Clinical Oral Investigations

Correction to: Sinus augmentation analysis of the gradient of graft consolidation: a split-mouth histomorphometric study Figure 1 was reused with permission from "Wiley", the publisher of a previous article by the same authors, DOI:10.1111/cid.12518.

Correction to: The fate of root canals obturated with Thermafil: 10-year data for patients treated in a master's program The author names in the original version of this article were inadvertently interchange. Correct presentation of author names is reflected here.

Systemic administration of curcumin or piperine enhances the periodontal repair: a preliminary study in rats Abstract Objectives Studies have documented the anti-inflammatory effects of spices, which may be related to treatment of chronic diseases. The purpose of this study was to evaluate the influence of curcumin and piperine and their association on experimental periodontal repair in rats. Materials and methods Periodontitis was induced via the installation of a ligature around the first molar. After 15 days, the ligatures were removed, and the rats were separated into groups (12 animals per group): (i) curcumin, (ii) piperine, (iii) curcumin+piperine, (iv) corn oil vehicle, and (v) control group (animals had ligature-induced periodontitis but were not treated). The compounds were administered daily, for 15 days by oral gavage. Animals were euthanized at 5 and 15 days, and hemimaxillae and gingival tissues were harvested. Bone repair was assessed by μCT (microcomputer tomography). Histological sections were stained with hematoxylin/eosin (H/E) for the assessment of cellular infiltrate or picrosirius red for quantification of collagen content, and subjected to immunohistochemistry for detecting NF-ĸB. Gingival tissues were used to evaluate levels of TGF-β and IL-10 (ELISA). Results Curcumin and piperine increased the TGF-β level, significantly improved the collagen repair, and decreased the cellularity and activation of NF-ĸB in the periodontal tissues, but only curcumin caused a significant increase in early bone repair. Conclusion Curcumin and piperine promoted a substantive effect on tissue repair; however, there was not synergistic effect of compounds administered in combination. Clinical relevance Curcumin and piperine stimulates the tissue repair and may be potential candidates for the treatment of periodontal disease.

Sinus augmentation analysis of the gradient of graft consolidation: a split-mouth histomorphometric study Abstract Objective The aim of this study was to histomorphometrically test the hypothesis that graft consolidation originates from the sinus floor. Materials and methods This prospective, randomized split-mouth study investigated patients undergoing bilateral maxillary lateral sinus floor augmentation using either freeze-dried bone allografts (FDBAs) or biphasic calcium phosphate (BCP) bone substitute. Apico-coronal core biopsies were harvested during implant placement 9 months after sinus floor augmentation, processed for histological observation, and measured histomorphometrically. Results Biopsies were taken from 26 bilateral sites in 13 patients. The density of new bone (NB) decreased with increasing distance from the sinus floor. The percentage mean surface of NB ranged from 31 ± 9.5% at 2 mm from the sinus floor (G1) to 27.7 ± 11.2% at 4 mm (G2) for the FDBA specimens and from 30.0 ± 11.0% at G1 to 23.5 ± 9.9% at G2 for the BCP specimens. Evaluation of the residual graft particle (GP) area alone as a function of distance from the floor revealed a clear inverse gradient of 7.1 ± 6.6 to 9.1 ± 10.3 between G1 and G2 for the FDBA allografts, with the same tendency for the BCP alloplasts (21.9 ± 9.9 to 27.7 ± 6.6, respectively). Conclusion Our results support the concept that osteogenesis initiates in regions proximal to the bony walls of the maxillary sinus and may be enhanced by them. Clinical relevance The nature of the grafting material had a greater influence on the degree of NB formation in regions distant from the native walls where there is reduced inherent osteogenic potential.

Should we fear direct oral anticoagulants more than vitamin K antagonists in simple single tooth extraction? A prospective comparative study Abstract Objectives The aim of this prospective comparative clinical study was to evaluate the effect of oral anticoagulants on peri- and post-operative bleeding during simple single tooth extractions, comparing patients in treatment with vitamin K antagonists (VKAs) and patients assuming direct oral anticoagulants (DOACs). Materials and methods Patients under oral anticoagulant therapy needing dental extraction were eligible for entering the study; patients were enrolled following inclusion and exclusion criteria and divided into VKAs and DOAC group according to the anticoagulation therapy. Included patients underwent a simple single dental extraction with elevators and forceps with a maximum surgical time of 15 minutes, without anticoagulation therapy discontinuation. All participants were assessed pre-operatively, during surgery, 30 min minutes and 7 days after surgery. Biological complications were registered and post-extraction bleeding was clinically defined according to Iwabuchi classification. Parametric and non-parametric tests were used to evaluate the variables between the groups. Results Sixty-five patients per group were enrolled and 130 teeth were extracted. The two groups were comparable for pre-, peri-, and post-operative variables. Only 1 patient of DOAC group and 2 patients for VKA group needed medical evaluation for post-extractive bleeding. No statistically significant difference resulted in post-operative bleeding events between the groups (p = 0.425). Conclusions DOAC and VKA patients showed the same incidence of bleeding complications after simple single tooth extraction. Bleeding events were not statistically significant and not clinically relevant. Clinical relevance Patients assuming DOACs can be treated similarly to patients in VKAs therapy with INR index between 2 and 3. Non-ceasing of DOAC therapy seems to be appropriate for simple single dental extractions.

