Publication date: March 2019
Source: Annals of Anatomy - Anatomischer Anzeiger, Volume 222
Author(s):
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Σάββατο 16 Φεβρουαρίου 2019
Future Oncology; +22 new citations
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Architecture evaluation of the main clear corneal incisions in femtosecond laser-assisted cataract surgery by optical coherence tomography imaging
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Primary vitreoretinal lymphoma: prevalence, impact, and management challenges
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The protective effects of the antioxidant N-acetylcysteine (NAC) against oxidative stress-associated apoptosis evoked by the organophosphorus insecticide malathion in normal human astrocytes.
The protective effects of the antioxidant N-acetylcysteine (NAC) against oxidative stress-associated apoptosis evoked by the organophosphorus insecticide malathion in normal human astrocytes.
Toxicology. 2019 Feb 12;:
Authors: Sheih P, Jan CR, Liang WZ
Abstract
Malathion is one of the most widely used organophosphorus insecticides in agriculture. However, malathion may be involved in the etiology of human brain dysfunction. Induction of ROS has been proposed as a mechanism of malathion-induced poisoning cases, but there are few data regarding the effects of malathion on oxidative stress-associated neurotoxicity in human glial cells. The aim was to explore the mechanism underlying effects of malathion on neurotoxicity in Gibco® Human Astrocytes (GHA cells) and evaluate the protective effects of the antioxidant (N-acetylcysteine, NAC). Cell viability was measured by the cell proliferation reagent (WST-1). Antioxidant enzymes (glutathione peroxidase and catalase) were measured by an ELISA reader. Cell cycle distribution and ROS productions were detected by flow cytometry. Cell cycle-related protein levels (cyclin E1, CDK2, cyclin A2, CDK1/CDC2, or cyclin B1) and apoptotic protein levels (Bcl-2, Bax, and cleaved caspase-9/caspase-3) were analyzed by Western blotting. In GHA cells, treatment with malathion (10-25 μM) for 24 h concentration-dependently induced cytotoxicity and cell cycle arrest. In terms of oxidative stresses, malathion elevated intracellular ROS levels, but reduced glutathion and antioxidant enzyme levels. Treatment with NAC (5 μM) reversed malathion-induced oxidative stress responses, and prevented malathion-evoked apoptosis by regulating apoptotic protein expressions. Together, in GHA cells, NAC mediated inhibition of malathion-activated mitochondrial apoptotic pathways that involved cell cycle arrest and ROS responses. These data provide further insights into the molecular mechanisms behind malathion poisoning, and might suggest that NAC with its protective effects may be a potential compound for prevention of malathion-induced brain injury.
PMID: 30769050 [PubMed - as supplied by publisher]
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Long Non-Coding RNA TFAP2A-AS1 Inhibits Cell Proliferation and Invasion in Breast Cancer via miR-933/SMAD2.
Long Non-Coding RNA TFAP2A-AS1 Inhibits Cell Proliferation and Invasion in Breast Cancer via miR-933/SMAD2.
Med Sci Monit. 2019 Feb 15;25:1242-1253
Authors: Zhou B, Guo H, Tang J
Abstract
BACKGROUND It is well documented that long non-coding RNAs (lncRNAs) are involved in the progression of multiple human tumors by sponging microRNAs (miRNAs). However, whether lncRNA TFAP2A-AS1 plays a role in the tumorigenesis of breast cancer (BC) remains undetermined. MATERIAL AND METHODS Real-time PCR (qRT-PCR) assay was performed to detect the relative mRNA expression of TFAP2A-AS1 and miR-933. Flow cytometry analysis, CCK-8 assay, and Transwell assay were applied to detect the effects of TFAP2A-AS1 overexpression on cell cycle, apoptosis, viability, and invasion of BC cells. In vivo proliferation assay was performed to evaluate the effects of TFAP2A-AS1 overexpression on tumor growth. Bioinformatics methods, dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays were used to predict and validate the interaction between TFAP2A-AS1 and miR-933, as well as SMAD2 and miR-933. Western blot assay was performed to examine the protein expression of SMAD2 in treated BC cells. RESULTS TFAP2A-AS1 expression was significantly lower in BC tissues and cell lines, and patients with high TFAP2A-AS1 expression exhibited a better prognosis than those with low TFAP2A-AS1 expression. Overexpression of TFAP2A-AS1 in BC cells caused cell cycle arrest, promoted cell apoptosis, suppressed cell ability, and attenuated cell invasion in vitro, and inhibited tumor growth in vivo. TFAP2A-AS1 was revealed to act as a miRNA sponge for miR-933 and then regulated the expression of Smad2. CONCLUSIONS Results from the present study suggest that TFAP2A-AS1 acts as a tumor suppressor in BC via the miR-933/SMAD2 axis.
PMID: 30768589 [PubMed - in process]
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A Novel Small Molecule p53 Stabilizer for Brain Cell Differentiation.
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A Novel Small Molecule p53 Stabilizer for Brain Cell Differentiation.
