The role of bone anabolic drugs in the management of periodontitis: a scoping review

The aim of this scoping review was to summarise current knowledge about the effects of bone anabolic drugs on periodontitis, in order to identify new therapeutic strategies for preventing disease progression and reducing tooth loss. A technical expert panel (TEP) was established of 11 medical specialists, including periodontists and bone specialists that followed the PRISMA-ScR model to perform the scoping review and considered for eligibility both pre-clinical and clinical studies published in the English language up to September 2020. 716 items were initially found. After duplicate removal and screening of articles for eligibility criteria, 25 articles published between 2001 and 2019 were selected. Only studies concerning teriparatide, strontium ranelate, sclerostin antibodies and DKK1 antibodies met the eligibility criteria. In particular, only for teriparatide were there both clinical studies and experimental studies available, while for other bone anabolic drugs only animal studies were found. Available evidence about the use of bone anabolic drugs in periodontology demonstrates beneficial effects of these agents on biological pathways and histological parameters involved in periodontal tissue regeneration that suggest relevant clinical implications for the management of periodontitis

Value of sarcopenia in the resection of colorectal liver metastases—a systematic review and meta-analysis

IntroductionSarcopenia is defined as a decline in muscle function as well as muscle mass. Sarcopenia itself and sarcopenic obesity, defined as sarcopenia in obese patients, have been used as surrogates for a worse prognosis in colorectal cancer. This review aims to determine if there is evidence for sarcopenia as a prognostic parameter in colorectal liver metastases (CRLM).MethodsPubMed, Embase, Cochrane Central, Web of Science, SCOPUS, and CINAHL databases were searched for articles that were selected in accordance with the PRISMA guidelines. The primary outcomes were overall survival (OS) and disease-free survival (DFS). A random effects meta-analysis was conducted.ResultsAfter eliminating duplicates and screening abstracts (n = 111), 949 studies were screened, and 33 publications met the inclusion criteria. Of them, 15 were selected after close paper review, and 10 were incorporated into the meta-analysis, which comprised 825 patients. No significant influence of sarcopenia for OS (odds ratio (OR), 2.802 (95% confidence interval (CI), 1.094–1.11); p = 0.4) or DFS (OR, 1.203 (95% CI, 1.162–1.208); p = 0.5) was found, although a trend was defined toward sarcopenia. Sarcopenia significantly influenced postoperative complication rates (OR, 7.905 (95% CI, 1.876–3.32); p = 0.001) in two studies where data were available.ConclusionExisting evidence on the influence of sarcopenia on postoperative OS as well as DFS in patients undergoing resection for CRLM exists. We were not able to confirm that sarcopenic patients have a significantly worse OS and DFS in our analysis, although a trend toward this hypothesis was visible. Sarcopenia seems to influence complication rates but prospective studies are needed

sclerostin a novel key to bone and dental treatment

Problem statement: Tooth loss can induce dramatical remodeling of alveolar bone because of mechanical loading impairment and strategies to help maintain adequate bone levels for subsequent therapies are sorely needed. Recent discoveries have shown that osteocytes, matrix-embedded cells in bone, respond to mechanical stimulation by modulating the expression of the Sost gene, which encodes for the protein sclerostin. This protein can oppose the WNT canonical pathway, a signaling cascade which regulates osteoblastic differentiation and bone homeostasis and thus orchestrate bone turn-over according to the skeleton's mechanical needs. Conclusion: Experimental attempts at Sclerostin inhibition have provided interesting data on a novel approach to decrease bone resorption and promote bone formation, with important implications for the orthopedic and dental field

