Clear Cell Renal Cell Carcinoma 2021–2022

Clear cell renal cell carcinoma is currently one of the most interesting areas of study in oncology. Despite the advances made in this field, this tumor continues to be a health problem of major concern in Western societies, seriously affecting public health services. Several characteristics of this tumor make it an exciting meeting point for translational collaboration between clinicians and basic researchers. Clear cell renal cell carcinoma is a paradigmatic example of inter- and intra-tumor heterogeneity from morphological, immunohistochemical, and molecular viewpoints. This tumor is also a good example to investigate the complexity of tumor/tumor and tumor/environment relationships from an ecological perspective. A deeper identification of the varied internal tumor self-organization through the specialization of cell clones and subclones as local invaders and metastasizers, on one hand, and the interactions of specific subsets of tumor cells with the local host microenvironment, on the other, will significantly enrich our knowledge of this neoplasm. Clear cell renal cell carcinoma is also a paradigmatic test bench for antiangiogenic and immune checkpoint blockage therapies. The refinement of these therapeutic tools administered alone or in combination is a hot issue in oncology, and several international trials are underway

TRANSPLANTATION WITH KIDNEYS REMOVED FOR SMALL RENAL TUMOURS: IMMUNOSUPPRESSIVE STRATEGIES AND ROLE OF REJECTION

Renal transplantation is the definitive treatment for the end-stage renal failure. Despite concerted efforts to increase the number of available organs there remains a wide gap. Kidneys with small renal cell carcinoma have been used for transplantation after ex vivo resection of tumours with excellent results. Concerns regarding the behaviour of tumour under standard immunosuppression prevent this source from being popularised. We studied tumour behaviour with standard immunosuppression and immunosuppressives with anti-proliferative properties and the effect of MHC matching on tumour behaviour. Luciferase labelled Wistar rat kidney tumour cells were injected subcutaneously into Wistar or Lewis rats to mimic well and poorly matched groups. These were divided into groups receiving Cyclosporine, Sirolimus high and Sirolimus low dose and Leflunomide. Effects of matching on tumour rejection were studied by immunosuppression withdrawal in half of the animals within each group. Tumour progression was monitored with IVIS spectrum imaging system. When the immunosuppression was continued for the length of the study period with Cyclosporine immunosuppression, the tumour continued to grow in both strains. With high dose Sirolimus, the tumour was eradicated within 2 weeks in both Wistar and Lewis rats (p <0.05). Both strains receiving low dose Sirolimus also eradicated the tumour within four weeks of treatment (p <0.05). In Leflunomide group, 4/7 animals rejected the tumour within the 4 weeks of study period (p <0.05). To study the effects of rejection and matching on the tumour behaviour, the immunosuppression was stopped after 2 weeks of treatment and the animals followed for another two weeks to study these effects. After treatment withdrawal, the tumour rejection was noted which was significantly stronger in poorly matched animals than in well-matched animals (p <0.05) in cyclosporine treated animals. These results appeared to be in line with our hypothesis, that newer immunosuppressive medications with anti-neoplastic effects may be better options after transplanting kidneys after small tumour ex-vivo resection. Acute rejection showed significant ability to lead to tumour eradication, more effectively in less well-matched animals than well-matched combinations. Thus perhaps clinically, recipients of such restored kidneys should be less well matched and immunosuppressed with agents with anti-proliferative properties. These results will need to be replicated with further studies including closely monitored clinical studies before it can be popularised at a significant new source of precious organs

PRELIMINARY FINDINGS OF A POTENZIATED PIEZOSURGERGICAL DEVICE AT THE RABBIT SKULL

The number of available ultrasonic osteotomes has remarkably increased. In vitro and in vivo studies have revealed differences between conventional osteotomes, such as rotating or sawing devices, and ultrasound-supported osteotomes (Piezosurgery®) regarding the micromorphology and roughness values of osteotomized bone surfaces. Objective: the present study compares the micro-morphologies and roughness values of osteotomized bone surfaces after the application of rotating and sawing devices, Piezosurgery Medical® and Piezosurgery Medical New Generation Powerful Handpiece. Methods: Fresh, standard-sized bony samples were taken from a rabbit skull using the following osteotomes: rotating and sawing devices, Piezosurgery Medical® and a Piezosurgery Medical New Generation Powerful Handpiece. The required duration of time for each osteotomy was recorded. Micromorphologies and roughness values to characterize the bone surfaces following the different osteotomy methods were described. The prepared surfaces were examined via light microscopy, environmental surface electron microscopy (ESEM), transmission electron microscopy (TEM), confocal laser scanning microscopy (CLSM) and atomic force microscopy. The selective cutting of mineralized tissues while preserving adjacent soft tissue (dura mater and nervous tissue) was studied. Bone necrosis of the osteotomy sites and the vitality of the osteocytes near the sectional plane were investigated, as well as the proportion of apoptosis or cell degeneration. Results and Conclusions: The potential positive effects on bone healing and reossification associated with different devices were evaluated and the comparative analysis among the different devices used was performed, in order to determine the best osteotomes to be employed during cranio-facial surgery