Front Chem. 2019;7:15
Authors: Amaral JD, Silva D, Rodrigues CMP, Solá S, Santos MMM
Abstract
Brain tumor, as any type of cancer, is assumed to be sustained by a small subpopulation of stem-like cells with distinctive properties that allow them to survive conventional therapies and drive tumor recurrence. Thus, the identification of new molecules capable of controlling stemness properties may be key in developing effective therapeutic strategies for cancer by inducing stem-like cells differentiation. Spiropyrazoline oxindoles have previously been shown to induce apoptosis and cell cycle arrest, as well as upregulate p53 steady-state levels, while decreasing its main inhibitor MDM2 in the HCT116 human colorectal carcinoma cell line. In this study, we made modifications in this scaffold by including combinations of different substituents in the pyrazoline ring in order to obtain novel small molecules that could modulate p53 activity and act as differentiation inducer agents. The antiproliferative activity of the synthesized compounds was assessed using the isogenic pair of HCT116 cell lines differing in the presence or absence of the p53 gene. Among the tested spirooxindoles, spiropyrazoline oxindole 1a was selective against the cancer cell line expressing wild-type p53 and presented low cytotoxicity. This small molecule induced neural stem cell (NSC) differentiation through reduced SOX2 (marker of multipotency) and increased βIII-tubulin (marker of neural differentiation) which suggests a great potential as a non-toxic inducer of cell differentiation. More importantly, in glioma cancer cells (GL-261), compound 1a reduced stemness, by decreasing SOX2 protein levels, while also promoting chemotherapy sensitization. These results highlight the potential of p53 modulators for brain cell differentiation, with spirooxindole 1a representing a promising lead molecule for the development of new brain antitumor drugs.
PMID: 30766866 [PubMed]
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MiR-219-5p suppresses cell proliferation and cell cycle progression in esophageal squamous cell carcinoma by targeting CCNA2.
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MiR-219-5p suppresses cell proliferation and cell cycle progression in esophageal squamous cell carcinoma by targeting CCNA2.
Cell Mol Biol Lett. 2019;24:4
Authors: Ma Q
Abstract
Background: We investigated the potential regulatory role of miR-219-5p in esophageal squamous cell carcinoma (ESCC) and looked at the underlying mechanisms in ESCC.
Methods: Real-time PCR was used to determine the levels of miR-219-5p in ESCC tissues and cell lines. The effects of miR-219-5p and cyclin A2 (CCNA2) on cell proliferation and cell cycle progression were evaluated using MTT, colony formation and flow cytometry assays with ESCC cell lines EC9706 and TE-9. Bioinformatics techniques and the luciferase reporter assay were applied to validate CCNA2 as the miR-219-5p target in ESCC cells. The mRNA and protein levels of CCNA2 were measured using real-time PCR and western blotting.
Results: MiR-219-5p expression was significantly lower in ESCC tissues and cells than in healthy tissues. Upregulation of miR-219-5p repressed cell proliferation and induced cell cycle arrest at the G2/M phase. CCNA2 was identified and confirmed as a direct downstream target of miR-219-5p and its expression negatively correlated with miR-219-5p profiles in ESCC tissues. Knockdown of CCNA2 potentiated the effects of miR-219-5p on cell proliferation and cell cycle distribution.
Conclusions: Our results demonstrate that miR-219-5p might function as a tumor suppressor by directly targeting CCNA2 expression. It could serve as a new therapeutic target for ESCC.
PMID: 30766610 [PubMed - in process]
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G-Protein-Coupled Receptor 120 Mediates DHA Induced Apoptosis by Regulating IP3R, ROS and, ER Stress Levels in Cisplatin-Resistant Cancer Cells.
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G-Protein-Coupled Receptor 120 Mediates DHA Induced Apoptosis by Regulating IP3R, ROS and, ER Stress Levels in Cisplatin-Resistant Cancer Cells.
Mol Cells. 2019 Nov 27;:
Authors: Shin JI, Jeon YJ, Lee S, Lee YG, Kim JB, Lee K
Abstract
The omega-3 fatty acid docosahexaenoic acid (DHA) is known to induce apoptosis and cell cycle arrest via the induction of reactive oxygen species (ROS) production and endoplasmic reticulum (ER) stress in many types of cancers. However, the roles of DHA in drug-resistant cancer cells have not been elucidated. In this study, we investigated the effects of DHA in cisplatin-resistant gastric cancer SNU-601/cis2 cells. DHA was found to induce ROS-dependent apoptosis in these cells. The inositol 1,4,5-triphosphate receptor (IP3R) blocker 2-aminoethyl diphenylboninate (2-APB) reduced DHA-induced ROS production, consequently reducing apoptosis. We also found that G-protein-coupled receptor 120 (GPR120), a receptor of long-chain fatty acids, is expressed in SNU-601/cis2 cells, and the knockdown of GPR120 using specific shRNAs alleviated DHA-mediated ROS production and apoptosis. GPR120 knockdown reduced the expression of ER stress response genes, similar to the case for the pre-treatment of the cells with N-acetyl-L-cysteine (NAC), an ROS scavenger, or 2-APB. Indeed, the knockdown of C/EBP homologous protein (CHOP), a transcription factor that functions under ER stress conditions, markedly reduced DHA-mediated apoptosis, indicating that CHOP plays an essential role in the anti-cancer activity of DHA. These results suggest that GPR120 mediates DHA-induced apoptosis by regulating IP3R, ROS, and ER stress levels in cisplatin-resistant cancer cells, and that GPR120 is an effective chemotherapeutic target for cisplatin resistance.
