA in blood in dogs with measurable disease remission. This is the first evaluation of intravenous oncolytic virus therapy for spontaneous canine cancer, demonstrating that VSV-IFNβ-NIS is well-tolerated and safe in dogs with advanced or metastatic disease. This approach has informed clinical translation, including dose and target indication selection, leading to a clinical investigation of intravenous VSV-IFNβ-NIS therapy, and provided preliminary evidence of clinical efficacy and potential biomarkers that correlate with therapeutic response. Mol Cancer Ther; 17(1); 316–26. ©2017 AACR.

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Evaluation of CDK12 Protein Expression as a Potential Novel Biomarker for DNA Damage Response-Targeted Therapies in Breast Cancer

Disruption of Cyclin-Dependent Kinase 12 (CDK12) is known to lead to defects in DNA repair and sensitivity to platinum salts and PARP1/2 inhibitors. However, CDK12 has also been proposed as an oncogene in breast cancer. We therefore aimed to assess the frequency and distribution of CDK12 protein expression by IHC in independent cohorts of breast cancer and correlate this with outcome and genomic status. We found that 21% of primary unselected breast cancers were CDK12 high, and 10.5% were absent, by IHC. CDK12 positivity correlated with HER2 positivity but was not an independent predictor of breast cancer–specific survival taking HER2 status into account; however, absent CDK12 protein expression significantly correlated with a triple-negative phenotype. Interestingly, CDK12 protein absence was associated with reduced expression of a number of DDR proteins including ATR, Ku70/Ku80, PARP1, DNA-PK, and H2AX, suggesting a novel mechanism of CDK12-associated DDR dysregulation in breast cancer. Our data suggest that diagnostic IHC quantification of CDK12 in breast cancer is feasible, with CDK12 absence possibly signifying defective DDR function. This may have important therapeutic implications, particularly for triple-negative breast cancers. Mol Cancer Ther; 17(1); 306–15. ©2017 AACR.

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"Wnt/{beta}-Catenin in GIST"--Letter

In an article published on September, 2017, in Molecular Cancer Therapeutics, Zeng and colleagues showed that the WNT/β-catenin oncogenic pathway was activated in a subset of human gastrointestinal stromal tumors (GIST) and that inhibiting its signaling alone or in combination with imatinib has antitumor efficacy in vitro and in vivo in imatinib-sensitive and resistant preclinical models. However, they concluded that "more investigation is needed to correlate β-catenin activation with clinicopathologic features in GIST clinical samples." Here, we examined the activation score of the β-catenin pathway in 160 clinically annotated clinical samples of operated primary GISTs. We showed that the β-catenin activation score, assessed as continuous variable, was heterogeneous across samples. Higher score was associated with certain prognostic clinicopathologic characteristics, including mutational status, tumor size, and AFIP classification, and even more importantly, with more postoperative relapses in uni- and multivariate analyses. Such unfavorable independent prognostic value of β-catenin activation reinforces the potential therapeutic value of this new target in GIST and nicely complements Zeng's study. Mol Cancer Ther; 17(1); 327–8. ©2018 AACR.

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Clinical Application of Circulating Tumor DNA in the Genetic Analysis of Patients with Advanced GIST

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of digestive tract. In the past, tissue biopsy was the main method for the diagnosis of GISTs. Although, circulating tumor DNA (ctDNA) detection by next-generation sequencing (NGS) may be a feasible and replaceable method for diagnosis of GISTs. We retrospectively analyzed the data for ctDNA and tissue DNA detection from 32 advanced GIST patients. We found that NGS obviously increased the positive rate of ctDNA detection. ctDNA detection identified rare mutations that were not detected in tissue DNA detection. Tumor size and Ki-67 were significant influencing factors of the positive rate of ctDNA detection and concordance between ctDNA and tissue DNA detection. In all patients, the concordance rate between ctDNA and tissue DNA detection was 71.9%, with moderate concordance, but the concordance was strong for patients with tumor size > 10 cm or Ki-67 > 5%. Tumor size, mitotic figure, Ki-67, and ctDNA mutation type were the significant influencing factors of prognosis, but only tumor size and ctDNA mutation type, were the independent prognostic factors for advanced GIST patients. We confirmed that ctDNA detection by NGS is a feasible and promising method for the diagnosis and prognosis of advanced GIST patients. Mol Cancer Ther; 17(1); 290–6. ©2017 AACR.

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CCL26 Participates in the PRL-3-Induced Promotion of Colorectal Cancer Invasion by Stimulating Tumor-Associated Macrophage Infiltration

Both phosphatase of regenerating liver-3 (PRL-3) and tumor-associated macrophages (TAM) influence cancer progression. Whether PRL-3 plays a critical role in colorectal cancer invasion and metastasis by inducing TAM infiltration remains unclear. In the current study, we investigated the effects of chemokine ligand 26 (CCL26) on TAM infiltration and colorectal cancer invasion and the underlying mechanism in colorectal cancer cells by overexpressing or silencing PRL-3. We found that PRL-3 upregulated CCL26 expression correlatively and participated in cell migration, according to the results of gene ontology analysis. In addition, IHC analysis results indicated that the PRL-3 and CCL26 levels were positively correlated and elevated in stage III and IV colorectal cancer tissues and were associated with a worse prognosis in colorectal cancer patients. Furthermore, we demonstrated that CCL26 induced TAM infiltration by CCL26 binding to the CCR3 receptor. When LoVo-P and HT29-C cells were cocultured with TAMs, CCL26 binding to the CCR3 receptor enhanced the invasiveness of LoVo-P and HT29-C cells by mobilizing intracellular Ca²⁺of TAMs to increase the expression of IL6 and IL8. In addition, IHC results indicated that protein levels of CCR3 and TAMs counts were higher in stage III and IV colorectal cancer tissues and correlated with CCL26. Moreover, similar results were observed in vivo using mice injected with LoVo-P and HT29-C cells. These data indicate that PRL-3 may represent a potential prognostic marker that promotes colorectal cancer invasion and metastasis by upregulating CCL26 to induce TAM infiltration. Mol Cancer Ther; 17(1); 276–89. ©2017 AACR.

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The Mutational Landscape of Gastrointestinal Malignancies as Reflected by Circulating Tumor DNA

We aimed to assess the utility of a novel, noninvasive method of detecting genomic alterations in patients with gastrointestinal malignancies, i.e., the use of liquid biopsies to obtain blood-derived circulating tumor DNA (ctDNA) through an analysis of the genomic landscape of ctDNA (68 genes) from 213 patients with advanced gastrointestinal cancers. The most common cancer types were colorectal adenocarcinoma (N = 55; 26%), appendiceal adenocarcinoma (N = 46; 22%), hepatocellular carcinoma (N = 31; 15%), and pancreatic ductal adenocarcinoma (N = 25; 12%). The majority of patients (58%) had ≥1 characterized alteration (excluded variants of unknown significance). The median number of characterized alterations was 1 (range, 0–13). The number of detected alterations per patient varied between different cancer types: in hepatocellular carcinoma, 74% of patients (23/31) had ≥1 characterized alteration(s) versus 24% of appendiceal adenocarcinoma patients (11/46). The median percent ctDNA among characterized alterations was 2.50% (interquartile range, 0.76%–8.96%). Overall, 95% of patients (117/123) had distinct molecular portfolios with 143 unique characterized alterations within 56 genes. Overall, concordance rates of 96%, 94%, 95%, and 91%, respectively, were found between ctDNA and tissue biopsy (N = 105 patients) in the four most common alterations (KRAS amplification, MYC amplification, KRAS G12V, and EGFR amplification). Of 123 patients with characterized alterations, >99% (122/123; 57% of entire population tested; 122/213) had one or more alterations potentially actionable by experimental or approved drugs. These observations suggest that many patients with gastrointestinal tumors, including difficult-to-biopsy malignancies like hepatocellular cancers, frequently have discernible and theoretically pharmacologically tractable ctDNA alterations that merit further studies in prospective trials. Mol Cancer Ther; 17(1); 297–305. ©2017 AACR.

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AKT1low Quiescent Cancer Cells Promote Solid Tumor Growth

Human tumor growth depends on rapidly dividing cancer cells driving population expansion. Even advanced tumors, however, contain slowly proliferating cancer cells for reasons that remain unclear. Here, we selectively disrupt the ability of rapidly proliferating cancer cells to spawn AKT1^low daughter cells that are rare, slowly proliferating, tumor-initiating, and chemotherapy-resistant, using β1-integrin activation and the AKT1-E17K–mutant oncoprotein as experimental tools in vivo. Surprisingly, we find that selective depletion of AKT1^low slow proliferators actually reduces the growth of a molecularly diverse panel of human cancer cell xenograft models without globally altering cell proliferation or survival in vivo. Moreover, we find that unusual cancer patients with AKT1-E17K–mutant solid tumors also fail to produce AKT1^low quiescent cancer cells and that this correlates with significantly prolonged survival after adjuvant treatment compared with other patients. These findings support a model whereby human solid tumor growth depends on not only rapidly proliferating cancer cells but also on the continuous production of AKT1^low slow proliferators. Mol Cancer Ther; 17(1); 254–63. ©2017 AACR.