Comparative study of articaine and lidocaine without palatal injection for maxillary teeth extraction Abstract Objectives There is significant evidence that articaine and lidocaine buccal injections alone are sufficient for painless extraction of maxillary teeth. The aim of this study was to evaluate the extraction of permanent maxillary teeth and to compare pain control between articaine and lidocaine without palatal injection. Materials and methods Group A received buccal and palatal injections of 2% lidocaine with 0.015 mg/ml epinephrine. Group B received only buccal local anesthetic injection of 2% lidocaine with 0.015 mg/ml epinephrine. Group C received only buccal injection of 4% articaine with 0.012 mg/ml epinephrine. The patients' perception of pain was assessed using visual analogue scale and verbal response scale after the injection and the extraction. Results Statistical analysis showed that the difference in pain perception of local anesthetic injection was statistically significant between groups A and B and between groups A and C (p < 0.05). Conclusion The extraction of permanent maxillary teeth is possible without palatal injections and there is no difference between articaine and lidocaine. Clinical relevance Local anesthetic agents are the most frequently administered drugs in dentistry and represent the primary method of pain control for patients undergoing intraoral procedures.

Chemical analysis of in vivo –irradiated dentine of head and neck cancer patients by ATR-FTIR and Raman spectroscopy Abstract Objectives To evaluate the effect of in vivo radiotherapy on the chemical properties of human dentine by Fourier-transform infrared spectroscopy (FTIR) and Raman analysis. Materials and methods Chemical composition was evaluated comparing control and irradiated group (n = 8). Irradiated teeth were obtained from radiotherapy patients subjected to fractionated X-ray radiation of 1.8 Gy daily totaling 72 Gy. The teeth were sectioned according to the type of dentine (crown or root dentine), obtaining 3-mm dentine cervical slices. The analyzed parameters by FTIR and Raman spectroscopies were mineral/matrix ratio (M:M), carbonate/mineral ratio (C:M), amide I/amide III ratio, and amide I/CH2 ratio. Raman also calculated the phosphate and carbonate crystallinity. Results FTIR revealed that M:M had a decrease in both factors (p = 0.008; p = 0.043, respectively) and root dentine showed a lower C:M in the irradiated group (p = 0.003). Raman revealed a higher phosphate crystallinity and a lower carbonate crystallinity in crown dentine of irradiated group (p = 0.021; p = 0.039). For amide I/amide III, the irradiated showed a lower ratio when compared to the control group (FTIR p = 0.002; Raman p = 0.017). For amide I/CH2, the root dentine showed a higher ratio than the crown dentine in both methods (p < 0.001). Conclusions Radiotherapy altered the chemical composition of human dentine. The exchange of phosphate-carbonate ions in the hydroxyapatite and higher concentration of organic components was found after radiotherapy. Clinical relevance The increased risk of radiation-related caries in patients undergoing head and neck radiotherapy is due not only to salivary, dietary, and microbiological changes but also to changes in tooth chemical composition.

Antimicrobial photodynamic therapy as adjunct to non-surgical periodontal treatment in smokers: a randomized clinical trial Abstract Objectives This study aims to investigate the additional influence of multiple applications of antimicrobial photodynamic therapy (aPDT) in smokers with chronic periodontitis. Materials and methods Twenty smokers with chronic periodontitis were treated in a split-mouth design study with aPDT adjunct to Scaling and Root Planing (SRP) or SRP. aPDT was performed by using a laser light source with 660 nm wavelength associated with a photosensitizer. The applications were performed in four episodes (at days 0, 2, 7, and 14). All patients were monitored for 90 days. Plaque index, probing depth, clinical attachment level, and bleeding on probing were performed at baseline, 30, and 90 days after the SRP. Gingival crevicular fluid and subgingival plaque samples were collected for immunological and microbiological analysis, respectively. Data obtained were statistically analyzed. Results aPDT as an adjunct to SRP did not demonstrate statistically significant advantages on clinical parameters when compared with SRP alone. No statistic significant differences between groups were observed (p < 0.05). Levels of anti-inflammatory cytokines and bacterial species were comparable in both groups at day 90 after treatment. Conclusion Periodontal treatment with SRP + aPDT in multiples episodes was not able to promote additional clinical, immunological, and microbiological benefits in smokers when compared SRP alone in patients with chronic periodontitis. Clinical relevance Multiple episodes of aPDT adjunctive to non-surgical treatment did not improve significantly the clinical, immunological, and microbiological parameters when compared with SRP alone. More randomized clinical trials are needed to evaluate adjuvant therapies for scaling and root planning in smokers with chronic periodontitis. ClinicalTrials.gov Identifier: NCT03039244