PMID: 30764601 [PubMed - as supplied by publisher]
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Activity of rutin, a potent flavonoid against SSG-sensitive and -resistant Leishmania donovani parasites in experimental leishmaniasis.
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Activity of rutin, a potent flavonoid against SSG-sensitive and -resistant Leishmania donovani parasites in experimental leishmaniasis.
Int Immunopharmacol. 2018 Nov;64:372-385
Authors: Chauhan K, Kaur G, Kaur S
Abstract
The current treatment approach for leishmaniasis has been questioned in terms of development of the resistance and life threatening side-effects. The utility of the drug can only be confirmed by inspecting its safety window along with its impact against different strains of parasite including the resistant ones. The aim of this study was to evaluate the therapeutic effects of a flavonoid, rutin (RTN) against sodium stibogluconate (SSG) sensitive (S-) and resistant (R-) strain of L. donovani. RTN exhibited its anti-promastigote activity via arresting the cells at sub G0/G1 phase. Further RTN resulted in decline of splenic parasite burden. The parasiticidal activity was associated with the elicitation of cell-mediated immune response in terms of increased DTH response, augmented levels of T cells (CD4+, CD8+), Th1 cytokines, NO and ROS. RTN also up-regulated the expression of NF-ĸB and iNOS gene in S- as well as R- strain infected mice. Where no therapeutic effect of SSG was seen in the R-strain infected mice, the RTN treatment was able to control the disease in even R-strain infected mice. Moreover RTN was found to be devoid of any hepatic or renal toxicity. RTN could control the infection and it even had the capacity to counteract the resistant parasite by restoring the ability of host to produce protective immune response and microbicidal NO via up-regulating NF-ĸB and iNOS gene. This finding elucidates RTN to be a strong candidate in the antileishmanial drug pipeline not only against the sensitive but resistant strains also.
PMID: 30245348 [PubMed - indexed for MEDLINE]
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Ectopic intranasal canine tooth in a child: A rare case report and literature review.
Ectopic intranasal canine tooth in a child: A rare case report and literature review.
Int J Surg Case Rep. 2019 Jan 31;55:202-205
Authors: AlMulhim A, AlMomen A, AlKhatib A
Abstract
INTRODUCTION: Intranasal teeth are a rare form of ectopic teeth. Their clinical manifestation are truly variable. In children, intranasal teeth are typically associated with cleft lip and alveolus.
PRESENTATION OF CASE: Here, we report a case of 11 years -old girl presented with right nasal obstruction and occasional headache without any obvious etiology. 0Computed tomography of the paranasal sinuses (coronal and axial view) revealed displaced right upper maxillary tooth with the crown oriented inferiorly and medially toward and within the lower right anterior nasal cavity. She underwent surgery by anterior rhinoscopy and endoscopic guidance. The patient's symptoms were resolved completely post-operatively and remained symptom-free for 18 months postoperatively.
DISCUSSION: Ectopic intranasal tooth is a rare phenomenon, with a male predominance and around half of all patients are diagnosed before adulthood. Ectopic intranasal tooth arising from inferior turbinate is very rare. No clear etiological factor has been suggested in most of the reported cases. Idiopathic etiology has been described as an etiologic factor for ectopic teeth. The treatment of intranasal teeth is early surgical extraction to alleviate the symptoms and prevent the possible morbidities.
CONCLUSION: Intranasal teeth are a rare form of ectopic teeth encountered to otolaryngology clinic and may cause a variety of symptoms and complications. CT is very useful; it confirms the diagnosis and facilitates surgical planning. Early diagnosis and treatment are very important to avoid their possible complications.
PMID: 30769299 [PubMed - as supplied by publisher]
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Unusual combination of elbow dislocation with a retained intraarticular fragment and trochlear fracture and ipsilateral distal radius fracture in an amateur snowboarder: A case report and review of literatures.
Unusual combination of elbow dislocation with a retained intraarticular fragment and trochlear fracture and ipsilateral distal radius fracture in an amateur snowboarder: A case report and review of literatures.
Int J Surg Case Rep. 2019 Feb 01;55:196-201
Authors: Moon DK, Hwang SC, Yoo JI, Park JS
Abstract
INTRODUCTION: The most common damage caused by snowboarding is wrist injury. However, Elbow injuries are relatively rare. In general, elbow dislocation with ipsilateral distal radius fracture is also very rare.
PRESENTATION OF CASE: We present an 18-year-old right hand dominant male with distal radius extra-articular fracture and elbow fracture dislocation. Computed tomographic scan and Magnetic resonance image of elbow joint showed retained intra-articular fragment, trochlear fracture, and the humeral attachment site of lateral collateral ligament (LCL) with rupture. The ruptured LCL was repaired, and then, the distal radius fracture was fixed with a volar distal radius locking plate. At one year after surgery, the patient did not complain of any subjective symptoms or functional deficit.
