European e-Delphi process to define expert consensus on electrochemotherapy treatment indications, procedural aspects, and quality indicators in melanoma.

BACKGROUND: Skin metastases are an important co-morbidity in melanoma. Despite broad adoption, electrochemotherapy implementation is hindered by a lack of treatment indications, uncertainty regarding procedural aspects, and the absence of quality indicators. An expert consensus may harmonize the approach among centres and facilitate comparison with other therapies. METHODS: An interdisciplinary panel was recruited for a three-round e-Delphi survey. A literature-based 113-item questionnaire was proposed to 160 professionals from 53 European centres. Participants rated each item for relevance and degree of agreement on a five-point Likert scale, and received anonymous controlled feedback to allow revision. The items that reached concordant agreement in two successive iterations were included in the final consensus list. In the third round, quality indicator benchmarks were defined using a real-time Delphi method. RESULTS: The initial working group included 122 respondents, of whom 100 (82 per cent) completed the first round, thus qualifying for inclusion in the expert panel (49 surgeons, 29 dermatologists, 15 medical oncologists, three radiotherapists, two nurse specialists, two clinician scientists). The completion rate was 97 per cent (97 of 100) and 93 per cent (90 of 97) in the second and third rounds respectively. The final consensus list included 54 statements with benchmarks (treatment indications, (37); procedural aspects, (1); quality indicators, (16)). CONCLUSION: An expert panel achieved consensus on the use of electrochemotherapy in melanoma, with a core set of statements providing general direction to electrochemotherapy users to refine indications, align clinical practices, and promote quality assurance programmes and local audits. The residual controversial topics set future research priorities to improve patient care.

Electrochemotherapy is an effective locoregional therapy for skin metastases from melanoma, a problem faced by almost half of patients with metastatic disease. The lack of comparative studies and the heterogeneity of its clinical application among centres make it challenging to support consistent, evidence-based recommendations. To address this unmet need, a three-round online survey was conducted to establish a consensus on treatment indications, standard operating procedures, and quality indicators. In the survey, a panel of 100 European melanoma experts agreed on 56 statements that can be used to improve patient selection, homogenize treatment application, and monitor outcomes.

Radiotherapy or Surgery of the Axilla After a Positive Sentinel Node in Breast Cancer: 10-Year Results of the Randomized Controlled EORTC 10981-22023 AMAROS Trial.

PURPOSE: The European Organisation for Research and Treatment of Cancer 10981-22023 AMAROS trial evaluated axillary lymph node dissection (ALND) versus axillary radiotherapy (ART) in patients with cT1-2, node-negative breast cancer and a positive sentinel node (SN) biopsy. At 5 years, both modalities showed excellent and comparable axillary control, with significantly less morbidity after ART. We now report the preplanned 10-year analysis of the axillary recurrence rate (ARR), overall survival (OS), and disease-free survival (DFS), and an updated 5-year analysis of morbidity and quality of life. METHODS: In this open-label multicenter phase III noninferiority trial, 4,806 patients underwent SN biopsy; 1,425 were node-positive and randomly assigned to either ALND (n = 744) or ART (n = 681). RESULTS: Per intention-to-treat analysis, 10-year ARR cumulative incidence was 0.93% (95% CI, 0.18 to 1.68; seven events) after ALND and 1.82% (95% CI, 0.74 to 2.94; 11 events) after ART (hazard ratio [HR], 1.71; 95% CI, 0.67 to 4.39). There were no differences in OS (HR, 1.17; 95% CI, 0.89 to 1.52) or DFS (HR, 1.19; 95% CI, 0.97 to 1.46). ALND was associated with a higher lymphedema rate in updated 5-year analyses (24.5% v 11.9%; P < .001). Quality-of-life scales did not differ by treatment through 5 years. Exploratory analysis showed a 10-year cumulative incidence of second primary cancers of 12.1% (95% CI, 9.6 to 14.9) after ART and 8.3% (95% CI, 6.3 to 10.7) after ALND. CONCLUSION: This 10-year analysis confirms a low ARR after both ART and ALND with no difference in OS, DFS, and locoregional control. Considering less arm morbidity, ART is preferred over ALND for patients with SN-positive cT1-2 breast cancer.