A continuum robotic platform for endoscopic non-contact laser surgery: design, control, and preclinical evaluation

The application of laser technologies in surgical interventions has been accepted in the clinical domain due to their atraumatic properties. In addition to manual application of fibre-guided lasers with tissue contact, non-contact transoral laser microsurgery (TLM) of laryngeal tumours has been prevailed in ENT surgery. However, TLM requires many years of surgical training for tumour resection in order to preserve the function of adjacent organs and thus preserve the patient’s quality of life. The positioning of the microscopic laser applicator outside the patient can also impede a direct line-of-sight to the target area due to anatomical variability and limit the working space. Further clinical challenges include positioning the laser focus on the tissue surface, imaging, planning and performing laser ablation, and motion of the target area during surgery. This dissertation aims to address the limitations of TLM through robotic approaches and intraoperative assistance. Although a trend towards minimally invasive surgery is apparent, no highly integrated platform for endoscopic delivery of focused laser radiation is available to date. Likewise, there are no known devices that incorporate scene information from endoscopic imaging into ablation planning and execution. For focusing of the laser beam close to the target tissue, this work first presents miniaturised focusing optics that can be integrated into endoscopic systems. Experimental trials characterise the optical properties and the ablation performance. A robotic platform is realised for manipulation of the focusing optics. This is based on a variable-length continuum manipulator. The latter enables movements of the endoscopic end effector in five degrees of freedom with a mechatronic actuation unit. The kinematic modelling and control of the robot are integrated into a modular framework that is evaluated experimentally. The manipulation of focused laser radiation also requires precise adjustment of the focal position on the tissue. For this purpose, visual, haptic and visual-haptic assistance functions are presented. These support the operator during teleoperation to set an optimal working distance. Advantages of visual-haptic assistance are demonstrated in a user study. The system performance and usability of the overall robotic system are assessed in an additional user study. Analogous to a clinical scenario, the subjects follow predefined target patterns with a laser spot. The mean positioning accuracy of the spot is 0.5 mm. Finally, methods of image-guided robot control are introduced to automate laser ablation. Experiments confirm a positive effect of proposed automation concepts on non-contact laser surgery.Die Anwendung von Lasertechnologien in chirurgischen Interventionen hat sich aufgrund der atraumatischen Eigenschaften in der Klinik etabliert. Neben manueller Applikation von fasergeführten Lasern mit Gewebekontakt hat sich die kontaktfreie transorale Lasermikrochirurgie (TLM) von Tumoren des Larynx in der HNO-Chirurgie durchgesetzt. Die TLM erfordert zur Tumorresektion jedoch ein langjähriges chirurgisches Training, um die Funktion der angrenzenden Organe zu sichern und damit die Lebensqualität der Patienten zu erhalten. Die Positionierung des mikroskopis chen Laserapplikators außerhalb des Patienten kann zudem die direkte Sicht auf das Zielgebiet durch anatomische Variabilität erschweren und den Arbeitsraum einschränken. Weitere klinische Herausforderungen betreffen die Positionierung des Laserfokus auf der Gewebeoberfläche, die Bildgebung, die Planung und Ausführung der Laserablation sowie intraoperative Bewegungen des Zielgebietes. Die vorliegende Dissertation zielt darauf ab, die Limitierungen der TLM durch robotische Ansätze und intraoperative Assistenz zu adressieren. Obwohl ein Trend zur minimal invasiven Chirurgie besteht, sind bislang keine hochintegrierten Plattformen für die endoskopische Applikation fokussierter Laserstrahlung verfügbar. Ebenfalls sind keine Systeme bekannt, die Szeneninformationen aus der endoskopischen Bildgebung in die Ablationsplanung und -ausführung einbeziehen. Für eine situsnahe Fokussierung des Laserstrahls wird in dieser Arbeit zunächst eine miniaturisierte Fokussieroptik zur Integration in endoskopische Systeme vorgestellt. Experimentelle Versuche charakterisieren die optischen Eigenschaften und das Ablationsverhalten. Zur Manipulation der Fokussieroptik wird eine robotische Plattform realisiert. Diese basiert auf einem längenveränderlichen Kontinuumsmanipulator. Letzterer ermöglicht in Kombination mit einer mechatronischen Aktuierungseinheit Bewegungen des Endoskopkopfes in fünf Freiheitsgraden. Die kinematische Modellierung und Regelung des Systems werden in ein modulares Framework eingebunden und evaluiert. Die Manipulation fokussierter Laserstrahlung erfordert zudem eine präzise Anpassung der Fokuslage auf das Gewebe. Dafür werden visuelle, haptische und visuell haptische Assistenzfunktionen eingeführt. Diese unterstützen den Anwender bei Teleoperation zur Einstellung eines optimalen Arbeitsabstandes. In einer Anwenderstudie werden Vorteile der visuell-haptischen Assistenz nachgewiesen. Die Systemperformanz und Gebrauchstauglichkeit des robotischen Gesamtsystems werden in einer weiteren Anwenderstudie untersucht. Analog zu einem klinischen Einsatz verfolgen die Probanden mit einem Laserspot vorgegebene Sollpfade. Die mittlere Positioniergenauigkeit des Spots beträgt dabei 0,5 mm. Zur Automatisierung der Ablation werden abschließend Methoden der bildgestützten Regelung vorgestellt. Experimente bestätigen einen positiven Effekt der Automationskonzepte für die kontaktfreie Laserchirurgie

