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BACKGROUND For locally advanced rectal cancer (LARC), standard therapy [consisting of neoadjuvant chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ChT)] achieves excellent local control. Unfortunately, survival is still poor due to distant metastases, which remains the leading cause of death among these patients. In recent years, the concept of total neoadjuvant treatment (TNT) has been developed, whereby all systemic ChT-mainly affecting micrometastases-is applied prior to surgery. AIM To compare standard therapy and total neoadjuvant therapy for LARC patients with high-risk factors for failure. METHODS In a retrospective study, we compared LARC patients with high-risk factors for failure who were treated with standard therapy or with TNT. High-risk for failure was defined according to the presence of at least one of the following factors: T4 stage; N2 stage; positive mesorectal fascia; extramural vascular invasion; positive lateral lymph node. TNT consisted of 12 wk of induction ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin, CRT with capecitabine, and 6-8 wk of consolidation ChT with capecitabine and oxaliplatin or folinic acid, fluorouracil and oxaliplatin prior to surgery. The primary endpoint was pathological complete response (pCR). In total, 72 patients treated with standard therapy and 89 patients treated with TNT were included in the analysis. RESULTS Compared to standard therapy, TNT showed a higher proportion of pCR (23% vs 7%; P = 0.01), a lower neoadjuvant rectal score (median: 8.43 vs 14.98; P < 0.05), higher T-and N-downstaging (70% and 94% vs 51% and 86%), equivalent R0 resection (95% vs 93%), shorter time to stoma closure (mean: 20 vs 33 wk; P < 0.05), higher compliance during systemic ChT (completed all cycles 87% vs 76%; P < 0.05), lower proportion of acute toxicity grade ≥ 3 during ChT (3% vs 14%, P < 0.05), and equivalent acute toxicity and compliance during CRT and in the postoperative period. The pCR rate in patients treated with TNT was significantly higher in patients irradiated with intensity-modulated radiotherapy/volumetric-modulated arc radiotherapy than with 3D conformal radiotherapy (32% vs 9%; P < 0.05). CONCLUSION Compared to standard therapy, TNT provides better outcome for LARC patients with high-risk factors for failure, in terms of pCR and neoadjuvant rectal score.

Objectives: The use of thermal ablative therapies in the pancreatic tumors is limited because of the risk of the vessel injury and potential pancreatitis or fistula formation. Electrochemotherapy (ECT) is an ablative therapy with established role in the treatment of cutaneous and liver tumors. This study was designed to evaluate the safety and feasibility of ECT of the pancreas in a porcine survival model. Methods: In the first group, 4 animals underwent computed tomography (CT)%guided percutaneous ECT with bleomycin of the pancreatic tail. In the second group (4 animals), the intraoperative ECTwith bleomycin of pancreatic tail and head was performed. Animals were followed for 7 days and then killed. Clinical parameters, CT imaging, laboratory, and histologic analysis were performed. Results: All pigs survived the ECT procedure and none of them developed clinical signs of acute pancreatitis or related complications. There were no signs of acute pancreatitis or damage to the large vessels present in the follow-up CT scans. No significant change in laboratory parameters was obtained after procedure. Conclusions: This study shows that ECT with bleomycin is feasible and safe in the pancreatic parenchyma. Clinical studies are needed to evaluate the efficacy of ECT in pancreatic cancer.