Sentinel Node Biopsy for Conjunctival Melanoma; Single Centre Experience and Review of Current Literature.

PURPOSE: To evaluate the role of sentinel lymph node (SLN) biopsy in patients with conjuctival melanoma (CjM). STUDY DESIGN: Retrospective observational cohort study and literature review. SUBJECTS: Slovenian patients with CjM are included in the study. METHODS: Prospectively collected data of CjM patients treated from June 2005 to December 2016 were retrospectively analyzed. MAIN OUTCOME MEASURES: The numbers of SLN biopsy procedures, positive and false positive SLN, and local and regional relapses have been described together with overall survival. RESULTS: From June 2005 until December 2016, 24 patients with CjM were treated. The median follow-up time was 65.3 months. The mean Breslow thickness was 1.5 mm (sd = 1.8 mm), and ulceration was present in 29% of cases. Altogether, 14/24 (58%) SLN biopsy procedures were performed. SLN was positive in 2/14 (14%) cases. The estimated 5-year overall survival (OS) of the group was 72.5%, with a median survival of 151 months (95% CI 77-224). From January 2013 to January 2020, five (5/140, 3%) authors reported results comparable to our study. CONCLUSION: Our results confirm that CjM is a rare disease with approximately 14% of positive SLN. At the moment, there are no firm conclusions regarding who would benefit most from SLN biopsy or whether or not CLND should be offered. Data from literature emphasize the need for consistent and uniform staging and future multicentric studies.

Early Cost-effectiveness Analysis of Electrochemotherapy as a Prospect Treatment Modality for Skin Melanoma.

PURPOSE: Electrochemotherapy is increasingly entering into national and international guidelines, requiring formal evaluation of treatment costs and cost-effectiveness to ensure that its uptake provides value to budget-constrained health care systems. This study analyzed the early cost-effectiveness of electrochemotherapy in patients with Stage IIIc/IV skin melanoma in clinical practice in Slovenia. The costs of electrochemotherapy were compared to those of the standard of care, consisting of palliative treatment and therapy for symptoms. METHODS: wThe study enrolled 23 patients treated with electrochemotherapy at the Institute of Oncology (Ljubljana, Slovenia). The mean cost of electrochemotherapy was estimated using patient-specific cost data on electrochemotherapy procedures and subsequent follow-up. Quality-adjusted life-years (QALYs) were estimated by collecting EQ-5D-3L questionnaires at baseline, after complete or partial response following the treatment, and after a relapse of skin lesions. A discrete-time Markov model was built to estimate the lifetime costs and consequences of using electrochemotherapy compared to standard of care, from the perspective of the Slovenian health care system. The analysis was conducted separately in the whole patient sample and in the subset of patients with bleeding lesions. Deterministic and probabilistic sensitivity analyses were conducted to test model assumptions and to characterize the uncertainty around model parameters. FINDINGS: In the whole patient population, electrochemotherapy for skin melanoma Stage IIIc/IV was expected to increase QALYs by 0.29 (95% credible interval [CrI], 0.10-0.50), at the higher cost of 6568 EUR (95% CrI, 4593-8928) in comparison to the standard of care. At the cost-effectiveness threshold of 20,000 EUR/QALY, the estimated probabilities of electrochemotherapy being cost-effective compared to standard of care were 0.30 and 0.91 in the whole patient sample and in patients with bleeding lesions, respectively. In the whole sample population, a 50% reduction in the price of the electrodes was expected to increase the probability of electrochemotherapy being cost-effective from 0.30 to ~0.64. IMPLICATIONS: The findings from this cost-effectiveness analysis of data from clinical practice were based on a small sample size (ie, 23 patents), which made the subgroup of patients with bleeding lesions very small. Therefore, the findings in this patient population should be carefully interpreted.

Radiotherapy-associated angiosarcoma in the breast reconstructed by autologous free-flap and treated with electrochemotherapy.

