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Background The aim of the study was to identify the value of extensive resection and reconstruction with flaps in the treatment of locoregionally advanced lateral skull-base cancer. Patients and methods The retrospective case review of patients with lateral skull-base cancer treated surgically with curative intent between 2011 and 2019 at a tertiary otorhinolaryngology referral centre was made. Results Twelve patients with locoregionally advanced cancer were analysed. Lateral temporal bone resection was performed in nine (75.0%), partial parotidectomy in six (50.0%), total parotidectomy in one (8.3%), ipsilateral selective neck dissection in eight (66.7%) and ipsilateral modified radical neck dissection in one patient (8.3%). The defect was reconstructed with anterolateral thigh free flap, radial forearm free flap or pectoralis major myocutaneous flap in two patients (17.0%) each. Mean overall survival was 3.1 years (SD = 2.5) and cancer-free survival rate 100%. At the data collection cut-off, 83% of analysed patients and 100% of patients with flap reconstruction were alive. Conclusions Favourable local control in lateral skull-base cancer, which mainly involves temporal bone is achieved with an extensive locoregional resection followed by free or regional flap reconstruction. Universal cancer registry should be considered in centres treating this rare disease to alleviate analysis and multicentric research.

Background Electrochemotherapy (ECT) is a local cancer treatment based on electroporation where the electric field is used to enhance cell membrane permeability and thereby facilitating the transition of chemotherapeutic agents into the cell. For the treatment of non-melanoma skin cancer, a standard dosage of 15,000 IU/m2 bleomycin (BLM) is used. The aim of the present study was to evaluate the long-term ECT response in the group of elderly patients with non-melanoma skin cancer treated with a reduced dose of BLM in comparison to the outcome in the patients treated with the standard dose of BLM. Patients and methods Twenty-eight patients older than 65 years, with a total of 52 non-melanoma skin lesions were included in the study. Twelve patients (24 lesions) in the experimental group received a reduced dose of BLM (10,000 IU/m2), 16 patients (28 lesions) were treated with a standard dose of BLM (15,000 IU/m2). Results No statistically significant difference in tumor control was observed between both groups. In the experimental group, tumors recurred in 39.0% of treated lesions in a median follow-up time of 28 months. In the control group, the recurrence rate of treated lesions was 15.4% in a median follow-up time of 40 months. Conclusions ECT with a reduced dose of BLM is a feasible treatment option for elderly patients with equal efficacy to standard dose treatment and should be considered as a treatment modality in advanced aged patients with comorbidities, where overall life expectancy is poor.

With extending life expectancy, more people are diagnosed with cutaneous malignancies at advanced ages and are offered nonsurgical treatment. We assessed outcomes of the oldest-old adults after electrochemotherapy (ECT).The International Network for Sharing Practices of ECT (InspECT) registry was queried for adults aged ≥90 years (ys) with skin cancers/cutaneous metastases of any histotype who underwent bleomycin-ECT (2006-2019). These were subanalysed with patients aged90 ys after matching 1:2 for tumor location, number, size, histotype, and previous treatments. We assessed ECT modalities, toxicity (CTCAE), response (RECIST), and patient perception (EQ-5D).Sixty-one patients represented the study cohort (median 92 ys, range 92-104), 122 the control group (median 77 ys, range 23-89). Among the oldest-old, 44 patients (72%) had primary/recurrent skin cancers, 17 (28%) cutaneous metastases. Median tumour size was 15 mm (range, 5-450). The oldest-old adults underwent ECT mainly under local/regional anaesthesia (59% vs 39% p = .012). We observed no differences regarding dose and route of chemotherapy (intravenous vs intratumoral, p = .308), electrode geometry (linear vs hexagonal, p = .172) and procedural duration (18 vs 21 min, p = .378). Complete response (57.4 [95%-CI 44.1%-70.0%] vs 64.7% [95%-CI 55.6%-73.2%], p = .222) and 1-year local control (76.7% vs 81.7, p = .092) rates were comparable. Pain and skin hyperpigmentation were mild in both groups. Skin ulceration persisted longer in the oldest-old patients (4.4 vs 2.4 months, p = .008).The oldest-old adults with cutaneous malignancies undergo ECT most commonly under local/regional anaesthesia with safety profiles and clinical effectiveness similar to their younger counterparts, except in case of ulcerated tumors.

