Oligometastatic Disease and Interventional Oncology: Rationale and Research Directions.

Oligometastatic disease (OMD) is generally defined as a stage of clinically or radiographically demonstrated metastatic disease limited in total disease burden and without rapid spread. Interventional oncology performs local therapies for primary and metastatic cancers, including OMD. Interventional oncology treatments can be pursued both as definitive therapy and for palliative purposes. Applied to OMD, these interventions can offer patients a decreasing overall tumor burden, minimizing cancer morbidity, and early evidence suggests a survival benefit. Here, we discuss the range of interventional oncology treatments, including ablation, chemoembolization, radioembolization, and irreversible electroporation. We describe the rationale for their application to OMD and discuss future directions for research.

Electrochemotherapy - Emerging applications technical advances, new indications, combined approaches, and multi-institutional collaboration.

The treatment of tumors with electrochemotherapy (ECT) has surged over the past decade. Thanks to the transient cell membrane permeabilization induced by the short electric pulses used by ECT, cancer cells are exposed to otherwise poorly permeant chemotherapy agents, with consequent increased cytotoxicity. The codification of the procedure in 2006 led to a broad diffusion of the procedure, mainly in Europe, and since then, the progressive clinical experience, together with the emerging technologies, have extended the range of its application. Herein, we review the key advances in the ECT field since the European Standard Operating Procedures on ECT (ESOPE) 2006 guidelines and discuss the emerging clinical data on the new ECT indications. First, technical developments have improved ECT equipment, with custom electrode probes and dedicated tools supporting individual treatment planning in anatomically challenging tumors. Second, the feasibility and short-term efficacy of ECT has been established in deep-seated tumors, including bone metastases, liver malignancies, and pancreatic and prostate cancers (long-needle variable electrode geometry ECT), and gastrointestinal tumors (endoscopic ECT). Moreover, pioneering studies indicate lung and brain tumors as suitable future targets. A further advance relates to new combination strategies with immunotherapy, gene electro transfer (GET), calcium EP, and radiotherapy. Finally and fourth, cross-institutional collaborative groups have been established to refine procedural guidelines, promote clinical research, and explore new indications.

Updated standard operating procedures for electrochemotherapy of cutaneous tumours and skin metastases.

Electrochemotherapy is now in routine clinical use to treat cutaneous metastases of any histology, and is listed in national and international guidelines for cutaneous metastases and primary skin cancer. Electrochemotherapy is used by dermatologists, surgeons, and oncologists, and for different degrees and manifestations of metastases to skin and primary skin tumours not amenable to surgery. This treatment utilises electric pulses to permeabilize cell membranes in tumours, thus allowing a dramatic increase of the cytotoxicity of anti-cancer agents. Response rates, often after only one treatment, are very high across all tumour types. The most frequent indications are cutaneous metastases from malignant melanoma and breast cancer. In 2006, standard operating procedures (SOPs) were written for this novel technology, greatly facilitating introduction and dissemination of the therapy. Since then considerable experience has been obtained treating a wider range of tumour histologies and increasing size of tumours which was not originally thought possible. A pan-European expert panel drawn from a range of disciplines from dermatology, general surgery, head and neck surgery, plastic surgery, and oncology met to form a consensus opinion to update the SOPs based on the experience obtained. This paper contains these updated recommendations for indications for electrochemotherapy, pre-treatment information and evaluation, treatment choices, as well as follow-up.

Recent Advances in Pancreatic Cancer Surgery of Relevance to the Practicing Pathologist.

Recent advances in pancreatic surgery have the potential to improve outcomes for patients with pancreatic cancer. We address 3 new, trending topics in pancreatic surgery that are of relevance to the pathologist. First, increasing awareness of the prognostic impact of intraoperatively detected extraregional and regional lymph node metastases and the international consensus definition on lymph node sampling and reporting. Second, neoadjuvant chemotherapy, which is capable of changing 10% to 20% of initially unresectable, to resectable disease. Third, in patients who remain unresectable following neoadjuvant chemotherapy, local ablative therapies may change indications for treatment and improve outcomes.

[The application of electrolaser myostimulation and laserophoresis of biologically active compounds in sports medicine (a review)].

This scientific review highlights peculiarities of the delivery of laser radiation to the tissues of the athlete's body by means of laser electrophoresis of biologically active substances and the possibilities for electrolaser myostimulation. The main features of electrical myostimulation based on the application of laser-generated radiation are described. The authors emphasize the necessity of taking into account the neurophysiological dependence of active and passive contractile muscular activity during training. They provide the scientifically grounded rationale for the combined use of coherent laser radiation and electrical stimulation. The list of scientific papers that confirm the effectiveness of the method being considered is presented. The authors compare this method with other techniques for the induced ion transfer. The beneficial influence of laserphoresis of succinic and hyaluronic acids on the athlete's body is reported with special reference to alleviating the pain syndrome. A number of phyto-extracts used for the purpose of laser electrophoresis are characterized. The authors demonstrate the application of the optional versions of this technique in various sports during the training and competition periods.