DISCUSSION: The injury mechanism would fall into the outstretched arm state, leading first to hyperextension of the wrist, resulting in fracture of the distal radius. The remaining force is then applied to the elbow joint by an external rotation and valgus moment arm, resulting in the rupture of the LCL of the elbow joint. In this state, the remaining force is transmitted through the olecranon to the trochlea as a shear force, resulting in osteochondral fracture and subsequent dislocation of the elbow joint.
CONCLUSION: Combined injury of extremity from snowboarding is relatively rare, but we experienced a case of elbow dislocation combined with distal radius fracture caused by fall on outstretched hand on the snow surface during snowboarding in a young adult.
PMID: 30769298 [PubMed - as supplied by publisher]
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Evaluation of the anti-oxidant and anti-inflammatory effects of the methanolic extract of Ferula szowitsiana root on PHA-induced inflammation in human lymphocytes.
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Evaluation of the anti-oxidant and anti-inflammatory effects of the methanolic extract of Ferula szowitsiana root on PHA-induced inflammation in human lymphocytes.
Drug Chem Toxicol. 2019 Feb 14;:1-8
Authors: Askari VR, Baradaran Rahimi V, Assaran A, Iranshahi M, Boskabady MH
Abstract
Inflammation is defined as a defensive response of the body against either the endogenous or exogenous triggers, while this process becomes chronic leading to various disorders such as asthma, cancers, and multiple sclerosis. Recently, pharmacological properties of different constituents of F. szowitsiana have been reported. In the present study, we aimed to evaluate the anti-oxidative and anti-inflammatory effects of the methanolic extract of F. szowitsiana root on human isolated lymphocytes. The effects of either F. szowitsiana (10, 40 and 160 μg/ml) or dexamethasone (0.1 mM) were evaluated on the levels of cell proliferation, reactive oxygen species (ROS), nitric oxide (NO) production, malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) activities, and total glutathione content (GSH) as well as the secretion of inflammatory cytokines [interleukin 6 (IL-6) and tumor necrosis factor (TNF)-α] in the presence or absence of phytohemagglutinin (PHA) stimulation (n = 8 for each group). PHA stimulation notably elevated ROS, NO, MDA, IL-6, and TNF-α levels as well as diminished GSH, CAT and SOD levels. In PHA-stimulated, the results also revealed that F. szowitsiana (10-160 µg/ml) significantly decreased MDA, ROS, NO, IL-6 and TNF-α levels as well as increased CAT, SOD and GSH levels. Collectively, F. szowitsiana is able to attenuate the overproduction of inflammatory and oxidative stress markers in the presence of PHA-stimulated T lymphocytes, while to propagate the anti-oxidative defense. Contextually, the plant has promising healing effects in the different inflammatory disorders associated with the interference of the acquired immune system such as multiple sclerosis and asthma.
PMID: 30764672 [PubMed - as supplied by publisher]
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Current situation and challenges regarding biosimilars in Japan: an example of trastuzumab biosimilars for breast cancer.
Current situation and challenges regarding biosimilars in Japan: an example of trastuzumab biosimilars for breast cancer.
Future Oncol. 2019 Feb 15;:
Authors: Hara F, Tajima K, Tanabe K
Abstract
Biologics have dramatically changed breast cancer treatment, and trastuzumab has been an essential treatment drug for HER2-positive breast cancer. The introduction of trastuzumab biosimilar offers the potential to deliver long-term cost savings plus efficiencies for healthcare systems in Japan. The goal of biosimilar development is to demonstrate comparability to the original biologic with a different development concept from that of the original biologic. Hence, a better understanding of the biosimilar itself is urgently needed for appropriate adoption and the integration of trastuzumab biosimilars into oncology clinical practice by all stakeholders. This article focuses on the current situation of biosimilars and future perspectives in Japan by using the trastuzumab biosimilar as an example.
PMID: 30767568 [PubMed - as supplied by publisher]
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Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial.
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Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial.
Lancet Oncol. 2019 Feb 11;:
Authors: Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G, Campone M, Biganzoli L, Bonnefoi H, Jerusalem G, Bartsch R, Rabaglio-Poretti M, Kammler R, Maibach R, Smyth MJ, Di Leo A, Colleoni M, Viale G, Regan MM, André F, International Breast Cancer Study Group and the Breast International Group
Abstract
BACKGROUND: HER2-positive breast cancers usually contain large amounts of T-cell infiltrate. We hypothesised that trastuzumab resistance in HER2-positive breast cancer could be mediated by immune mechanisms. We assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer.
