A pilot study of electrical resistance in feline squamous cell carcinoma treated with electrochemotherapy

A pilot study of electrical resistance in feline squamous cell carcinoma treated with electrochemotherapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A pilot study of electrical resistance in feline squamous cell carcinoma treated with electrochemotherapy Delia Franchini, Stefano Ciccarelli, Cosimo Assumma, Ilaria Laino, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8592493/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 11 You are reading this latest preprint version Abstract Tumors are complex microenvironments in which uncontrolled cell proliferation alters biochemical pathways as well as the physical and electrical properties of tissues. Electrochemotherapy (ECT) exploits electroporation-induced transient increases in cell membrane permeability to enhance intracellular delivery of chemotherapeutic agents. Electroporation is associated with a reduction in tissue electrical resistance due to aqueous pore formation, influenced by electric field intensity, pulse number, and tissue architecture. This study aimed to evaluate changes in tumor electrical resistance during ECT in 39 cats with squamous cell carcinoma (SCC) and to investigate potential correlations between resistance reduction and therapeutic response. Lesions were located on the nasal planum or eyelids and staged as T 1 –T 4 N 0 M 0 . Tumor electrical resistance (Ω) was recorded in real time for each pulse during all ECT sessions using a veterinary-modified clinical electroporator with integrated resistance-measurement software. Resistance values ranged from 600 to 4900 Ω. Statistical analysis revealed a significant decrease in resistance across sessions and pulses. Resistance was higher in eyelid lesions compared with nasal planum tumors and lower in cats achieving complete response. Additionally, resistance varied significantly among tumor grading, with a significant interaction between tumor stage and localization. In conclusion, tumor electrical resistance decreases during ECT in feline SCC, and lower resistance values are associated with improved local tumor control. Real-time resistance monitoring may represent a non-invasive surrogate marker of effective electroporation and treatment adequacy. Biological sciences/Cancer Health sciences/Medical research Health sciences/Oncology resistance tumor biphasic pulses bleomycin cat Figures Figure 1 Figure 2 Introduction Tumors represent composite microenvironments where unrestrained proliferation alters not only biochemical pathways but also the physical and electrical properties of tissues 1 – 4 . Over the past decade, there has been increasing attention toward the mechanical and electrical properties of cancer cells and tissues and their possible exploitation for enhanced diagnosis and treatment 1 – 11 . Electrochemotherapy (ECT) is a treatment that exploits the susceptibility of neoplastic cells to permeabilization by appropriately shaped electrical pulses through the process known as electroporation (EP) 12 – 14 , representing a highly flexible approach for the treatment of solid tumors, both as an adjuvant and a neoadjuvant therapy in cases of incompletely resected malignant neoplasms or inoperable tumors 12 – 16 . EP consists of exposing cells to specific electrical pulses of sufficient amplitude to increase cell membrane permeability, thereby allowing chemotherapeutic molecules to access the cytoplasm 17 , 18 . Tissue EP depends on the local distribution of the electric field and on tissue anatomy 19 . Moreover, the electrical properties change during the application of voltage pulses due to cell membrane modifications induced by the applied electric field 20 . The electric field required to maintain a given current density is proportional to resistivity, following relationship holds: E = ρJ Where E is the electric field, J is the current density, and ρ is the resistivity of the material 19 . Tissue resistivity decreases following electroporation, and this effect becomes more pronounced with increasing numbers of pulses and higher electric field intensities 20 , as predicted by Ohm’s first law: R = V/I where R is the resistance in Ohm (Ω), V is the voltage across the circuit, and I is the current flowing through it. The reduction in resistivity is attributable to the formation of aqueous pores in the cell membrane. The presence of these aqueous pores increases the number of ions crossing the membrane 19 . Biological tissue behaves as an assorted concoction of conductors and insulators. Cell membranes act as capacitive barriers. Cytoplasm and extracellular fluids provide conductive pathways due to their ionic content. Extracellular matrix proteins contribute resistive and dielectric properties 1 – 4 . Tumors typically alter this equilibrium through amplified angiogenesis, disrupted extracellular matrix, necrotic foci or even areas, and variable hydration, which together impact resistance measurements 10 , 11 . ECT is an effective local treatment for cutaneous neoplasms in particular feline squamous cell carcinoma (fSCC). fSCC is a malignant tumor arising from epidermal cells that differentiate into keratinocytes and primarily affects older, white-coated cats, accounting for approximately 15–50% of all cutaneous tumors in cats 21 – 33 . Chronic exposure to ultraviolet radiation is considered the main etiologic factor. fSCC often presents deceptively as non-healing, scabbing lesions on the eyelids, nasal planum, or auricles of light-colored cats, which gradually progress to ulceration. fSCC is locally invasive and metastatic spread is uncommon and, when it occurs, it generally involves the regional lymph nodes and lungs 15 , 16 , 21 , 24 – 32 . The response rate ECT is generally high, reaching up to 85%, with early-stage SCC associated with a more favorable prognosis 15 , 16 , 21 , 24 – 28 , 30 , 31 . Adverse effects are usually mild and include local inflammation, edema, exuberant scab formation (occasionally associated with transient secondary anosmia), as well as changes in pigmentation or alopecia. Side effects are mitigated by the administration of anti-inflammatory drugs, primarily non-steroidal agents such as cyclooxygenase inhibitors, and analgesics, including gabapentin 32 . To date, there are no data available on in vivo measurements of tumor electrical resistance in pets treated with ECT. fSCC was selected as the tumor histotype for this preliminary investigation because of its high response rate to ECT and low metastatic potential, which allow for long-term follow-up and make it an easily accessible model for electrical resistance measurements. On this basis, the aim of this study was to evaluate changes in electrical resistance in fSCC during ECT sessions and to explore potential correlations between decreasing resistance values and treatment efficacy. Material and Methods Patients From 2021 to 2025 privately owned cats and shelters cats diagnosed with T 1 -T 4 N 0 M 0 fSCC were enrolled in this prospective observational non randomized clinical trial and treated with ECT at Clinica Veterinaria Casal Monastero, Rome, Italy and Ambulatorio Veterinario “Le Accademie”, Rome, Italy. This study was approved by the Ethics Committee of the CESA Department of Veterinary Medicine-University of Bari with number protocol 31/2021. All experiments were performed in accordance with relevant guidelines and regulations. Inclusion criteria were confirmed diagnosis of fSCC, absence of metastases, and completed treatment. Cats with concurrent systemic diseases, and other neoplastic diseases were excluded. Collected data included signalment (breed, sex, and age), tumor location, complete blood count, serum biochemistry profile, and urinalysis. Tumor staging was performed using three-view thoracic radiographs, abdominal ultrasonography, and fine-needle aspiration of regional lymph nodes. Additional variables included the number of ECT sessions, treatment response, local and systemic adverse effects, recurrence rate, and electrical tissue resistance, which was recorded for each pulse delivered during every ECT session until the end of treatment. Follow-up evaluations were conducted at 1 and 2 weeks after each ECT session, monthly for the first 6 months, and every 3 months thereafter until the end of the observation period (November 2025). ECT protocol and post-ECT management ECT sessions were performed under general anesthesia using modified clinical electroporator Onkodisruptor® (Biopulse Biotech Italia) with implemented software for the measurement of tumor electrical resistance. The anesthetic protocol included premedication with medetomidine (Domitor, Pfizer Italia, Milan, Italy) 40 µg/kg and butorphanol (Dolorex, Intervet Italia, Milan, Italy) 0.1 mg/kg EV and induction with propofol (Propovet, Zoetis Italia S.r.l., Rome, Italy) 2 mg/kg IV. The ECT protocol included the administration of bleomycin (Bleoprim®, Hikma Italia S.p.A., Pavia, Italy) at the dose of 15 mg/m 2 as a bolus injection. Seven minutes after the bleomicyn administration, trains of biphasic pulses were administered at the voltage of 1200 V/cm, 1 Herz frequency, until the tumor area was covered using needle electrodes. Treatments were repeated every two weeks until tumor resolution or progression was observed. During the ECT sessions the cats were monitored using an electrocardiogram and a pulse oximeter. Post-treatment care included analgesia with meloxicam (Meloxoral®; Dechra Veterinary Products S.r.l.) at 0.1 mg/kg on day 1, followed by 0.05 mg/kg orally for the subsequent 3 days and antibiotic therapy with amoxicillin–clavulanic acid (Synulox®; Zoetis Italia S.r.l.) at 20 mg/kg orally every 12 hours for 5 days, in case of secondary infection on the treated area. In cases of reduced appetite, transdermal mirtazapine ointment (Mirataz® Dechra Veterinary Products S.r.l.) was administered to minimise the risk of anorexia 33 . Ethical considerations and euthanasia procedure Cats exhibiting uncontrolled tumor progression associated with severe clinical deterioration or an unacceptable quality of life were humanely euthanized. Euthanasia was performed under deep general anesthesia induced by premedication with intravenous dexmedetomidine (5 µg/kg; Dexdomitor, Vétoquinol Italia S.r.l., Italy) combined with butorphanol (0.1 mg/kg; Dolorex, Intervet Italia, Milan, Italy), followed by intravenous administration of propofol (Propovet, Zoetis Italia S.r.l., Italy) to effect, in accordance with established veterinary and ethical guidelines. After confirmation of an adequate depth of anesthesia, euthanasia was completed by intravenous administration of potassium chloride (1–2 mmol/kg), in compliance with accepted veterinary guidelines for humane euthanasia in cats with terminal neoplastic disease. Resistance measurement Electrical tissue resistance was measured using a modified electroporator designed for veterinary applications (Onkodisruptor®). The device calculates resistance based on the electric voltage generated at the electrode extremities in accordance with Ohm’s first law. The instrument was configured to measure electrical resistance values ranging from 0 to 500000 Ω. Measurements exceeding this range were displayed by the system as “too high”. Electrical resistance values were automatically recorded by the electroporator during each pulse delivery and subsequently transcribed by the operator at the conclusion of each ECT session. Response Treatment response was evaluated according to VCOG RECIST v1.1 34 . Complete Response (CR) was defined as the complete disappearance of the treated lesion. Partial Response (PR) was defined as a reduction of more than 30% in the size of lesion. Stable Disease (SD) was defined as a reduction of less than 30% or an increase of less than 20% in the size of the treated lesion. Progressive disease (PD) was defined as a greater than 20% increase in the size of the treated lesion or the development of one or more new lesions. Overall response rate (ORR) was defined by the percentage of cats achieving CR or PR. Adverse Events Adverse events were categorized according to VCOG-CTCAE, v.2 35 . Pruritus, alopecia, erythema, skin ulcerations, tissue necrosis were assessed. Grade 1 (mild) was defined as clinical signs or observations