Ales Groselj

Coupling treatment planning with navigation system: a new technological approach in treatment of head and neck tumors by electrochemotherapy

BackgroundElectrochemotherapy provides highly effective local treatment for a variety of tumors. In deep-seated tumors of the head and neck, due to complex anatomy of the region or inability to cover the whole tumor with standard electrodes, the use of long single needle electrodes is mandatory. In such cases, a treatment plan provides the information on the optimal configuration of the electrodes to adequately cover the tumor with electric field, while the accurate placement of the electrodes in the surgical room in patients can remain a problem. Therefore, during electrochemotherapy of two head and neck lymph-node metastases of squamous cell carcinoma origin, a navigation system for placement of electrodes was used.Patient and methodsElectrochemotherapy of two lymph-node metastases of cutaneous squamous cell carcinoma, one in the left parotid gland and the other in the neck just behind the left mandibular angle, was performed using intravenous administration of bleomycin and long single needle electrodes. The tumors were treated according to the prepared treatment plan, and executed with the use of navigation system.ResultsCoupling of treatment plan with the navigation system aided to an accurate placement of the electrodes. The navigation system helped the surgeon to identify the exact location of the tumors, and helped with the positioning of the long needle electrodes during their insertion, according to treatment plan. Five electrodes were inserted for each metastasis, one centrally in the tumor and four in the periphery of the tumor. Five weeks after electrochemotherapy, computed tomography images demonstrated partial response of the first metastasis and complete response of the second one. Six weeks after electrochemotherapy, fine-needle aspiration biopsy specimen obtained from the treated lesions revealed necrosis and inflammatory cells, without any viable tumor cells.ConclusionWe describe a new technological approach for electrochemotherapy of deep-seated head and neck tumors, coupling of the treatment planning with navigation system for accurate placement of the single long needle electrodes into and around the tumors, according to the treatment plan. Evidence of its effectiveness on two lymph-node metastases of cutaneous squamous cell carcinoma origin in neck lymph is provided.

Identification and quantification of bleomycin in serum and tumor tissue by liquid chromatography coupled to high resolution mass spectrometry

Bleomycin is a cytotoxic antibiotic available as a compost of structurally strongly related glycopeptides, which is in vivo found chelated with several metals. Its pharmacotherapy has merely been based on experimental dose - response data, whereas its biodistribution and pharmacokinetics remain fundamentally unknown. This is reasoned by an absence of a specific and sensitive mass spectrometry-based analytical method for its determination in biological tissues. We herein reveal the results of our study on the mass spectrometric behavior of two main bleomycin fractions A2 and B2, including their metal complexes, particularly the predominant copper chelates. In the electrospray ion source bleomycin forms double charged species, where for the metal-free fraction A2 and its copper complex m/z 707.76 and m/z 707.21 are seen, respectively. Hence, the second isotopic ion of the chelate (m/z 707.71) nearly coincides with the first isotopic ion of the metal-free fraction. This phenomenon can only be followed by high-resolution mass spectrometry, and is considered the plausible reason, why the attempts to determine bleomycin with mass spectrometry have been so scarce. The presented paper further describes a sensitive and selective liquid chromatography - mass spectrometry analytical method for determination of bleomycin in serum and tumor tissues. This newly developed method was employed for bleomycin pharmacokinetic studies in serum and tumors of laboratory animals. Additionally, the method was employed for determination of bleomycin pharmacokinetic parameters in elderly patients in order to determine the effective therapeutic window of electrochemotherapy with bleomycin.

Efficiency of electrochemotherapy with reduced bleomycin dose in the treatment of nonmelanoma head and neck skin cancer: Preliminary results

In the present study, effectiveness of electrochemotherapy was compared in patients with nonmelanoma skin cancer (NMSC) of the head and neck using standard and reduced doses of bleomycin.

Vascularization of the tumours affects the pharmacokinetics of bleomycin and the effectiveness of electrochemotherapy