99mTc-PEI-MP and 188Re-PEI-MP for imaging and therapy of the bladder malignant tumours: an experimental study

Programa doutoral em Biologia Molecular e Ambiental, especialidade em Biologia Celular e SaúdeBladder cancer is the most common malignancy of the urinary tract, and is the fifth most common tumour world-wide, being responsible for about 2% of all cancer deaths. Current methods of diagnosis of the bladder cancer are mainly morphologic imaging techniques, while physiological imaging techniques, like nuclear medicine imaging that would enable to detect the disease in a very early stage, is not being fully availed for this type of cancer. The main methods to treat bladder cancer are aggressive and invasive to the patient, in a time where conservative management, with organ preservation, is now the standard of care in numerous malignancies. There is no reference to the use of radiopharmaceuticals for bladder cancer therapy, nevertheless, the existence of a specific radiopharmaceutical to bladder cancer could enable the delivery of high doses of radiation to the target tissue with minimal side effects, and some current therapy modalities could be substituted. Searching for a molecule for use in the palliative therapy of bone metastasis, the water soluble polymer polyethyleneiminomethyl phosphonic acid (PEI-MP), was synthesized. Pre-clinical studies performed with PEI-MP labelled with several radionuclides, demonstrated the high value of accumulation and retention by the bladder wall, which could demonstrate some affinity of PEI-MP to bladder cells, and possibly by bladder cancer cells. Thus, the aim of this work was to explore in vitro and in vivo the potential of PEI-MP radiolabelled with 99mTc or 188Re, for imaging and radionuclide therapy of bladder cancer. In a first stage it was prepared the PEI-MP kits for a quick and easy radiolabelling with 99mTc or 188Re, and to ensure high radiochemical purity. For in vitro studies, the cell lines of human bladder carcinoma (HT-1376) and human osteosarcoma (MNNG/HOS) were used. The osteosarcoma cells were used considering the original intent of using PEI-MP, and in order to make comparisons. Considering that PEI-MP should act only as a carrier for nuclear medicine imaging and therapy, cellular cytotoxicity of PEI-MP was analysed by the evaluation of the cellular metabolic activity and viability through spectrophotometry and flow cytometry. Cellular uptake and retention studies of 99mTc-PEI-MP and 188Re-PEI-MP were also performed. In vivo and ex vivo studies consisted on imaging and biodistribution studies performed in balb/c mice and balb/c n/nu mice with xenografts of bladder carcinoma and osteosarcoma, after the administration of 99mTc-PEI-MP and 188Re-PEI-MP. The PEI-MP kits demonstrated to be suitable for radiolabelling, allowing to achieve a high radiochemical purity over 5 hours, revealing the stability of the kit formulation. PEI-MP didn’t inhibit the metabolic activity or decreased the cell viability significantly and therefore would act as a carrier. Cellular uptake studies demonstrated that the uptake and retention of 99mTc-PEI-MP was, respectively, at least 5 and 4 times superior than the 99mTc-Pertechenetate for both cell lines. The same studies demonstrated that the uptake and retention of 188Re-PEI-MP was, respectively, at least 62 and 194 times superior than the 188Re-Perrhenate for both cell lines. These studies demonstrated the specificity of PEI-MP. In vivo and ex vivo studies demonstrated that 99mTc-PEI-MP and 188Re-PEI-MP were mainly excreted through the renal system and a small amount by enterohepatic circulation. Also it was confirmed the uptake of 99mTc-PEI-MP and 188Re-PEI-MP by lungs. The uptake of 99mTc-PEI-MP and 188Re-PEI-MP by the xenografts of bladder carcinoma or osteosarcoma, that demonstrated to be superior to 1 in relation to muscle, may be related not only with the blood perfusion to the tumour or the enhanced permeability and retention effect associated with PEI-MP, but also with the presence of specific membrane receptors in the case of bladder carcinoma and high concentrations of Ca2+ in both tumour types. Tumour/bladder, tumour/liver, tumour/lung and tumour/bone were always inferior to one. These results demonstrated that for diagnostic nuclear medicine a bladder carcinoma and its metastases would present as cold lesions allowing identifying them in the images. One the other hand the therapy of bladder carcinoma and its metastasis seem not to be feasible if administered intravenously, considering the high dosimetry to other