BACKGROUND: Radiotherapy-associated angiosarcoma (RAA) of the breast is a rare complication of radiotherapy, which is often difficult to identify and has poor prognosis. It usually presents as violaceous skin, erythema or rapidly growing palpable firm mass that can be confused with other benign skin lesions. PATIENTS AND METHODS: After reviewing the literature, we found only four cases with RAA after mastectomy and autologous breast reconstruction. The presented case is the first that was treated by electrochemotherapy. The patient presented with secondary angiosarcoma of the breast five years after mastectomy, immediate breast reconstruction with deep inferior epigastric artery perforator free flap and adjuvant radiotherapy. RESULTS: Electrochemotherapy was feasible, safe and effective in treatment of radiation induced sarcoma. Most of the treated lesions in several consecutive electrochemotherapy sessions responded with complete response, but multiple recurrences occurred in non-treated areas. CONCLUSIONS: Patients with breast cancer after skin-sparing mastectomy and immediate breast reconstruction, who receive radiotherapy, need regular long-term follow up and low threshold for biopsy of any suspicious lesions is mandatory. Electrochemotherapy proved as one of feasible modalities of treatment for RAA.

Electrochemotherapy for advanced cutaneous angiosarcoma: A European register-based cohort study from the International Network for Sharing Practices of electrochemotherapy (InspECT).

BACKGROUND: Cutaneous angiosarcoma (cAS) is a highly aggressive malignancy that challenges the radicality of surgical treatment. Electrochemotherapy (ECT), a skin-directed treatment based on cytotoxic chemotherapy combined with local electric pulses, may be an intraoperative adjunct and a new opportunity in the therapeutic strategy. This cohort study reports the experience with ECT as an option. METHODS: Data on patients with locally-advanced/metastatic cAS who underwent ECT between October 2013 and October 2018 at eight European centres were prospectively submitted to the InspECT (International network for sharing practices of ECT) register. Patients received therapy according to the European Standard Operating Procedures of ECT (ESOPE). Treatment feasibility was assessed based on tumour coverage with electrodes and recorded tissue current; treatment toxicity and tumour response were graded according to CTCAE v5.0 and RECIST v1.1 criteria, respectively; patient-reported outcomes (PRO) were evaluated using a visual analogue score (VAS) for pain, acceptance of retreatment and the EQ-5D questionnaire. RESULTS: We enrolled 20 patients with advanced cAS in the scalp/face (n = 7), breast/trunk (n = 10) or limbs (n = 3). Target tumours (n = 51) had a median size of 2.3 cm (range, 1-20). We administered 24 ECT courses using 1-4 cm treatment safety margin around tumours. In five patients, ECT was combined/sequenced with surgery. Median tissue current was 3 A (range, 1.5-10), tumour margins coverage rate was 75% (15/20 patients). The objective response rate (ORR) was 80% (complete, 40%). Grade-3 toxicity included skin ulceration (15%) and pain (10%), with no significant change of PRO scores. Bleeding control was achieved in 13/14 patients with ulcerated tumours. With a median overall survival of 12.5 months, the local progression-free survival (LPFS) was 10.9 months. CONCLUSION: ECT produces sustained response rate with minimal side effects and should be considered an option for advanced cAS. Palliative benefits include patient tolerability, local haemostasis and durable local control. Definition of optimal timing, treatment safety margins and combination with surgery need further investigation.

Large Liver Blood Vessels and Bile Ducts Are Not Damaged by Electrochemotherapy with Bleomycin in Pigs.

The first clinical studies on the use of electrochemotherapy to treat liver tumours that were not amenable to surgery or thermal ablation techniques have recently been published. However, there is still a lack of data on the effects of electrochemotherapy on normal liver tissue. Therefore, we designed a translational animal model study to test whether electrochemotherapy with bleomycin causes clinically significant damage to normal liver tissue, with emphasis on large blood vessels and bile ducts. We performed electrochemotherapy with bleomycin or delivered electric pulses alone using a potentially risky treatment strategy in eight pigs. Two and seven days after treatment, livers were explanted, and histological analysis was performed. Blood samples were collected before treatment and again before euthanasia to evaluate blood biomarkers of liver function and systemic inflammatory response. We found no thrombosis or other clinically significant damage to large blood vessels and bile ducts in the liver. No clinical or laboratory findings suggested impaired liver function or systemic inflammatory response. Electrochemotherapy with bleomycin does not cause clinically significant damage to normal liver tissue. Our study provides further evidence that electrochemotherapy with bleomycin is safe for treatment of patients with tumours near large blood vessels in the liver.