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Caveolae-Mediated Endocytosis as a Novel Mechanism of Resistance to Trastuzumab Emtansine (T-DM1)

Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) that has demonstrated clinical benefit for patients with HER2⁺ metastatic breast cancer; however, its clinical activity is limited by inherent or acquired drug resistance. The molecular mechanisms that drive clinical resistance to T-DM1, especially in HER2⁺ tumors, are not well understood. We used HER2⁺ cell lines to develop models of T-DM1 resistance using a cyclical dosing schema in which cells received T-DM1 in an "on-off" routine until a T-DM1–resistant population was generated. T-DM1–resistant N87 cells (N87-TM) were cross-resistant to a panel of trastuzumab-ADCs (T-ADCs) with non–cleavable-linked auristatins. N87-TM cells do not have a decrease in HER2 protein levels or an increase in drug transporter protein (e.g., MDR1) expression compared with parental N87 cells. Intriguingly, T-ADCs using auristatin payloads attached via an enzymatically cleavable linker overcome T-DM1 resistance in N87-TM cells. Importantly, N87-TM cells implanted into athymic mice formed T-DM1 refractory tumors that remain sensitive to T-ADCs with cleavable-linked auristatin payloads. Comparative proteomic profiling suggested enrichment in proteins that mediate caveolae formation and endocytosis in the N87-TM cells. Indeed, N87-TM cells internalize T-ADCs into intracellular caveolin-1 (CAV1)–positive puncta and alter their trafficking to the lysosome compared with N87 cells. T-DM1 colocalization into intracellular CAV1-positive puncta correlated with reduced response to T-DM1 in a panel of HER2⁺ cell lines. Together, these data suggest that caveolae-mediated endocytosis of T-DM1 may serve as a novel predictive biomarker for patient response to T-DM1. Mol Cancer Ther; 17(1); 243–53. ©2017 AACR.

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Metabolite Profiling Reveals the Glutathione Biosynthetic Pathway as a Therapeutic Target in Triple-Negative Breast Cancer

Cancer cells can exhibit altered dependency on specific metabolic pathways and targeting these dependencies is a promising therapeutic strategy. Triple-negative breast cancer (TNBC) is an aggressive and genomically heterogeneous subset of breast cancer that is resistant to existing targeted therapies. To identify metabolic pathway dependencies in TNBC, we first conducted mass spectrometry–based metabolomics of TNBC and control cells. Relative levels of intracellular metabolites distinguished TNBC from nontransformed breast epithelia and revealed two metabolic subtypes within TNBC that correlate with markers of basal-like versus non-basal–like status. Among the distinguishing metabolites, levels of the cellular redox buffer glutathione were lower in TNBC cell lines compared to controls and markedly lower in non-basal–like TNBC. Significantly, these cell lines showed enhanced sensitivity to pharmacologic inhibition of glutathione biosynthesis that was rescued by N-acetylcysteine, demonstrating a dependence on glutathione production to suppress ROS and support tumor cell survival. Consistent with this, patients whose tumors express elevated levels of -glutamylcysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, had significantly poorer survival. We find, further, that agents that limit the availability of glutathione precursors enhance both glutathione depletion and TNBC cell killing by -glutamylcysteine ligase inhibitors in vitro. Importantly, we demonstrate the ability to this approach to suppress glutathione levels and TNBC xenograft growth in vivo. Overall, these findings support the potential of targeting the glutathione biosynthetic pathway as a therapeutic strategy in TNBC and identify the non-basal-like subset as most likely to respond. Mol Cancer Ther; 17(1); 264–75. ©2017 AACR.

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Therapeutic Impact of Nanoparticle Therapy Targeting Tumor-Associated Macrophages

Antiangiogenic therapies, despite initial encouragement, have demonstrated a limited benefit in ovarian cancer. Laboratory studies suggest antiangiogenic therapy–induced hypoxia can induce tumor "stemness" as resistance to antiangiogenic therapy develops and limits the therapeutic benefit. Resistance to antiangiogenic therapy and an induction of tumor stemness may be mediated by proangiogenic tumor-associated macrophages (TAM). As such, TAMs have been proposed as a therapeutic target. We demonstrate here that ovarian TAMs express high levels of the folate receptor-2 (FOLR2) and can be selectively targeted using G5-dendrimer nanoparticles using methotrexate as both a ligand and a toxin. G5-methotrexate (G5-MTX) nanoparticles deplete TAMs in both solid tumor and ascites models of ovarian cancer. As a therapeutic agent, these nanoparticles are more effective than cisplatin. Importantly, these nanoparticles could (i) overcome resistance to antiangiogenic therapy, (ii) prevent antiangiogenic therapy–induced increases in cancer stem–like cells in both murine and human tumor cell models, (iii) prevent antiangiogenic therapy–induced increases in VEGF-C, and (iv) prevent antiangiogenic therapy–induced BRCA1 gene expression. Combined, this work strongly supports the development of TAM-targeted nanoparticle therapy. Mol Cancer Ther; 17(1); 96–106. ©2017 AACR.

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Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol

Overexpression and activation of the EGFR have been linked to poor prognosis in several human cancers. Cetuximab is a mAb against EGFR that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or will acquire resistance to cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anticancer properties without appreciable toxicity. In this study, we hypothesized that combining cetuximab and honokiol treatments could overcome acquired resistance to cetuximab. We previously developed a model of acquired resistance to cetuximab in non–small cell lung cancer H226 cell line. Treatment of cetuximab-resistant clones with honokiol and cetuximab resulted in a robust antiproliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. In addition, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in cetuximab-resistant clones, which may signify a change in mitochondrial function. Furthermore, we utilized cetuximab-resistant HNSCC patient-derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo. There was significant growth delay in PDX tumors after combination treatment with a subsequent downregulation of active MAPK, AKT, and DRP1 signaling as seen in vitro. Collectively, these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to cetuximab. Mol Cancer Ther; 17(1); 204–14. ©2017 AACR.

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JQ1 Induces DNA Damage and Apoptosis, and Inhibits Tumor Growth in a Patient-Derived Xenograft Model of Cholangiocarcinoma

Cholangiocarcinoma (CCA) is a fatal disease with a 5-year survival of <30%. For a majority of patients, chemotherapy is the only therapeutic option, and virtually all patients relapse. Gemcitabine is the first-line agent for treatment of CCA. Patients treated with gemcitabine monotherapy survive ~8 months. Combining this agent with cisplatin increases survival by ~3 months, but neither regimen produces durable remissions. The molecular etiology of this disease is poorly understood. To facilitate molecular characterization and development of effective therapies for CCA, we established a panel of patient-derived xenograft (PDX) models of CCA. We used two of these models to investigate the antitumor efficacy and mechanism of action of the bromodomain inhibitor JQ1, an agent that has not been evaluated for the treatment of CCA. The data show that JQ1 suppressed the growth of the CCA PDX model CCA2 and demonstrate that growth suppression was concomitant with inhibition of c-Myc protein expression. A second model (CCA1) was JQ1-insensitive, with tumor progression and c-Myc expression unaffected by exposure to this agent. Also selective to CCA2 tumors, JQ1 induced DNA damage and apoptosis and downregulated multiple c-Myc transcriptional targets that regulate cell-cycle progression and DNA repair. These findings suggest that c-Myc inhibition and several of its transcriptional targets may contribute to the mechanism of action of JQ1 in this tumor type. We conclude that BET inhibitors such as JQ1 warrant further investigation for the treatment of CCA. Mol Cancer Ther; 17(1); 107–18. ©2017 AACR.

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A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin-Drug Conjugate (LDC)

Various cancers, including pancreatic ductal adenocarcinoma (PDAC), remain intractable even with costly tumor-targeting antibody drugs. Because the outermost coatings of cancer cells are composed of cell-specific glycan layers (glycocalyx), lectins, proteins with glycan-binding potential, were evaluated for possible use as drug carriers in PDAC treatment. A human PDAC cell line with well-to-moderately differentiated properties (Capan-1) was subjected to lectin microarray analysis to identify specific lectin–glycan pairs. The selected lectin was fused with a bacterial exotoxin for the construction of a lectin–drug conjugate (LDC), and its safety and antitumor effects were evaluated. A specific affinity between a recombinant bacterial C-type lectin (rBC2LC-N) and Capan-1 was identified, and its positivity was confirmed in 69 human samples. In contrast to the belief that all lectins mediate harmful hemagglutination, rBC2LC-N did not cause hemagglutination with human erythrocytes and was safely administered to mice. The 50% inhibitory concentration of LDC to Capan-1 (1.04 pg/mL = 0.0195 pmol/L) was 1/1,000 lower than that reported for conventional immunotoxins. The intraperitoneal administration of LDC reduced the tumor weight from 390 to 130.8 mg (P < 0.01) in an orthotopic model and reduced the number of nodules from 48 to 3 (P < 0.001) and improved survival from 62 to 105 days in a peritoneal dissemination model (P < 0.0001). In addition, the effect of LDC was reproduced in nodules from patient-derived PDAC xenografts through intravenous injection. Herein, we show the concept of utilizing lectins as drug carriers to target glycans on the cancer cell surface, highlighting new insights into cancer treatments. Mol Cancer Ther; 17(1); 183–95. ©2017 AACR.