not requiring intervention, grade 2 (moderate) was defined as clinical signs requiring outpatient or non-invasive intervention, grade 3 (severe) was defined as clinical signs requiring hospitalization or prolonged hospitalization, grade 4 (life-threatening) clinical signs required urgent interventions and grade 5 (death) clinical signs led to euthanasia or natural death. Statistical analysis Data were analyzed using inferential statistical methods. Survival curves were estimated by the Kaplan–Meier method, and differences between groups were evaluated using the log-rank test 36 , 37 . The variables evaluated in relation to overall survival (OS) included tumor grading, tumor localization, and number of ECT sessions. OS was defined as the time from first ECT to death from any cause. A Generalized Linear Mixed Model (GLMM) was performed to assess the effect of the number of treatment sessions, impulses, clinical outcomes (CR or PR), recurrence and fSCC grading on the resistance values measured by the device. Normality of data distribution was evaluated using the Shapiro–Wilk and Kolmogorov–Smirnov tests. As the data did not meet the assumptions of normality, a Gamma distribution with a log-link function was specified in the model. Pairwise comparisons among groups were conducted using Fisher’s Least Significant Difference (LSD) method. Statistical significance was set at p-value < 0.05. All analyses were performed using IBM SPSS Statistics software (version 27.0.1.0.; IBM Corp., Armonk, NY, USA). Results A total of 45 cats were enrolled in the study, including 24 privately owned cats and 21 shelters cats, captured and treated through animal welfare associations. Thirty-nine shorthair cats met the inclusion criteria. The age of the cats ranged from 3 to 16 years (median, 12 years). Of these 25,6% (n = 10) were spayed females, 36% (n = 14) intact females, 25,6% (n = 10) intact males, and 12.8% (n = 5) neutered males. Recorded clinical signs included abnormal upper respiratory tract sounds, hyporexia, and sneezing. Overall, 28.2% of cases (n = 11) were classified as T 1 N 0 M 0 , 41% (n = 16) as T 2 N 0 M 0 , 18% (n = 7) as T 3 N 0 M 0 and 12.8% (n = 5) as T 4 N 0 M 0 . The majority of fSCC lesions were located on the nasal planum (76.9%, n = 30), including 9 T 1 N 0 M 0 , 13 T 2 N 0 M 0 , 5 T 3 N 0 M 0 , and 3 T 4 N 0 M 0 , while eyelid lesions were observed in 23.1% (n = 9) of cats, comprising 1 T 1 N 0 M 0, 4 T 2 N 0 M 0 , 2 T 3 N 0 M 0 , and 2 T 4 N 0 M 0 . A single ECT session was performed in 53,8% of cats (n = 21), two ECT sessions in 33,3% (n = 13) and three ECT sessions in 12,8% (n = 5). The number of ECT sessions according to tumor stage is reported in Table 1 . The interval between two consecutive sessions was two weeks. Table 1 Relationship between tumor stage and number of ECT sessions in the study population Number of ECT Sessions number of Cats T 1 N 0 M 1 T 2 N 0 M 0 T 3 N 0 M 0 T 4 N 0 M 0 One session 21 (53,8%) 10 10 0 1 Two sessions 13 (33,3%) 2 5 4 2 Three sessions 5 (12,8%) 0 0 3 2 Total 40 (100%) 12 15 7 5 Recorded resistance values ranged from 600 to 4900 Ω (mean, 1811,8 Ω). After the first ECT session, 20 cats achieved a CR, 16 achieved a PR, and 3 showed SD. Among cats that underwent a second ECT session, 11 achieved CR and 7 achieved PR. In cats treated with a third ECT session, 3 achieved CR and 2 achieved PR. At the end of treatment, 87.2% of cats (n = 34) achieved a CR, while 12.8% (n = 5) showed a PR, resulting in an ORR of 100%. CR cases included 10 T 1 N 0 M 0 , 15 T 2 N 0 M 0 , 6 T 3 N 0 M 0 , and 3 T 4 N 0 M 0 tumors, whereas PR cases comprised 1 T 2 N 0 M 0 , 2 T 3 N 0 M 0 , and 2 T 4 N 0 M 0 . At the time of analysis, 43.6% of cats (n = 17) were alive. Ten cats (4 T 2 N 0 M 0 , 2 T 3 N 0 M 0 , 4 T 4 N 0 M 0 ) were euthanized due to tumor progression, and 32.5% (n = 12) died from unrelated causes, including renal disease (n = 4; 1 T 1 N 0 M 0 , 2 T 2 N 0 M 0 , 1 T 3 N 0 M 0 ), cardiac disease (n = 1 T 2 N 0 M 0 ), liver disease (n = 1 T 2 N 0 M 0 ), and road traffic accidents (n = 6; 1 T 2 N 0 M 0 , 4 T 3 N 0 M 0 , 1 T 4 N 0 M 0 ). Tumor localization in relation to treatment outcomes, OS, vital status, and cause of death are summarized in Table 2 . Table 2 Individual clinicopathological characteristics and survival outcomes of cats treated for the disease. For each case, tumor localization, TNM grading, treatment response (CR or PR), overall survival (OS, days), vital status at last follow-up, and cause of death are reported. A dash indicates censored observations (alive at last follow-up) ID LOCALIZATION GRADING OUTCOME OS STATUS CAUSE OF DEATH 1 Nasal planum T 1 N 0 M 0 CR 1558 Dead Renal disease 2 Nasal planum T 3 N 0 M 0 CR 419 Dead Road traffic accidents 3 Eyelids T 4 N 0 M 0 CR 125 Dead Road traffic accidents 4 Nasal planum T 2 N 0 M 0 CR - Alive 5 Nasal planum T 1 N 0 M 0 CR - Alive 6 Nasal planum T 3 N 0 M 0 CR 184 Dead Road traffic accidents 7 Nasal planum T 1 N 0 M 0 CR - Alive 8 Nasal planum T 2 N 0 M 0 CR - Alive 9 Nasal planum T 2 N 0 M 0 CR - Alive 10 Nasal planum T 3 N 0 M 0 CR 842 Dead Road traffic accidents 11 Nasal planum T 1 N 0 M 0 CR - Alive 12 Nasal planum T 3 N 0 M 0 CR - Alive 13 Nasal planum T 2 N 0 M 0 CR 625 Dead Tumor progression 14 Nasal planum T 2 N 0 M 0 CR 764 Dead Renal disease 15 Nasal planum T 1 N 0 M 0 CR - Alive 16 Nasal planum T 2 N 0 M 0 CR - Alive 17 Nasal planum T 2 N 0 M 0 CR 747 Dead Cardiac disease 18 Multiple T 3 N 0 M 0 CR 1223 Dead Road traffic accidents 19 Nasal planum T 1 N 0 M 0 CR - Alive 20 Multiple T 1 N 0 M 0 CR - Alive 21 Nasal planum T 2 N 0 M 0 CR 520 Dead Road traffic accidents 22 Nasal planum T 2 N 0 M 0 CR - Alive 23 Nasal planum T 2 N 0 M 0 CR 1012 Dead Liver disease 24 Eyelids T 4 N 0 M 0 CR 192 Dead Tumor progression 25 Nasal planum T 2 N 0 M 0 CR - Alive 26 Multiple T 2 N 0 M 0 CR 615 Dead Tumor progression 27 Nasal planum T 1 N 0 M 0 CR - Alive 28 Nasal planum T 1 N 0 M 0 CR - Alive 29 Nasal planum T 4 N 0 M 0 CR 293 Dead Tumor progression 30 Nasal planum T 2 N 0 M 0 CR 893 Dead Renal disease 31 Nasal planum T 1 N 0 M 0 CR - Alive 32 Eyelids T 2 N 0 M 0 CR 604 Dead Tumor progression 33 Eyelids T 2 N 0 M 0 CR 618 Dead Renal disease 34 Nasal planum T 1 N 0 M 0 CR - Alive 35 Multiple T 2 N 0 M 0 PR 805 Dead Tumor progression 36 Nasal planum T 3 N 0 M 0 PR 483 Dead Tumor progression 37 Nasal planum T 4 N 0 M 0 PR 97 Dead Tumor progression 38 Nasal planum T 4 N 0 M 0 PR 96 Dead Tumor progression 39 Eyelids T 3 N 0 M 0 PR 482 Dead Tumor progression ECT-related adverse events, including erythema and crusting, pruritus, alopecia, and hyporexia, are summarized in Table 3 . No systemic adverse events were recorded, and no arrhythmias or respiratory complications associated with the procedure were observed. All cats received meloxicam and secondary infections in two cats T 4 N 0 M 0 were treated with systemic antibiotics. Five cats T 4 N 0 M 0 required mitarzapine. Table 3 Grade, frequency, and tumor stage distribution of treatment-related adverse events in cats Adverse Event Grade OVERALL (%) T 1 N 0 M 0 T 2 N 0 M 0 T 3 N 0 M 0 T 4 N 0 M 0 Erythema and crusting 2 18 (46,1%) 1 4 6 7 Pruritus 1 21 (53,8%) 2 4 7 8 Alopecia 1 9 (23,1%) 0 0 0 9 Hyporexia 2 5 (12,8%) 0 0 0 5 Resistance values significantly decreased across ECT sessions (p < 0.001; GLMM analysis, Fig. 1 a), with each session showing lower values than the previous one (p < 0.001 for all pairwise comparisons). Mean resistance values were 2391.2 Ω in the first ECT session, 1431.8 Ω in the second session, and 900.9 Ω in the third session. A similar decreasing trend was observed across impulses (p < 0.001; GLMM analysis, Fig. 1 b). Pairwise comparisons indicated that all contrasts between impulses were statistically significant (p < 0.001). Mean resistance values were 1978.7 Ω in the first impulse, 1629.4 Ω in the second impulse, 1281.2 Ω in the third impulse, and 1086.7 Ω in the fourth impulse. Resistance differed significantly by localization (p < 0.001; GLMM analysis, Fig. 1 c), with higher resistance values in the palpebral localization (mean, 1811.5 Ω) compared with the nasal planum (mean, 1169.7 Ω). Cats achieving a CR exhibited significantly lower SCC resistance values (mean, 1,323.5 Ω) compared with cats achieving a PR (mean, 1,601.0 Ω; p = 0.004; GLMM analysis; Fig. 1 d). Resistance values differed significantly across grading categories (p < 0.001; GLMM analysis, Fig. 1 e). The lowest resistance values were observed in T 1 N 0 M 0 (mean, 1086.7 Ω), which were significantly lower than those of all other grading categories (all pairwise comparisons, p < 0.001). T 2 N 0 M 0 also showed lower resistance values (mean, 1410.6 Ω) compared with T 3 N 0 M 0 (mean, 1690.8 Ω) and T 4 N 0 M 0 (mean, 1732.1 Ω) (both p < 0.001). A significant interaction between grading and localization was detected (p < 0.001; GLMM analysis, Fig. 1 f). In the nasal planum, T 1 N 0 M 0 showed the lowest resistance values (mean, 784 Ω), followed by T 2 N 0 M 0 (mean, 1102 Ω), which was significantly higher than T 1 N 0 M 0 (p < 0.001) but significantly lower than T 3 N 0 M 0 (mean, 1462 Ω) and T 4 N 0 M 0 (mean, 1481 Ω) (both p < 0.001). In palpebral lesions, resistance values were higher overall, with T 1 N 0 M 0 tumors showing lower resistance (mean, 1,506 Ω) than T 3 N 0 M 0 (mean, 1,955 Ω; p = 0.047) and T 4 N 0 M 0 tumors (mean, 2,025 Ω; p = 0.025), while T 2 N 0 M 0 tumors had intermediate values (mean, 1,806 Ω). Number of ECT sessions (p = 0.002; KM survival analysis, Fig. 2a), tumor location (p = 0.020; KM survival analysis, Fig. 2b), treatment response (p < 0.001; KM survival analysis, Fig. 2c) and tumor stage (p < 0.001; KM survival analysis, Fig. 2d) were significantly associated with OS. Median OS differed according to the number of ECT sessions, being longest in cats treated with one session (1558 days), followed by two sessions (1223 days) and three sessions (482 days). Median OS also differed according to tumor location, with longer survival observed in cats with nasal planum lesions (1446.8 days) compared with those with eyelid lesions (915.3 days). Cats achieving a CR showed a longer median OS (1223 days) compared with those achieving a PR (482 days). Median OS also varied according to tumor stage: it was not reached in T1N0M0, while it was 893 days for T2N0M0, 483 days for T3N0M0, and 125 days for T4N0M0. In the overall population, median OS was 1012 days. Discussion ECT is a well-established therapeutic modality for the management of solid tumors in veterinary oncology 12 and has demonstrated particularly favorable outcomes in feline SCC, with high response rates and durable local control 15 , 16 , 21 , 24 – 32 . Consistent with previous reports, ECT in the present study was highly effective and well tolerated for nasal planum and palpebral SCC, achieving an ORR of 100% and a CR exceeding 85%. Survival analysis confirmed that tumor stage, localization, treatment response, and number of ECT sessions were significantly associated with overall survival. Cats with nasal planum lesions, early-stage disease, and complete response experienced the longest survival times, in line with the established prognostic factors for fSCC 12 . Adverse effects were generally mild and self-limiting, confirming the favorable safety profile of ECT when appropriately applied. No severe systemic complications related to the procedure were observed. Previous studies have identified several clinical and pathological prognostic factors influencing treatment outcome, including tumor stage, anatomical location and extent of tissue involvement 15 , 16 , 24 , 26 . However, to date, in vivo data concerning the electrical properties of tumors undergoing ECT in companion animals have been lacking. The present study represents, to the best of the authors’ knowledge, the first clinical investigation aimed at characterizing tumor resistance during ECT in feline SCC and exploring its potential relationship with treatment efficacy and disease control. It is widely acknowledged that electrical states of tissue vary during the flow of the current pulses, due to the induction of aqueous pores in the cell membrane. In particular, tissue resistivity declines following electroporation, and this phenomenon gets more evident with the rising number of voltage