Recommendations for improving the quality of reporting clinical electrochemotherapy studies based on qualitative systematic review.

BACKGROUND: Electrochemotherapy is becoming a well-established treatment for malignancies of skin and non-skin origin and its use is widening across Europe. The technique was developed and optimized from solid experimental and clinical evidence. A consensus document is now warranted to formalize reporting results, which should strengthen evidence-based practice recommendations. This consensus should be derived from high quality clinical data collection, clinical expertise and summarizing patient feedback. The first step, which is addressed in this paper, aims to critically analyze the quality of published studies and to provide the recommendations for reporting clinical trials on electrochemotherapy. METHODS: The quality of reporting in published studies on electrochemotherapy was analyzed in order to produce procedure specific reporting recommendations. A comprehensive literature search of studies published from 2006 to 2015 was performed followed by qualitative analysis of manuscripts assessing for 47 quality criteria grouped into four major clusters: (1) trial design, (2) description of patient population, (3) description of treatment delivery and patient outcome, (4) analysis of results and their interpretation. The summary measure during literature assessment was the proportion of studies fulfilling each manuscript quality criteria. RESULTS: A total of 56 studies were screened, from the period 2006 to 2015, of which 33 were included in the qualitative analysis, with a total of 1215 patients. Overall, the quality of reporting was highly variable. Twenty-four reports (73%) were single-center, non-comparative studies, and only 15 (45%) were prospective in nature (only 2 of them were entered into a clinical trials registry). Electrochemotherapy technique was consistently reported, with most studies (31/33) adhering closely to published standard operating procedures. The quality of reporting the patient population was variable among the analyzed studies, with only between 45% and 100% achieving dedicated quality criteria. Reporting of treatment delivery and patient outcome was also highly variable with studies only fulfilling between 3% and 100%. Finally, reporting study results critically varied, fulfilling from 27% to 100% of the quality criteria. Based on the critical issues emerging from this analysis, recommendations and minimal requirements for reporting clinical data on electrochemotherapy were prepared and summarized into a checklist. CONCLUSIONS: There is an increasing body of published clinical data on electrochemotherapy, but more high quality clinical data are needed. Published papers often lack accurate description of study population, treatment delivery as well as patient outcome. Our recommendations, provided in the form of a summary checklist, are intended to ameliorate data reporting in future studies on electrochemotherapy and help researchers to provide a solid evidence basis for clinical practice.

Effectiveness of electrochemotherapy after IFN-α adjuvant therapy of melanoma patients.

BACKGROUND: The combination of electrochemotherapy with immuno-modulatory treatments has already been explored and proven effective. However, the role of interferon alpha (IFN-α) adjuvant therapy of melanoma patients and implication on electrochemotherapy effectiveness has not been explored yet. Therefore, the aim of the study was to retrospectively evaluate the effectiveness and safety of electrochemotherapy after the previous adjuvant treatment with IFN-α in melanoma patients. PATIENTS AND METHODS: The study was a retrospective single-center observational analysis of the patients with advanced melanoma, treated with electrochemotherapy after previous IFN-α adjuvant therapy. Five patients, treated between January 2008 and December 2014, were included into the study, regardless of the time point of IFN-α adjuvant therapy. RESULTS: Electrochemotherapy of recurrent melanoma after the IFN-α adjuvant therapy proved to be a safe and effective treatment. Patients with one or two metastases responded completely. Among patients with multiple metastases, there was a variable response rate. In one patient all 23 metastases responded completely, in second patient more than 85% of all together 80 metastases responded completely and in third patient all 5 metastases had partial response. Taking into account all metastases from all patients together there was an 85% complete response rate. CONCLUSIONS: The study showed that electrochemotherapy of recurrent melanoma after the IFN-α adjuvant therapy is a safe and effective treatment modality, which results in a high complete response rate, not only in single metastasis, but also in multiple metastases. The high complete response rate might be due to an IFN-α immune-editing effect, however, further studies with a larger number of patients are needed to support this presumption.

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial.