organs.O cancro da bexiga é a neoplasia maligna mais comum do trato urinário, e é o quinto tumor mais comum em todo o mundo, sendo responsável por cerca de 2% de todas as mortes relacionadas com o cancro. Os métodos actuais de diagnóstico para o cancro da bexiga são principalmente técnicas de imagem morfológicas, sendo que as técnicas de imagem fisiológicas, como as da medicina nuclear que permitiriam detectar a doença numa fase inicial, não estão ser totalmente aproveitadas para este tipo de cancro. Os principais métodos de terapia para o cancro da bexiga são agressivos e invasivos para o doente, numa época em que o tratamento conservador, com preservação de órgãos, é agora o padrão para o tratamento de diversas neoplasias. Não há nenhuma referência à utilização de radiofármacos para a terapia do cancro da bexiga, no entanto, a existência de um radiofármaco específico pode permitir a entrega de elevadas doses de radiação ao tecido alvo e com mínimos efeitos secundários, e algumas modalidades de tratamento actuais poderão vir a ser substituídas. Na procura de uma molécula para o tratamento paliativo de metástases ósseas, o ácido fosfónico solúvel em água polietilenoiminometil (PEI-MP), foi sintetizado. Estudos pré-clínicos realizados com o PEI-MP marcado com vários radionuclídeos, demonstraram uma elevada captação e retenção pela parede da bexiga, evidenciando a possível afinidade do PEI-MP para as células da bexiga e possivelmente para células de cancro da bexiga. Assim, o objetivo deste trabalho foi explorar in vitro e in vivo o potencial do PEI-MP radiomarcado com 99mTc ou 188Re, para a imagiologia e terapia com radionuclídeos do cancro da bexiga. Numa primeira fase, foram preparados os kits de PEI-MP para uma radiomarcação rápida e fácil com o 99mTc ou 188Re, e para assegurar a alta pureza radioquímica. Para os estudos in vitro, foram utilizadas as linhas celulares humanas de carcinoma da bexiga (HT-1376) e de osteossarcoma (MNNG/HOS). As células de osteossarcoma foram usadas tendo em conta a intenção inicial do PEI-MP, e de modo a fazer comparações. Considerando que o PEI-MP deve servir apenas como um veículo para a imagiologia e terapia de medicina nuclear, a citotoxicidade celular do PEI-MP foi analisada avaliando a actividade metabólica e viabilidade celular através da espectrofotometria e citometria de fluxo. Também foram realizados estudos de captação e retenção celulares do 99mTc-PEI-MP e 188Re-PEI-MP. Os estudos in vivo consistiram na realização de imagens e na análise da biodistribuição em ratinhos balb/c e balb/c nu/nu com xenoenxertos de carcinoma da bexiga e osteossarcoma após a administração de 99mTc-PEI-MP e 188Re-PEI-MP. Os kits de PEI-MP mostraram-se adequados para a marcação radioactiva, permitindo obter um elevado grau de pureza radioquímica 5 horas após a marcação, revelando a estabilidade da formulação do kit. O PEI-MP não inibiu a actividade metabólica ou diminuiu de forma significativa a viabilidade celular, podendo assim ser usado como um veículo. Os estudos de captação celular demonstraram que a captação e retenção do 99mTc-PEI-MP foi, respecivamente, 5 e 4 vezes superior à do 99mTc-pertecnetato para ambas as linhas celulares. Os mesmos estudos demonstraram que a captação e retenção do 188Re-PEI-MP foi, respectivamente, 62 e 194 vezes superior à do 188Re-perrenato para ambas a linhas celulares. Estes estudos demonstraram a especificidade de PEI-MP. Os estudos in vivo e ex vivo demonstraram que o 99mTc-PEI-MP e 188Re-PEI-MP são excretados maioritariamente por via renal e uma pequena quantidade pela circulação entero-hepática. A captação do 99mTc-PEI-MP e 188Re-PEI-MP pelos xenotransplantes de carcinoma da bexiga ou osteosarcoma, que demonstrou ser superior ao valor de um em relação ao músculo, pode estar relacionada não só com a perfusão de sanguínea para o tumor ou o efeito do aumento e permeabilidade e retenção associado ao PEI-MP, mas também com a presença de receptores de membrana específicos, no caso de carcinoma da bexiga e de concentrações elevadas de Ca2+ em ambos os tipos de tumores. As razões tumor/bexiga, tumor/fígado, tumor/pulmão e tumor/osso foram sempre inferiores ao valor de um. Estes resultados demonstraram que para o diagnóstico de carcinoma da bexiga e suas metástases em medicina nuclear, o tumor e as metástases surgiriam nas imagens como lesões frias, permitindo a sua identificação. Por outro lado, a terapia de carcinoma da bexiga e suas metástases parece não ser viável se administrado por via intravenosa, considerando a dosimetria elevada para outros órgãos