Proceedings XXIII Congresso SIAMOC 2023

Il congresso annuale della Società Italiana di Analisi del Movimento in Clinica (SIAMOC), giunto quest’anno alla sua ventitreesima edizione, approda nuovamente a Roma. Il congresso SIAMOC, come ogni anno, è l’occasione per tutti i professionisti che operano nell’ambito dell’analisi del movimento di incontrarsi, presentare i risultati delle proprie ricerche e rimanere aggiornati sulle più recenti innovazioni riguardanti le procedure e le tecnologie per l’analisi del movimento nella pratica clinica. Il congresso SIAMOC 2023 di Roma si propone l’obiettivo di fornire ulteriore impulso ad una già eccellente attività di ricerca italiana nel settore dell’analisi del movimento e di conferirle ulteriore respiro ed impatto internazionale. Oltre ai qualificanti temi tradizionali che riguardano la ricerca di base e applicata in ambito clinico e sportivo, il congresso SIAMOC 2023 intende approfondire ulteriori tematiche di particolare interesse scientifico e di impatto sulla società. Tra questi temi anche quello dell’inserimento lavorativo di persone affette da disabilità anche grazie alla diffusione esponenziale in ambito clinico-occupazionale delle tecnologie robotiche collaborative e quello della protesica innovativa a supporto delle persone con amputazione. Verrà infine affrontato il tema dei nuovi algoritmi di intelligenza artificiale per l’ottimizzazione della classificazione in tempo reale dei pattern motori nei vari campi di applicazione

Expression of Fibroblast Activation Protein in lungs of dogs with idiopathic pulmonary fibrosis and dogs with lung cancer

peer reviewedCanine Idiopathic Pulmonary Fibrosis (CIPF) is a progressive fibrotic interstitial lung disease of unknown aetiology, affecting predominantly the West Highland White Terrier (WHWT) breed. Currently, there is no curative treatment option available. Fibroblast Activation Protein (FAP) is a cell surface protease usually absent from normal tissue but specifically expressed in areas of active tissue remodelling such as in fibroblast foci in human idiopathic pulmonary fibrosis. In humans, it is also upregulated in various types of cancers, either in cancer-associated fibroblasts (CAFs), in cancer cells or in both, depending on the tumour type. The aim of this study was to assess the expression and localization of FAP in the lungs of WHWTs affected with CIPF, in comparison with WHWTs with healthy lungs and dogs with lung cancer. Post-mortem formalin-fixed lung biopsies prepared from WHWTs with CIPF (n=17, age from 10 to 15y), control WHWTs exempt from lung disease (n=4, age from 11 to 15y) and dogs from various breeds with lung cancer (n=8, age from 8 to 14y) were retrospectively used. Included lung neoplasia were adenocarcinomas (n=6), histiocytic sarcoma (n=1) and metastasized mammary adenocarcinoma (n=1). Immunohistochemistry (IHC) was performed using a rabbit anti-human FAP monoclonal antibody (#ab207178). An IHC staining index (absent, low, moderate or high) was attributed according to the percentage of positive cells combined with the staining intensity. FAP was identified in the lungs of 16 out of 17 (94%) WHWTs with CIPF (IHC index high, moderate, or low in respectively 10, 4 and 2 dogs), 2 out of 4 (50%) WHWTs with healthy lungs (1 of each moderate and low), and 7 out of 8 (88%) dogs with lung cancer (high and moderate in respectively 6 and 1 dogs). FAP was expressed by fibroblasts in areas of active fibrosis in CIPF and by CAFs (all types of cancer) and cancer cells (adenocarcinomas only, n=5) in lung tumours. Results of this study showed that FAP is moderately to markedly expressed by fibroblasts in most dogs affected with either CIPF or lung cancer. Accordingly, FAP should be considered as an interesting potential therapeutic target for both diseases and should encourage further studies in the future. The expression of FAP in healthy lungs of WHWTs should be further investigated, particularly in comparison with FAP expression in dogs from other breeds, as it might serve as an indicator of early fibrosis

Bone regeneration in patient-specific scaffolds from microfluidics to computational simulation