pulses. These data have been extrapolated through mathematical modeling, cell culture investigations, murine models using magnetic resonance and ex vivo studied on excised neoplasms 38 – 43 . One of the principal findings of this study was the progressive decrease in tumor electrical resistance, observed both across successive ECT sessions and within individual treatment sessions as the number of delivered pulses increased. This observation is consistent with the established biophysical mechanisms underlying electroporation. Exposure to electric fields of sufficient magnitude induces the formation of transient aqueous pores within the cell membrane, leading to increased membrane permeability and enhanced ionic flux 2 . As a consequence, tissue resistivity decreases, resulting in lower measured resistance values 44 . This phenomenon has previously been described in theoretical models, in vitro cell culture systems, murine models and ex vivo tumor specimens 1 – 4 , but had not yet been demonstrated in a clinical veterinary setting. Furthermore, the temporal profile of resistance changes during pulse sequences appears to be particularly informative. A rapid and sustained decrease in resistance may indicate effective membrane permeabilization across a critical volume of tumor tissue, whereas minimal or transient changes could suggest suboptimal electrode positioning or insufficient electric field strength 41 – 43 . In this context, real-time resistance monitoring may offer a practical tool for adaptive ECT, enabling on-the-fly adjustments to electrode configuration or pulse parameters to improve treatment coverage. The overall response rate observed in this cohort was excellent, with all treated cats achieving either complete or partial response. Notably, a significant association was identified between lower resistance values and a complete response. This finding supports the hypothesis that decreased tissue resistance reflects more effective and homogeneous electroporation, thereby facilitating increased intracellular uptake of bleomycin and enhancing cytotoxic efficacy. While causality cannot be inferred from this observational study, the relationship between resistance and response suggests that tumor resistance measurements could serve as a predictive or prognostic indicator, representing a real-time, non-invasive surrogate marker of treatment adequacy and biological response during ECT. Similar concepts have been proposed in human oncology, where resistance monitoring has been investigated as a potential predictor of therapeutic response 5 – 20 , 44 . Consistent with previous reports 26 – 29 , tumor stage emerged as a strong prognostic factor, with cats affected by early-stage disease demonstrating significantly longer overall survival than those with advanced-stage tumors. This observation is likely attributable to lower tumor burden, reduced tissue infiltration, and more favorable anatomical conditions for effective electric field distribution in smaller lesions. Similarly, the number of ECT sessions was associated with survival outcomes: most single-session treatments were performed in cats with low-stage tumors, which corresponded to longer survival, whereas advanced-stage tumors generally required multiple sessions. In line with these clinical findings, tumor stage was strongly associated with tissue resistance measurements. Early-stage tumors (T 1 N 0 M 0 ) consistently exhibited the lowest resistance values, while advanced tumors (T 3 –T 4 N 0 M 0 ) showed significantly higher resistance. Tumor progression is typically accompanied by architectural disorganization, fibrosis, necrosis, and heterogeneous vascularization, all of which may impair uniform electric field distribution and limit current flow. Consequently, the higher resistance observed in advanced tumors likely reflects increased tissue complexity and reduced electrical conductivity, potentially contributing to less effective electroporation and intracellular drug delivery. Tumor location also emerged as a significant factor influencing both survival and tissue resistance. Cats with nasal planum SCC exhibited the longest median survival, which aligns with the lower resistance values measured in these lesions compared with palpebral tumors. This difference is likely attributable to variations in tissue composition, thickness, vascularization, and cartilage involvement, all of which can affect electrical conductivity and the distribution of the applied electric field. Palpebral lesions demonstrated higher resistance, likely due to the greater proportion of dense connective tissue, adnexal structures, and layered musculature in the eyelid region, compared with the thinner, more vascularized tissues of the nasal planum. These findings underscore the importance of local tissue architecture in modulating electrical behavior during ECT and may partly explain the observed differences in treatment efficacy across anatomical sites. In this study, fSCC proved to be an excellent model for the first in vivo assessment of tumor electrical resistance during ECT, due to its high treatment responsiveness, low metastatic potential, and superficial localization, which together enable reliable, real-time monitoring of tissue electrical properties and their correlation with therapeutic outcomes. In human medicine, tumor electrical properties have been considered in the context of ECT, although existing evidence remains limited. ECT has been widely adopted clinically as a local treatment modality for cutaneous and subcutaneous tumors, with early human trials demonstrating its effectiveness in achieving tumor regression and local control across multiple histotypes 45 – 46 . However, while several clinical ECT studies in patients have reported monitoring of delivered electrical parameters such as voltage and current—which allow indirect assessment of tissue electrical behavior during pulse application—these efforts have primarily focused on feasibility, safety, and therapeutic outcomes rather than dedicated measurement of tissue resistance 13 , 45 , 47 . Direct, systematic, and real-time in vivo measurements of tumor electrical resistance during ECT have rarely been reported in humans and available evidence in humans remains largely derived from theoretical models, in vitro investigations, animal studies, or ex vivo analyses of surgical specimens, such as studies quantifying electrical resistance in human soft tissue sarcomas shortly after resection following electroporation protocols 44 . In clinical practice, electrical resistance has generally not been evaluated as a dedicated biological parameter during treatment, nor routinely correlated with therapeutic response. Consequently, current knowledge regarding the clinical significance of in vivo resistance dynamics during ECT in human patients remains incomplete. Within this context, our present study in a spontaneous, naturally occurring cancer model provides novel in vivo insights into tumor electrical resistance, which may also enhance understanding of these dynamics in human tumors and help bridge the gap between experimental electroporation research and clinical ECT applications. Despite these promising implications, several limitations must be acknowledged. Its observational design and relatively limited sample size —especially for advanced-stage tumors and palpebral lesions— restrict the ability to draw definitive conclusions. Additionally, resistance measurements were obtained using a single electroporation device and protocol, which may limit generalizability to other equipment or treatment settings. Resistance measurements during ECT are influenced not only by tumor biology and local anatomy but also by technical factors, including electrode placement, inter-electrode distance and contact quality, factors that could not be fully standardized in a clinical setting. Nonetheless, the consistent trends observed across sessions and pulses, together with the significant association between resistance and response, provide a strong rationale for further investigation. Integrating resistance data with imaging, histopathological features (such as fibrosis, necrosis, and vascular density), and computational electric field modelling could improve our understanding of the relationship between electrical properties and biological effects. Standardization of measurement protocols will also be essential to enable meaningful comparisons across studies and centers. In conclusion, the present work provides the first clinical evidence that tumor electrical resistance decreases during ECT in feline SCC and that lower resistance values are associated with improved local tumor control. These findings open new perspectives for the integration of electrical parameter monitoring into ECT protocols, with the potential to optimize treatment delivery, identify early predictors of response and refine patient selection. Further prospective studies involving larger cohorts, different tumor histotypes and additional species are warranted to validate these preliminary observations and to fully elucidate the prognostic value of tumor electrical properties in veterinary oncology. Declarations Competing Interests Spugnini EP is stockholder of Biopulse Srl, Assumma C. was employed by Biopulse Srl to develop the clinical electroporator used in this study. Informed consent All cat owners and representatives of animal welfare associations managing the shelters provided written informed consent for the administration of electrochemotherapy and intravenous chemotherapy with bleomycin. All procedures were carried out by licensed veterinary personnel for diagnostic and therapeutic purposes. All animal experiments were conducted in accordance with relevant guidelines and regulations. The study was approved by the Ethics Committee of the Department of Veterinary Medicine, University of Bari (Authorization No. 31/21). Funding This research did not receive funding. Author Contribution Conceptualization: E.P.S. and D.F.; Methodology: E.P.S., D.F., C.A. and I.L; Investigation: E.P.S. and C.A.; Visualization: I.L, S.C., A.D.B., C.P. and C.D’A; Funding acquisition: not applicable. Project administration: E.P.S., and D.F. Supervision: D.F. and E.P.S.; Writing- original draft: D.F., E.P.S., and I.L Writing -review and editing: D.F., IL, S.C., A.D.B., C.P., C.D’A. Data Availability The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request. References Gebuza, M. et al. Exploring the mechanical and electrical properties of cancer cells for improved diagnosis and treatment. Arch. Biochem. Biophys. 773 , 110599. https://doi.org/10.1016/j.abb.2025.110599 (2025). Di Gregorio, E. et al. The distinguishing electrical properties of cancer cells. Phys. Life Rev. 43 , 139–188. https://doi.org/10.1016/j.plrev.2022.09.003 (2022). Baghban, R. et al. Tumor microenvironment complexity and therapeutic implications at a glance. Cell. Commun. Signal. 18 , 59. https://doi.org/10.1186/s12964-020-0530-4 (2020). Frantz, C., Stewart, K. M. & Weaver, V. M. The extracellular matrix at a glance. J. Cell. Sci. 123 , 4195–4200. https://doi.org/10.1242/jcs.023820 (2010). Ataee, H. et al. Impedance-based detection of cervical lymph-node involvement in thyroid cancer patients: a human model study. Surg. Today . 55 , 1497–1505. https://doi.org/10.1007/s00595-025-03033-x (2025). Morimoto, T. et al. A study of the electrical bio-impedance of tumors. J. Invest. Surg. 6 , 25–32. https://doi.org/10.3109/08941939309141189 (1993). Gariani, J. et al. Noninvasive pulmonary nodule characterization using transcutaneous bioconductance: preliminary results of an observational study. Med. (Baltim). 97 , e11924. https://doi.org/10.1097/MD.0000000000011924 (2018). Dowlatabad, H. M. et al. Advancing upper gastrointestinal cancer detection: a single-center pilot study exploring the potential of electrical impedance spectroscopy in endoscopic procedures. Dig. Dis. Sci. 70 , 2433–2443. https://doi.org/10.1007/s10620-025-08983-3 (2025). Wen, J. et al. Application of bioelectrical impedance detection techniques: cells and tissues. Biosens. Bioelectron. 