METHODS: We did this single-arm, multicentre, phase 1b-2 trial in 11 centres based in five countries. Eligible participants were women aged 18 years or older, who had advanced, histologically confirmed, HER2-positive breast cancer; documented progression during previous trastuzumab-based therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a formalin-fixed, paraffin-embedded metastatic tumour biopsy for central assessment of programmed cell death 1 ligand 1 (PD-L1) status. In phase 1b, we enrolled patients with PD-L1-positive tumours in a 3 + 3 dose-escalation of intravenous pembrolizumab (2 mg/kg and 10 mg/kg, every 3 weeks) plus 6 mg/kg of intravenous trastuzumab. The primary endpoint of the phase 1b study was the incidence of dose-limiting toxicity and recommended phase 2 dose; however, a protocol amendment on Aug 28, 2015, stipulated a flat dose of pembrolizumab of 200 mg every 3 weeks in all Merck-sponsored trials. In phase 2, patients with PD-L1-positive and PD-L1-negative tumours were enrolled in parallel cohorts and received the flat dose of pembrolizumab plus standard trastuzumab. The primary endpoint of the phase 2 study was the proportion of PD-L1-positive patients achieving an objective response. This trial is registered in ClinicalTrials.gov, number NCT02129556, and with EudraCT, number 2013-004770-10, and is closed.
FINDINGS: Between Feb 2, 2015, and April 5, 2017, six patients were enrolled in phase 1b (n=3 received 2 mg/kg pembrolizumab, n=3 received 10 mg/kg pembrolizumab) and 52 patients in phase 2 (n=40 had PD-L1-positive tumours, n=12 had PD-L1-negative tumours). The data cutoff for this analysis was Aug 7, 2017. During phase 1b, there were no dose-limiting toxicities in the dose cohorts tested. Median follow-up for the phase 2 cohort was 13·6 months (IQR 11·6-18·4) for patients with PD-L1-positive tumours, and 12·2 months (7·9-12·2) for patients with PD-L1-negative tumours. Six (15%, 90% CI 7-29) of 40 PD-L1-positive patients achieved an objective response. There were no objective responders among the PD-L1-negative patients. The most common treatment-related adverse event of any grade was fatigue (12 [21%] of 58 patients). Grade 3-5 adverse events occurred in 29 (50%) of patients, treatment-related grade 3-5 adverse events occurred in 17 (29%), and serious adverse events occurred in 29 (50%) patients. The most commonly occurring serious adverse events were dyspnoea (n=3 [5%]), pneumonitis (n=3 [5%]), pericardial effusion (n=2 [3%]), and upper respiratory infection (n=2 [3%]). There was one treatment-related death due to Lambert-Eaton syndrome in a PD-L1-negative patient during phase 2.
INTERPRETATION: Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1-positive population and be done in less heavily pretreated patients.
FUNDING: Merck, International Breast Cancer Study Group.
PMID: 30765258 [PubMed - as supplied by publisher]
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Is There a Benefit of HER2-Positive Breast Cancer Subtype Determination in Clinical Practice?
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Is There a Benefit of HER2-Positive Breast Cancer Subtype Determination in Clinical Practice?
Klin Onkol. 2019;32(1):25-30
Authors: Kolářová I, Vaňásek J, Odrážka K, Dušek L, Šinkorová Z, Hlávka A, Štuk J, Stejskal J, Dvořáková D, Sákra L, Mergancová J, Vilasová Z
Abstract
BACKGROUND: Breast cancer (BC) with increased expression of human epidermal growth factor receptor 2 with tyrosine kinase activity (HER2+) is a clinically and bio-logically heterogeneous dis-ease. In terms of gene expression, there are four major molecular subtypes - Luminal A, Luminal B, HER2-enriched (HER2-E), and Basal-like. The most common subtype is HER2-E (50- 60%). In hormone-dependent (HR+) HER2-positive tumors, the subgroup HER2-E represents 40- 50% of cases; others are luminal A and B subtypes.
PURPOSE: The aim of this review is to provide information on the significance of the distribution of HER2-positive tumors accord-ing to subtype, which is considered a predictive parameter for guid-ing treatment decisions. For example, HER2-E subtype is characterized by a higher probability of achiev-ing complete pathological remission when treated with chemother-apy and antiHER2 ther-apy, and it is thought that it could be treated us-ing a dual HER2 blockade without chemother-apy. Currently, triple-positive tumors, a specific subtype of breast cancer characterized by HER2+ and HR+, are more often subjects of interest. Their unique bio-logical properties are due to complex interactions between HER2 and estrogen receptor (ER) signalling, which result in lower effectiveness of endocrine ther-apy in these patients than in HR+ and HER2-negative patients and, at the same time, the ER positivity in HER2+ tumors can result in resistance to antiHER2 ther-apy. This type of BC is a non-homogeneous group where the impacts of HER2 positivity on tumor malignant behavior and activity of the estrogen-driven signal-ing pathway are inconsistent. Current studies focus on test-ing new treatments such as dual HER2 block-ing or immunother-apy, in combination with antiHER2 targeted ther-apy with fulvestrant, aromatase inhibitors, cyclin dependent kinase 4/ 6 inhibitors, or inhibitors of the PI3K (phosphatidylinositol-3-kinase) pathway.
CONCLUSION: The distribution of HER2+ BC accord-ing to individual subtype provides information that can contribute to achiev-ing more accurate decisions about the most appropriate ther-apy. Key words breast cancer - subtype - HER2 - trastuzumab - HER2 positive - triple positive - HER2 enriched The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 27. 9. 2018 Accepted: 26. 11. 2018.