Los trastornos musculoesqueléticos y sus correspondientes enfermedades óseas son una de las principales causas de dolor y discapacidad, así como una carga social y económica para nuestra sociedad. Cuando la función articular se ve afectada o los defectos óseos son demasiado grandes para los injertos óseos, los implantes protésicos son el método estándar para tratar los trastornos musculoesqueléticos graves, aunque existe la necesidad clínica de que los implantes permanezcan activos durante un período de tiempo más largo y reduzcan las tasas de revisión. Para abordar la mayor durabilidad de los implantes ortopédicos, recientemente han surgido implantes impresos en tres dimensiones (3D) para fabricar superficies porosas específicas del paciente en la superficie del hueso-implante, mejorando así la fijación biológica del implante. La traslación de los principios de la medicina regenerativa a la ortopedia permitiría definir una nueva generación de implantes que completen la transición de materiales inertes a andamios bioactivos que guíen el proceso de regeneración ósea. A corto plazo, es probable que los andamios ortopédicos regenerativos impresos en 3D aumenten la vida útil del implante, mientras que a largo plazo puedan degradarse una vez que el tejido huésped esté completamente reparado. El objetivo global de esta tesis es evaluar el potencial regenerativo asociado a los andamiajes óseos impresos en 3D para aplicaciones ortopédicas específicas del paciente.Para ello, el primer estudio tuvo como objetivo determinar el papel del entorno mecánico del huésped en el proceso de regeneración ósea guiado por andamios óseos impresos en 3D en aplicaciones de carga. Se desarrolló un modelo computacional de regeneración ósea impulsada por un mecanismo en andamios porosos y se basó en la especificidad del sujeto, el sitio de implantación y la sensibilidad al entorno mecánico. A continuación, se simuló el crecimiento óseo en el interior de andamiajes porosos de titanio implantados en el fémur distal y la tibia proximal de tres cabras y se comparó con los resultados experimentales. Los resultados mostraron que el crecimiento óseo en el interior cambió de un patrón de distribución homogéneo, cuando los andamios estaban en contacto con el hueso trabecular, a un crecimiento óseo localizado cuando los andamios se implantaron en una ubicación diafisaria. En general, la dependencia de la respuesta osteogénica de la biomecánica del huésped sugirió que, desde una perspectiva mecánica, el potencial regenerativo dependía tanto del andamio como del entorno del huésped.El segundo estudio de esta tesis tuvo como objetivo evaluar la actividad osteogénica específica del paciente en un entorno controlado in vitro donde las células óseas humanas, aisladas de sujetos individuales, imitan los rasgos esenciales del proceso de formación ósea. Los sistemas in vitro tradicionales ya permitieron demostrar que los osteoblastos humanos primarios embebidos en una matriz fibrada de colágeno se diferencian en osteocitos en condiciones específicas. Por lo tanto, se planteó la hipótesis de que la traslación de este entorno a la escala de órgano en un chip crea una unidad funcional mínima para recapitular la maduración de los osteoblastos hacia los osteocitos y la mineralización de la matriz. Con este propósito, se sembraron osteoblastos humanos primarios en un hidrogel de colágeno de tipo I, para conocer mejor el papel de la densidad de siembra de células en su diferenciación a osteocitos. Los resultados muestran que las células cultivadas a mayor densidad aumentan la longitud de la dendrita con el tiempo, dejan de proliferar, exhiben morfología dendrítica, regulan positivamente la actividad de la fosfatasa alcalina y expresan marcadores de osteocitos. Este estudio reveló que los sistemas de microfluídica son una estrategia funcional que permite crear un modelo de tejido óseo específico del paciente e investigar el potencial osteogénico individual de las células óseas del paciente.En conjunto, los resultados de esta tesis enfatizan la importancia de utilizar un sistema de modelado múltiple al investigar el proceso de regeneración in vivo guiado por armazones óseos específicos adecuados al paciente. Ambos actores de una estrategia regenerativa libre de células in situ, a saber, el andamio y el paciente, tienen un efecto significativo en el resultado regenerativo final y necesitan ser modelados. Las técnicas avanzadas de in vitro e in silico, combinadas con datos de in vivo, evalúan aspectos distintivos del proceso de regeneración ósea para aplicaciones específicas del paciente. Las futuras estrategias personalizadas de ingeniería de tejidos podrían depender de la integración de esos modelos para mitigar en última instancia la variabilidad en el proceso de regeneración ósea guiado por un andamio específico para el paciente.<br /