273 , 117159. https://doi.org/10.1016/j.bios.2025.117159 (2025). Atkins, R. M. et al. Impedance spectroscopy as an indicator for successful in vivo electric field-mediated gene delivery in a murine model. Bioelectrochemistry 115 , 33–40. https://doi.org/10.1016/j.bioelechem.2017.01.004 (2017). Atkins, R. M. et al. Real-time impedance feedback to enhance cutaneous gene electrotransfer in a murine skin model. Bioelectrochemistry 142 , 107885. https://doi.org/10.1016/j.bioelechem.2021.107885 (2021). Spugnini, E. P. & Baldi, A. Electrochemotherapy in veterinary oncology: state-of-the-art and perspectives. Vet. Clin. North Am. Small Anim. Pract. 49 , 967–979 (2019). Condello, M. et al. Electrochemotherapy: an alternative strategy for improving therapy in drug-resistant solid tumors. Cancers (Basel) . 14 , 4341. https://doi.org/10.3390/cancers14174341 (2022). de Caro, A. et al. New effective and less painful high-frequency electrochemotherapy protocols: from optimization on 3D models to pilot study on veterinary patients. J. Control Release . 381 , 113592. https://doi.org/10.1016/j.jconrel.2025 (2025). Ramos, S. C. et al. Electrochemotherapy in dogs and cats: a review. Vet. Comp. Oncol. 22 , 311–321. https://doi.org/10.1111/vco.12980 (2024). Tozon, N. et al. Electrochemotherapy with intravenous bleomycin injection: an observational study in superficial squamous cell carcinoma in cats. J. Feline Med. Surg. 16 , 291–299. https://doi.org/10.1177/1098612X13507071 (2014). Batista Napotnik, T., Polajžer, T. & Miklavčič, D. Cell death due to electroporation: a review. Bioelectrochemistry 141 , 107871. https://doi.org/10.1016/j.bioelechem.2021.107871 (2021). Teissié, J., Golzio, M. & Rols, M. P. Mechanisms of cell membrane electropermeabilization: a minireview of our present (lack of?) knowledge. Biochim. Biophys. Acta . 1724 , 270–280. https://doi.org/10.1016/j.bbagen.2005.05.006 (2005). Woloszyn, M. et al. An analytical four-layer horizontal electric current dipole model for analysing underwater electric potential in shallow seawater. Sci. Rep. 12 , 8727. https://doi.org/10.1038/s41598-022-12645-z (2022). Miklavčič, D. et al. Electrochemotherapy: technological advancements for efficient electroporation-based treatment of internal tumors. Med. Biol. Eng. Comput. 50 , 1213–1225. https://doi.org/10.1007/s11517-012-0991-8 (2012). Murphy, S. Cutaneous squamous cell carcinoma in the cat: current understanding and treatment approaches. J. Feline Med. Surg. 15 , 401–407. https://doi.org/10.1177/1098612X13483238 (2013). Manuali, E. et al. Tumours in European Shorthair cats: a retrospective study of 680 cases. J. Feline Med. Surg. 22 , 1095–1102. https://doi.org/10.1177/1098612X20905035 (2020). Cannon, C. M. Cats, cancer and comparative oncology. Vet. Sci. 2 , 111–126. https://doi.org/10.3390/vetsci2030111 (2015). Spugnini, E. P. et al. Electroporation enhances bleomycin efficacy in cats with periocular carcinoma and advanced squamous cell carcinoma of the head. J. Vet. Intern. Med. 29 , 1368–1375. https://doi.org/10.1111/jvim.13586 (2015). Dos Anjos, D. S. et al. Comparison of two different doses of bleomycin in electrochemotherapy protocols for feline cutaneous squamous cell carcinoma non-segregated from ultraviolet light exposure. Sci. Rep. 10 , 18362. https://doi.org/10.1038/s41598-020-75472-0 (2020). Simčič, P. et al. A retrospective multicentric study of electrochemotherapy in the treatment of feline nasal planum squamous cell carcinoma. Vet. Sci. 8 , 53. https://doi.org/10.3390/vetsci8030053 (2021). Tellado, M. et al. Electrochemotherapy using thin-needle electrode improves recovery in feline nasal planum squamous cell carcinoma: a translational model. Cancer Drug Resist. 5 , 595–611. https://doi.org/10.20517/cdr.2022.24 (2022). Dos Santos, F. F. Q. et al. Perineural invasion as a predictor of local recurrence in cats with squamous cell carcinoma treated with electrochemotherapy. Front. Vet. Sci. 11 , 1408260. https://doi.org/10.3389/fvets.2024.1408260 (2024). Ferrer-Jordà, E. & Rodríguez-Pizà, I. Description of outcome and adverse events in 21 cats with locally advanced nasal planum squamous cell carcinoma treated with electrochemotherapy. J. Feline Med. Surg. 26 , 1098612X241248043. https://doi.org/10.1177/1098612X241248043 (2024). Diop, N. et al. Comparison of three chemotherapy protocols with electrochemotherapy for the treatment of feline cutaneous squamous cell carcinoma. Vet. Comp. Oncol. 22 , 437–446. https://doi.org/10.1111/vco.12995 (2024). Foo, M. et al. Electrochemotherapy is effective in the treatment of early-stage feline cutaneous squamous cell carcinoma. J. Feline Med. Surg. 27 , 1098612X251347152. https://doi.org/10.1177/1098612X251347152 (2025). Ciccarelli, S. et al. Efficacy of gabapentin as pain management of T2–T4 feline facial squamous cell carcinoma treated with electrochemotherapy. Sci. Rep. 15 , 27874. https://doi.org/10.1038/s41598-025-13767-w (2025). Ferro, L. et al. Appetite stimulant and anti-emetic effect of mirtazapine transdermal ointment in cats following chemotherapy. Animals 12 , 155 (2022). Nguyen, S. M. et al. Response evaluation criteria for solid tumours in dogs (v1.0): a Veterinary Cooperative Oncology Group consensus document. Vet. Comp. Oncol. 13 , 176–183. https://doi.org/10.1111/vco.12032 (2015). LeBlanc, A. K. et al. Veterinary Cooperative Oncology Group–Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) following investigational therapy in dogs and cats. Vet. Comp. Oncol. 19 , 311–352. https://doi.org/10.1111/vco.12677 (2021). Peto, R. et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br. J. Cancer . 35 , 1–39. https://doi.org/10.1038/bjc.1977.1 (1977). Kaplan, E. L. & Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53 , 457–481. https://doi.org/10.2307/228186 (1958). Gabriel, C., Gabriel, S. & Corthout, E. The dielectric properties of biological tissues: I. Literature survey. Phys. Med. Biol. 41 , 2231–2249. https://doi.org/10.1088/0031-9155/41/11/001 (1996). Gabriel, S., Lau, R. W. & Gabriel, C. The dielectric properties of biological tissues: II. Measurements in the frequency range 10 Hz to 20 GHz. Phys. Med. Biol. 41 , 2251–2269. https://doi.org/10.1088/0031-9155/41/11/002 (1996). Gabriel, S., Lau, R. W. & Gabriel, C. The dielectric properties of biological tissues: III. Parametric models for the dielectric spectrum of tissues. Phys. Med. Biol. 41 , 2271–2293. https://doi.org/10.1088/0031-9155/41/11/003 (1996). García-Sánchez, T. et al. Electrical impedance measurements on electropermeabilized cells attached to microelectrodes. In 6th European Conference of the International Federation for Medical and Biological Engineering (eds Lacković, I. & Vasić, D.) 553–556 (2015). Kranjc, M. et al. In situ monitoring of electric field distribution in mouse tumor during electroporation. Radiology 274 , 115–123. https://doi.org/10.1148/radiol.14140311 (2015). Garcia, P. A. et al. Intracranial nonthermal irreversible electroporation: in vivo analysis. J. Membr. Biol. 236 , 127–136. https://doi.org/10.1007/s00232-010-9284-z (2010). Campana, L. G. et al. Electrical resistance of human soft tissue sarcomas: an ex vivo study on surgical specimens. Med. Biol. Eng. Comput. 54 , 773–787. https://doi.org/10.1007/s11517-015-1368-6 (2016). Jaroszeski, M. J. et al. Clinical applications of electrochemotherapy: an early experience. Adv. Drug Deliv Rev. 35 , 119–129 (1999). Spugnini, E. P. et al. Electrochemotherapy for the treatment of human tumors: early clinical experience and perspectives. Curr. Opin. Oncol. 24 , 155–161 (2012). Miklavčič, D. et al. Electrochemotherapy: from the drawing board into medical practice. Biomed. Eng. Online . 13 , 29 (2014). Additional Declarations Competing interest reported. Spugnini EP is stockholder of Biopulse Srl, Assumma C. was employed by Biopulse Srl to develop the clinical electroporator used in this study. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 13 May, 2026 Reviews received at journal 25 Apr, 2026 Reviews received at journal 20 Apr, 2026 Reviewers agreed at journal 20 Apr, 2026 Reviewers agreed at journal 17 Apr, 2026 Reviewers agreed at journal 15 Apr, 2026 Reviewers invited by journal 15 Apr, 2026 Editor assigned by journal 13 Apr, 2026 Editor invited by journal 21 Jan, 2026 Submission checks completed at journal 20 Jan, 2026 First submitted to journal 20 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8592493","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":626599868,"identity":"8e27c82c-5592-4d40-8fe5-a12b40d6cec9","order_by":0,"name":"Delia Franchini","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIie3OMWvCQBTA8RcEpxDXOyr6FV4IVP02HgWztHR1CifCufgBFL+Eo2NCoC75AAcVNEsml24WMvgCqdsd7dbh/sPxEvjdOwCX6z+WdmQKMGjGLkyB0eQp+mAW4jUkepDoh5gNEXgQSsh2MJLguFikN8D33m5ZXcrDON5/LtXlBuPERHiRyWwNONmcPkYoCva2P2WrcG15GGohUx9qBP3aZUIR0XT6NnIuZVYD4rAlMV2ieG3d4sncJ4ItmTbkybaFF0LmfRKhnj03JNxqsYr6yLg0kOCY51/XOeJAv1T8WyXDQMdVeZ0nPdOW9nm/+ONyuVyuP3QHNuxYev4jFJcAAAAASUVORK5CYII=","orcid":"","institution":"University of Bari","correspondingAuthor":true,"prefix":"","firstName":"Delia","middleName":"","lastName":"Franchini","suffix":""},{"id":626599869,"identity":"f0ffbe61-fe43-4253-8efc-0971cca52f4c","order_by":1,"name":"Stefano Ciccarelli","email":"","orcid":"","institution":"University of Bari","correspondingAuthor":false,"prefix":"","firstName":"Stefano","middleName":"","lastName":"Ciccarelli","suffix":""},{"id":626599870,"identity":"6b431e47-fa6d-4e68-b242-f2691d708c30","order_by":2,"name":"Cosimo Assumma","email":"","orcid":"","institution":"Biopulse srl","correspondingAuthor":false,"prefix":"","firstName":"Cosimo","middleName":"","lastName":"Assumma","suffix":""},{"id":626599871,"identity":"5869e1af-d196-4c07-b283-67a708aa10e9","order_by":3,"name":"Ilaria Laino","email":"","orcid":"","institution":"University of Bari","correspondingAuthor":false,"prefix":"","firstName":"Ilaria","middleName":"","lastName":"Laino","suffix":""},{"id":626599872,"identity":"e26d2c25-9d9f-4ab0-b22c-48d74cc196d5","order_by":4,"name":"Antonio Di Bello","email":"","orcid":"","institution":"University of Bari","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"Di","lastName":"Bello","suffix":""},{"id":626599873,"identity":"ed1be0de-0084-45ae-acaf-10a1808916de","order_by":5,"name":"Chiara D’Abramo","email":"","orcid":"","institution":"University of Bari","correspondingAuthor":false,"prefix":"","firstName":"Chiara","middleName":"","lastName":"D’Abramo","suffix":""},{"id":626599874,"identity":"dd869b61-5581-4f44-9f23-355966a75b55","order_by":6,"name":"Chiara Perrone","email":"","orcid":"","institution":"University of Bari","correspondingAuthor":false,"prefix":"","firstName":"Chiara","middleName":"","lastName":"Perrone","suffix":""},{"id":626599875,"identity":"961fae68-431c-4ff1-9054-a77e4b88ee9b","order_by":7,"name":"Enrico Paolo Spugnini","email":"","orcid":"","institution":"Biopulse srl","correspondingAuthor":false,"prefix":"","firstName":"Enrico","middleName":"Paolo","lastName":"Spugnini","suffix":""}],"badges":[],"createdAt":"2026-01-13 13:23:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8592493/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8592493/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107657840,"identity":"1261c72b-29a6-4494-a08a-50ce9fd985de","added_by":"auto","created_at":"2026-04-23 16:20:24","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":103674,"visible":true,"origin":"","legend":"\u003cp\u003e(\u003cstrong\u003ea\u003c/strong\u003e) Resistance (Ω) across electrochemotherapy (ECT) sessions as derived from the GLMM. Resistance values show a progressive decrease from the first to the third session. (\u003cstrong\u003eb\u003c/strong\u003e) resistance (Ω) across impulses derived from the GLMM analysis. Resistance values decrease progressively from the first to the fourth impulse. (\u003cstrong\u003ec\u003c/strong\u003e) resistance (Ω) across fSCC localization derived from the GLMM analysis. Resistance values are higher in the eyelids compared with the nasal planum. (\u003cstrong\u003ed\u003c/strong\u003e) resistance (Ω) across outcome derived from the GLMM analysis. Resistance values were higher in cats achieving a partial response (PR) compared with those achieving a complete response (CR). (\u003cstrong\u003ee\u003c/strong\u003e)\u003cstrong\u003e \u003c/strong\u003eresistance (Ω) across fSCC grading (T\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e–T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e) derived from the GLMM