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Targeted Delivery of STAT-3 Modulator to Breast Cancer Stem-Like Cells Downregulates a Series of Stemness Genes

Cancer stem cells are known to be controlled by pathways that are dormant in normal adult cells, for example, PTEN, which is a negative regulator of transcription factor STAT3. STAT3 regulates genes that are involved in stem cell self-renewal and thus represents a novel therapeutic target of enormous clinical significance. Studies on breast cancer stem cells (BCSC) have been also significantly correlated with STATs. We describe here for the first time a novel strategy to selectively target CSCs and to induce downregulation of STAT3 downstream target genes reducing expression of series of "stem-ness genes" in treated tumors. In vitro and in vivo experiments were performed to evaluate functional activity with gene and protein expression studies. The results of the study indicate that this targeted delivery approach deactivates STAT3 causing a reduction of CD44⁺/CD24^– CSC populations with aptly tracked gene and protein regulations of "stemness" characteristics. Mol Cancer Ther; 17(1); 119–29. ©2017 AACR.

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ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms

Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK (ALK^ATI) was reported in 11% of melanomas but the response of melanomas expressing ALK^ATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for ALK mRNA and protein expression. ALK expression was identified in 11 of 45 (24.4%) melanomas. Ten melanomas express wild-type (wt) ALK and/or ALK^ATI and one mucosal melanoma expresses multiple novel EML4-ALK fusion variants. Melanoma cells expressing different ALK variants were tested for response to ALK inhibitors. Whereas the melanoma expressing EML4-ALK were sensitive to ALK inhibitors in vitro and in vivo, the melanomas expressing wt ALK or ALK^ATI were not sensitive to ALK inhibitors. In addition, a patient with mucosal melanoma expressing ALK^ATI was treated with an ALK/ROS1/TRK inhibitor (entrectinib) on a phase I trial but did not respond. Our results demonstrate ALK fusions occur in malignant melanomas and respond to targeted therapy, whereas melanomas expressing ALK^ATI do not respond to ALK inhibitors. Targeting ALK fusions is an effective therapeutic option for a subset of melanoma patients, but additional clinical studies are needed to determine the efficacy of targeted therapies in melanomas expressing wt ALK or ALK^ATI. Mol Cancer Ther; 17(1); 222–31. ©2017 AACR.

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miR-20a Regulates FAS Expression in Osteosarcoma Cells by Modulating FAS Promoter Activity and Can be Therapeutically Targeted to Inhibit Lung Metastases

The metastatic potential of osteosarcoma cells is inversely correlated to cell surface FAS expression. Downregulation of FAS allows osteosarcoma cells to escape FAS ligand–mediated apoptosis when they enter a FAS ligand–positive microenvironment such as the lung. We have previously demonstrated that miR-20a, encoded by the miR-17-92 cluster, downregulates FAS expression in osteosarcoma. We further demonstrated an inverse correlation between FAS expression and miR-20a expression. However, the mechanism of FAS regulation by miR-20a was still unclear. The purpose of the current study was to evaluate the mechanism of FAS regulation by miR-20a in vitro and test the effect of targeting miR-20a in vivo. We investigated whether miR-20a's downregulation of FAS was mediated by binding to the 3'-untranslated region (3'-UTR) of FAS mRNA with the consequent induction of mRNA degradation or translational suppression. We identified and mutated two miR-20a binding sites on the FAS mRNA 3'-UTR. Using luciferase reporter assays, we demonstrated that miR-20a did not bind to either the wild-type or mutated FAS 3'-UTR. In contrast, overexpression of miR-20a resulted in downregulation of FAS promoter activity. Similarly, the inhibition of miR-20a increased FAS promoter activity. The critical region identified on the FAS promoter was between –240 bp and –150 bp. Delivery of anti-miR-20a in vivo using nanoparticles in mice with established osteosarcoma lung metastases resulted in upregulation of FAS and tumor growth inhibition. Taken together, our data suggest that miR-20a regulates FAS expression through the modulation of the FAS promoter and that targeting miR-20a using anti-miR-20a has therapeutic potential. Mol Cancer Ther; 17(1); 130–9. ©2017 AACR.

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Targeting Phosphatidylserine with Calcium-Dependent Protein-Drug Conjugates for the Treatment of Cancer

In response to cellular stress, phosphatidylserine is exposed on the outer membrane leaflet of tumor blood vessels and cancer cells, motivating the development of phosphatidylserine-specific therapies. The generation of drug-conjugated phosphatidylserine-targeting agents represents an unexplored therapeutic approach, for which antitumor effects are critically dependent on efficient internalization and lysosomal delivery of the cytotoxic drug. In the current study, we have generated phosphatidylserine-targeting agents by fusing phosphatidylserine-binding domains to a human IgG1-derived Fc fragment. The tumor localization and pharmacokinetics of several phosphatidylserine-specific Fc fusions have been analyzed in mice and demonstrate that Fc-Syt1, a fusion containing the synaptotagmin 1 C2A domain, effectively targets tumor tissue. Conjugation of Fc-Syt1 to the cytotoxic drug monomethyl auristatin E results in a protein–drug conjugate (PDC) that is internalized into target cells and, due to the Ca²⁺ dependence of phosphatidylserine binding, dissociates from phosphatidylserine in early endosomes. The released PDC is efficiently delivered to lysosomes and has potent antitumor effects in mouse xenograft tumor models. Interestingly, although an engineered, tetravalent Fc-Syt1 fusion shows increased binding to target cells, this higher avidity variant demonstrates reduced persistence and therapeutic effects compared with bivalent Fc-Syt1. Collectively, these studies show that finely tuned, Ca²⁺-switched phosphatidylserine-targeting agents can be therapeutically efficacious. Mol Cancer Ther; 17(1); 169–82. ©2017 AACR.

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HIF2{alpha}-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma

Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80%–90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2α (HIF2α) and that an overabundance of HIF2α functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2α that utilizes a targeting ligand that selectively binds to integrins αvβ3 and αvβ5 frequently overexpressed in ccRCC. We demonstrate that functional delivery of a HIF2α-specific RNAi trigger resulted in HIF2α gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model. Mol Cancer Ther; 17(1); 140–9. ©2017 AACR.

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Selective and Concentrated Accretion of SN-38 with a CEACAM5-Targeting Antibody-Drug Conjugate (ADC), Labetuzumab Govitecan (IMMU-130)

Labetuzumab govitecan (IMMU-130), an antibody–drug conjugate (ADC) with an average of 7.6 SN-38/IgG, was evaluated for its potential to enhance delivery of SN-38 to human colonic tumor xenografts. Mice bearing LS174T or GW-39 human colonic tumor xenografts were injected with irinotecan or IMMU-130 (SN-38 equivalents ~500 or ~16 μg, respectively). Serum and homogenates of tumors, liver, and small intestine were extracted, and SN-38, SN-38G (glucuronidated SN-38), and irinotecan concentrations determined by reversed-phase HPLC. Irinotecan cleared quickly from serum, with only 1% to 2% injected dose/mL after 5 minutes; overall, approximately 20% was converted to SN-38 and SN-38G. At 1 hour with IMMU-130, 45% to 63% injected dose/mL of the SN-38 was in the serum, with >90% bound to the ADC over 3 days, and with low levels of SN-38G. Total SN-38 levels decreased more quickly than the IgG, confirming a gradual SN-38 release from the ADC. AUC analysis found that SN-38 levels were approximately 11- and 16-fold higher in LS174T and GW-39 tumors, respectively, in IMMU-130–treated animals. This delivery advantage is amplified >30-fold when normalized to SN-38 equivalents injected for each product. Levels of SN-38 and SN-38G were appreciably lower in the liver and small intestinal contents in animals given IMMU-130. On the basis of the SN-38 equivalents administered, IMMU-130 potentially delivers >300-fold more SN-38 to CEA-producing tumors compared with irinotecan, while also reducing levels of SN-38 and SN-38G in normal tissues. These observations are consistent with preclinical and clinical data showing efficacy and improved safety. Mol Cancer Ther; 17(1); 196–203. ©2017 AACR.

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Ceritinib Enhances the Efficacy of Trametinib in BRAF/NRAS-Wild-Type Melanoma Cell Lines

Targeted therapy options are currently lacking for the heterogeneous population of patients whose melanomas lack BRAF or NRAS mutations (~35% of cases). We undertook a chemical biology screen to identify potential novel drug targets for this understudied group of tumors. Screening a panel of 8 BRAF/NRAS-WT melanoma cell lines against 240 targeted drugs identified ceritinib and trametinib as potential hits with single-agent activity. Ceritinib enhanced the efficacy of trametinib across the majority of the BRAF/NRAS-WT cell lines, and the combination showed increased cytotoxicity in both three-dimensional spheroid culture and long-term colony formation experiments. Coadministration of ceritinib and trametinib led to robust inhibition of tumor growth in an in vivo xenograft BRAF/NRAS-WT melanoma model; this was not due to ALK inhibition by ceritinib. Mechanistic studies showed the ceritinib–trametinib combination to increase suppression of MAPK and TORC1 signaling. Similar results were seen when BRAF/NRAS-WT melanoma cells were treated with a combination of trametinib and the TORC1/2 inhibitor INK128. We next used mass spectrometry–based chemical proteomics and identified known and new ceritinib targets, such as IGF1R and ACK1, respectively. Validation studies suggested that ceritinib could suppress mTORC1 signaling in the presence of trametinib through inhibition of IGF1R and/or ACK1 in a cell line–dependent manner. Together, our studies demonstrated that combining a specific inhibitor (trametinib) with a more broadly targeted agent (ceritinib) has efficacy against tumors with heterogeneous mutational profiles. Mol Cancer Ther; 17(1); 73–83. ©2017 AACR.