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.

The plasma concentration profile of bleomycin in the distribution phase of patients younger than 65 years is needed to determine the suitable time interval for efficient application of electric pulses during electrochemotherapy. Additionally, bleomycin concentrations in the treated tumors for effective tumor response are not known. In this study, the pharmacokinetic profile of bleomycin in the distribution phase in 12 patients younger than 65 years was determined. In 17 patients, the intratumoral bleomycin concentration was determined before the application of electric pulses. In younger patients, the pharmacokinetics of intravenously injected bleomycin demonstrated a faster plasma clearance rate than that in patients older than 65 years. This outcome might indicate that the lowering of the standard bleomycin dose of 15,000 IU/m2 with intravenous bleomycin injection for electrochemotherapy is not recommended in younger patients. Based on the plasma concentration data gathered, a time interval for electrochemotherapy of 5–15 min after bleomycin injection was determined. The median bleomycin concentration in tumors 8 min after bleomycin injection, at the time of electroporation, was 170 ng/g. Based on collected data, the reduction of the bleomycin dose is not recommended in younger patients, however, a shortened time interval for application of electric pulses in electrochemotherapy to 5–15 min after intravenous bleomycin injection should be considered.

Simple Summary Electrochemotherapy is a topical ablative treatment based on the formation of electropores in the cell membrane exposed to an external electric field. The consequent intracellular accumulation of hydrophilic bleomycin or cisplatin molecules greatly increases their cytotoxicity. Currently, electrochemotherapy is recognized as an effective treatment for tumors of different histological types and also for some deep-seated tumors. In mucosal cancer of the head and neck, experience with electrochemotherapy is limited, primarily due to the anatomical complexity of the region and the poor accessibility of tumors, as well as the design limitations of the electrodes used to create an electric field. A systematic review of the literature and subsequent analysis of 164 patients from 16 studies treated between 1998 and 2020 confirmed that electrochemotherapy is an effective and safe treatment for mucosal cancer of the head and neck as well. Electrochemotherapy (ECT) is a local ablative treatment that is based on the reversible electroporation and intracellular accumulation of hydrophilic drug molecules, which greatly increases their cytotoxicity. In mucosal head and neck cancer (HNC), experience with ECT is limited due to the poor accessibility of tumors. In order to review the experience with ECT in mucosal HNC, we undertook a systematic review of the literature. In 22 articles, published between 1998 and 2020, 16 studies with 164 patients were described. Curative and palliative intent treatment were given to 36 (22%) and 128 patients (78%), respectively. The majority of tumors were squamous cell carcinomas (79.3%) and located in the oral cavity (62.8%). In the curative intent group, complete response after one ECT treatment was achieved in 80.5% of the patients, and in the palliative intent group, the objective (complete and partial) response rate was 73.1% (31.2% and 41.9%). No serious adverse events were reported during or soon after ECT and late effects were rare (19 events in 17 patients). The quality-of-life assessments did not show a significant deterioration at 12 months post-ECT. Provided these preliminary data are confirmed in randomized controlled trials, ECT may be an interesting treatment option in selected patients with HNC not amenable to standard local treatment.

Final goal of the study is to estimate the cost-e ectiveness of electrochemotherapy for the tre- atment of basal-cell carcinoma and skin melanoma. Paper consists of two parts: the first part presents basic principles and concepts of health technology assessment and cost-e ectiveness analysis, and the second part reports an early cost-e ectiveness analysis of electrochemothe - rapy for the treatment of basal-cell carcinoma and skin melanoma that we are developing. Few cost-e ectiveness analyses of electrochemotherapy have already been done, but with a lack of information about intervention e ectiveness in terms of quality of life, which may result in inac- curate or even inadequate conclusions. In order to obtain the most realistic results, two general Markov models and their reduced versions for initial calculations are presented. The models were designed specifically to assess electrochemotherapy of basal-cell carcinoma and skin me- lanoma. Also, data required for successful calculations have been identified, some of which are missing and will be collected within di erent studies which are still under way, including rando- mized control trials. Additionally, recommendations for data collection process and follow-up reporting are made. With this paper we want to raise awareness about the importance of nume- ric quality of life reporting and usefulness/meaning of EQ-5D questionnaire that might not be self-evident at first sight, but are crucial for cost-e ectiveness analysis.