Textbook on Scar Management

This text book is open access under a CC BY 4.0 license. Written by a group of international experts in the field and the result of over ten years of collaboration, it allows students and readers to gain to gain a detailed understanding of scar and wound treatment – a topic still dispersed among various disciplines. The content is divided into three parts for easy reference. The first part focuses on the fundamentals of scar management, including assessment and evaluation procedures, classification, tools for accurate measurement of all scar-related elements (volume density, color, vascularization), descriptions of the different evaluation scales. It also features chapters on the best practices in electronic-file storage for clinical reevaluation and telemedicine procedures for safe remote evaluation. The second section offers a comprehensive review of treatment and evidence-based technologies, presenting a consensus of the various available guidelines (silicone, surgery, chemical injections, mechanical tools for scar stabilization, lasers). The third part evaluates the full range of emerging technologies offered to physicians as alternative or complementary solutions for wound healing (mechanical, chemical, anti-proliferation). Textbook on Scar Management will appeal to trainees, fellows, residents and physicians dealing with scar management in plastic surgery, dermatology, surgery and oncology, as well as to nurses and general practitioners ; Comprehensive reference covering the complete field of wounds and scar management: semiology, classifications and scoring Highly educational contents for trainees as well as professionals in plastic surgery, dermatology, surgery, oncology as well as nurses and general practitioners Fast access to information through key points, take home messages, highlights, and a wealth of clinical cases Book didactic contents enhanced by supplementary material and video

Textbook on Scar Management

This text book is open access under a CC BY 4.0 license. Written by a group of international experts in the field and the result of over ten years of collaboration, it allows students and readers to gain to gain a detailed understanding of scar and wound treatment – a topic still dispersed among various disciplines. The content is divided into three parts for easy reference. The first part focuses on the fundamentals of scar management, including assessment and evaluation procedures, classification, tools for accurate measurement of all scar-related elements (volume density, color, vascularization), descriptions of the different evaluation scales. It also features chapters on the best practices in electronic-file storage for clinical reevaluation and telemedicine procedures for safe remote evaluation. The second section offers a comprehensive review of treatment and evidence-based technologies, presenting a consensus of the various available guidelines (silicone, surgery, chemical injections, mechanical tools for scar stabilization, lasers). The third part evaluates the full range of emerging technologies offered to physicians as alternative or complementary solutions for wound healing (mechanical, chemical, anti-proliferation). Textbook on Scar Management will appeal to trainees, fellows, residents and physicians dealing with scar management in plastic surgery, dermatology, surgery and oncology, as well as to nurses and general practitioners ; Comprehensive reference covering the complete field of wounds and scar management: semiology, classifications and scoring Highly educational contents for trainees as well as professionals in plastic surgery, dermatology, surgery, oncology as well as nurses and general practitioners Fast access to information through key points, take home messages, highlights, and a wealth of clinical cases Book didactic contents enhanced by supplementary material and video