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Differential efficacy of cisplatin plus pemetrexed between L858R and Del-19 in advanced EGFR -mutant non-squamous non-small cell lung cancer

Abstract

Background

LUX-Lung 3 showed afatinib improved progression-free survival (PFS) compared with cisplatin plus pemetrexed in patients with epidermal growth factor receptor (EGFR) mutations. In this study, chemotherapy efficacy tended to differ between patients with Leu858Arg (L858R) point mutation and Exon 19 deletion (Del-19); PFS in L858R patients (8.1 months) was greater than in Del-19 patients (5.6 months). We investigated whether there is any difference in efficacy of cisplatin plus pemetrexed between Del-19 and L858R.

Methods

This study is a multicenter retrospective study. We reviewed medical records of patients who had received cisplatin plus pemetrexed as first line chemotherapy. Efficacies were evaluated between EGFR mutation status: Del-19 and L858R. Wild type cases were reference arm only, and not included in any statistical analysis.

Results

Among 304 patients, 78 (25.7%) harbored EGFR mutations: Del-19 (36/78 patients, 46.2%); and L858R (42/78, 53.8%). Median PFS of L858R group (9.4 months, 95% confidence interval [CI]: 7.0–12.6) was significantly longer than Del-19 group (5.5 months, 95% CI, 3.6–8.6) (p = 0.049). Response rate (RR) and OS presented no significant difference between L858R and Del-19. In multivariate analysis, EGFR mutation status (L858R versus Del-19) was the only significant factor for longer PFS (Hazard ratio [HR]: 0.78, 95% CI: 0.62–0.98) (p = 0.033).

Conclusion

Our study indicated better efficacy of cisplatin plus pemetrexed in L858R than in Del-19 patients. In EGFR-mutant NSCLC, EGFR-TKIs are undoubtedly the premier therapy. However, in second line or later settings, cisplatin plus pemetrexed regimen may confer higher efficacy for L858R patients.

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Heterogeneity of PD-L1 expression in primary tumors and paired lymph node metastases of triple negative breast cancer

Abstract

Background

Programmed cell death ligand 1 (PD-L1) is a potential predictive biomarker of the response to anti-PD-L1/anti- programmed cell death 1 (PD-1) therapy in multiple cancers, including triple negative breast cancer(TNBC). The purpose of this study was to investigate whether PD-L1 expression is homogenous in primary tumors(PTs) and synchronous axillary lymph node metastases(LNMs) of TNBC.

Methods

PD-L1 expression was immunohistochemically evaluated in 101 TNBC patients' PTs and paired LNMs. PD-L1 expression in tumor cells and infiltrating immune cells or node lymphocytes in the PTs and associated LNMs was scored separately and was correlated with patients' clinical parameters and prognoses.

Results

PD-L1 expression exhibited spatial heterogeneity in both the tumor cells and the infiltrating immune cells or node lymphocytes of PTs and LNMs. The PD-L1 expression levels were significantly higher in the lymphocytes and tumor cells of the LNMs than in the PTs. PD-L1 expression was also more frequent among the LNMs. PD-L1 expression was associated with high grade and more stromal tumor-infiltrating lymphocytes(TILs). Furthermore, the disease-free survival and overall survival were similar between the PT- negative/LNM- positive and PT- positive/LNM- positive patients, both of which exhibited worse disease-free survival(DFS) thanPT -negative/LNM -negative patients.

Conclusions

The differential expression of PD-L1 between the PTs and LNMs suggests that LNMs PD-L1 status may be used to indicate whether PD-1/PD-L1-targeted therapy would be suitable for a node-positive TNBC patient in the future.

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Improving zebrafish embryo xenotransplantation conditions by increasing incubation temperature and establishing a proliferation index with ZFtool

Abstract

Background

Zebrafish (Danio rerio) is a model organism that has emerged as a tool for cancer research, cancer being the second most common cause of death after cardiovascular disease for humans in the developed world. Zebrafish is a useful model for xenotransplantation of human cancer cells and toxicity studies of different chemotherapeutic compounds in vivo. Compared to the murine model, the zebrafish model is faster, can be screened using high-throughput methods and has a lower maintenance cost, making it possible and affordable to create personalized therapies. While several methods for cell proliferation determination based on image acquisition and quantification have been developed, some drawbacks still remain. In the xenotransplantation technique, quantification of cellular proliferation in vivo is critical to standardize the process for future preclinical applications of the model.

Methods

This study improved the conditions of the xenotransplantation technique – quantification of cellular proliferation in vivo was performed through image processing with our ZFtool software and optimization of temperature in order to standardize the process for a future preclinical applications. ZFtool was developed to establish a base threshold that eliminates embryo auto-fluorescence and measures the area of marked cells (GFP) and the intensity of those cells to define a 'proliferation index'.

Results

The analysis of tumor cell proliferation at different temperatures (34 °C and 36 °C) in comparison to in vitro cell proliferation provides of a better proliferation rate, achieved as expected at 36°, a maintenance temperature not demonstrated up to now. The mortality of the embryos remained between 5% and 15%. 5- Fluorouracil was tested for 2 days, dissolved in the incubation medium, in order to quantify the reduction of the tumor mass injected. In almost all of the embryos incubated at 36 °C and incubated with 5-Fluorouracil, there was a significant tumor cell reduction compared with the control group. This was not the case at 34 °C.

Conclusions

Our results demonstrate that the proliferation of the injected cells is better at 36 °C and that this temperature is the most suitable for testing chemotherapeutic drugs like the 5-Fluorouracil.

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Identification of fluorescence in situ hybridization assay markers for prediction of disease progression in prostate cancer patients on active surveillance

Abstract

Background

Prostate Cancer (PCa) is the second most prevalent cancer among U.S. males. In recent decades many men with low risk PCa have been over diagnosed and over treated. Given significant co-morbidities associated with definitive treatments, maximizing patient quality of life while recognizing early signs of aggressive disease is essential. There remains a need to better stratify newly diagnosed men according to the risk of disease progression, identifying, with high sensitivity and specificity, candidates for active surveillance versus intervention therapy. The objective of this study was to select fluorescence in situ hybridization (FISH) panels that differentiate non-progressive from progressive disease in patients with low and intermediate risk PCa.

Methods

We performed a retrospective case-control study to evaluate FISH biomarkers on specimens from PCa patients with clinically localised disease (T1c-T2c) enrolled in Watchful waiting (WW)/Active Surveillance (AS). The patients were classified into cases (progressed to clinical intervention within 10 years), and controls (did not progress in 10 years). Receiver Operating Characteristic (ROC) curve analysis was performed to identify the best 3–5 probe combinations. FISH parameters were then combined with the clinical parameters ─ National Comprehensive Cancer Network (NNCN) risk categories ─ in the logistic regression model.

Results

Seven combinations of FISH parameters with the highest sensitivity and specificity for discriminating cases from controls were selected based on the ROC curve analysis. In the logistic regression model, these combinations contributed significantly to the prediction of PCa outcome. The combination of NCCN risk categories and FISH was additive to the clinical parameters or FISH alone in the final model, with odds ratios of 5.1 to 7.0 for the likelihood of the FISH-positive patients in the intended population to develop disease progression, as compared to the FISH-negative group.

Conclusions

Combinations of FISH parameters discriminating progressive from non-progressive PCa were selected based on ROC curve analysis. The combination of clinical parameters and FISH outperformed clinical parameters alone, and was complimentary to clinical parameters in the final model, demonstrating potential utility of multi-colour FISH panels as an auxiliary tool for PCa risk stratification. Further studies with larger cohorts are planned to confirm these findings.

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An inflammation-based cumulative prognostic score system in patients with diffuse large B cell lymphoma in rituximab era

Abstract

Background

Systemic inflammatory parameters are associated with poor outcomes in malignant patients. Several inflammation-based cumulative prognostic score systems were established for various solid tumors. However, there is few inflammation based cumulative prognostic score system for patients with diffuse large B cell lymphoma (DLBCL).

Methods

We retrospectively reviewed 564 adult DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy between Nov 1 2006 and Dec 30 2013 and assessed the prognostic significance of six systemic inflammatory parameters evaluated in previous studies by univariate and multivariate analysis:C-reactive protein(CRP), albumin levels, the lymphocyte-monocyte ratio (LMR), the neutrophil-lymphocyte ratio(NLR), the platelet-lymphocyte ratio(PLR)and fibrinogen levels.