Background Immune checkpoint inhibitors have changed the paradigm of cancer treatment; however, non-invasive biomarkers of response are still needed to identify candidates for non-responders. We aimed to investigate whether immunotherapy [18F]FDG PET radiomics signature (iRADIOMICS) predicts response of metastatic non-small-cell lung cancer (NSCLC) patients to pembrolizumab better than the current clinical standards. Patients and methods Thirty patients receiving pembrolizumab were scanned with [18F]FDG PET/CT at baseline, month 1 and 4. Associations of six robust primary tumour radiomics features with overall survival were analysed with Mann-Whitney U-test (MWU), Cox proportional hazards regression analysis, and ROC curve analysis. iRADIOMICS was constructed using univariate and multivariate logistic models of the most promising feature(s). Its predictive power was compared to PD-L1 tumour proportion score (TPS) and iRECIST using ROC curve analysis. Prediction accuracies were assessed with 5-fold cross validation. Results The most predictive were baseline radiomics features, e.g. Small Run Emphasis (MWU, p = 0.001; hazard ratio = 0.46, p = 0.007; AUC = 0.85 (95% CI 0.69–1.00)). Multivariate iRADIOMICS was found superior to the current standards in terms of predictive power and timewise with the following AUC (95% CI) and accuracy (standard deviation): iRADIOMICS (baseline), 0.90 (0.78–1.00), 78% (18%); PD-L1 TPS (baseline), 0.60 (0.37–0.83), 53% (18%); iRECIST (month 1), 0.79 (0.62–0.95), 76% (16%); iRECIST (month 4), 0.86 (0.72–1.00), 76% (17%). Conclusions Multivariate iRADIOMICS was identified as a promising imaging biomarker, which could improve management of metastatic NSCLC patients treated with pembrolizumab. The predicted non-responders could be offered other treatment options to improve their overall survival.

BAP1 cancer syndrome is a rare and highly penetrant hereditary cancer predisposition. Uveal melanoma, mesothelioma, renal cell carcinoma (RCC) and cutaneous melanoma are considered BAP1 cancer syndrome core cancers, whereas association with breast cancer has previously been suggested but not confirmed so far. In view of BAP1 immunomodulatory functions, BAP1 alterations could prove useful as possible biomarkers of response to immunotherapy in patients with BAP1-associated cancers. We present a case of a patient with BAP1 cancer syndrome who developed a metastatic breast cancer with loss of BAP1 demonstrated on immunohistochemistry. She carried a germline BAP1 likely pathogenic variant (c.898_899delAG p.(Arg300Glyfs*6)). In addition, tumor tissue sequencing identified a concurrent somatic variant in BAP1 (partial deletion of exon 12) and a low tumor mutational burden. As her triple negative tumor was shown to be PD-L1 positive, the patient was treated with combination of atezolizumab and nab-paclitaxel. She had a complete and sustained response to immunotherapy even after discontinuation of nab-paclitaxel. This case strengthens the evidence for including breast cancer in the BAP1 cancer syndrome tumor spectrum with implications for future cancer prevention programs. It also indicates immune checkpoint inhibitors might prove to be an effective treatment for BAP1-deficient breast cancer.

Background In the light of a high rate of distant recurrence and poor compliance of adjuvant chemotherapy in high risk rectal cancer patients the total neoadjuvant treatment was logical approach to gaining acceptance. We aimed to evaluate toxicity and efficiency of this treatment in patients with rectal cancer and high risk factors for local or distant recurrence. Patients and methods Patients with rectal cancer stage II and III and with at least one high risk factor: T4, presence of extramural vein invasion (EMVI), positive extramesorectal lymph nodes or mesorectal fascia (MRF) involvement were treated with four cycles of induction CAPOX/FOLFOX, followed by capecitabine-based radiochemotherapy (CRT) and two consolidation cycles of CAPOX/FOLFOX before the operation. Surgery was scheduled 8–10 weeks after completition of CRT. Results From November 2016 to July 2018 66 patients were evaluable. All patients had stage III disease, 24 (36.4%) had T4 tumors, in 46 (69.7%) EMVI was present and in 47 (71.2%) MRF was involved. After induction chemotherapy, which was completed by 61 (92.4%) of patients, radiologic downstaging of T, N, stage, absence of EMVI or MRF involvement was observed in 42.4%, 62.1%, 36.4%, 69.7% and 68.2%, respectively. All patients completed radiation and 54 (81.8%) patients received both cycles of consolidation chemotherapy. Grade 3 adverse events of neoadjuvant treatment was observed in 4 (6%) patients. Five patients rejected surgery, 3 of them with radiologic complete clinical remissions. One patient did not have definitive surgery of primary tumor due to unexpected cardiac arrest few days after sigmoid colostomy formation. Among 60 operated patients pathological complete response rate was 23.3%, the rate of near complete response was 20% and in 96.7% radical resection was achieved. Pathological T, N and stage downstaging was 65%, 96.7% and 83.4%, respectively. Grade ≥ 3 perioperative complications were anastomotic leakage in 3, pelvic abscess in 1 and paralytic ileus in 2 patients. The rate of pathologic complete response (pCR) in patients irradiated with 3D conformal technique was 12.1% while with IMRT and VMAT it was 37% (p < 0.05). Hypofractionation with larger dose per fraction and simultaneous integrated boost used in the latest two was the only factor associated with pCR. Conclusions Total neoadjuvant treatment of high risk rectal cancer is well tolerated and highly effective with excellent tumor and node regression rate and with low toxicity rate. Longer follow up will show if this strategy will improve distant disease control and survival.