PMID: 30764626 [PubMed - in process]
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A systematic review of clinical outcomes and radiotherapy-associated toxicity in multicatheter accelerated partial breast irradiation.
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A systematic review of clinical outcomes and radiotherapy-associated toxicity in multicatheter accelerated partial breast irradiation.
Medicine (Baltimore). 2019 Feb;98(6):e14407
Authors: Lv Y, He L, Wang C, Zhang L, Zhang B, Song Y
Abstract
BACKGROUND: To integrate relevant clinical data of multicatheter accelerated partial breast irradiation (mAPBI) for reaching a comprehensive conclusion.
METHODS: We did 3 meta-analyses for clinical outcomes including 1740 women from 4 articles, for acute radiotherapy (RT)-associated toxicity including 1255 patients from 5 articles, and for late RT-related toxicity involving 1565 patients from 9 papers. Clinical outcomes analyses were stratified by molecular subtypes, lymph nodes status, receptor status, and human epidermal growth factor receptor 2 (HER2) status.
RESULTS: For the Luminal A/B phenotypes, the disease relapse and failure in survival significantly decreased when compared with triple negative (TN)/HER2-amplified subtypes (P < .00001). The 5-year regional nodal recurrence (RNR), 5-year distant metastasis-free survival (DMFS) and 5-year disease free-survival (DFS) of TN patients were significantly superior to HER2-overexpression patients (P < .00001). The 5-year cause-specific survival (CSS), 5-year DMFS and 5-year overall survival (OS) in women with lymph nodes-negative were significantly improved versus patients with lymph nodes-positive (P = .0001). Conversely, the positive status of HER2 compared with negative one significantly increased the rate of local recurrence (LR) (P = .02). For acute toxicity, the morbidity of dermatitis was significantly higher than hematoma and implant infection (P = .01, P < .0001, respectively). For late toxicity, the occurrences of fibrosis (32%) and telangiectasia (14%) were significantly higher than other complications (P < .0001).
CONCLUSION: HER2-enriched subtype compared with other subtypes has significantly increased disease relapse and failure in survival. HER2-positive status is positively associated with an increased incidence of LR. Dermatitis is the most common acute RT-related toxicity and fibrosis is the first rife late RT-related toxicity.
PMID: 30732191 [PubMed - indexed for MEDLINE]
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Investigating the Nasal Cycle Using Unilateral Peak Nasal Inspiratory Flow and Acoustic Rhinometry Minimal Cross‐Sectional Area Measurements
Abstract
Objective
To plot the nasal cycle using unilateral peak nasal inspiratory flow (UPNIF) and unilateral minimal cross‐sectional area (UMCA) readings demonstrating a linear relationship in normal nasal function. Additionally, to determine how this changes in abnormal nasal function.
Design
A cross‐sectional study measuring UPNIF and UMCA in controls demonstrating normal nasal function and in patients with nasal obstruction.
Setting
Royal National Throat Nose and Ear Hospital, London.
Participants
39 participants, 26 controls and 13 patients, were recruited. Controls exhibited normal nasal function with SNOT‐22 <5. Patients nasal obstruction symptoms secondary to inflammation or structural abnormality with SNOT‐22 >9.
Main Outcome Measures and Results
Airflow rates and resistance values were derived from UPNIF and UMCA measurements respectively based on Poiseuille's laws. Ratios between right and left UPNIF and UMCA values were taken to adjust for confounding factors. The relationship of 1/Resistance Ratio and Airflow Rate Ratio demonstrated a linear of direct proportionality of strong correlation and statistical significance (correlation coefficient =0.76, p<<0.01). This suggests that data points from controls with a normal nasal cycle lie closely along the regressed line, while those lying significantly away were shown to belong to patients with nasal dysfunction. Olfactory dysfunction appears to be a sensitive discriminator in predicting this.
Conclusion
This study demonstrates the directly proportional relationship of 1/Resistance Ratio and Airflow Rate Ratio in normal nasal function. Furthermore, nasal pathology can be predicted if data points lie significantly outside these normal limits. Further studies are needed to validate exact normal and abnormal thresholds.
This article is protected by copyright. All rights reserved.
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Neuro-Oncology Diet and risk of glioma
| Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool Abstract Background Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985–2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors.Methods A multi-institutional retrospective institutional review board–approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively.Results The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0–1.0, 1.5–2.0, 2.5–3, and 3.5–4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively.Conclusion The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.