The improvement of biocompatibility of adhesives Abstract Objective The aim of this in vitro study is to evaluate the effects of resveratrol (RES) addition on the cytotoxicity and microtensile bond strength (μTBS) of different adhesives. Materials and methods Five self-etching adhesives (G-aenial Bond-GC, Optibond All in One-Kerr, Gluma Self Etch-Kulzer, Clearfil S3 Bond-Kuraray, and Nova Compo-B Plus-Imicryl) were tested. They were applied to L-929 cell culture by the extract method. In the test groups, 0.5 μM RES (Sigma-Aldrich) was added into the medium. Cell viability was assessed by MTT assay after 24 h. Human extracted third molars were used for μTBS test (n = 7). The adhesives with or without 0.5 μM RES addition were applied on dentin surfaces. A composite build-up was constructed. Then, the specimens were sectioned into multiple beams with the non-trimming version of the microtensile test and subjected to microtensile forces. Statistical analysis was performed using ANOVA and post hoc Tukey test (p ˂ 0.05). Results The extracts of all adhesives decreased the cell viability. However, RES addition increased the cell viability in all groups (p ˂ 0.05). RES addition did not cause any decrease in μTBS values of the adhesives compared to baseline. Optibond All in One showed the highest μTBS after RES addition. It was followed by Clerafil S3 Bond and Nova Compo-B Plus. No difference was determined between the Optibond All in One and Clearfil S3 Bond. There was difference between Optibond All in One and Nova Compo-B Plus (p ˂ 0.05). Conclusion RES addition may improve the biocompatibility without causing negative influence on μTBS of the adhesives. Clinical relevance RES addition has clinical applicable potential to overcome the adverse biocompatibility of adhesives.

Expression of growth mediators in the gingival crevicular fluid of patients with aggressive periodontitis undergoing periodontal surgery Abstract Objectives To describe changes in growth factor mediators in the gingival crevicular fluid (GCF) of patients with aggressive periodontitis (AgP) undergoing regenerative (GTR) and access flap (AF) surgery. Materials and methods This was a 12-month, single-blind, split-mouth RCT involving 18 AgP patients with a bilateral intrabony defect which was treated with GTR or AF. GCF was collected prior to surgery and at subsequent follow-up visits from 3 days to 12 months post-operatively, and the levels of angiopoietin-1 (Ang-1), vascular-endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), bone morphogenetic protein-2 (BMP-2), osteoprotegerin (OPG), tissue inhibitor of metalloproteinase 1 (TIMP-1), keratinocyte growth factor (KGF) and platelet-derived growth factor-AB (PDGF-AB) were measured. At baseline, 6 and 12 months post-surgery, periodontal clinical parameters were evaluated. ANOVA was applied to test for differences in the amount of mediators (p < 0.05). Results Higher amounts of BMP-2 and OPG and a higher area under the curve (AUC) of KGF at the GTR versus AF sites were observed. The maximum change in the amount of KGF correlated significantly with periodontal clinical parameters at the GTR sites at 6 and 12 months. The AUC over 30 days of the amount of Ang-1, VEGF and KGF significantly correlated with periodontal clinical parameters at the AF sites at 6 months. Conclusions AF and GTR differentially affected the profile of the growth mediators in GCF, and significant correlations between certain GCF mediators and periodontal clinical outcomes were identified. Clinical relevance GCF components represent attractive prognostic markers for periodontal tissues undergoing repair or regeneration. However, the available evidence is not robust enough to suggest the use of a specific marker, and future adequately powered studies are warranted to identify the most relevant mediators that could be applied in clinical practice.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Cardiovascular Translational Research

Application of Proteomics Profiling for Biomarker Discovery in Hypertrophic Cardiomyopathy Abstract High-throughput proteomics profiling has never been applied to discover biomarkers in patients with hypertrophic cardiomyopathy (HCM). The objective was to identify plasma protein biomarkers that can distinguish HCM from controls. We performed a case-control study of patients with HCM (n = 15) and controls (n = 22). We carried out plasma proteomics profiling of 1129 proteins using the SOMAscan assay. We used the sparse partial least squares discriminant analysis to identify 50 most discriminant proteins. We also determined the area under the curve (AUC) of the receiver operating characteristic curve using the Monte Carlo cross validation with balanced subsampling. The average AUC was 0.94 (95% confidence interval, 0.82–1.00) and the discriminative accuracy was 89%. In HCM, 13 out of the 50 proteins correlated with troponin I and 12 with New York Heart Association class. Proteomics profiling can be used to elucidate protein biomarkers that distinguish HCM from controls.