analysis. Resistance values increase progressively from T\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e to T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e. (\u003cstrong\u003ef\u003c/strong\u003e) interaction between fSCC grading and localization on resistance (Ω) derived from the GLMM analysis. Resistance values are consistently higher in the palpebral localization than in the nasal planum across all grading categories. The pattern of resistance across FSCC grading differs between localizations\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8592493/v1/91400463fe11d65d1caa7303.jpeg"},{"id":107657844,"identity":"2adf2218-007a-41ce-910e-6b5f53a3fe5e","added_by":"auto","created_at":"2026-04-23 16:20:26","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":156748,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(a)\u003c/strong\u003e Kaplan–Meier curves for overall survival stratified by the number of ECT sessions. Overall survival differed significantly according to the number of sessions, with the longest survival observed in cats treated with one session, followed by two sessions, and the shortest survival in cats treated with three sessions. Tick marks indicate censored observations. (\u003cstrong\u003eb\u003c/strong\u003e) Kaplan–Meier curves for overall survival stratified by fSCC localization. Cats with tumors localized in the eyelids show longer overall survival compared with those with tumors in the nasal planum. Tick marks indicate censored observations. (\u003cstrong\u003ec\u003c/strong\u003e) Kaplan–Meier curves for overall survival stratified by treatment outcome. Cats achieving a complete response (CR) show significantly longer overall survival compared with those achieving a partial response (PR). Tick marks indicate censored observations. (\u003cstrong\u003ed\u003c/strong\u003e) Kaplan–Meier curves for overall survival stratified by fSCC grading. Overall survival differed significantly among grading categories, with the longest survival observed in cats with T\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e tumors and progressively shorter survival in T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, T\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, and T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e. Tick marks indicate censored observations\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8592493/v1/724e5785e33692271ba38c6c.jpeg"},{"id":108490789,"identity":"f72eab6d-8c37-4146-8a63-94da401e9163","added_by":"auto","created_at":"2026-05-05 09:48:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":923107,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8592493/v1/3cd2355a-5321-46e5-82dd-7843ad6523e3.pdf"}],"financialInterests":"Competing interest reported. Spugnini EP is stockholder of Biopulse Srl, Assumma C. was employed by Biopulse Srl to develop the clinical electroporator used in this study.","formattedTitle":"A pilot study of electrical resistance in feline squamous cell carcinoma treated with electrochemotherapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTumors represent composite microenvironments where unrestrained proliferation alters not only biochemical pathways but also the physical and electrical properties of tissues \u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Over the past decade, there has been increasing attention toward the mechanical and electrical properties of cancer cells and tissues and their possible exploitation for enhanced diagnosis and treatment \u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eElectrochemotherapy (ECT) is a treatment that exploits the susceptibility of neoplastic cells to permeabilization by appropriately shaped electrical pulses through the process known as electroporation (EP) \u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, representing a highly flexible approach for the treatment of solid tumors, both as an adjuvant and a neoadjuvant therapy in cases of incompletely resected malignant neoplasms or inoperable tumors \u003csup\u003e\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. EP consists of exposing cells to specific electrical pulses of sufficient amplitude to increase cell membrane permeability, thereby allowing chemotherapeutic molecules to access the cytoplasm \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Tissue EP depends on the local distribution of the electric field and on tissue anatomy \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Moreover, the electrical properties change during the application of voltage pulses due to cell membrane modifications induced by the applied electric field \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. The electric field required to maintain a given current density is proportional to resistivity, following relationship holds:\u003c/p\u003e \u003cp\u003eE\u0026thinsp;=\u0026thinsp;ρJ\u003c/p\u003e \u003cp\u003eWhere E is the electric field, J is the current density, and ρ is the resistivity of the material \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTissue resistivity decreases following electroporation, and this effect becomes more pronounced with increasing numbers of pulses and higher electric field intensities \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, as predicted by Ohm\u0026rsquo;s first law:\u003c/p\u003e\n\u003cp\u003eR = V/I\u003c/p\u003e\n\u003cp\u003ewhere R is the resistance in Ohm (Ω), V is the voltage across the circuit, and I is the current flowing through it. The reduction in resistivity is attributable to the formation of aqueous pores in the cell membrane. The presence of these aqueous pores increases the number of ions crossing the membrane \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Biological tissue behaves as an assorted concoction of conductors and insulators. Cell membranes act as capacitive barriers. Cytoplasm and extracellular fluids provide conductive pathways due to their ionic content. Extracellular matrix proteins contribute resistive and dielectric properties \u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Tumors typically alter this equilibrium through amplified angiogenesis, disrupted extracellular matrix, necrotic foci or even areas, and variable hydration, which together impact resistance measurements \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. ECT is an effective local treatment for cutaneous neoplasms in particular feline squamous cell carcinoma (fSCC). fSCC is a malignant tumor arising from epidermal cells that differentiate into keratinocytes and primarily affects older, white-coated cats, accounting for approximately 15\u0026ndash;50% of all cutaneous tumors in cats \u003csup\u003e\u003cspan additionalcitationids=\"CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Chronic exposure to ultraviolet radiation is considered the main etiologic factor. fSCC often presents deceptively as non-healing, scabbing lesions on the eyelids, nasal planum, or auricles of light-colored cats, which gradually progress to ulceration. fSCC is locally invasive and metastatic spread is uncommon and, when it occurs, it generally involves the regional lymph nodes and lungs \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan additionalcitationids=\"CR25 CR26 CR27 CR28 CR29 CR30 CR31\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. The response rate ECT is generally high, reaching up to 85%, with early-stage SCC associated with a more favorable prognosis \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan additionalcitationids=\"CR25 CR26 CR27\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Adverse effects are usually mild and include local inflammation, edema, exuberant scab formation (occasionally associated with transient secondary anosmia), as well as changes in pigmentation or alopecia. Side effects are mitigated by the administration of anti-inflammatory drugs, primarily non-steroidal agents such as cyclooxygenase inhibitors, and analgesics, including gabapentin \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. To date, there are no data available on in vivo measurements of tumor electrical resistance in pets treated with ECT. fSCC was selected as the tumor histotype for this preliminary investigation because of its high response rate to ECT and low metastatic potential, which allow for long-term follow-up and make it an easily accessible model for electrical resistance measurements. On this basis, the aim of this study was to evaluate changes in electrical resistance in fSCC during ECT sessions and to explore potential correlations between decreasing resistance values and treatment efficacy.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eFrom 2021 to 2025 privately owned cats and shelters cats diagnosed with T\u003csub\u003e1\u003c/sub\u003e-T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e fSCC were enrolled in this prospective observational non randomized clinical trial and treated with ECT at Clinica Veterinaria Casal Monastero, Rome, Italy and Ambulatorio Veterinario \u0026ldquo;Le Accademie\u0026rdquo;, Rome, Italy. This study was approved by the Ethics Committee of the CESA Department of Veterinary Medicine-University of Bari with number protocol 31/2021. All experiments were performed in accordance with relevant guidelines and regulations.\u003c/p\u003e \u003cp\u003eInclusion criteria were confirmed diagnosis of fSCC, absence of metastases, and completed treatment. Cats with concurrent systemic diseases, and other neoplastic diseases were excluded.\u003c/p\u003e \u003cp\u003eCollected data included signalment (breed, sex, and age), tumor location, complete blood count, serum biochemistry profile, and urinalysis. Tumor staging was performed using three-view thoracic radiographs, abdominal ultrasonography, and fine-needle aspiration of regional lymph nodes. Additional variables included the number of ECT sessions, treatment response, local and systemic adverse effects, recurrence rate, and electrical tissue resistance, which was recorded for each pulse delivered during every ECT session until the end of treatment. Follow-up evaluations were conducted at 1 and 2 weeks after each ECT session, monthly for the first 6 months, and every 3 months thereafter until the end of the observation period (November 2025).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eECT protocol and post-ECT management\u003c/h3\u003e\n\u003cp\u003eECT sessions were performed under general anesthesia using modified clinical electroporator Onkodisruptor\u0026reg; (Biopulse Biotech Italia) with implemented software for the measurement of tumor electrical resistance. The anesthetic protocol included premedication with medetomidine (Domitor, Pfizer Italia, Milan, Italy) 40 \u0026micro;g/kg and butorphanol (Dolorex, Intervet Italia, Milan, Italy) 0.1 mg/kg EV and induction with propofol (Propovet, Zoetis Italia S.r.l., Rome, Italy) 2 mg/kg IV. The ECT protocol included the administration of bleomycin (Bleoprim\u0026reg;, Hikma Italia S.p.A., Pavia, Italy) at the dose of 15 mg/m\u003csup\u003e2\u003c/sup\u003e as a bolus injection. Seven minutes after the bleomicyn administration, trains of biphasic pulses were administered at the voltage of 1200 V/cm, 1 Herz frequency, until the tumor area was covered using needle electrodes. Treatments were repeated every two weeks until tumor resolution or progression was observed. During the ECT sessions the cats were monitored using an electrocardiogram and a pulse oximeter. Post-treatment care included analgesia with meloxicam (Meloxoral\u0026reg;; Dechra Veterinary Products S.r.l.) at 0.1 mg/kg on day 1, followed by 0.05 mg/kg orally for the subsequent 3 days and antibiotic therapy with amoxicillin\u0026ndash;clavulanic acid (Synulox\u0026reg;; Zoetis Italia S.r.l.) at 20 mg/kg orally every 12 hours for 5 days, in case of secondary infection on the treated area. In cases of reduced appetite, transdermal mirtazapine ointment (Mirataz\u0026reg; Dechra Veterinary Products S.r.l.) was administered to minimise the risk of anorexia \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003ch3\u003eEthical considerations and euthanasia procedure\u003c/h3\u003e\n\u003cp\u003eCats exhibiting uncontrolled tumor progression associated with severe clinical deterioration or an unacceptable quality of life were humanely euthanized. Euthanasia was performed under deep general anesthesia induced by premedication with intravenous dexmedetomidine (5 \u0026micro;g/kg; Dexdomitor, V\u0026eacute;toquinol Italia S.r.l., Italy) combined with butorphanol (0.1 mg/kg; Dolorex, Intervet Italia, Milan, Italy), followed by intravenous administration of propofol (Propovet, Zoetis Italia S.r.l., Italy) to effect, in accordance with established veterinary and ethical guidelines. After confirmation of an adequate depth of anesthesia, euthanasia was completed by intravenous administration of potassium chloride (1\u0026ndash;2 mmol/kg), in compliance with accepted veterinary guidelines for humane euthanasia in cats with terminal neoplastic disease.