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| Highlights from the Literature |
| Forthcoming Meetings Edited by Albert H. Kim and Jennie W. Taylor |
| Glioblastoma: a prognostic value of AMT-PET? See the article by John et al, pp. 264–273. |
| Old meet new—the path to combination treatments in pediatric low-grade gliomas See the article by Poore et al, pp. 252–263. |
| Disparities along the glioblastoma clinical trials landscape We read with interest the recent work by Vanderbeek et al1 regarding the current clinical trials landscape for glioblastoma (GBM) patients. An unexplored dimension of their analysis centers on disparities and demographic discrepancies between clinical trial participants and the broader GBM population. We therefore examined clinical trials with published results as highlighted by the authors, totaling 51 trials.1 While most of these trials reported details regarding patient age (48/51, 94%) and gender (47/51, 92%), only 14 trials (27%) provided information regarding ethnicity and/or race in either peer-reviewed publications or ClinicalTrials.gov. The rate of reporting ethnicity/race was particularly low among phase I/II studies (9/43, 21%) compared with phase III trials (5/8, 63%, chi-squared test P = 0.02). |
| Multimodal imaging-defined subregions in newly diagnosed glioblastoma: impact on overall survival Abstract Background Although glioblastomas are heterogeneous brain-infiltrating tumors, their treatment is mostly focused on the contrast-enhancing tumor mass. In this study, we combined conventional MRI, diffusion-weighted imaging (DWI), and amino acid PET to explore imaging-defined glioblastoma subregions and evaluate their potential prognostic value.Methods Contrast-enhanced T1, T2/fluid attenuated inversion recovery (FLAIR) MR images, apparent diffusion coefficient (ADC) maps from DWI, and alpha-[11C]-methyl-L-tryptophan (AMT)-PET images were analyzed in 30 patients with newly diagnosed glioblastoma. Five tumor subregions were identified based on a combination of MRI contrast enhancement, T2/FLAIR signal abnormalities, and AMT uptake on PET. ADC and AMT uptake tumor/contralateral normal cortex (T/N) ratios in these tumor subregions were correlated, and their prognostic value was determined.Results A total of 115 MRI/PET-defined subregions were analyzed. Most tumors showed not only a high-AMT uptake (T/N ratio > 1.65, N = 27) but also a low-uptake subregion (N = 21) within the contrast-enhancing tumor mass. High AMT uptake extending beyond contrast enhancement was also common (N = 25) and was associated with low ADC (r = −0.40, P = 0.05). Higher AMT uptake in the contrast-enhancing tumor subregions was strongly prognostic for overall survival (hazard ratio: 7.83; 95% CI: 1.98–31.02, P = 0.003), independent of clinical and molecular genetic prognostic variables. Nonresected high-AMT uptake subregions predicted the sites of tumor progression on posttreatment PET performed in 10 patients.Conclusions Glioblastomas show heterogeneous amino acid uptake with high-uptake regions often extending into non-enhancing brain with high cellularity; nonresection of these predict the site of posttreatment progression. High tryptophan uptake values in MRI contrast-enhancing tumor subregions are a strong, independent imaging marker for longer overall survival. |
| Supratotal resection in glioma: a systematic review Abstract Background Emerging evidence suggests survival benefit from resection beyond all MRI abnormalities present on T1-enhanced and T2‒fluid attenuated inversion recovery (FLAIR) modalities in glioma (supratotal resection); however, the quality of evidence is unclear. We addressed this question via systematic review of the literature.Methods EMBASE, MEDLINE, Scopus, and Web of Science databases were queried. Case studies, reviews or editorials, non-English, abstract-only, brain metastases, and descriptive works were excluded. All others were included.Results Three hundred and nine unique references yielded 41 studies for full-text review, with 7 included in the final analysis. Studies were mostly of Oxford Center for Evidence-Based Medicine Level 4 quality. A total of 88 patients underwent supratotal resection in a combined cohort of 492 patients (214 males and 278 females, age 18 to 82 years). Fifty-one supratotal resections were conducted on high-grade gliomas, and 37 on low-grade gliomas. Karnofsky performance status, overall survival, progression-free survival, neurological deficits postoperatively, and anaplastic transformation were the main measured outcomes. No randomized controlled trials were identified. Preliminary low-quality support was found for supratotal resection in increasing overall survival and progression-free survival for both low-grade and high-grade glioma.Conclusion The literature suggests insufficient evidence for carte blanche application of supratotal resection, particularly in lower-grade gliomas where neurological deficits can result in long-term disability. While the preliminary studies discussed here, containing data from only a few centers, have reported increased progression-free and overall survival, these claims require validation in prospective research studies involving larger patient populations with clearly defined appropriate outcome metrics in order to reduce potential bias. |
| Uncommon low-grade brain tumors Abstract The 2016 World Health Organization (WHO) classification of primary central nervous system (CNS) tumors includes numerous uncommon (representing ≤1% of tumors) low-grade (grades I–II) brain neoplasms with varying clinical behaviors and outcomes. Generally, gross tumor or maximal safe resection is the primary treatment. Adjuvant treatments, though their exact role is unknown, may be considered individually based on pathological subtypes and a proper assessment of risks and benefits. Targetable mutations such as BRAF (proto-oncogene B-Raf), TRAIL (tumor necrosis factor apoptosis inducing ligand), and PDGFR (platelet derived growth factor receptor) have promising roles in future management. |