Aim Electrochemotherapy is an effective local treatment for cutaneous tumours and metastases. In this prospective trial, six European institutions investigated electrochemotherapy in recurrent, mucosal head and neck tumours. Patient and methods Forty-three patients with recurrent mucosal head and neck tumours and no further curative or reasonably effective palliative treatment options were enrolled and treated with electrochemotherapy. Patients were treated in general anaesthesia using intravenous or local injection of bleomycin followed by delivery of electric pulses to the tumour area. Primary end-point was local tumour response. Secondary end-points were safety and toxicity, overall and progression free survival, and quality-of-life. Results Thirty-seven patients were evaluable for tumour response, pain score, side-effects and quality of life questionnaires. Six patients were not evaluable due to lost follow-up, disease progression or death before evaluation. Intention to treat analysis revealed an objective response of 56% (complete response 8 (19%), partial response 16 (37%), stable disease 10 (23%), progressive disease 3 (7%), and not evaluable 6 (14%)). Three patients (7%) remained in complete response at 30, 34, and 84 months post-treatment. The treatment procedure was generally well tolerated. Swelling of the mucosa was observed in the first days after treatment. Pain and use of pain medication rose temporarily; fatigue and dysphagia were also noted in the quality of life assessment. Conclusion Electrochemotherapy can be applied to mucosal head and neck recurrent tumours accessible to the procedure with promising objective response, survival and toxicity profile. Attention should be paid to post-treatment swelling and planning of pain medication. These favourable results indicate that electrochemotherapy could play a role in patients with recurrent head and neck cancer.

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.

Background 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. Methods Twenty-eight patients older than 65 years were prospectively treated with electrochemotherapy for nonmelanoma head and neck skin cancer. In the experimental group (n = 12 patients; 24 lesions), reduced bleomycin doses (10 000 IU/m2 ) were used. In the control group (n = 16 patients; 28 lesions), the standard bleomycin doses (15 000 IU/m2 ) were used. Tumor responses and side effects were monitored. These two groups were pair matched for the characteristics of patients (age, gender) and their tumors (diameter, histology type, recurrent lesions). Results Complete tumor response at 2 months post-electrochemotherapy with the reduced bleomycin dose was 100% and with the standard bleomycin dose it was 96%. No statistically significant difference regarding skin toxicity was observed between the 2 groups (P = .20). Skin toxicity of grade 3 or less was recorded only in the control group (7% of treated lesions). Conclusion Presented results show the comparable antitumor effectiveness of electrochemotherapy when using standard or reduced bleomycin dose in elderly patients with nonmelanoma head and neck skin cancer.

Malignant salivary gland tumours are rare histologically and clinically heterogeneous group of tumours, missing prognostic factors and therapeutic targets. MicroRNAs (miRNAs), small noncoding RNAs, and posttranscriptional regulators of mRNA are poorly described in different subtypes of salivary gland tumours. Epidermal growth factor receptor (EGFR), an important therapeutic target and target of certain miRNAs (i.e.,miR-133b), shows variable degrees of expression in salivary gland tumours. Our study included 70 parotid gland tumours of different histological subtypes. Expression, mutations, and copy number variations (CNVs) of EGFR were determined using immunohistochemistry, single-stranded conformation polymorphism, quantitative polymerase chain reaction (qPCR), and fluorescence in situ hybridization. Expression ofmiR-99b,miR-133b,miR-140,miR-140-3p, andlet-7awas analysed using qPCR. Expression of EGFR was observed in 37% of tumours with low and 40% of tumours with high malignant potential. There were no mutations, with the majority of samples showing polysomy of chromosome 7. Based on histological subtypes, we found differential expression of all five miRNAs. We confirmed association of reactivity of EGFR,miR-133b,miR-140,miR-140-3p, andlet-7awith CNV of EGFR and a positive association betweenmiR-133b/let-7aand reactivity of EGFR. Age and need for postoperative radiotherapy were characterized as significant in multivariate survival analysis.