Changes in Citric Acid Cycle and Nucleoside Metabolism Are Associated with Anthracycline Cardiotoxicity in Patients with Breast Cancer Abstract Anthracyclines and HER2-targeted antibodies are very effective for the treatment of breast cancer, but their use is limited by cardiotoxicity. In this nested case-control study, we assessed the role of intermediary metabolism in 38 women with breast cancer treated with anthracyclines and trastuzumab. Using targeted mass spectrometry to measure 71 metabolites in the plasma, we identified changes in citric acid and aconitic acid that differentiated patients who developed cardiotoxicity from those who did not. In patients with cardiotoxicity, the magnitude of change in citric acid at three months correlated with the change in left ventricular ejection fraction (LVEF) and absolute LVEF at nine months. Patients with cardiotoxicity also demonstrated more pronounced changes in purine and pyrimidine metabolism. Early metabolic changes may therefore provide insight into the mechanisms associated with the development of chemotherapy-associated cardiotoxicity.

The Influence of Sex on Cardiac Physiology and Cardiovascular Diseases Abstract Cardiovascular disease (CVD) is the leading cause of death world-wide. Most of treatment strategies were based on studies conducted on male patients. Studies have shown that significant differences exist between the two sexes in the development of CVD. There are certain differences between men and women in the structure and physiological functions of the heart such as left ventricular mass index, resting heart rate, and contractile function. Accordingly, the pathological features of the heart such as the extend of hypertrophy, fibrosis, and remodeling are also different. In addition, different genders also affect clinical symptoms, responses to treatment and prognosis in the development of CVD. Therefore, it is important to take these differences into consideration when design treatment options for men and women.

Prevalence of Cardiac Amyloidosis in Patients with Carpal Tunnel Syndrome Abstract Carpal tunnel syndrome (CTS) is a common finding among patients with cardiac amyloidosis. We sought to determine the prevalence of cardiac amyloidosis in patients who had undergone CTS surgery. From 2005 to 2014, 308 patients ≥ 60 years underwent CTS surgery. Of these, 233 (76%) agreed to participate in the study and 101 (73 ± 8 years; 68% females) showed left ventricular hypertrophy (LVH) ≥ 12 mm and underwent additional studies to diagnose AL and ATTR amyloidosis. Based on complementary studies, three patients were diagnosed with cardiac amyloidosis (two wild-type ATTR and one AL). The three patients showed bilateral CTS with no occupational risk factors. Prevalence of cardiac amyloidosis in the overall cohort was only 1.2% (3/233), but among patients with LVH and bilateral CTS, the prevalence was 5.5% (3/55) and 13.6% (3/22) if cases with an occupational risk factor were excluded. Cardiac amyloidosis should be excluded in the presence of bilateral CTS and particularly if an occupational risk factor is absent.

Exercise Attenuates Acute β-Adrenergic Overactivation – Induced Cardiac Fibrosis by Modulating Cytokines Abstract During acute sympathetic stress, the overactivation of β-adrenergic receptors (β-ARs) causes cardiac fibrosis by triggering inflammation and cytokine expression. It is unknown whether exercise training inhibits acute β-AR overactivation–induced cytokine expression and cardiac injury. Here, we report that running exercise inhibited cardiac fibrosis and improved cardiac function in mice treated with isoproterenol (ISO), a β-AR agonist. A cytokine antibody array revealed that running exercise prevented most of the changes in cytokine expression induced by ISO. Specifically, ISO-induced upregulation of 18 cytokines was prevented by running exercise. A Kyoto encyclopedia of genes and genomes analysis of these cytokines revealed that Hedgehog and RAP1 signaling pathways were involved in the regulation of cytokine expression by exercise. The changes in the expression of some cytokines that were prevented by exercise were verified by an enzyme-linked immunosorbent assay and real-time PCR. In conclusion, running exercise prevented the cytokine expression changes after acute β-AR overactivation and therefore attenuated cardiac fibrosis. Acute sympathetic stress is an important risk factor for the patients with cardiovascular diseases, and the present study revealed that exercise training can prevent against the upregulation of cytokines and the subsequent cardiac injury induced by acute sympathetic stress, suggesting that exercise training may be beneficial for cardiovascular patients who are in risk of acute sympathetic stress. This finding provides a theoretical basis for the application of exercise training in patients who may suffer from acute sympathetic stress.