\u003c/p\u003e\n\u003ch3\u003eResistance measurement\u003c/h3\u003e\n\u003cp\u003eElectrical tissue resistance was measured using a modified electroporator designed for veterinary applications (Onkodisruptor\u0026reg;). The device calculates resistance based on the electric voltage generated at the electrode extremities in accordance with Ohm\u0026rsquo;s first law. The instrument was configured to measure electrical resistance values ranging from 0 to 500000 Ω. Measurements exceeding this range were displayed by the system as \u0026ldquo;too high\u0026rdquo;. Electrical resistance values were automatically recorded by the electroporator during each pulse delivery and subsequently transcribed by the operator at the conclusion of each ECT session.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eResponse\u003c/h2\u003e \u003cp\u003eTreatment response was evaluated according to VCOG RECIST v1.1 \u003csup\u003e34\u003c/sup\u003e. Complete Response (CR) was defined as the complete disappearance of the treated lesion. Partial Response (PR) was defined as a reduction of more than 30% in the size of lesion. Stable Disease (SD) was defined as a reduction of less than 30% or an increase of less than 20% in the size of the treated lesion. Progressive disease (PD) was defined as a greater than 20% increase in the size of the treated lesion or the development of one or more new lesions. Overall response rate (ORR) was defined by the percentage of cats achieving CR or PR.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAdverse Events\u003c/h3\u003e\n\u003cp\u003eAdverse events were categorized according to VCOG-CTCAE, v.2 \u003csup\u003e35\u003c/sup\u003e. Pruritus, alopecia, erythema, skin ulcerations, tissue necrosis were assessed. Grade 1 (mild) was defined as clinical signs or observations not requiring intervention, grade 2 (moderate) was defined as clinical signs requiring outpatient or non-invasive intervention, grade 3 (severe) was defined as clinical signs requiring hospitalization or prolonged hospitalization, grade 4 (life-threatening) clinical signs required urgent interventions and grade 5 (death) clinical signs led to euthanasia or natural death.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData were analyzed using inferential statistical methods. Survival curves were estimated by the Kaplan\u0026ndash;Meier method, and differences between groups were evaluated using the log-rank test \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. The variables evaluated in relation to overall survival (OS) included tumor grading, tumor localization, and number of ECT sessions. OS was defined as the time from first ECT to death from any cause. A Generalized Linear Mixed Model (GLMM) was performed to assess the effect of the number of treatment sessions, impulses, clinical outcomes (CR or PR), recurrence and fSCC grading on the resistance values measured by the device. Normality of data distribution was evaluated using the Shapiro\u0026ndash;Wilk and Kolmogorov\u0026ndash;Smirnov tests. As the data did not meet the assumptions of normality, a Gamma distribution with a log-link function was specified in the model. Pairwise comparisons among groups were conducted using Fisher\u0026rsquo;s Least Significant Difference (LSD) method.\u003c/p\u003e \u003cp\u003eStatistical significance was set at \u003cem\u003ep-value\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All analyses were performed using IBM SPSS Statistics software (version 27.0.1.0.; IBM Corp., Armonk, NY, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 45 cats were enrolled in the study, including 24 privately owned cats and 21 shelters cats, captured and treated through animal welfare associations. Thirty-nine shorthair cats met the inclusion criteria. The age of the cats ranged from 3 to 16 years (median, 12 years). Of these 25,6% (n\u0026thinsp;=\u0026thinsp;10) were spayed females, 36% (n\u0026thinsp;=\u0026thinsp;14) intact females, 25,6% (n\u0026thinsp;=\u0026thinsp;10) intact males, and 12.8% (n\u0026thinsp;=\u0026thinsp;5) neutered males. Recorded clinical signs included abnormal upper respiratory tract sounds, hyporexia, and sneezing.\u003c/p\u003e\n\u003cp\u003eOverall, 28.2% of cases (n\u0026thinsp;=\u0026thinsp;11) were classified as T\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 41% (n\u0026thinsp;=\u0026thinsp;16) as T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 18% (n\u0026thinsp;=\u0026thinsp;7) as T\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e and 12.8% (n\u0026thinsp;=\u0026thinsp;5) as T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e. The majority of fSCC lesions were located on the nasal planum (76.9%, n\u0026thinsp;=\u0026thinsp;30), including 9 T\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 13 T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 5 T\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, and 3 T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, while eyelid lesions were observed in 23.1% (n\u0026thinsp;=\u0026thinsp;9) of cats, comprising 1 T\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0,\u003c/sub\u003e 4 T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 2 T\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, and 2 T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e.\u003c/p\u003e\n\u003cp\u003eA single ECT session was performed in 53,8% of cats (n\u0026thinsp;=\u0026thinsp;21), two ECT sessions in 33,3% (n\u0026thinsp;=\u0026thinsp;13) and three ECT sessions in 12,8% (n\u0026thinsp;=\u0026thinsp;5). The number of ECT sessions according to tumor stage is reported in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The interval between two consecutive sessions was two weeks.\u0026nbsp;\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eRelationship between tumor stage and number of ECT sessions in the study population\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNumber of ECT Sessions\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003enumber of Cats\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e1\u003c/sub\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOne session\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (53,8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTwo sessions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (33,3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThree sessions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (12,8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003eRecorded resistance values ranged from 600 to 4900 Ω (mean, 1811,8 Ω). After the first ECT session, 20 cats achieved a CR, 16 achieved a PR, and 3 showed SD. Among cats that underwent a second ECT session, 11 achieved CR and 7 achieved PR. In cats treated with a third ECT session, 3 achieved CR and 2 achieved PR. At the end of treatment, 87.2% of cats (n\u0026thinsp;=\u0026thinsp;34) achieved a CR, while 12.8% (n\u0026thinsp;=\u0026thinsp;5) showed a PR, resulting in an ORR of 100%. CR cases included 10 T\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 15 T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 6 T\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, and 3 T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e tumors, whereas PR cases comprised 1 T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 2 T\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, and 2 T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e. At the time of analysis, 43.6% of cats (n\u0026thinsp;=\u0026thinsp;17) were alive. Ten cats (4 T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 2 T\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 4 T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e) were euthanized due to tumor progression, and 32.5% (n\u0026thinsp;=\u0026thinsp;12) died from unrelated causes, including renal disease (n\u0026thinsp;=\u0026thinsp;4; 1 T\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 2 T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 1 T\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e), cardiac disease (n\u0026thinsp;=\u0026thinsp;1 T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e), liver disease (n\u0026thinsp;=\u0026thinsp;1 T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e), and road traffic accidents (n\u0026thinsp;=\u0026thinsp;6; 1 T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 4 T\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e, 1 T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e). Tumor localization in relation to treatment outcomes, OS, vital status, and cause of death are summarized in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/div\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eIndividual clinicopathological characteristics and survival outcomes of cats treated for the disease. For each case, tumor localization, TNM grading, treatment response (CR or PR), overall survival (OS, days), vital status at last follow-up, and cause of death are reported. A dash indicates censored observations (alive at last follow-up)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eID\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLOCALIZATION\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGRADING\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOUTCOME\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSTATUS\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCAUSE OF DEATH\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1558\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e419\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRoad traffic accidents\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEyelids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRoad traffic accidents\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e184\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRoad traffic accidents\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e842\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRoad traffic accidents\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e625\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor progression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e764\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e747\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCardiac disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMultiple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1223\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRoad traffic accidents\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMultiple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e520\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRoad traffic accidents\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiver disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEyelids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e192\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor progression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMultiple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e615\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor progression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e293\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor progression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e893\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEyelids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e604\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor progression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEyelids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e618\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRenal disease\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMultiple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e805\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor progression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e483\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor progression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor progression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNasal planum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor progression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEyelids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e482\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTumor progression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"char\"\u003eECT-related adverse events, including erythema and crusting, pruritus, alopecia, and hyporexia, are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. No systemic adverse events were recorded, and no arrhythmias or respiratory complications associated with the procedure were observed. All cats received meloxicam and secondary infections in two cats T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e were treated with systemic antibiotics. Five cats T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e required mitarzapine.