Health technology assessment in evolution - focal therapy in localised prostate cancer.

Focal therapy in prostate cancer aims to treat only the part of the gland harboring clinically significant disease while preserving the rest of the tissue. This approach may substantially reduce treatment-related toxicity without compromising disease control outcomes. Short- to medium-term functional and oncological results in prospective interventional studies are promising, but comparative effectiveness research against standard of care is required to incorporate focal therapy among standard options. In this review, we discuss the actual stage of assessment and results of sources of energy commonly used to deliver focal therapy. We also provide our viewpoint on how the field will evolve in the near future.

Ultrasound-mediated drug/gene delivery in solid tumor treatment.

Ultrasound is an emerging modality for drug delivery in chemotherapy. This paper reviews this novel technology by first introducing the designs and characteristics of three classes of drug/gene vehicles, microbubble (including nanoemulsion), liposomes, and micelles. In comparison to conventional free drug, the targeted drug-release and delivery through vessel wall and interstitial space to cancerous cells can be activated and enhanced under certain sonication conditions. In the acoustic field, there are several reactions of these drug vehicles, including hyperthermia, bubble cavitation, sonoporation, and sonodynamics, whose physical properties are illustrated for better understanding of this approach. In vitro and in vivo results are summarized, and future directions are discussed. Altogether, ultrasound-mediated drug/gene delivery under imaging guidance provides a promising option in cancer treatment with enhanced agent release and site specificity and reduced toxicity.

Novel methods for renal tissue ablation.

PURPOSE OF REVIEW: To provide an overview of the current research on renal tissue ablation, highlighting novel ablation techniques and technologies. RECENT FINDINGS: As long-term data on renal radio frequency ablation (RFA) and cryoablation confirming their oncologic efficacy emerge, ongoing research aims at improving the treatment profiles of these techniques as well as developing novel methods for renal tissue ablation. SUMMARY: Although nephron-sparing surgery is the gold standard treatment for small renal masses confirmed malignant, ablative therapies are an option in elderly patients, who may be poor surgical candidates. RFA and cryoablation have each been used for renal tissue ablation for over a decade but their efficacy in ablation of central lesions or lesions more than 3 cm in size is limited. Increasing ablation size and improving efficiency of thermal energy delivery are the goals of research in RFA and cryoablation. Novel ablation technologies including microwave ablation, irreversible electroporation and high-intensity focused ultrasound among others have undergone preliminary preclinical and clinical evaluation in select series but require further development and assessment of outcomes prior to routine clinical use for renal tumor ablation.

Electrochemotherapy of solid tumors--preclinical and clinical experience.

Electrochemotherapy consists of administration of the chemotherapeutic drug followed by application of electric pulses to the tumor, in order to facilitate the drug uptake into the cells. Only two chemotherapeutics are currently used in electrochemotherapy, bleomycin and cisplatin, which both have hampered transport through the plasma membrane without electroporation of tumors. Based on extensive preclinical studies, elaborating on parameters for effective tumor treatment and elucidating the mechanisms of this therapy, electrochemotherapy is now in clinical use. It is in standard treatment of melanoma cutaneous metastases in Europe. However it is effective also for cutaneous metastases of other tumor types. Currently the technology is being developed also for treatment of bigger, deep seated tumors. With long needle electrodes and new electric pulse generators, clinical trials are on-going for treatment of liver metastases, bone metastases and soft tissue sarcomas.

Utilização de eletroquimioterapia em neoplasias de origem epitelial ou mesenquimal localizadas em pele ou mucosas de cães / Employment of electrochemotherapy in canine neoplasms of epithelial or mesenchymal origin located in the skin or mucosal membranes

A eletroquimioterapia é caracterizada como um protocolo que agrega o uso de fármacos antineoplásicos à aplicação regional de pulsos elétricos, maximizando a concentração intracelular destes agentes, assim propiciando maior ação citotóxica dos mesmos. A bleomicina, um antimicrobiano dotado de propriedade antineoplásica, demonstra restrição no transporte através da membrana celular dada sua composição molecular hidrofílica. Todavia, uma vez administrada via intralesional ou endovenosa associada à eletroporação, exibe citotoxicidade potencializada. Foram utilizados 34 cães acometidos por neoformações solitárias de origem epitelial ou mesenquimal, situadas em pele ou membranas mucosas. Padronizou-se o protocolo eletroquimioterápico empregando-se sulfato de bleomicina, pela via intralesional, na dose de 1U/cm3 de tumor. A eletroporação foi perfilada com eletrodo composto por agulhas, pulsos elétricos com tensão de 1000 V, em onda quadrada unipolar, com duração de 100 microsegundos, totalizando-se oito ciclos. Constatou-se remissão neoplásica integral em 30 cães (88,3%) e refratariedade ao protocolo em apenas quatro animais (11,7%). Inexistiram complicações e/ou efeitos adversos decorrentes do procedimento. O protocolo neste trabalho estudado revelou-se aplicável, eficaz e seguro na terapêutica antineoplásica em cães.