Results

Multivariate analysis identified CRP, albumin levels and the LMR are three independent prognostic parameters for overall survival (OS). Based on these three factors, we constructed a novel inflammation-based cumulative prognostic score (ICPS) system. Four risk groups were formed: group ICPS = 0, ICPS = 1, ICPS = 2 and ICPS = 3. Advanced multivariate analysis indicated that the ICPS model is a prognostic score system independent of International Prognostic Index (IPI) for both progression-free survival (PFS) (p < 0.001) and OS (p < 0.001). The 3-year OS for patients with ICPS =0, ICPS =1, ICPS =2 and ICPS =3 were 95.6, 88.2, 76.0 and 62.2%, respectively (p < 0.001). The 3-year PFS for patients with ICPS = 0–1, ICPS = 2 and ICPS = 3 were 84.8, 71.6 and 54.5%, respectively (p < 0.001).

Conclusions

The prognostic value of the ICPS model indicated that the degree of systemic inflammatory status was associated with clinical outcomes of patients with DLBCL in rituximab era. The ICPS model was shown to classify risk groups more accurately than any single inflammatory prognostic parameters. These findings may be useful for identifying candidates for further inflammation-related mechanism research or novel anti-inflammation target therapies.

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Positron emission tomography-magnetic resonance imaging (PET-MRI) for response assessment after radiation therapy of cervical carcinoma: a pilot study

Abstract

Background

Advanced stage cervical cancer is primarily treated by radiotherapy. Local tumor control is a prerequisite for cure. Imaging after treatment is controversial. Positron emission tomography (PET) combined with computer tomography (PET-CT) shows great promise for detecting metastases. On the other hand, magnetic resonance imaging (MRI) is superior in depicting anatomical details. The combination of PET-MRI could result in more accurate evaluation of cervical cancer treatment outcome. The aim of this pilot study is to share our initial experience with PET-MRI in the evaluation of treatment response in cervical cancer after radiation treatment.

Methods

Ten patients with cervical carcinoma (FIGO ≥IB2) were prospectively evaluated. Eleven weeks (median; range 8–15 weeks) after radiation therapy, treatment response was evaluated by PET-MRI. The PET, MRI, and combined PET-MRI images were evaluated for the presence of local residual tumor and metastasis. Diagnostic performance was assessed by area under the receiver operator characteristic (ROC) curve for evaluation of local residual tumor. The readers were blinded for outcome data. Local residual disease, metastasis, diagnostic confidence, and change of opinion were scored on a 5-point Likert scale. The reference standard consisted of pathology and/or follow-up according to the clinical guidelines.

Results

Three out of ten patients had local residual abnormalities suggestive for tumor residue after radiation treatment. The availability of both PET and MRI resulted in an increase in diagnostic confidence in 80–90% of all patients. Change of opinion was observed in 70% and change of policy in 50%, especially in the group with residual tumor. The diagnostic accuracy increased significantly for the radiologist if PET-MRI was combined (AUC .54 versus .83).

Conclusions

PET-MRI shows promise for evaluation of treatment response after radiation for cervical cancer, especially increasing diagnostic confidence, while potentially increasing diagnostic performance.

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Prognostic parameters of luminal A and luminal B intrinsic breast cancer subtypes of Pakistani patients

Abstract

Background

Prognosis of breast cancer and success of therapeutic interventions largely rely on the clinico-pathologic and biological characteristics of the tumor and vary due to the heterogeneous nature of breast cancers. The aim of this study was to determine the frequency and prognostic parameters of luminal breast cancers in our population to devise targeted and personalized therapeutic regimens tailored to the needs of the loco-regional population.

Methods

A retrospective cross-sectional study including 1951 cases of primary breast cancer treated at Liaquat National Hospital Karachi was conducted during the year 2011–2016. The clinico-pathologic characteristics were observed and semiquantitative immunohistochemical analysis was performed to study the luminal subtypes A and B. The cross-tabulated statistics of the observed characteristics were performed between the two subtypes. The significance level of each characteristic was estimated utilizing the chi-square test.

Results

Luminal cancers comprised 62.7% of the total number of cases diagnosed with breast cancers in the study period. Out of these 1224 cases of luminal cancers, 845 cases (69%) were luminal B, while 379 (31%) cases were of luminal A. Luminal B cancers were significantly more common in younger age groups as compared to luminal A cancers. Comparison of the two subtypes of luminal breast cancers revealed significant differences. Luminal B cancers were associated with higher grade (26% grade III in luminal B compared to 8% in luminal A), micropapillary histology, and high frequency of nodal metastasis (54 vs. 43%).

Conclusions

Luminal B comprised the most frequent subtype of breast cancer in our study and they were found more constantly in a younger age group. Moreover, they were associated with adverse clinico-histologic parameters like higher grade and nodal metastasis. Therefore, we suggest that, despite lack of widespread availability of molecular studies in our setup, IHC-based typing should be done in every case of breast cancer to individualize therapy.

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Proximal carious lesions infiltration—a 3-year follow-up study of a randomized controlled clinical trial

Abstract

Introduction

Infiltration of carious lesion has been claimed as a promising approach for the management of non-cavitated proximal lesions (NCPL). Clinical studies have suggested that this approach may reduce NCPL progression in individuals whose caries risk was not change over the studied period.

Objective

This study aimed to assess the additional benefit of infiltration of NCPL over a 3-year period in a group of individuals who received treatment and control of carious activity.

Materials and methods

Twenty-two caries-active subjects that possessed at least a pair of NCPL in posterior teeth were selected for this study totalizing 36 pairs of lesion. In a split-mouth design, lesions were randomly allocated to test (infiltration) or placebo treatments. At follow-up, lesions were radiographically analyzed, progression was determined by radiographic pair-wise comparison and differences in number of progressing lesions between test, and placebo-treated surfaces were compared.

Results

Seventeen subjects (27 pairs of lesions) were followed up. Only four subjects were caries-active at the follow-up. In the test group, 2/27 (7.4%) lesions and in the placebo group 5/27 (18.5%) lesions had progressed. No statistical difference was observed between the studied groups (p = 0.453).

Conclusion

Subjects under treatment focusing on controlling caries activity presented low progression rates in both infiltrated and non-infiltrated NCPL. As only very few lesions progressed in both groups, no significant additional effect could be found. Further studies with larger sample sizes are necessary.

Clinical relevance

Infiltration of NCPL may have limited additional effect if other treatments focused on controlling caries activity are successful.

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Assessment of periodontal bone level revisited: a controlled study on the diagnostic accuracy of clinical evaluation methods and intra-oral radiography

Abstract

Objectives

The accuracy of analogue and especially digital intra-oral radiography in assessing interdental bone level needs further documentation. The aim of this study was to compare clinical and radiographic bone level assessment to intra-surgical bone level registration (1) and to identify the clinical variables rendering interdental bone level assessment inaccurate (2).

Materials and methods

The study sample included 49 interdental sites in 17 periodontitis patients. Evaluation methods included vertical relative probing attachment level (RAL-V), analogue and digital intra-oral radiography and bone sounding without and with flap elevation. The latter was considered the true bone level. Five examiners evaluated all radiographs.

Results

Significant underestimation of the true bone level was observed for all evaluation methods pointing to 2.7 mm on average for analogue radiography, 2.5 mm for digital radiography, 1.8 mm for RAL-V and 0.6 mm for bone sounding without flap elevation (p < 0.001). Radiographic underestimation of the true bone level was higher in the (pre)molar region (p ≤ 0.047) and increased with defect depth (p < 0.001). Variation between clinicians was huge (range analogue radiography 2.2–3.2 mm; range digital radiography 2.1–3.0 mm).

Conclusion

All evaluation methods significantly underestimated the true bone level. Bone sounding was most accurate, whereas intra-oral radiographs were least accurate. Deep periodontal defects in the (pre)molar region were most underrated by intra-oral radiography.

Clinical relevance

Bone sounding had the highest accuracy in assessing interdental bone level.

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Role of HIF-1α and CASPASE-3 in cystogenesis of odontogenic cysts and tumors

Abstract

Objectives

Odontogenic cysts and tumors are the most relevant lesions that affect the gnathic bones. These lesions have in common the formation of cystic areas and this common feature may suggest involvement of similar mechanisms. The hypoxia inducible factor 1 alpha (HIF-1α), a responsive protein to hypoxia and caspase-3, an irreversible apoptosis marker, may contribute to cyst formation. Thus, this study aimed to investigate the immunoexpression of these proteins in odontogenic cysts and tumors.

Material and methods

Twenty cases of ameloblastoma, keratocystic odontogenic tumor (KOT) (n = 20), radicular cyst (RC) (n = 18), dentigerous cyst (DC) (n = 11), calcifying cystic odontogenic tumor (n = 8), and dental follicle (DF) (n = 10) were used to investigate HIF-1α and caspase-3 expression in sequential serial cuts by immunohistochemistry.

Results

HIF-1α was overexpressed in RC, DC, and ameloblastoma when compared with DF. The basal and sometimes the lower suprabasal layer showed no or very low expression in DC, KOT, and ameloblastoma, the last also showing strong expression in solid epithelial areas and initial cystic formation regions. Caspase-3 was found to be overexpressed in all lesions, with the highest expression in odontogenic cysts compared to tumors. HIF-1α and caspase-3 were localized in similar areas of the same lesions, especially in the epithelium surrounding cystic formations.

Conclusions

This study showed distinct immunoexpression of HIF-1α and caspase-3 in odontogenic cyst and tumors, with higher expression observed in odontogenic cysts.