BACKGROUND: If treatment of the axilla is indicated in patients with breast cancer who have a positive sentinel node, axillary lymph node dissection is the present standard. Although axillary lymph node dissection provides excellent regional control, it is associated with harmful side-effects. We aimed to assess whether axillary radiotherapy provides comparable regional control with fewer side-effects. METHODS: Patients with T1-2 primary breast cancer and no palpable lymphadenopathy were enrolled in the randomised, multicentre, open-label, phase 3 non-inferiority EORTC 10981-22023 AMAROS trial. Patients were randomly assigned (1:1) by a computer-generated allocation schedule to receive either axillary lymph node dissection or axillary radiotherapy in case of a positive sentinel node, stratified by institution. The primary endpoint was non-inferiority of 5-year axillary recurrence, considered to be not more than 4% for the axillary radiotherapy group compared with an expected 2% in the axillary lymph node dissection group. Analyses were by intention to treat and per protocol. The AMAROS trial is registered with ClinicalTrials.gov, number NCT00014612. FINDINGS: Between Feb 19, 2001, and April 29, 2010, 4823 patients were enrolled at 34 centres from nine European countries, of whom 4806 were eligible for randomisation. 2402 patients were randomly assigned to receive axillary lymph node dissection and 2404 to receive axillary radiotherapy. Of the 1425 patients with a positive sentinel node, 744 had been randomly assigned to axillary lymph node dissection and 681 to axillary radiotherapy; these patients constituted the intention-to-treat population. Median follow-up was 6·1 years (IQR 4·1-8·0) for the patients with positive sentinel lymph nodes. In the axillary lymph node dissection group, 220 (33%) of 672 patients who underwent axillary lymph node dissection had additional positive nodes. Axillary recurrence occurred in four of 744 patients in the axillary lymph node dissection group and seven of 681 in the axillary radiotherapy group. 5-year axillary recurrence was 0·43% (95% CI 0·00-0·92) after axillary lymph node dissection versus 1·19% (0·31-2·08) after axillary radiotherapy. The planned non-inferiority test was underpowered because of the low number of events. The one-sided 95% CI for the underpowered non-inferiority test on the hazard ratio was 0·00-5·27, with a non-inferiority margin of 2. Lymphoedema in the ipsilateral arm was noted significantly more often after axillary lymph node dissection than after axillary radiotherapy at 1 year, 3 years, and 5 years. INTERPRETATION: Axillary lymph node dissection and axillary radiotherapy after a positive sentinel node provide excellent and comparable axillary control for patients with T1-2 primary breast cancer and no palpable lymphadenopathy. Axillary radiotherapy results in significantly less morbidity. FUNDING: EORTC Charitable Trust.

Intraoperative electrochemotherapy of colorectal liver metastases.

BACKGROUND AND OBJECTIVES: Electrochemotherapy is effective in treatment of various cutaneous tumors and could be translated into treatment of deep-seated tumors. With this aim a prospective pilot study was conducted to evaluate feasibility, safety, and efficacy of intraoperative electrochemotherapy in the treatment of colorectal liver metastases. METHODS: Electrochemotherapy with bleomycin was performed during open surgery, by insertion of long needle electrodes into and around the tumor according to the individualized pretreatment plan. RESULTS: A 29 metastases in 16 patients were treated in 16 electrochemotherapy sessions. No immediate (intraoperative) and/or postoperative serious adverse events related to electrochemotherapy were observed. Radiological evaluation of all the treated metastases showed 85% complete responses and 15% partial responses. In a group of seven patients that underwent a second operation at 6-12 weeks after the first one, during which electrochemotherapy was performed, the histology of resected metastases treated by electrochemotherapy showed less viable tissue (P = 0.001) compared to non-treated ones. CONCLUSIONS: Electrochemotherapy of colorectal liver metastases proved to be feasible, safe, and efficient treatment modality, providing its specific place in difficult to treat metastases, located in the vicinity of major hepatic vessels, not amenable to surgery or radiofrequency ablation.

Gene electrotransfer of plasmid antiangiogenic metargidin peptide (AMEP) in disseminated melanoma: safety and efficacy results of a phase I first-in-man study.