Electrochemotherapy is characterized as a protocol which combines the use of antineoplastic agents with localized application of electric pulses to improve the intracellular concentration of these agents, increasing, thus, its cytotoxic action. Bleomycin, an antibiotic agent with antineoplastic properties, is a hydrophilic molecule, having a restricted transport through the cellular membrane. However, when it is administered intralesionally or intravenously and associated to electroporation, its cytotoxicity is maximized. There were utilized 34 dogs affected by a single lesion of epithelial or mesenchymal origin, located in the skin or mucosal membranes. The electrochemotherapy protocol was standardized using intralesional bleomycin sulfate at a dose of 1U/cm3of tumoral area. Electroporation was performed using an electrode composed of needles and electric pulses with a 1000 V voltage, in unipolar square wave and 100 microseconds duration, totalizing eight cycles. There was complete neoplastic remission in 30 dogs (88.3%) and refractoriness to the protocol in four animals (11.7%). There were no complications or side effects associated with the procedure. The protocol studied in this work showed to be feasible, effective and safe for antineoplastic therapy in dogs.

Application of electroporation gene therapy: past, current, and future.

Twenty-five years after the publication of the first report on gene transfer in vitro in cultured cells by the means of electric pulse delivery, reversible cell electroporation for gene transfer and gene therapy (DNA electrotransfer) is at a crossroad in its development. Present knowledge on the effects of cell exposure to appropriate electric field pulses, particularly at the level of the cell membrane, is reported here as an introduction to the large range of applications described in this book. The importance of the models of electric field distribution in tissues and of the correct choice of electrodes and applied voltages is highlighted. The mechanisms involved in DNA electrotransfer, which include cell electropermeabilization and DNA electrophoresis, are also surveyed. The feasibility of electric pulse for gene transfer in humans is discussed taking into account that electric pulse delivery is already regularly used for localized drug delivery in the treatment of cutaneous and subcutaneous solid tumors by electrochemotherapy. Because recent technological developments have made DNA electrotransfer more efficient and safer, this nonviral gene therapy approach is now ready to reach the clinical stage. A good understanding of DNA electrotransfer principles and a respect for safe procedures will be key elements for the successful future transition of DNA electrotransfer to the clinics.

Applicator and electrode design for in vivo DNA delivery by electroporation.

As in vivo electroporation advances from the preclinical phase to clinical studies and eventually to routine medical practice, the design of electroporation devices becomes increasingly important. Achieving safety and efficacy levels that meet regulatory requirements, as well as user and patient friendliness, are major design considerations. In addition, the devices will have to be economical to manufacture. This chapter will focus on the design of applicators and electrodes, the pieces of hardware in direct contact with the user and the patient, and thus key elements responsible for the safety and efficacy of the procedure. The two major foreseeable applications of the technology in the DNA field are for gene therapy and DNA vaccination. Design requirements differ considerably for these applications and for the diseases to be treated or prevented. In addition to the trend of device differentiation, there is also a trend to build devices capable of performing both the step of delivering the DNA to the target tissue and the subsequent step of electroporation. This chapter presents the electrical and biological principles underlying applicator and electrode design, gives an overview of existing devices, and discusses their advantages and disadvantages. The chapter also outlines major design considerations, including regulatory pathways, and points out potential future developments.

Electrotransfer of therapeutic molecules into tissues.

Electroporation is a physical method for the delivery of various molecules into cells by application of controlled external electrical fields that transiently increase permeability of the cell membrane. This technique is now widely used as an alternative to viral gene delivery for transfection of therapeutic genes into different tissues. Gene electrotransfer holds great potential for clinical application due to the ease of preparation of large quantities of endotoxin-free plasmid DNA, the control and reproducibility of this method, and the development of electric pulse generators approved for clinical use. Electroporation has been utilized mainly for DNA vaccination against infectious diseases and cancer. It has also been used for the delivery of other therapeutic genes, mainly cytokines, used in the treatment of various diseases, including cancer, arthritis, multiple sclerosis and inflammation, following organ transplantation. Electroporation as a delivery system for chemotherapeutic drugs, termed antitumor electrochemotherapy, is already at the clinical stage and is being used routinely in several oncology centers in Europe. In addition, the first clinical trials for electrogene therapy of cancer are ongoing. Therefore, it can be presumed that electrotransfer of therapeutic genes into tissues will soon form a validated alternative to viral delivery systems in a clinical setting.