With the aim to determine effective therapeutic window of electrochemotherapy, we analyzed bleomycin pharmacokinetic parameters in elderly patients. In prospective clinical study in the treatment of tumors with electrochemotherapy, blood samples of patients older than 65 years were collected after the bolus intravenous injection of bleomycin (15,000 IU/m2). In serum samples, quantitative analysis was performed with liquid chromatography coupled to high-resolution mass spectrometry. Based on the data, the pharmacokinetic parameters of bleomycin elimination were determined. Pharmacokinetic analysis of the data revealed a monophasic serum clearance curve, which demonstrates slow elimination of bleomycin, being less than 500 ml/min and a half-time of 30 min. Slow monophasic elimination of bleomycin from serum in elderly patients implies on the longer therapeutic window, from 8 to up to 40 min or even longer post-bleomycin injection for electrochemotherapy. However, prolonged therapeutic bleomycin serum concentrations may also affect the possible adverse effects, such as lung fibrosis and extensive necrosis of tumors due to the uptake of toxic bleomycin concentrations into the tumors. This may imply on lowering of bleomycin dosage, in particular in the elderly patients.

Treatment with electrochemotherapy is by far used for treatment of cutaneous cancers. Its potential for treating deep-seated head and neck lesions, but also those in other areas of the body is yet to be fully understood and appreciated. Emphasizing the importance of proper patient and treatment parameters selection, their education about the possible drawbacks of treatment and, last but not least, outcomes are of utmost importance. We present two patients, both with squamous cell carcinomas of head and neck, but with very different outcomes.

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.

Electroporation-based treatments provide highly effective local treatment for a variety of tumors. For deep seated tumors in the head and neck region, the complex anatomy and difficult access often warrants the use of single long needle electrodes for which a treatment plan provides the information on optimal voltages and electrode positions in the highly constrained environment. The feasibility of such treatments can be enhanced by use of a navigation system for the positioning of electrodes. Treatment planning is performed using finite element method to compute electric fields in the tumor and surrounding tissues and using this to optimize delivered voltages. Navigation systems consist of optical tracking system, which tracks an instrument in space to introduce it along predefined trajectories. This paper aims to present a technical method for coupling treatment planning with a navigation device and using that to treat tumors in the head and neck area illustrated with a case of electrochemotherapy treatment of tumors in the neck and in the left parotid gland.

Background. Cervical necrotizing fasciitis is an infectious disease with serious complications and grave prognosis. We report a case of the cervical necrotizing fasciitis with consequent bilateral dysfunction of superior laryngeal nerves and describe the characteristics of this exceptional complication.Case report. A 71-year-old female patient, surgically treated for cervical necrotizing fasciitis, suffered from severe dysphagia after surgery. Radiographic and fiberendoscopic evaluation showed aspiration and hyposensibility of glottis and supraglottis. Apart from inadequate laryngeal elevation, we explain the dysphagia also by the sensory deficit of the supraglottic mucosa with consequent lack of vocal folds adduction during swallowing. The sensory deficit was attributed to the toxic neuritis-mediated dysfunction of both internal branches of superior laryngeal nerves. The healing of both cervical necrotizing fasciitis and toxic neuritis led to the restoration of sensory function and the swallowing.Conclusions. Although only occasionally reported in the literature, the patients with cervical necrotizing fasciitis are prone to toxic neuritis-mediated neurologic deficits of cranial nerves. They are considered to be another complication of this entity.

Background Electrochemotherapy 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 methods Electrochemotherapy 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. Results Coupling 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. Conclusion We 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.