Antiangiogenic metargidin peptide (AMEP) is a novel anticancer agent exerting antiproliferative and antiangiogenic effects by binding to αvß3 and α5ß1 integrins. Electrotransfer designates the use of electric pulses (electroporation) to transfer plasmid DNA into tissues. This first-in-man phase I study investigated safety and tolerability of intratumoral plasmid AMEP electrotransfer into cutaneous metastatic melanoma. Secondary objectives were efficacy and pharmacokinetics. Five patients with disseminated melanoma without further treatment options were treated at two dose levels (1 and 2 mg DNA). In each patient, two cutaneous lesions were identified (one treated and one control). At day 1 and day 8, plasmid AMEP was injected intratumorally followed by electrotransfer. Patients were monitored weekly until day 29, and at day 64. Local efficacy was assessed at day 29 by direct measurement, and posttreatment biopsies for AMEP mRNA levels were evaluated by reverse transcriptase quantitative polymerase chain reaction. Plasmid copy number in blood and urine was determined by quantitative polymerase chain reaction. Minimal systemic toxicity was observed, including transient fever and transitory increase in C-reactive protein. No related serious adverse events occurred. Plasmid AMEP was detected in plasma but not in urine. AMEP mRNA was found in three of five treated lesions and none of the control lesions. At day 29, all five treated lesions were stable in diameter, whereas four of five control lesions increased more than 20%. No response occurred in distant lesions. This first-in-man study on electrotransfer of plasmid AMEP into cutaneous melanoma shows that the procedure and drug are safe and that local transfection was obtained.

Tumor size and effectiveness of electrochemotherapy.

BACKGROUND: Electrochemotherapy (ECT) is an effective and safe method for local treatment of tumors. However, relatively large variability in effectiveness of ECT has been observed, which likely results from different treatment conditions and tumor characteristics. The aim of this study was to investigate the relationship between tumor size and effectiveness of a single-session ECT. MATERIALS AND METHODS: A systematic search of various bibliographic databases was performed and nine studies eligible for this study were extracted. Different statistical methods including meta-analysis were applied to analyze the data. RESULTS: The results of analysis based on data from 1466 tumors of any histotype show significantly lower effectiveness of ECT on tumors with maximal diameter equal to or larger than 3 cm (complete response (CR) of 33.3%, objective response (OR) of 68.2%) in comparison to smaller tumors (CR% of 59.5%, OR% of 85.7%). The results of meta-analysis indicated that ECT performed on tumors smaller than 3 cm statistically significantly increases the probability of CR by 31.0% and OR by 24.9% on average in comparison to larger tumors. The analysis of raw data about the size and response of tumors showed statistically significant decrease in effectiveness of ECT progressively with increasing tumor diameter. The biggest drop in CR% was detected at tumor diameters as small as 2 cm. CONCLUSIONS: The standard operating procedures for ECT should be reexamined and refined for the treatment of large tumors. We propose that future clinical trials should include accurate ECT treatment planning and/or multiple ECT cycles, besides a prolonged observation for tumor response evaluation.

Outcome of MRI-guided vacuum-assisted breast biopsy - initial experience at Institute of Oncology Ljubljana, Slovenia.

BACKGROUND: Like all breast imaging modalities MRI has limited specificity and the positive predictive value for lesions detected by MRI alone ranges between 15 and 50%. MRI guided procedures (needle biopsy, presurgical localisation) are mandatory for suspicious findings visible only at MRI, with potential influence on therapeutic decision. The aim of this retrospective study was to evaluate our initial clinical experience with MRI-guided vacuum-assisted breast biopsy as an alternative to surgical excision and to investigate the outcome of MRI-guided breast biopsy as a function of the MRI features of the lesions. PATIENTS AND METHODS.: In 14 women (median age 51 years) with 14 MRI-detected lesions, MRI-guided vacuum-assisted breast biopsy was performed. We evaluated the MRI findings that led to biopsy and we investigated the core and postoperative histology results and follow-up data. RESULTS: The biopsy was technically successful in 14 (93%) of 15 women. Of 14 biopsies in 14 women, core histology revealed 6 malignant (6/14, 43%), 6 benign (6/14, 43%) and 2 high-risk (2/14, 14%) lesions. Among the 6 cancer 3 were invasive and 3 were ductal carcinoma in situ (DCIS). The probability of malignancy in our experience was higher for non-mass lesion type and for washout and plateau kinetics. CONCLUSIONS: Our initial experience confirms that MRI-guided vacuum-assisted biopsy is fast, safe and accurate alternative to surgical biopsy for breast lesions detected at MRI only.