Measurement of treatment response and survival prediction in malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare cancer of the mesothelial cells of the visceral and parietal pleurae that is heterogeneous in terms of biology, prognosis and response to systemic anti-cancer therapy (SACT). The primary tumour forms an unusual, complex shape which makes survival prediction and response measurement uniquely challenging. Computed tomography (CT) imaging is the bedrock of radiological quantification and response assessment, but it has major limitations that translate into low sensitivity and high inter-observer variation when classifying response using Response Evaluation Classification In Solid Tumours (mRECIST) criteria. Magnetic resonance imaging (MRI) tools have been developed that overcome some of these problems but cost and availability of MRI mean that optimisation of CT and better use for data acquired by this method are important priorities in the short term. In this thesis, I conducted 3 studies focused on, 1) development of a semi-automated volumetric segmentation method for CT based on recently positive studies in MRI, 2) training and external validation of a deep learning artificial intelligence (AI) tool for fully automated volumetric segmentation based on CT data, and, 3) use of non-tumour imaging features available from CT related to altered body composition for development of new prognostic models, which could assist in selection of patients for treatment and improving tolerance to treatment by targeting the systemic consequences of MPM. The aim of Chapter 3 is to develop a semi-automated MPM tumour volume segmentation method that would serve as the ground truth for the training of a fully automated AI algorithm. A semi-automated approach to pleural tumour segmentation has been developed using MRI scans which calculated volumetric measurements from seed points - defined by differential tumour enhancement - placed within a pre-defined volume of pleural tumour. I extrapolated this MRI method using contrast-enhanced CT scans in 23 patients with MPM. Radiodensity values – defined by Hounsfield units (HU) - were calculated for the different thoracic tissues by placing regions of interest (ROI) on visible areas of pleural tumour with similar ROIs placed on other thoracic tissues. Pleural volume contours were drawn on axial CT slices and propagated throughout the volume by linear interpolation using volumetric software (Myrian Intrasense® software v2.4.3 (Paris, France)). Seed points based on the radiodensity range of pleural tumour were placed on representative areas of tumour with regions grown. There were similarities in median thoracic tissue HU values: pleural tumour, 52 [IQR 46 to 60] HU; intercostal muscle, 20.4 [IQR 11.9 to 32.3] HU; diaphragm, 40.4 [IQR 26.4 to 56.4] HU and pleural fluid, 11.8 [IQR 8.3 to 17.8] HU. There was also reduced definition between MPM tumour and neighbouring structures. The mean time taken to complete semi-automated volumetric segmentations for the 8 CT scans examined was 25 (SD 7) minutes. The semi-automated CT volumes were larger than the MRI volumes with a mean difference between MRI and CT volumes of -457.6 cm3 (95% limits of agreement -2741 to +1826 cm3). The complex shape of MPM tumour and overlapping thoracic tissue HU values precluded HU threshold-based region growing and meant that semi-automated volumetry using CT was not possible in this thesis. Chapter 4 describes a multicentre retrospective cohort study that developed and validated an automated AI algorithm – termed a deep learning Convolutional Neural Network (CNN) - for volumetric MPM tumour segmentation. Due to the limitations of the semi-automated approach described in Chapter 3, manually annotated tumour volumes were used to train the CNN. The manual segmentation method ensured that all the parietal pleural tumour was included in the respective volumes. Although the manual CT volumes were consistently smaller than semi-automated MRI volumes (average difference between AI and human volumes 74.8 cm3), they were moderately correlated (Pearson’s r=0.524, p=0.0103). There was strong correlation (external validation set r=0.851, p<0.0001) and agreement (external validation set mean AI minus human volume difference of +31 cm3 between human and AI tumour volumes). AI segmentation errors (4/60 external validation set cases) were associated with complex anatomical features. There was agreement between human and AI volumetric responses in 20/30 (67%) cases. There was agreement between AI volumetric and mRECIST classification responses in 16/30 (55%) cases. Overall survival (OS) was shorter in patients with higher AI-defined pre-chemotherapy tumour volumes (HR=2.40, 95% CI 1.07 to 5.41, p=0.0114). Survival prediction in MPM is difficult due to the heterogeneity of the disease. Previous survival prediction models have not included measures of body composition which are prognostic in other solid organ cancers. In Chapter 5, I explore the impact of loss of skeletal muscle and adipose tissue at the level of the third lumbar vertebra (L3) and the loss of skeletal muscle at the fourth thoracic (T4) vertebrae on survival and response to treatment in patients with MPM receiving chemotherapy. Skeletal and adipose muscle areas at L3 and T4 were quantified by manual delineation of relevant muscle and fat groups using ImageJ software (U.S. National Institutes of Health, Bethesda, MD) on pre-chemotherapy and response assessment CT scans, with normalisation for height. Sarcopenia at L3 was not associated with shorter OS at the pre-chemotherapy (HR 1.49, 95% CI 0.95 to 2.52, p=0.077) or response assessment time points (HR 1.48, 95% CI 0.97 to 2.26, p=0.0536). A higher visceral adipose tissue index (VFI) measured at L3 was associated with shorter OS (HR 1.95, 95% CI 1.05 to 3.62, p=0.0067). In multivariate analysis, obesity was associated with improved OS (HR 0.36, 95% CI 0.20 to 0.65, p<0.001) while interval VFI loss (HR 1.81, 95% CI 1.04 to 3.13, p=0.035) was associated with reduced OS. Overall loss of skeletal muscle index at the fourth thoracic vertebra (T4SMI) during treatment was associated with poorer OS (HR 2.79, 95% CI 1.22 to 6.40, p<0.0001). Skeletal muscle index on the ipsilateral side of the tumour at the fourth thoracic vertebra (Ipsilateral T4SMI) loss was also associated with shorter OS (HR 2.91, 95% CI 1.28 to 6.59, p<0.0001). In separate multivariate models, overall T4SMI muscle loss (HR 2.15, 95% CI 102 to 4.54, p=0.045) and ipsilateral T4SMI muscle loss (HR 2.85, 95% CI 1.17 to 6.94, p=0.021) were independent predictors of OS. Response to chemotherapy was not associated with decreasing skeletal muscle or adipose tissue indices