Interleukin-1 Receptor-Like 1 (IL1R1) Levels Are Not Increased in Healthy Centenarians

Bioresorbable Scaffold-Based Controlled Drug Delivery for Restenosis Abstract Bioresorbable scaffolds have emerged as a potential alternative to non-erodible metal implants to alleviate the long-term risk of permanent device vascular implant-related adverse events. Bioresorbable scaffolds provide a temporary mechanical support function until the vessel reaches complete healing, and the implant progressively disappears and vasomotion resumes. A polymer matrix with embedded drugs coated onto the scaffold surface degrades slowly, reducing the size from the exterior toward the interior, and this allows controlled drug release to a local vascular segment. Drug elution from a bioresorbable scaffold system is characterized by a rapid initial release that achieves high concentration along the intimal surface, which is designed to prevail vascular dilation-induced injury and formation of neointimal hyperplasia. This review highlights diverse types of bioresorbable biomaterials as vascular scaffolds, drug release kinetics, adaptive arterial wall remodeling, and complexities in the advancement of vascular scaffolds to treat restenosis.

Splanchnic Circulation and Intraabdominal Metabolism in Two Porcine Models of Low Cardiac Output Abstract The impact of acute cardiac dysfunction on the gastrointestinal tract was investigated in anesthetized and instrumented pigs by sequential reductions of cardiac output (CO). Using a cardiac tamponade (n = 6) or partial inferior caval vein balloon inflation (n = 6), CO was controllably reduced for 1 h each to 75% (CO75%), 50% (CO50%), and 35% (CO35%) of the baseline value. Cardiac output in controls (n = 6) was not manipulated and maintained. Mean arterial pressure, superior mesenteric arterial blood flow, and intestinal mucosal perfusion started to decrease at CO50% in the intervention groups. The decrease in superior mesenteric arterial blood flow was non-linear and exaggerated at CO35%. Systemic, venous mesenteric, and intraperitoneal lactate concentrations increased in the intervention groups from CO50%. Global and mesenteric oxygen uptake decreased at CO35%. In conclusion, gastrointestinal metabolism became increasingly anaerobic when CO was reduced by 50%. Anaerobic gastrointestinal metabolism in low CO can be detected using intraperitoneal microdialysis.

Advance for Cardiovascular Health in China Abstract As the most populous country worldwide, China has ≈ 290 million patients with cardiovascular diseases (CVDs), representing the leading cause of death in Chinese population. The morbidity and mortality of CVDs are continuously rising. Here, we will first summarize the recent advance in the management of CVDs such as coronary arterial disease, arrhythmia, and heart failure in China. In particular, we will introduce the development of chest pain centers and indicate the novel techniques and methods applied for the management of CVDs. Then, we will discuss and point out the importance of improving the clinical and basic research for Traditional Chinese medicine in the treatment of CVDs. Finally, we will emphasize the efforts made to promote cardiac rehabilitation and cardiovascular prevention system in China. We are striving to establish a practical prevention-treatment-rehabilitation system and looking forward to a bright future with reduced morbidity and mortality from CVDs in China.

Release of Mitochondrial and Nuclear DNA During On-Pump Heart Surgery: Kinetics and Relation to Extracellular Vesicles Abstract During heart surgery with cardiopulmonary bypass (CPB), the release of mitochondrial (mtDNA) and nuclear DNA (nDNA) and their association to extracellular vesicles were investigated. In patients undergoing elective coronary artery bypass grafting (CABG, n = 12), blood was sampled before, during, and after surgery from peripheral artery, pulmonary artery, and the coronary sinus. Plasma was separated in three fractions: microvesicles, exosomes, and supernatant. mtDNA and nDNA were measured by qPCR. mtDNA and nDNA levels increased after start of surgery, but before CPB, and increased further during CPB. mtDNA copy number was about 1000-fold higher than nDNA. mtDNA was predominantly localized to the vesicular fractions in plasma, whereas nDNA was predominantly in the supernatant. The amount of free mtDNA increased after surgery. There was no net release or disappearance of DNAs across the pulmonary, systemic, or coronary circulation. Extracellular DNAs, in particular mtDNA, may be important contributors to the whole-body inflammation during CPB.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Clinical & Experimental Metastasis