\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"char\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eGrade, frequency, and tumor stage distribution of treatment-related adverse events in cats\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAdverse Event\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGrade\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOVERALL (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eT\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eErythema and crusting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (46,1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePruritus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (53,8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlopecia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (23,1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHyporexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (12,8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eResistance values significantly decreased across ECT sessions (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; GLMM analysis, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ea), with each session showing lower values than the previous one (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all pairwise comparisons). Mean resistance values were 2391.2 Ω in the first ECT session, 1431.8 Ω in the second session, and 900.9 Ω in the third session. A similar decreasing trend was observed across impulses (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; GLMM analysis, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eb). Pairwise comparisons indicated that all contrasts between impulses were statistically significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Mean resistance values were 1978.7 Ω in the first impulse, 1629.4 Ω in the second impulse, 1281.2 Ω in the third impulse, and 1086.7 Ω in the fourth impulse.\u003c/p\u003e\n\u003cp\u003eResistance differed significantly by localization (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; GLMM analysis, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ec), with higher resistance values in the palpebral localization (mean, 1811.5 Ω) compared with the nasal planum (mean, 1169.7 Ω). Cats achieving a CR exhibited significantly lower SCC resistance values (mean, 1,323.5 Ω) compared with cats achieving a PR (mean, 1,601.0 Ω; p\u0026thinsp;=\u0026thinsp;0.004; GLMM analysis; Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ed).\u003c/p\u003e\n\u003cp\u003eResistance values differed significantly across grading categories (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; GLMM analysis, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ee). The lowest resistance values were observed in T\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e (mean, 1086.7 Ω), which were significantly lower than those of all other grading categories (all pairwise comparisons, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e also showed lower resistance values (mean, 1410.6 Ω) compared with T\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e (mean, 1690.8 Ω) and T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e (mean, 1732.1 Ω) (both p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). A significant interaction between grading and localization was detected (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; GLMM analysis, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003ef). In the nasal planum, T\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e showed the lowest resistance values (mean, 784 Ω), followed by T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e (mean, 1102 Ω), which was significantly higher than T\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) but significantly lower than T\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e (mean, 1462 Ω) and T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e (mean, 1481 Ω) (both p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In palpebral lesions, resistance values were higher overall, with T\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e tumors showing lower resistance (mean, 1,506 Ω) than T\u003csub\u003e3\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e (mean, 1,955 Ω; p\u0026thinsp;=\u0026thinsp;0.047) and T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e tumors (mean, 2,025 Ω; p\u0026thinsp;=\u0026thinsp;0.025), while T\u003csub\u003e2\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e tumors had intermediate values (mean, 1,806 Ω). Number of ECT sessions (p\u0026thinsp;=\u0026thinsp;0.002; KM survival analysis, Fig.\u0026nbsp;2a), tumor location (p\u0026thinsp;=\u0026thinsp;0.020; KM survival analysis, Fig.\u0026nbsp;2b), treatment response (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; KM survival analysis, Fig.\u0026nbsp;2c) and tumor stage (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; KM survival analysis, Fig.\u0026nbsp;2d) were significantly associated with OS. Median OS differed according to the number of ECT sessions, being longest in cats treated with one session (1558 days), followed by two sessions (1223 days) and three sessions (482 days). Median OS also differed according to tumor location, with longer survival observed in cats with nasal planum lesions (1446.8 days) compared with those with eyelid lesions (915.3 days). Cats achieving a CR showed a longer median OS (1223 days) compared with those achieving a PR (482 days). Median OS also varied according to tumor stage: it was not reached in T1N0M0, while it was 893 days for T2N0M0, 483 days for T3N0M0, and 125 days for T4N0M0. In the overall population, median OS was 1012 days.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eECT is a well-established therapeutic modality for the management of solid tumors in veterinary oncology \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e and has demonstrated particularly favorable outcomes in feline SCC, with high response rates and durable local control \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan additionalcitationids=\"CR25 CR26 CR27 CR28 CR29 CR30 CR31\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Consistent with previous reports, ECT in the present study was highly effective and well tolerated for nasal planum and palpebral SCC, achieving an ORR of 100% and a CR exceeding 85%. Survival analysis confirmed that tumor stage, localization, treatment response, and number of ECT sessions were significantly associated with overall survival. Cats with nasal planum lesions, early-stage disease, and complete response experienced the longest survival times, in line with the established prognostic factors for fSCC \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Adverse effects were generally mild and self-limiting, confirming the favorable safety profile of ECT when appropriately applied. No severe systemic complications related to the procedure were observed. Previous studies have identified several clinical and pathological prognostic factors influencing treatment outcome, including tumor stage, anatomical location and extent of tissue involvement \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. However, to date, in vivo data concerning the electrical properties of tumors undergoing ECT in companion animals have been lacking. The present study represents, to the best of the authors\u0026rsquo; knowledge, the first clinical investigation aimed at characterizing tumor resistance during ECT in feline SCC and exploring its potential relationship with treatment efficacy and disease control. It is widely acknowledged that electrical states of tissue vary during the flow of the current pulses, due to the induction of aqueous pores in the cell membrane. In particular, tissue resistivity declines following electroporation, and this phenomenon gets more evident with the rising number of voltage pulses. These data have been extrapolated through mathematical modeling, cell culture investigations, murine models using magnetic resonance and ex vivo studied on excised neoplasms \u003csup\u003e\u003cspan additionalcitationids=\"CR39 CR40 CR41 CR42\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. One of the principal findings of this study was the progressive decrease in tumor electrical resistance, observed both across successive ECT sessions and within individual treatment sessions as the number of delivered pulses increased. This observation is consistent with the established biophysical mechanisms underlying electroporation. Exposure to electric fields of sufficient magnitude induces the formation of transient aqueous pores within the cell membrane, leading to increased membrane permeability and enhanced ionic flux \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. As a consequence, tissue resistivity decreases, resulting in lower measured resistance values \u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. This phenomenon has previously been described in theoretical models, in vitro cell culture systems, murine models and ex vivo tumor specimens \u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, but had not yet been demonstrated in a clinical veterinary setting. Furthermore, the temporal profile of resistance changes during pulse sequences appears to be particularly informative. A rapid and sustained decrease in resistance may indicate effective membrane permeabilization across a critical volume of tumor tissue, whereas minimal or transient changes could suggest suboptimal electrode positioning or insufficient electric field strength \u003csup\u003e\u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. In this context, real-time resistance monitoring may offer a practical tool for adaptive ECT, enabling on-the-fly adjustments to electrode configuration or pulse parameters to improve treatment coverage. The overall response rate observed in this cohort was excellent, with all treated cats achieving either complete or partial response. Notably, a significant association was identified between lower resistance values and a complete response. This finding supports the hypothesis that decreased tissue resistance reflects more effective and homogeneous electroporation, thereby facilitating increased intracellular uptake of bleomycin and enhancing cytotoxic efficacy. While causality cannot be inferred from this observational study, the relationship between resistance and response suggests that tumor resistance measurements could serve as a predictive or prognostic indicator, representing a real-time, non-invasive surrogate marker of treatment adequacy and biological response during ECT. Similar concepts have been proposed in human oncology, where resistance monitoring has been investigated as a potential predictor of therapeutic response \u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Consistent with