| Outcomes following stereotactic radiosurgery for small to medium-sized brain metastases are exceptionally dependent upon tumor size and prescribed dose Abstract Background At our institution, we have historically treated brain metastasis (BM) ≤2 cm in eloquent brain with a radiosurgery (SRS) lower prescription dose (PD) to reduce the risk of radionecrosis (RN). We sought to evaluate the impact of this practice on outcomes.Methods We analyzed a prospective registry of BM patients treated with SRS between 2008 and 2017. Incidences of local failure (LF) and RN were determined and Cox regression was performed for univariate and multivariate analyses (MVAs).Results We evaluated 1533 BM ≤2 cm. Median radiographic follow-up post SRS was 12.7 months (1.4–100). Overall, the 2-year incidence of LF was lower for BM treated with PD ≥21 Gy (9.3%) compared with PD ≤15 Gy (19.5%) (sub–hazard ratio, 2.3; 95% CI: 1.4–3.7; P = 0.0006). The 2-year incidence of RN was not significantly higher for the group treated with PD ≥21 Gy (9.5%) compared with the PD ≤15 Gy group (7.5%) (P = 0.16). MVA demonstrated that PD (≤15 Gy) and tumor size (>1 cm) were significantly correlated (P < 0.05) with higher rates of LF and RN, respectively. For tumors ≤1 cm, when comparing PD ≤15 Gy with ≥21 Gy, the risks of LF and RN are equivalent. However, for lesions >1 cm, PD ≥21 Gy is associated with a lower incidence of LF without significantly increasing the risk of RN.Conclusion Our results indicate that rates of LF or RN following SRS for BM are strongly correlated with size and PD. Based on our results, we now, depending upon the clinical context, consider increasing PD to 21 Gy for BM in eloquent brain, excluding the brainstem. |
| Sex difference of mutation clonality in diffuse glioma evolution Abstract Background Sex differences in glioma incidence and outcome have been previously reported but remain poorly understood. Many sex differences that affect the cancer risk were thought to be associated with cancer evolution.Methods In this study, we used an integrated framework to infer the timing and clonal status of mutations in ~600 diffuse gliomas from The Cancer Genome Atlas (TCGA) including glioblastomas (GBMs) and low-grade gliomas (LGGs), and investigated the sex difference of mutation clonality.Results We observed higher overall and subclonal mutation burden in female patients with different grades of gliomas, which could be largely explained by the mutations of the X chromosome. Some well-established drivers were identified showing sex-biased clonality, such as CDH18 and ATRX. Focusing on glioma subtypes, we further found a higher subclonal mutation burden in females than males in the majority of glioma subtypes, and observed opposite clonal tendency of several drivers between male and female patients in a specific subtype. Moreover, analysis of clinically actionable genes revealed that mutations in genes of the mitogen-activated protein kinase (MAPK) signaling pathway were more likely to be clonal in female patients with GBM, whereas mutations in genes involved in the receptor tyrosine kinase signaling pathway were more likely to be clonal in male patients with LGG.Conclusions The patients with diffuse glioma showed sex-biased mutation clonality (eg, different subclonal mutation number and different clonal tendency of cancer genes), highlighting the need to consider sex as an important variable for improving glioma therapy and clinical care. |
Susceptibility to Oral Antiseptics and Virulence Factors Ex Vivo Associated with Candida spp. Isolated from Dental Prostheses
Abstract
Purpose
To isolate Candida spp. from dental prosthesis users' saliva and to evaluate the isolates for the presence of several virulence factors. This research also aimed to investigate the antifungal activity of 3 commercial mouthwashes/oral antiseptic formulations containing 0.12% chlorhexidine, 0.07% cetylpyridinium, or 0.075% cetylpyridinium against planktonic and sessile (biofilm mode) yeast cells.
Materials and Methods
Forty‐three Candida yeasts were isolated from 32 of 70 selected patients, and the virulence factors of C. albicans, C. krusei, C. glabrata, C. tropicalis, and C. parapsilosis species were investigated by the polymerase chain reaction (PCR) and proteinase in plates. Minimum inhibitory concentration (MIC), and in vitro biofilm assay evaluated the antifungal activity of antiseptics.
Results
C. albicans, C. krusei, C. glabrata, C. tropicalis, and C. parapsilosis were detected in mono and mixed cultures. Only C. albicans displayed genes related to adhesion and proteinases (ALS2, ALS3, SAP1, and SAP3). The aspartate proteinase activity was found in 60.46% of isolates. The tested antiseptic formulations exhibited a MIC less than 1.25% toward yeasts in the planktonic mode. According to XTT ((2,3‐bis(2‐methoxy‐4‐nitro‐5‐sulfophenyl)‐2H‐tetrazolium‐5‐carboxanilide) assay results, most Candida isolates and all mixed cultures formed biofilms within 24 hours. The evaluated antiseptic formulations were also active against biofilms.
Conclusion
Most virulence factors investigated here (ALS2, ALS3, SAP1, and SAP3) occurred in the majority of the Candida spp. isolates, especially in C. albicans. The tested mouthwash formulations were effective against all the yeast isolates in both the planktonic and sessile growth modes. Developing alternative therapies that can avoid or control biofilm formation is necessary to prevent oral candidiasis and other Candida spp. infections.
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