Diagnostics of metastasis: an increasing challenge with high clinical importance

Histopathological growth patterns of colorectal liver metastasis exhibit little heterogeneity and can be determined with a high diagnostic accuracy Abstract Colorectal liver metastases (CRLM) exhibit distinct histopathological growth patterns (HGPs) that are indicative of prognosis following surgical treatment. This study aims to assess the reliability and replicability of this histological biomarker. Within and between metastasis HGP concordance was analysed in patients who underwent surgery for CRLM. An independent cohort was used for external validation. Within metastasis concordance was assessed in CRLM with ≥ 2 tissue blocks. Similarly, concordance amongst multiple metastases was determined in patients with ≥ 2 resected CRLM. Diagnostic accuracy [expressed in area under the curve (AUC)] was compared by number of blocks and number of metastases scored. Interobserver agreement (Cohen's k) compared to the gold standard was determined for a pathologist and a PhD candidate without experience in HGP assessment after one and two training sessions. Both the within (95%, n = 825) and the between metastasis (90%, n = 363) HGP concordance was high. These results could be replicated in the external validation cohort with a within and between metastasis concordance of 97% and 94%, respectively. Diagnostic accuracy improved when scoring 2 versus 1 blocks(s) or CRLM (AUC = 95.9 vs. 97.7 [p = 0.039] and AUC = 96.5 vs. 93.3 [p = 0.026], respectively), but not when scoring 3 versus 2 blocks or CRLM (both p > 0.2). After two training sessions the interobserver agreement for both the pathologist and the PhD candidate were excellent (k = 0.953 and k = 0.951, respectively). The histopathological growth patterns of colorectal liver metastasis exhibit little heterogeneity and can be determined with a high diagnostic accuracy, making them a reliable and replicable histological biomarker.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for endometrial cancer-derived peritoneal metastases: a systematic review Abstract Cytoreductive surgery (CRS) is an appropriate treatment for selected patients with endometrial cancer (EC)-derived peritoneal metastases (PM). Hyperthermic intraperitoneal chemotherapy (HIPEC) may enhance the therapeutic efficacy of CRS in these patients. We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify clinical trials and case reports reporting on the safety and efficacy of CRS and HIPEC in patients with EC-derived PM. Eight publications reporting on 68 patients were identified. The mean patient age was 57.1 years and the mean time from initial treatment of EC to CRS and HIPEC was 22.3 months. 41/64 patients had adenocarcinomas, type II cancers were present in 23/64 patients. The mean peritoneal carcinomatosis index (PCI) was 16.7. A complete surgical resection CC-0 was achieved in 44/63 (70%) patients. The chemotherapy regimens used for HIPEC were variable, but all included cisplatin, administered either alone (39/68 patients) or combined with doxorubicin or paclitaxel or mitomycin (29/68 patients). The duration of HIPEC was 60 min in 51/68 patients and 90 min in 17/68 patients. Mostly, the closed technique was used (55/68 patients). Adverse events grades 1/2, 3, and 4 were observed in 23/63, 12/63, and 6/63 patients, respectively. Treatment-associated mortality was 1% (1/63). After CRS and HIPEC, most patients received systemic chemotherapy (46/63 patients). Median disease-free and overall survival ranged from 7 to 18 and 12 to 33 months, respectively. In conclusion, CRS and HIPEC in EC with PM is safe and feasible. An additional therapeutic value of HIPEC is suggested, but prospective comparative trials are warranted.

Metastasis is impaired by endothelial-specific Dll4 loss-of-function through inhibition of epithelial-to-mesenchymal transition and reduction of cancer stem cells and circulating tumor cells Abstract Systemic inhibition of Dll4 has been shown to thoroughly reduce cancer metastasis. The exact cause of this effect and whether it is endothelial mediated remains to be clarified. Therefore, we proposed to analyze the impact of endothelial Dll4 loss-of-function on metastasis induction on three early steps of the metastatic process, regulation of epithelial-to-mesenchymal transition (EMT), cancer stem cell (CSC) frequency and circulating tumor cell (CTC) number. For this, Lewis Lung Carcinoma (LLC) cells were used to model mouse tumor metastasis in vivo, by subcutaneous transplantation into endothelial-specific Dll4 loss-of-function mice. We observed that endothelial-specific Dll4loss-of-function is responsible for the tumor vascular regression that leads to the reduction of tumor burden. It induces an increase in tumoral blood vessel density, but the neovessels are poorly perfused, with increased leakage and reduced perivascular maturation. Unexpectedly, although hypoxia was increased in the tumor, the number and burden of macro-metastasis was significantly reduced. This is likely to be a consequence of the observed reduction in both EMT and CSC numbers caused by the endothelial-specific Dll4 loss-of-function. This multifactorial context may explain the concomitantly observed reduction of the circulating tumor cell count. Furthermore, our results suggest that endothelial Dll4/Notch-function mediates tumor hypoxia-driven increase of EMT. Therefore, it appears that endothelial Dll4 may constitute a promising target to prevent metastasis.