Clinical relevance

These findings suggest a possible correlation between hypoxia, apoptosis, and cystogenesis, leading to understand the mechanisms responsible to cystic formation in odontogenic lesions.

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Evaluation of metal artefact reduction in cone-beam computed tomography images of different dental materials

Abstract

Objective

The aim of this study is to evaluate the efficacy of metal artefact reduction (MAR) in different dental materials with Picasso Trio cone-beam computed tomography (CBCT) scanner.

Materials and methods

Three imaging phantoms were custom-made of acrylic resin. Each phantom presented three cylinders of the same material: dental amalgam alloy, gutta-percha or aluminium-copper alloy. CBCT scans were performed on Picasso Trio unit with and without MAR, and artefact expression (standard deviation of grey values) was obtained and compared by Kruskal-Wallis and Student-Newman-Keuls (post hoc) (α = 0.05).

Results

Significant reduction of artefact expression (p < 0.05) was observed with MAR on areas around dental alloys. No significant difference (p > 0.05) was observed with or without MAR when gutta-percha was scanned.

Conclusion

MAR was effective in reducing artefacts arising from dental alloys on CBCT images.

Clinical relevance

Dental materials of high atomic number and density are widely used in dentistry and can produce artefact that compromise CBCT image. The present study demonstrated that metal artefact reduction algorithm is an effective tool to improve image quality.

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pH influences the biocompatibility of methylene blue solutions

Abstract

Objective

The aim of this study was to investigate the biocompatibility of methylene blue at different pH levels through the method of implantation in subcutaneous tissue.

Materials and methods

Eighty-four sterilized polyethylene tubes were allocated in the subcutaneous tissue of 28 rats, each one receiving four tubes, set into four groups: group tube (G-T)—empty tube, fibrin group (G-F)—tube filled with fibrin sponge, group methylene blue pH 7 (G-MB/pH 7)—tube filled with fibrin sponge soaked by methylene blue (100 μg/ml) at pH 7.0, and group methylene blue pH 1 (G-MB/pH 1)—tube filled with fibrin sponge and soaked by methylene blue (100 μg/ml) at pH 1.0. After 7, 15, and 30 days, seven animals from each group were euthanized, and the tubes involved by the surrounding tissue were removed and fixed with 4% buffered formaldehyde solution. The collected pieces were processed and histological sections (4 μm) were stained with hematoxylin and eosin and analyzed by light microscopy. Scores were assigned to analysis of histopathologic parameters. The results were statistically analyzed by the Kruskal–Wallis test (p ≤ 0.05).

Results

At 7 and 30 days, the G-MB/pH 1 group showed no significant difference in the G-T control group, while G-MB/pH 7 had a significant increase on tissue reaction, also when compared to G-T. At 15 days, there was no statistical difference between the groups.

Conclusion

Within the limits of this study, it is concluded that methylene blue at pH 1.0 provides better biocompatibility than at pH 7.0.

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Three-year survival of ART high-viscosity glass-ionomer and resin composite restorations in people with disability

Abstract

Objectives

To assess the 3-year cumulative survival rate of atraumatic restorative treatment (ART) and conventional resin composite restorations (CRT) placed in persons with disability.

Materials and methods

Patients referred for restorative care to the Haemophilia Foundation special care service were treated by one of two specialists. Patients and/or caregivers were provided with written and verbal information regarding treatment options and selected the alternative they preferred. Treatment was provided as selected unless this option proved clinically unfeasible when an alternative technique was proposed. The treatment protocols were ART (hand instruments/high-viscosity glass-ionomer) in the clinic or CRT (rotary instrumentation/resin composite) in the clinic or under general anaesthesia (GA). After 6, 12, 24 and 36 months, two independent, trained and calibrated examiners evaluated restoration survival using established ART codes. The proportional hazard model with frailty corrections gave survival estimates over 3 years.

Results

Sixty-six patients (13.6 ± 7.8 years) with 16 different disability profiles participated. CRT in the clinic proved feasible for five patients (13%), and 14 patients received CRT under GA (21%). ART was used for 47 patients (71.2%). Altogether, 298 dentine carious lesions were restored in primary and permanent teeth (182 ART; 116 CRT). The 3-year cumulative survival rates and jackknife standard errors for the 182 ART and 116 CRT restorations were 94.8 ± 2.1 and 82.8 ± 5.3%, respectively (p = 0.01).

Conclusions

The 3-year follow-up results confirm that ART is an effective treatment protocol.

Clinical relevance

Patients with disability, many of whom have difficulty coping with CRT, may benefit from the ART approach.

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Reducing dentine hypersensitivity with nano-hydroxyapatite toothpaste: a double-blind randomized controlled trial

Abstract

Objectives

The present randomized double-blind clinical trial aimed to compare the efficacy in reducing dentin hypersensitivity of a dentifrice formulation containing nano-hydroxyapatite with a fluoride dentifrice and a placebo.

Methods and materials

One hundred and five subjects were recruited to participate in the study. A computer-generated random table with blocking to one of the three study treatments was used in order to have 35 subjects per group: (1) nano-hydroxyapatite 2% gel toothpaste fluoride free; (2) fluoride gel toothpaste; (3) placebo. Groups 1, 2, and 3 were instructed to treat their teeth for 10 min twice a day with the provided toothpaste gel. The participant's dentin hypersensitivity was evaluated at baseline and after 2 and 4 weeks using airblast and tactile tests. In addition, a subjective evaluation using a visual analogue scale was used.

Results

Significant lower values of cold air sensitivity and tactile sensitivity (p < 0.05) were found for the test group at 2 weeks and 4 weeks. In addition, statistically significant (p < 0.05) lower values of sensitivity were reported for group 1 compared to those for groups 2 and 3 at 2 and 4 weeks, respectively. The VAS scores were significantly lower (p < 0.05) in the test group at 2 and 4 weeks compared to those at baseline and in the control groups.

Conclusion

The application of nano-hydroxyapatite in gel toothpaste fluoride free is an effective desensitizing agent providing relief from symptoms after 2 and 4 weeks.

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Bacterial colonization in the apical part of extracted human teeth following root-end resection and filling: a confocal laser scanning microscopy study

Abstract

Objectives

The purpose of this study was to evaluate Enterococcus faecalis colonization at the apical part of root canals following root-end resection and filling using confocal laser scanning microscopy (CLSM).

Materials and methods

The apical 3-mm root-ends of 55 extracted single rooted human teeth were resected, and 3-mm retrograde cavities were prepared and filled using either mineral trioxide aggregate (MTA), intermediate restorative material (IRM), or Biodentine (n = 10 each); 25 teeth served as controls. The roots were placed in an experimental model, sterilized, and coronally filled with E. faecalis bacterial suspension for 21 days. Then, the apical 3-mm segments were cut to get two slabs (coronal and apical). The slabs were stained using LIVE/DEAD BacLight Bacterial Viability Kit and evaluated using CLSM.

Results

The fluorescence-stained areas were larger in the bucco-lingual directions compared with the mesio-distal directions (p < 0.05). The mean and maximal depths of bacterial colonization into the dentinal tubules were 755 and 1643 μm, respectively, with no differences between the root-end filling materials (p > 0.05). However, more live bacteria were found in the MTA group in comparison to IRM and Biodentine groups (p < 0.05).

Conclusions

CLSM can be used to histologically demonstrate bacterial root-end colonization following root-end filling. This colonization at the filling-dentine interfaces and deeper into the dentinal tubules may be inhomogeneous, favoring the bucco-lingual aspects of the root.

Clinical relevance

Following root-end resection and filling bacterial colonization may lead to inflammatory reactions at the periapical tissues; the viability of the colonized bacteria may be affected by the type of root-end filling material.

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Genome-wide gene expression profiling of tongue squamous cell carcinoma by RNA-seq

Abstract

Objective

Tongue squamous cell carcinoma (TSCC) is significantly more malignant than other type of oral squamous cell carcinoma (OSCC). In this study, we aimed to identify specific global gene expression signatures of TSCC to investigate the more invasive behavior of the deeply infiltrating cancer.

Methods

Using RNA-seq technology, we detected gene expression of 20 TSCCs, 20 matched paratumor tissues, and 10 healthy normal mucosa tissues. Enrichment analysis of gene ontology (GO) and pathway was conducted using online tools DAVID for the dysregulated genes. Additionally, we performed the quantitative real-time RT-PCR (qRT-PCR) to validate the findings of RNA-Seq in 10 samples of TSCC, matched paratumor, and normal mucosa, respectively.

Results

We detected 252 differentially expressed genes (DEGs) between TSCC and matched paratumor tissue, including 117 up-regulated and 135 down-regulated genes. For comparison between TSCC and normal mucosa, 234 DEGS were identified, consisting of 67 up-regulated and 167 down-regulated genes. For both two comparisons, GO categories of muscle contraction (GO: 0006936), epidermis development (GO: 0008544), epithelial cell differentiation (GO: 0030855), and keratinization (GO: 0031424) were commonly enriched. Altered gene expression affected some cancer-related pathways, such as tight junction. The qRT-PCR validation showed that gene expression patterns of FOLR1, NKX3-1, TFF3, PIGR, NEFL, MMP13, and HMGA2 were fully in concordance with RNA-Seq results.