Inguinal or inguino-iliac/obturator lymph node dissection after positive inguinal sentinel lymph node in patients with cutaneous melanoma.

BACKGROUND: The aim of the study was to determine whether the presence of inguinal sentinel lymph node (SLN) metastases smaller than 2 mm (micrometastases) subdivided according to the number of micrometastases predicts additional, non-sentinel inguinal, iliac or obturator lymph node involvement in completion lymph node dissection (CLND). PATIENTS AND METHODS.: Positive inguinal SLN was detected in 58 patients (32 female, 26 male, median age 55 years) from 743 consecutive and prospectively enrolled patients with primary cutaneous melanoma stage I and II who were treated with SLN biopsy between 2001 and 2007. RESULTS: Micrometastases in inguinal SLN were detected in 32 patients, 14 were single, 2 were double, and 16 were multiple. Twenty-six patients had macrometastases. CONCLUSIONS: No patient with any micrometastases or a single SLN macrometastasis in the inguinal region had any iliac/obturator non-sentinel metastases after CLND in our series. Furthermore, no patient with single SLN micrometastasis in the inguinal region had any non-sentinel metastases at all after CLND in our series. In these cases respective CLND might be omitted.

Electrochemotherapy of chest wall breast cancer recurrence.

Chest wall breast cancer recurrence after mastectomy is a disease difficult to treat. Its incidence varies between 5% and 30% in different subset of patients. When possible, radical surgical therapy represents the main treatment approach, however when the disease progresses and/or treatments are not successful, ulceration, bleeding, lymphedema and psychological distress of progressive disease significantly decrease the quality of the remaining life of a patient. When surgical excision of chest wall recurrence is not possible, other local treatments such as radiotherapy, radiotherapy with hyperthermia, topical chemotherapy and electrochemotherapy might be taken into account. Electrochemotherapy provides safe, efficient and non-invasive locoregional treatment approach for chest wall breast cancer recurrence. Several clinical studies have demonstrated high efficacy and a good safety profile of electrochemotherapy applied in single or multiple consecutive sessions, till clinical response was reached. Electrochemotherapy can be performed either with cisplatin injected intratumorally or with bleomycin given intratumorally or intravenously. Furthermore, it can be effectively used in heavily pre-treated areas, after surgery, radiotherapy or systemic chemotherapy. These are the advantages that might demand its use especially in patients with pre-treated extensive disease and in frail elderly patients. With development of the technology electrochemotherapy could even be suggested as a primary local therapy in patients not suitable for surgical removal of the primary tumor.

Robustness of treatment planning for electrochemotherapy of deep-seated tumors.

Treatment of cutaneous and subcutaneous tumors with electrochemotherapy has become a regular clinical method, while treatment of deep-seated tumors is still at an early stage of development. We present a method for preparing a dedicated patient-specific, computer-optimized treatment plan for electrochemotherapy of deep-seated tumors based on medical images. The treatment plan takes into account the patient's anatomy, tissue conductivity changes during electroporation and the constraints of the pulse generator. Analysis of the robustness of a treatment plan made with this method shows that the effectiveness of the treatment is not affected significantly by small single errors in electrode positioning. However, when many errors occur simultaneously, the resulting drop in effectiveness is larger, which means that it is necessary to be as accurate as possible in electrode positioning. The largest effect on treatment effectiveness stems from uncertainties in dielectric properties and electroporation thresholds of treated tumors and surrounding tissues, which emphasizes the need for more accurate measurements and more research. The presented methods for treatment planning and robustness analysis allow quantification of the treatment reproducibility and enable the setting of suitable safety margins to improve the likelihood of successful treatment of deep-seated tumors by electrochemotherapy.

Sentinel node identification rate and nodal involvement in the EORTC 10981-22023 AMAROS trial.