The clinical outcome of eribulin treatment in Japanese patients with advanced soft tissue sarcoma: a Tokai Musculoskeletal Oncology Consortium study Abstract The efficacy and safety of eribulin in Japanese patients with advanced soft-tissue sarcomas (STS) have not been evaluated in a large-scale cohort study. Thus, we aimed to investigate the clinical outcome of 82 Japanese patients with STS receiving eribulin across multiple study centers retrospectively. Of 82 STS patients receiving eribulin treatment, 13 were treated for locally unresectable tumor, 46 for metastasis, and 23 for both. The primary endpoint of this study was to evaluate the efficacy of eribulin against STS. The median age was 60 years. Thirty-seven were diagnosed with L-sarcoma (leiomyosarcoma or liposarcoma) and 45 had non-L-sarcoma. The median progression-free survival (PFS) for all patients was 2.7 months, with 3.4 months in those with L-sarcoma and 2.2 months in those with non-L-sarcoma. Patients with L-sarcoma showed a better PFS than those with non-L-sarcoma. Overall, the median survival time was 11.1 months, and 12.3 months and 7.9 months in patients with L-sarcoma and non-L-sarcoma, respectively; however, there was no significant differences between the groups. The prognostic significance of PS = 0 and both existence of local and metastatic STS was evaluated by multivariate analysis. We also evaluated the overall survival (OS) in patients with undifferentiated pleomorphic sarcoma (UPS) and other non-L-sarcomas. Patients with UPS had better OS than those with the other non-L-sarcomas. In conclusion, there was a significant difference in PFS between patients with L-sarcoma and non-L-sarcoma following treatment with eribulin. The anti-tumor potential of eribulin was evident in patients with UPS.

CTHRC1 promotes M2-like macrophage recruitment and myometrial invasion in endometrial carcinoma by integrin-Akt signaling pathway Abstract The infiltration of tumor-associated macrophages (TAMs) is associated with tumor progression and poor prognosis in endometrial cancer (EC). Collagen triple helix repeat containing 1 (CTHRC1), a secreted ECM protein, has been reported to have important roles in promoting cancer invasion and metastasis, but the functional role of CTHRC1 and its association with TAMs in EC remain unclear. Here we report that, in EC patients, CTHRC1 expression was up-regulated in endometrial cancer tissues compared with normal endometrium (P < 0.0001), and is positively correlated with tumor grade and depth of myometrial invasion (P = 0.024 and P = 0.0002, respectively). Meanwhile, CTHRC1 expression was positively correlated with an increased number of infiltrating TAMs, especially M2-like TAMs (P = 0.003, P = 0.001). In the tumor microenvironment of EC, CTHRC1 not only promoted myometrial invasion by interacting with Integrin β3-Akt signaling pathway, but also promoted infiltration of M2-like TAMs by upregulating Fractalkine chemokine receptor (CX3CR1) expression in macrophages. Changing levels of recombinant CTHRC1 protein (rCTHRC1) promoted tumor migration and invasion via enhancing macrophage recruitment in vitro. In summary, our findings eventually provided a novel role for CTHRC1 in remodeling the tumor immune microenvironment to promote tumor metastasis in EC patients.

Stereotactic radiation therapy in oligometastatic colorectal cancer: outcome of 102 patients and 150 lesions Abstract To evaluate the local control (LC), progression free survival (PFS), out-field PFS, overall survival (OS), toxicity and failure predictors of SRT in a series of various sites oligometastatic CRC patients. Patients with oligometastatic CRC disease were analyzed retrospectively. The SRT prescribed dose was dependent on the lesion volume and its location. 102 consecutive oligometastatic CRC patients (150 lesions) were included. They underwent SRT between 2012 and 2015. Median prescription dose was 45 Gy (median dose/fraction was 15 Gy/3 fractions biological equivalent dose (BED10) 112.5 Gy). Median follow-up was 11.4 months. No patients experienced G3 and G4 toxicity. No progression was found in 82% (radiological response at 3 months) and 85% (best radiological response) out of 150 evaluable lesions. At 1 and 2 years: LC was 70% and 55%; OS was 90% and 90%; PFS was 37% and 27%; out-field PFS was 37% and 23% respectively. Progressive disease was correlated with BED10 (better LC when BED10 was ≥ 75 Gy (p < 0.0001)). In multivariate analysis, LC was higher in lesions with a Plpnning target volume (PTV) volume < 42 cm3 and BED10 ≥ 75 Gy. Patients with Karnofsky performance status < 90 showed higher out-field progression. SRT is an effective treatment for patients with oligometastases from CRC. Its low treatment-associated morbidity and acceptable LC make of SRT an option not only in selected cases. Further studies should be focused to clarify which patient subgroup will benefit most from this treatment modality and to define the optimal dose to improve LC while maintaining low toxicity profile.