Serum 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D in dogs with sinonasal aspergillosis

peer reviewedSinonasal aspergillosis (SNA) is a common cause of chronic nasal disease with a still poorly understood pathophysiology and which remains a challenge to treat. There is increasing evidence that vitamin D plays a role in both innate and adaptative immunity. A preliminary retrospective study showed that serum 25-hydroxyvitamin D concentration, measured by high performance liquid chromatography (HPLC), was significantly lower in dogs affected with SNA compared to healthy dogs. Objectives of this prospective study were 1) to compare serum 25(OH)D and 24,25(OH)2D concentrations in dogs with SNA to healthy control dogs and dogs with lymphoplasmacytic rhinitis (LPR) or nasal neoplasia; and 2) to determine if serum 25(OH)D and 24,25(OH)2D concentrations in dogs with SNA change from the time of diagnosis to when a cure is achieved. Twenty dogs with a novel diagnosis of SNA, 12 healthy control dogs, 9 dogs with LPR, 10 dogs with nasal neoplasia were included. Nine dogs with SNA were available for follow up until cure. Serum vitamin D concentrations were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS) and compared: 1) among the different groups using a One-way ANOVA and 2) from diagnosis to cure with a paired t-test (significant p-value <0,05 for both tests). The vitamin D metabolite ratio (VMR) was calculated by dividing the 25(OH)D by the 24,25(OH)2D concentration. Serum 25(OH)D and 24,25(OH)2D were lower in dogs with SNA at the time of diagnosis (mean ± standard deviation = 23.5 ± 7,1 ng/ml – 10,5 ± 4,2 ng/ml, respectively) than in healthy dogs (34,1 ± 7,5 ng/ml; p=0,017 - 18,2 ± 5.4 ng/ml; p = 0,005) while there was no difference between healthy and dogs with tumor (27,8 ± 10,9 ng/ml – 15,4 ± 6,5 ng/ml) or LPR (27,4 ± 13,7 ng/ml – 14,3 ± 8,7 ng/ml). There was no significant difference in serum 25(OH)D and 24,25(OH)2D between dogs with SNA at the time of diagnosis and dogs achieving cure. The VMR was higher in SNA dogs (2,4 ± 0,7) than in control dogs (1,9 ± 0,3; p=0,031 t-test), indicating a decreased catabolic clearance of vitamin D in SNA dogs. These results further support the rationale that vitamin D could play a role in dogs with SNA as it does in human with aspergillosis. Whether hypovitaminosis D could contribute to the development of SNA or if oral supplementation could be a beneficial adjunctive therapy in affected dogs is unknown and warrants future investigations