Conclusion

Findings in this study demonstrated the genetic and molecular alterations associated with TSCC, providing new clues for understanding the molecular mechanisms of TSCC pathogenesis.

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How deep is the inflammation in chronic rhinosinusitis? Sinus wall thickness and blood eosinophilia.

Related Articles

How deep is the inflammation in chronic rhinosinusitis? Sinus wall thickness and blood eosinophilia.

Rhinology. 2017 Dec 31;:

Authors: Lin KY, Chen PY, Yeh TH

Abstract
Various factors have been proposed to be related to refractory chronic rhinosinusitis (CRS). Treatment for refractory CRS is challenging for ear, nose, and throat (ENT) surgeons. The aim of the study was to determine the clinical features associated with the severity of CRS that may necessitate revision surgery by eliminating the bias of the surgeons technique using standardizing surgical procedures. Sinus wall thickness and blood eosinophilia, which may represent the depth of inflammation in CRS, are associated with the need for revision surgery. We found that, when the thickness of the postero-lateral maxillary sinus wall is more than 3.03 mm, there is an increased probability for a need for revision surgery. CRS patients with thickened sinus walls were found to have poorer outcomes. Further research is needed in order to justify this type of surgical procedure for CRS.

PMID: 29289975 [PubMed - as supplied by publisher]

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Proximal carious lesions infiltration—a 3-year follow-up study of a randomized controlled clinical trial

Abstract

Introduction

Infiltration of carious lesion has been claimed as a promising approach for the management of non-cavitated proximal lesions (NCPL). Clinical studies have suggested that this approach may reduce NCPL progression in individuals whose caries risk was not change over the studied period.

Objective

This study aimed to assess the additional benefit of infiltration of NCPL over a 3-year period in a group of individuals who received treatment and control of carious activity.

Materials and methods

Twenty-two caries-active subjects that possessed at least a pair of NCPL in posterior teeth were selected for this study totalizing 36 pairs of lesion. In a split-mouth design, lesions were randomly allocated to test (infiltration) or placebo treatments. At follow-up, lesions were radiographically analyzed, progression was determined by radiographic pair-wise comparison and differences in number of progressing lesions between test, and placebo-treated surfaces were compared.

Results

Seventeen subjects (27 pairs of lesions) were followed up. Only four subjects were caries-active at the follow-up. In the test group, 2/27 (7.4%) lesions and in the placebo group 5/27 (18.5%) lesions had progressed. No statistical difference was observed between the studied groups (p = 0.453).

Conclusion

Subjects under treatment focusing on controlling caries activity presented low progression rates in both infiltrated and non-infiltrated NCPL. As only very few lesions progressed in both groups, no significant additional effect could be found. Further studies with larger sample sizes are necessary.

Clinical relevance

Infiltration of NCPL may have limited additional effect if other treatments focused on controlling caries activity are successful.

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Assessment of periodontal bone level revisited: a controlled study on the diagnostic accuracy of clinical evaluation methods and intra-oral radiography

Abstract

Objectives

The accuracy of analogue and especially digital intra-oral radiography in assessing interdental bone level needs further documentation. The aim of this study was to compare clinical and radiographic bone level assessment to intra-surgical bone level registration (1) and to identify the clinical variables rendering interdental bone level assessment inaccurate (2).

Materials and methods

The study sample included 49 interdental sites in 17 periodontitis patients. Evaluation methods included vertical relative probing attachment level (RAL-V), analogue and digital intra-oral radiography and bone sounding without and with flap elevation. The latter was considered the true bone level. Five examiners evaluated all radiographs.

Results

Significant underestimation of the true bone level was observed for all evaluation methods pointing to 2.7 mm on average for analogue radiography, 2.5 mm for digital radiography, 1.8 mm for RAL-V and 0.6 mm for bone sounding without flap elevation (p < 0.001). Radiographic underestimation of the true bone level was higher in the (pre)molar region (p ≤ 0.047) and increased with defect depth (p < 0.001). Variation between clinicians was huge (range analogue radiography 2.2–3.2 mm; range digital radiography 2.1–3.0 mm).

Conclusion

All evaluation methods significantly underestimated the true bone level. Bone sounding was most accurate, whereas intra-oral radiographs were least accurate. Deep periodontal defects in the (pre)molar region were most underrated by intra-oral radiography.

Clinical relevance

Bone sounding had the highest accuracy in assessing interdental bone level.

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Role of HIF-1α and CASPASE-3 in cystogenesis of odontogenic cysts and tumors

Abstract

Objectives

Odontogenic cysts and tumors are the most relevant lesions that affect the gnathic bones. These lesions have in common the formation of cystic areas and this common feature may suggest involvement of similar mechanisms. The hypoxia inducible factor 1 alpha (HIF-1α), a responsive protein to hypoxia and caspase-3, an irreversible apoptosis marker, may contribute to cyst formation. Thus, this study aimed to investigate the immunoexpression of these proteins in odontogenic cysts and tumors.

Material and methods

Twenty cases of ameloblastoma, keratocystic odontogenic tumor (KOT) (n = 20), radicular cyst (RC) (n = 18), dentigerous cyst (DC) (n = 11), calcifying cystic odontogenic tumor (n = 8), and dental follicle (DF) (n = 10) were used to investigate HIF-1α and caspase-3 expression in sequential serial cuts by immunohistochemistry.

Results

HIF-1α was overexpressed in RC, DC, and ameloblastoma when compared with DF. The basal and sometimes the lower suprabasal layer showed no or very low expression in DC, KOT, and ameloblastoma, the last also showing strong expression in solid epithelial areas and initial cystic formation regions. Caspase-3 was found to be overexpressed in all lesions, with the highest expression in odontogenic cysts compared to tumors. HIF-1α and caspase-3 were localized in similar areas of the same lesions, especially in the epithelium surrounding cystic formations.

Conclusions

This study showed distinct immunoexpression of HIF-1α and caspase-3 in odontogenic cyst and tumors, with higher expression observed in odontogenic cysts.

Clinical relevance

These findings suggest a possible correlation between hypoxia, apoptosis, and cystogenesis, leading to understand the mechanisms responsible to cystic formation in odontogenic lesions.

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Evaluation of metal artefact reduction in cone-beam computed tomography images of different dental materials

Abstract

Objective

The aim of this study is to evaluate the efficacy of metal artefact reduction (MAR) in different dental materials with Picasso Trio cone-beam computed tomography (CBCT) scanner.

Materials and methods

Three imaging phantoms were custom-made of acrylic resin. Each phantom presented three cylinders of the same material: dental amalgam alloy, gutta-percha or aluminium-copper alloy. CBCT scans were performed on Picasso Trio unit with and without MAR, and artefact expression (standard deviation of grey values) was obtained and compared by Kruskal-Wallis and Student-Newman-Keuls (post hoc) (α = 0.05).

Results

Significant reduction of artefact expression (p < 0.05) was observed with MAR on areas around dental alloys. No significant difference (p > 0.05) was observed with or without MAR when gutta-percha was scanned.

Conclusion

MAR was effective in reducing artefacts arising from dental alloys on CBCT images.

Clinical relevance

Dental materials of high atomic number and density are widely used in dentistry and can produce artefact that compromise CBCT image. The present study demonstrated that metal artefact reduction algorithm is an effective tool to improve image quality.

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pH influences the biocompatibility of methylene blue solutions

Abstract

Objective

The aim of this study was to investigate the biocompatibility of methylene blue at different pH levels through the method of implantation in subcutaneous tissue.

Materials and methods

Eighty-four sterilized polyethylene tubes were allocated in the subcutaneous tissue of 28 rats, each one receiving four tubes, set into four groups: group tube (G-T)—empty tube, fibrin group (G-F)—tube filled with fibrin sponge, group methylene blue pH 7 (G-MB/pH 7)—tube filled with fibrin sponge soaked by methylene blue (100 μg/ml) at pH 7.0, and group methylene blue pH 1 (G-MB/pH 1)—tube filled with fibrin sponge and soaked by methylene blue (100 μg/ml) at pH 1.0. After 7, 15, and 30 days, seven animals from each group were euthanized, and the tubes involved by the surrounding tissue were removed and fixed with 4% buffered formaldehyde solution. The collected pieces were processed and histological sections (4 μm) were stained with hematoxylin and eosin and analyzed by light microscopy. Scores were assigned to analysis of histopathologic parameters. The results were statistically analyzed by the Kruskal–Wallis test (p ≤ 0.05).

Results

At 7 and 30 days, the G-MB/pH 1 group showed no significant difference in the G-T control group, while G-MB/pH 7 had a significant increase on tissue reaction, also when compared to G-T. At 15 days, there was no statistical difference between the groups.

Conclusion

Within the limits of this study, it is concluded that methylene blue at pH 1.0 provides better biocompatibility than at pH 7.0.

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Three-year survival of ART high-viscosity glass-ionomer and resin composite restorations in people with disability

Abstract

Objectives

To assess the 3-year cumulative survival rate of atraumatic restorative treatment (ART) and conventional resin composite restorations (CRT) placed in persons with disability.