Pre‐clinical and clinical data indicate differences in the responses of melanoma and carcinoma tumours to electrochemotherapy. The purpose of this study was to investigate the origin of this difference, whether it is due to the intrinsic difference in tumour cell susceptibility to the chemotherapeutic, or due to the tumour micro‐environment. For this purpose, we performed a pre‐clinical study in B16F1 melanoma and TS/A carcinoma tumours in mice, in which the antitumour effectiveness of electrochemotherapy with bleomycin, the intrinsic sensitivity of tumour cells in vitro, the pharmacokinetics of bleomycin in plasma and tumours, and the vascularization of tumours in vivo were evaluated. The results of the treatment show that carcinoma was significantly more responsive to electrochemotherapy than melanoma. This effect cannot be ascribed to the intrinsic sensitivity of these cells, as melanoma cells were more sensitive than carcinoma cells in vitro. The difference in responses could be ascribed to differences in the pharmacokinetics of bleomycin; at the time of electroporation in carcinomas, more bleomycin was accumulated. This effect could be due to differences in tumour vascularization, as carcinoma tumours had numerous well‐distributed, small blood vessels, while melanomas were less vascularized, exhibiting predominantly larger vessels. In conclusion, this study provides evidence on the importance of the tumour micro‐environment, particularly the tumour vasculature, in the responses of the tumours to bleomycin electrochemotherapy. Vasculature is important for the pharmacokinetics of bleomycin, influencing drug accumulation and drug distribution in tumours, and might be used as a predictive factor for the tumour response to electrochemotherapy.

Early stage Health Technology Assessment of Electrochemotherapy of skin-directed therapy for skin melanoma and Basal Cell Carcinoma

One of the most successful medical application exploiting electroporation is an antitumor therapy called electrochemotherapy (ECT). Clinical use of electroporation in medicine is in full swing and in need of Health Technology Assessment (HTA) analysis. The early stage HTA would enable easier equipment purchase and increase opportunities for including ECT in the list of treatments covered by health insurance and raise the general awareness of electrochemotherapy cost in comparison to benchmark treatments. Few cost efficacy analysis have already been performed [1] but they are lacking information on Quality of Life (QoL) increase. The cost effectiveness of electrochemotherapy will be evaluated for treatment of skin melanoma and Basal Cell Carcinoma (BCC). Because cancer is a recurrent disease, we choose Markov modeling strategy. The article is composed of a detailed model description and procedures defined for future data collection. With this article we would also like to emphasize the importance of EQ_5D questioners, a standardised instrument for use as a measure of health outcome and numerical reporting of QoL increase.

Electrochemotherapy of Head and Neck Cancer

In the head and neck area, electrochemotherapy (ECT) is currently implemented for the treatment of recurrent and/or metastatic cutaneous, subcutaneous, mucosal, or deep-seated tumors of any kind of histology. However, its particular efficiency in the treatment of small, primary, and treatment-naïve tumors has already been demonstrated. Nevertheless, ECT has different effectiveness in tumors of various histotypes. Basal cell carcinomas proved to be a most responsive tumor with almost 100 % objective response rate and excellent cosmetic results without any functional impairment of treated sites. For the treatment of deep-seated tumors in the head and neck region, long single needle electrodes are used. These electrodes can be placed in various patterns with the aim to cover large and irregular-shaped tumors, hidden under the visible surface. Moreover, M. Benazzo • G. Bertino (*) Department of Otolaryngology Head & Neck Surgery, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy e-mail: m.benazzo@smatteo.pv.it; giulia.bertino@tin.it A. Groselj Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia e-mail: ales.groselj@kclj.si # Springer International Publishing Switzerland 2016 D. Miklavcic, Handbook of Electroporation, DOI 10.1007/978-3-319-26779-1_102-1 1 coupling treatment planning and navigation system enables precise insertion of long, single needle electrodes into deep-seated tumors of the head and neck region. Further developments in the application of ECT in the head and neck cancers are orientated to reduced dose of bleomycin in elderly patients and combining ECT with immunotherapy and/or immunogene electrotransfer.

Distant metastasis of rectal adenocarcinoma in a temporary tracheostoma.

Abstract Background. The temporary tracheostoma’s metastases of head and neck cancer had already been reported in the literature. So far, they had been considered as regional dissemination of the malignant disease. We report a case of temporary tracheostoma’s metastasis of carcinoma from non-head-and-neck primary site, what has not been reported in the literature, yet. Therefore, it is the first reported case of the systemic dissemination of malignant tumour into temporary tracheostoma. Case report. Fifty-four-year-old female patient, previously treated for a rectal adenocarcinoma, reported in our office with exophytic pink tissue masses around the temporary tracheostoma. The biopsy and immunohistochemistry findings were consistent with temporary tracheostoma’s metastasis of the rectal adenocarcinoma. The patient received palliative radiotherapy and died of systemic progression of the disease. Conclusions. The patients with history of primary cancer of any origin and exophytic proliferating changes around the tracheostoma require an appropriate diagnostic work-up including a biopsy. The type of treatment depends on the extent of the disease, previous therapy and general condition of the patient