BACKGROUND: The randomized EORTC 10981-22023 AMAROS trial investigates whether breast cancer patients with a tumor-positive sentinel node biopsy (SNB) are best treated with an axillary lymph node dissection (ALND) or axillary radiotherapy (ART). The aim of the current substudy was to evaluate the identification rate and the nodal involvement. METHODS: The first 2,000 patients participating in the AMAROS trial were evaluated. Associations between the identification rate and technical, patient-, and tumor-related factors were evaluated. The outcome of the SNB procedure and potential further nodal involvement was assessed. RESULTS: In 65 patients, the sentinel node could not be identified. As a result, the sentinel node identification rate was 97% (1,888 of 1,953). Variables affecting the success rate were age, pathological tumor size, histology, year of accrual, and method of detection. The SNB results of 65% of the patients (n = 1,220) were negative and the patients underwent no further axillary treatment. The SNB results were positive in 34% of the patients (n = 647), including macrometastases (n = 409, 63%), micrometastases (n = 161, 25%), and isolated tumor cells (n = 77, 12%). Further nodal involvement in patients with macrometastases, micrometastases, and isolated tumor cells undergoing an ALND was 41, 18, and 18%, respectively. CONCLUSIONS: With a 97% detection rate in this prospective international multicenter study, the SNB procedure is highly effective, especially when the combined method is used. Further nodal involvement in patients with micrometastases and isolated tumor cells in the sentinel node was similar-both were 18%.

Towards treatment planning and treatment of deep-seated solid tumors by electrochemotherapy.

BACKGROUND: Electrochemotherapy treats tumors by combining specific chemotherapeutic drugs with an intracellular target and electric pulses, which increases drug uptake into the tumor cells. Electrochemotherapy has been successfully used for treatment of easily accessible superficial tumor nodules. In this paper, we present the first case of deep-seated tumor electrochemotherapy based on numerical treatment planning. METHODS: The aim of our study was to treat a melanoma metastasis in the thigh of a patient. Treatment planning for electrode positioning and electrical pulse parameters was performed for two different electrode configurations: one with four and another with five long needle electrodes. During the procedure, the four electrode treatment plan was adopted and the patient was treated accordingly by electrochemotherapy with bleomycin. The response to treatment was clinically and radiographically evaluated. Due to a partial response of the treated tumor, the metastasis was surgically removed after 2 months and pathological analysis was performed. RESULTS: A partial response of the tumor to electrochemotherapy was obtained. Histologically, the metastasis showed partial necrosis due to electrochemotherapy, estimated to represent 40-50% of the tumor. Based on the data obtained, we re-evaluated the electrical treatment parameters in order to correlate the treatment plan with the clinical response. Electrode positions in the numerical model were updated according to the actual positions during treatment. We compared the maximum value of the measured electric current with the current predicted by the model and good agreement was obtained. Finally, tumor coverage with an electric field above the reversible threshold was recalculated and determined to be approximately 94%. Therefore, according to the calculations, a small volume of tumor cells remained viable after electrochemotherapy, and these were sufficient for tumor regrowth. CONCLUSIONS: In this, the first reported clinical case, deep-seated melanoma metastasis in the thigh of the patient was treated by electrochemotherapy, according to a treatment plan obtained by numerical modeling and optimization. Although only a partial response was obtained, the presented work demonstrates that treatment of deep-seated tumor nodules by electrochemotherapy is feasible and sets the ground for numerical treatment planning-based electrochemotherapy. TRIAL REGISTRATION: EudraCT:2008-008290-54.

Mammographycally occult high grade ductal carcinoma in situ (DCIS) as second primary breast cancer, detected with MRI: a case report.

BACKGROUND: Contralateral breast cancer (CLB) is the most common second primary breast cancer in patients diagnosed with breast cancer. The majority of patients harbouring CLB tumours develop the invasive disease. Almost all invasive carcinomas are believed to begin as ductal carcinoma in situ (DCIS) lesions. The sensitivity of MRI for DCIS is much higher than that of mammography. CASE REPORT: We report the case of a woman who was treated with breast conserving therapy 10 years ago. At that time the invasive medullary carcinoma was diagnosed in the left breast. Ten years later mammographically occult DCIS was diagnosed with MRI-guided core biopsy in contralateral breast. CONCLUSIONS: There might be a potential role of MRI screening as part of an annual follow-up for patients diagnosed with breast cancer.