Hypermethylation-mediated inactivation of miR-124 predicts poor prognosis and promotes tumor growth at least partially through targeting EZH2/H3K27me3 in ESCC Abstract Accumulating evidences indicated that some microRNAs (miRNAs) play a critical role during the carcinogenesis. In the present study, we found that miR-124 is down-regulated in esophageal squamous cell carcinoma (ESCC) tissues. Three miR-124 encoding genes, including mir-124-1, mir-124-2, and mir-124-3, harboring CpG islands undergo methylation-mediated miR-124 inactivation in ESCC tissues. The methylation status of all these three genes was negatively associated with the expression of miR-124. The low expression of miR-124 and the hypermethylation of mir-124-1 and mir-124-3 were associated with the clinico-pathological parameters indicating the poor prognosis. In addition, promoter methylation of all three genes plus low expression of miR-124 was the independent poor prognostic marker for ESCC patients. In conclusion, miR-124 may function as a tumor suppressive miRNA, and hypermethylation-mediated inactivation of miR-124 may be useful for a poor prognostic marker for ESCC patients.

Identification of S100A14 as a metastasis-promoting molecule in a murine organotropic metastasis model Abstract Cancer metastasis shows great diversity in target organs, routes and molecular mechanisms depending on the type of cancer and even on the individual patients. To identify key molecules involved in metastasis, we constructed a murine model system including multiple sublines with different organotropism and pathways of metastasis. We selected metastatic sublines from a murine mammary tumor cell line MCH66. Using this model, we extracted metastasis-related molecules by gene expression screening methods and verified their metastasis-promoting effects by gene knockdown or overexpression experiments. For the candidates promoting metastasis, we analyzed molecular functions involved in metastasis: cell growth, motility and invasive activity. We established a metastasis model including low metastatic sublines (66C8, 66LM, 66-4) and highly metastatic counterparts with various organotropism, such as to the lung (66Lu10), liver (HM-KAN5) and general organs (66HM and its clones: HM1-6 and HM1-7). The sublines basically exhibited the invasion-independent metastasis pathway characterized by endothelial cell-covered tumor emboli, whereas 66HM and HM-KAN5 showed an alternative metastasis pathway based on invasion in part and in whole, respectively. Comprehensive gene analysis extracted several molecular candidates responsible for metastasis. S100A14 was identified as one of the promissing candidates promoting lung-metastasis, which was verified by gene knockdown experiments in vivo. In addition, in vivo and in vitro functional analyses demonstrated that S100A14 enhanced scattering, motility and invasiveness of mouse tumor cells. Our model system may be adaptable to the diversity of metastasis in human cancers and useful for exploring the molecular mechanism responsible for metastasis.

The importance of developing therapies targeting the biological spectrum of metastatic disease Abstract Great progress has been made in cancer therapeutics. However, metastasis remains the predominant cause of death from cancer. Importantly, metastasis can manifest many years after initial treatment of the primary cancer. This is because cancer cells can remain dormant before forming symptomatic metastasis. An important question is whether metastasis research should focus on the early treatment of metastases, before they are clinically evident ("overt"), or on developing treatments to stop overt metastasis (stage IV cancer). In this commentary we want to clarify why it is important that all avenues of treatment for stage IV patients are developed. Indeed, future treatments are expected to go beyond the mere shrinkage of overt metastases and will include strategies that prevent disseminated tumor cells from emerging from dormancy.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Scalp ulcers – differential diagnoses

that should be sought!
Eran Shavit MD  Mona Alkallabi MD  Afsaneh Alavi MD, MSc
First published: 02 July 2019 https://doi.org/10.1111/ijd.14539
Funding: This research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors.
Conflict of interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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Abstract
Background
Ulceration of the scalp is an uncommon clinical presentation, and it may be caused by myriads of cutaneous etiologies such as infections, inflammatory disorders, and malignancies. We sought to reveal the underlying etiology of scalp ulcers referred to our tertiary wound healing clinic; we would also like to propose a classification for scalp ulcerations.

Methods
A retrospective study was conducted in an academic tertiary wound healing clinic between January 2015 and June 2018. The study was approved by the Women's College Hospital Institutional Research Ethics Board. We have also conducted a review of the literature to recognize the major causes of scalp ulceration reported in the literature.

Results
We have identified a total number of 15 patients with scalp ulceration. Twelve patients with atypical scalp ulcers underwent a skin biopsy. A malignancy rate of 73% (11/15) was diagnosed histologically. The review of the literature showed 237 articles. After screening the title and the abstracts, we have selected 41 case reports for the full text review.

Conclusion
Scalp ulcers are uncommon but important. Our sample study indicates the high frequency of malignant etiologies presenting as scalp ulcers. These results emphasize not only the need for clinicians to be on the watch for the possibility of this option but rather highlights the need for early biopsy to prevent further complications. We hope that our paper helps to shed some light on this topic and guide clinicians on how to approach scalp ulceration.