previous reports \u003csup\u003e\u003cspan additionalcitationids=\"CR27 CR28\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, tumor stage emerged as a strong prognostic factor, with cats affected by early-stage disease demonstrating significantly longer overall survival than those with advanced-stage tumors. This observation is likely attributable to lower tumor burden, reduced tissue infiltration, and more favorable anatomical conditions for effective electric field distribution in smaller lesions. Similarly, the number of ECT sessions was associated with survival outcomes: most single-session treatments were performed in cats with low-stage tumors, which corresponded to longer survival, whereas advanced-stage tumors generally required multiple sessions. In line with these clinical findings, tumor stage was strongly associated with tissue resistance measurements. Early-stage tumors (T\u003csub\u003e1\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e) consistently exhibited the lowest resistance values, while advanced tumors (T\u003csub\u003e3\u003c/sub\u003e\u0026ndash;T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e) showed significantly higher resistance. Tumor progression is typically accompanied by architectural disorganization, fibrosis, necrosis, and heterogeneous vascularization, all of which may impair uniform electric field distribution and limit current flow. Consequently, the higher resistance observed in advanced tumors likely reflects increased tissue complexity and reduced electrical conductivity, potentially contributing to less effective electroporation and intracellular drug delivery. Tumor location also emerged as a significant factor influencing both survival and tissue resistance. Cats with nasal planum SCC exhibited the longest median survival, which aligns with the lower resistance values measured in these lesions compared with palpebral tumors. This difference is likely attributable to variations in tissue composition, thickness, vascularization, and cartilage involvement, all of which can affect electrical conductivity and the distribution of the applied electric field. Palpebral lesions demonstrated higher resistance, likely due to the greater proportion of dense connective tissue, adnexal structures, and layered musculature in the eyelid region, compared with the thinner, more vascularized tissues of the nasal planum. These findings underscore the importance of local tissue architecture in modulating electrical behavior during ECT and may partly explain the observed differences in treatment efficacy across anatomical sites. In this study, fSCC proved to be an excellent model for the first in vivo assessment of tumor electrical resistance during ECT, due to its high treatment responsiveness, low metastatic potential, and superficial localization, which together enable reliable, real-time monitoring of tissue electrical properties and their correlation with therapeutic outcomes. In human medicine, tumor electrical properties have been considered in the context of ECT, although existing evidence remains limited. ECT has been widely adopted clinically as a local treatment modality for cutaneous and subcutaneous tumors, with early human trials demonstrating its effectiveness in achieving tumor regression and local control across multiple histotypes \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. However, while several clinical ECT studies in patients have reported monitoring of delivered electrical parameters such as voltage and current\u0026mdash;which allow indirect assessment of tissue electrical behavior during pulse application\u0026mdash;these efforts have primarily focused on feasibility, safety, and therapeutic outcomes rather than dedicated measurement of tissue resistance \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. Direct, systematic, and real-time in vivo measurements of tumor electrical resistance during ECT have rarely been reported in humans and available evidence in humans remains largely derived from theoretical models, in vitro investigations, animal studies, or ex vivo analyses of surgical specimens, such as studies quantifying electrical resistance in human soft tissue sarcomas shortly after resection following electroporation protocols \u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. In clinical practice, electrical resistance has generally not been evaluated as a dedicated biological parameter during treatment, nor routinely correlated with therapeutic response. Consequently, current knowledge regarding the clinical significance of in vivo resistance dynamics during ECT in human patients remains incomplete. Within this context, our present study in a spontaneous, naturally occurring cancer model provides novel in vivo insights into tumor electrical resistance, which may also enhance understanding of these dynamics in human tumors and help bridge the gap between experimental electroporation research and clinical ECT applications. Despite these promising implications, several limitations must be acknowledged. Its observational design and relatively limited sample size \u0026mdash;especially for advanced-stage tumors and palpebral lesions\u0026mdash; restrict the ability to draw definitive conclusions. Additionally, resistance measurements were obtained using a single electroporation device and protocol, which may limit generalizability to other equipment or treatment settings. Resistance measurements during ECT are influenced not only by tumor biology and local anatomy but also by technical factors, including electrode placement, inter-electrode distance and contact quality, factors that could not be fully standardized in a clinical setting. Nonetheless, the consistent trends observed across sessions and pulses, together with the significant association between resistance and response, provide a strong rationale for further investigation. Integrating resistance data with imaging, histopathological features (such as fibrosis, necrosis, and vascular density), and computational electric field modelling could improve our understanding of the relationship between electrical properties and biological effects. Standardization of measurement protocols will also be essential to enable meaningful comparisons across studies and centers.\u003c/p\u003e \u003cp\u003eIn conclusion, the present work provides the first clinical evidence that tumor electrical resistance decreases during ECT in feline SCC and that lower resistance values are associated with improved local tumor control. These findings open new perspectives for the integration of electrical parameter monitoring into ECT protocols, with the potential to optimize treatment delivery, identify early predictors of response and refine patient selection. Further prospective studies involving larger cohorts, different tumor histotypes and additional species are warranted to validate these preliminary observations and to fully elucidate the prognostic value of tumor electrical properties in veterinary oncology.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting Interests\u003c/h2\u003e\u003cp\u003eSpugnini EP is stockholder of Biopulse Srl, Assumma C. was employed by Biopulse Srl to develop the clinical electroporator used in this study.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e \u003ch2\u003eInformed consent\u003c/h2\u003e \u003cp\u003eAll cat owners and representatives of animal welfare associations managing the shelters provided written informed consent for the administration of electrochemotherapy and intravenous chemotherapy with bleomycin. All procedures were carried out by licensed veterinary personnel for diagnostic and therapeutic purposes. All animal experiments were conducted in accordance with relevant guidelines and regulations. The study was approved by the Ethics Committee of the Department of Veterinary Medicine, University of Bari (Authorization No. 31/21).\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research did not receive funding.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization: E.P.S. and D.F.; Methodology: E.P.S., D.F., C.A. and I.L; Investigation: E.P.S. and C.A.; Visualization: I.L, S.C., A.D.B., C.P. and C.D\u0026rsquo;A; Funding acquisition: not applicable. Project administration: E.P.S., and D.F. 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Online\u003c/em\u003e. \u003cb\u003e13\u003c/b\u003e, 29 (2014).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"resistance, tumor, biphasic pulses, bleomycin, cat","lastPublishedDoi":"10.21203/rs.3.rs-8592493/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8592493/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTumors are complex microenvironments in which uncontrolled cell proliferation alters biochemical pathways as well as the physical and electrical properties of tissues. Electrochemotherapy (ECT) exploits electroporation-induced transient increases in cell membrane permeability to enhance intracellular delivery of chemotherapeutic agents. Electroporation is associated with a reduction in tissue electrical resistance due to aqueous pore formation, influenced by electric field intensity, pulse number, and tissue architecture. This study aimed to evaluate changes in tumor electrical resistance during ECT in 39 cats with squamous cell carcinoma (SCC) and to investigate potential correlations between resistance reduction and therapeutic response. Lesions were located on the nasal planum or eyelids and staged as T\u003csub\u003e1\u003c/sub\u003e\u0026ndash;T\u003csub\u003e4\u003c/sub\u003eN\u003csub\u003e0\u003c/sub\u003eM\u003csub\u003e0\u003c/sub\u003e. Tumor electrical resistance (Ω) was recorded in real time for each pulse during all ECT sessions using a veterinary-modified clinical electroporator with integrated resistance-measurement software. Resistance values ranged from 600 to 4900 Ω. Statistical analysis revealed a significant decrease in resistance across sessions and pulses. Resistance was higher in eyelid lesions compared with nasal planum tumors and lower in cats achieving complete response. Additionally, resistance varied significantly among tumor grading, with a significant interaction between tumor stage and localization. In conclusion, tumor electrical resistance decreases during ECT in feline SCC, and lower resistance values are associated with improved local tumor control. Real-time resistance monitoring may represent a non-invasive surrogate marker of effective electroporation and treatment adequacy.\u003c/p\u003e","manuscriptTitle":"A pilot study of electrical resistance in feline squamous cell carcinoma treated with electrochemotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-23 16:20:19","doi":"10.21203/rs.3.rs-8592493/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-13T04:23:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-25T23:17:33+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-20T22:00:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"323476577199996491784808816559804835014","date":"2026-04-20T17:29:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"309545029801195647564873897749242134747","date":"2026-04-17T22:51:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"125611061594009913966240077164948824309","date":"2026-04-15T23:29:11+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-15T20:27:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-13T13:12:32+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-01-21T11:48:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-20T11:03:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-01-20T10:53:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7de1d9c2-6983-4b79-a002-e90334dbd530","owner":[],"postedDate":"April 23rd, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-13T04:23:28+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":66688404,"name":"Biological sciences/Cancer"},{"id":66688405,"name":"Health sciences/Medical research"},{"id":66688406,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-05-13T04:41:45+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-23 16:20:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8592493","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8592493","identity":"rs-8592493","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}