Materials and methods

Patients referred for restorative care to the Haemophilia Foundation special care service were treated by one of two specialists. Patients and/or caregivers were provided with written and verbal information regarding treatment options and selected the alternative they preferred. Treatment was provided as selected unless this option proved clinically unfeasible when an alternative technique was proposed. The treatment protocols were ART (hand instruments/high-viscosity glass-ionomer) in the clinic or CRT (rotary instrumentation/resin composite) in the clinic or under general anaesthesia (GA). After 6, 12, 24 and 36 months, two independent, trained and calibrated examiners evaluated restoration survival using established ART codes. The proportional hazard model with frailty corrections gave survival estimates over 3 years.

Results

Sixty-six patients (13.6 ± 7.8 years) with 16 different disability profiles participated. CRT in the clinic proved feasible for five patients (13%), and 14 patients received CRT under GA (21%). ART was used for 47 patients (71.2%). Altogether, 298 dentine carious lesions were restored in primary and permanent teeth (182 ART; 116 CRT). The 3-year cumulative survival rates and jackknife standard errors for the 182 ART and 116 CRT restorations were 94.8 ± 2.1 and 82.8 ± 5.3%, respectively (p = 0.01).

Conclusions

The 3-year follow-up results confirm that ART is an effective treatment protocol.

Clinical relevance

Patients with disability, many of whom have difficulty coping with CRT, may benefit from the ART approach.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2lCxMw4

Reducing dentine hypersensitivity with nano-hydroxyapatite toothpaste: a double-blind randomized controlled trial

Abstract

Objectives

The present randomized double-blind clinical trial aimed to compare the efficacy in reducing dentin hypersensitivity of a dentifrice formulation containing nano-hydroxyapatite with a fluoride dentifrice and a placebo.

Methods and materials

One hundred and five subjects were recruited to participate in the study. A computer-generated random table with blocking to one of the three study treatments was used in order to have 35 subjects per group: (1) nano-hydroxyapatite 2% gel toothpaste fluoride free; (2) fluoride gel toothpaste; (3) placebo. Groups 1, 2, and 3 were instructed to treat their teeth for 10 min twice a day with the provided toothpaste gel. The participant's dentin hypersensitivity was evaluated at baseline and after 2 and 4 weeks using airblast and tactile tests. In addition, a subjective evaluation using a visual analogue scale was used.

Results

Significant lower values of cold air sensitivity and tactile sensitivity (p < 0.05) were found for the test group at 2 weeks and 4 weeks. In addition, statistically significant (p < 0.05) lower values of sensitivity were reported for group 1 compared to those for groups 2 and 3 at 2 and 4 weeks, respectively. The VAS scores were significantly lower (p < 0.05) in the test group at 2 and 4 weeks compared to those at baseline and in the control groups.

Conclusion

The application of nano-hydroxyapatite in gel toothpaste fluoride free is an effective desensitizing agent providing relief from symptoms after 2 and 4 weeks.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2Eumd2R

Bacterial colonization in the apical part of extracted human teeth following root-end resection and filling: a confocal laser scanning microscopy study

Abstract

Objectives

The purpose of this study was to evaluate Enterococcus faecalis colonization at the apical part of root canals following root-end resection and filling using confocal laser scanning microscopy (CLSM).

Materials and methods

The apical 3-mm root-ends of 55 extracted single rooted human teeth were resected, and 3-mm retrograde cavities were prepared and filled using either mineral trioxide aggregate (MTA), intermediate restorative material (IRM), or Biodentine (n = 10 each); 25 teeth served as controls. The roots were placed in an experimental model, sterilized, and coronally filled with E. faecalis bacterial suspension for 21 days. Then, the apical 3-mm segments were cut to get two slabs (coronal and apical). The slabs were stained using LIVE/DEAD BacLight Bacterial Viability Kit and evaluated using CLSM.

Results

The fluorescence-stained areas were larger in the bucco-lingual directions compared with the mesio-distal directions (p < 0.05). The mean and maximal depths of bacterial colonization into the dentinal tubules were 755 and 1643 μm, respectively, with no differences between the root-end filling materials (p > 0.05). However, more live bacteria were found in the MTA group in comparison to IRM and Biodentine groups (p < 0.05).

Conclusions

CLSM can be used to histologically demonstrate bacterial root-end colonization following root-end filling. This colonization at the filling-dentine interfaces and deeper into the dentinal tubules may be inhomogeneous, favoring the bucco-lingual aspects of the root.

Clinical relevance

Following root-end resection and filling bacterial colonization may lead to inflammatory reactions at the periapical tissues; the viability of the colonized bacteria may be affected by the type of root-end filling material.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2lCbvP2

Genome-wide gene expression profiling of tongue squamous cell carcinoma by RNA-seq

Abstract

Objective

Tongue squamous cell carcinoma (TSCC) is significantly more malignant than other type of oral squamous cell carcinoma (OSCC). In this study, we aimed to identify specific global gene expression signatures of TSCC to investigate the more invasive behavior of the deeply infiltrating cancer.

Methods

Using RNA-seq technology, we detected gene expression of 20 TSCCs, 20 matched paratumor tissues, and 10 healthy normal mucosa tissues. Enrichment analysis of gene ontology (GO) and pathway was conducted using online tools DAVID for the dysregulated genes. Additionally, we performed the quantitative real-time RT-PCR (qRT-PCR) to validate the findings of RNA-Seq in 10 samples of TSCC, matched paratumor, and normal mucosa, respectively.

Results

We detected 252 differentially expressed genes (DEGs) between TSCC and matched paratumor tissue, including 117 up-regulated and 135 down-regulated genes. For comparison between TSCC and normal mucosa, 234 DEGS were identified, consisting of 67 up-regulated and 167 down-regulated genes. For both two comparisons, GO categories of muscle contraction (GO: 0006936), epidermis development (GO: 0008544), epithelial cell differentiation (GO: 0030855), and keratinization (GO: 0031424) were commonly enriched. Altered gene expression affected some cancer-related pathways, such as tight junction. The qRT-PCR validation showed that gene expression patterns of FOLR1, NKX3-1, TFF3, PIGR, NEFL, MMP13, and HMGA2 were fully in concordance with RNA-Seq results.

Conclusion

Findings in this study demonstrated the genetic and molecular alterations associated with TSCC, providing new clues for understanding the molecular mechanisms of TSCC pathogenesis.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2ExMVY3

Feasibility and acceptability of combining cognitive behavioural therapy techniques with swallowing therapy in head and neck cancer dysphagia

Abstract

Background

Head and neck cancer squamous cell carcinoma (HNSSC) patients report substantial rates of clinically significant depression and/or anxiety, with dysphagia being a predictor of distress and poorer quality of life. Evidence-based dysphagia interventions largely focus on the remediation of physical impairment. This feasibility study evaluates an intervention which simultaneously uses a psychological therapy approach combined with swallowing impairment rehabilitation.

Methods

This prospective single cohort mixed-methods study, recruited HNSCC patients with dysphagia, from two institutions. The intervention combined Cognitive Behavioural Therapy with swallowing therapy (CB-EST), was individually tailored, for up to 10 sessions and delivered by a speech and language therapist. Primary acceptability and feasibility measures included recruitment and retention rates, data completion, intervention fidelity and the responsiveness of candidate outcome measures. Measures included a swallowing questionnaire (MDADI), EORTC-QLQH&N35, dietary restrictions scale, fatigue and function scales and the Hospital Anxiety and Depression Scale (HADS), administered pre-, post-CB-EST with three month follow-up and analysed using repeated measures ANOVA. Qualitative interviews were conducted to evaluate intervention processes.

Results

A total of 30/43 (70%) eligible patients agreed to participate and 25 completed the intervention. 84% were male, mean age 59 yrs. Patients were between 1 and 60 months (median 4) post-cancer treatment. All patients had advanced stage disease, treated with surgery and radiotherapy (38%) or primary chemoradiotherapy (62%). Pre to post CB-EST data showed improvements in MDADI scores (p = 0.002), EORTC-QLQH&N35 (p = 0.006), dietary scale (p < 0.0001), fatigue (p = 0.002) but no change in function scales or HADS. Barriers to recruitment were the ability to attend regular appointments and patient suitability or openness to a psychological-based intervention.

Conclusions

CB-EST is a complex and novel intervention, addressing the emotional, behavioural and cognitive components of dysphagia alongside physical impairment. Preliminary results are promising. Further research is required to evaluate efficacy and effectiveness.

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Front cover

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Table of contents

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IEEE Journal on Translational Engineering in Medicine and Biology publication information

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Radiation dose management for pediatric cardiac computed tomography: a report from the Image Gently ‘Have-A-Heart’ campaign

Abstract

Children with congenital or acquired heart disease can be exposed to relatively high lifetime cumulative doses of ionizing radiation from necessary medical imaging procedures including radiography, fluoroscopic procedures including diagnostic and interventional cardiac catheterizations, electrophysiology examinations, cardiac computed tomography (CT) studies, and nuclear cardiology examinations. Despite the clinical necessity of these imaging studies, the related ionizing radiation exposure could pose an increased lifetime attributable cancer risk. The Image Gently "Have-A-Heart" campaign is promoting the appropriate use of medical imaging studies in children with congenital or acquired heart disease while minimizing radiation exposure. The focus of this manuscript is to provide a comprehensive review of radiation dose management and CT performance in children with congenital or acquired heart disease.

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