Background and objectives A previous pilot study proved the feasibility, safety and efficacy of electrochemotherapy in the treatment of colorectal liver metastases. The aim of this study was to evaluate long-term effectiveness and safety of electrochemotherapy in the treatment of unresectable colorectal liver metastases. Patients and methods In this prospective phase II study, patients with metachronous colorectal liver metastases were included. In all patients, at least one metastasis was unresectable due to its central location or a too-small future remnant liver volume. Patients were treated by electrochemotherapy using intravenously administered bleomycin during open surgery. Treated were 84 metastases in 39 patients. Local tumor control, progression-free survival and overall survival were evaluated. Results The objective response was 75% (63% CR, 12% PR). The median duration of the response was 20.8 months for metastases in CR and 9.8 months for metastases in PR. The therapy was significantly more effective for metastases smaller than 3 cm in diameter than for larger ones. There was no difference in response according to the metastatic location, i.e., metastases in central vs. peripheral locations. Progression-free survival was better in patients who responded well to electrochemotherapy compared to those metastases that had a partial response or progressive disease. However, there was no difference in overall survival, with a median of 29.0 months. Conclusions Electrochemotherapy has proven to be safe and effective in the treatment of colorectal liver metastases, with a durable response. It provides local tumor control that enables patients with unresectable metastases to receive further treatments.

Background The aim of the study was to characterize ultrasonographic (US) findings during and after electrochem-otherapy of liver tumors to determine the actual ablation zone and to verify the coverage of the treated tumor with a sufficiently strong electric field for effective electrochemotherapy. Patients and methods US findings from two representative patients that describe immediate and delayed tumor changes after electrochemotherapy of colorectal liver metastases are presented. Results The US findings were interrelated with magnetic resonance imaging (MRI). Electrochemotherapy-treated tumors were exposed to electric pulses based on computational treatment planning. The US findings indicate immediate appearance of hyperechogenic microbubbles along the electrode tracks. Within minutes, the tumors became evenly hyperechogenic, and simultaneously, an oedematous rim was formed presenting as a hypoechogenic formation which persisted for several hours after treatment. The US findings overlapped with computed electric field distribution in the treated tissue, indicating adequate coverage of tumors with sufficiently strong electric field, which may predict an effective treatment outcome. Conclusions US provides a tool for assessment of appropriate electrode insertion for intraoperative electrochemo-therapy of liver tumors and assessment of the appropriate coverage of a tumor with a sufficiently strong electric field and can serve as predictor of the response of tumors.

Endoscopic colorectal tattooing with carbon-based dyes is commonly employed in order to assist with later localization of the lesion. Although carbon is thought to be nontoxic, there usually is some inflammatory reaction with fibrosis and granuloma formation after tissue injection. The aim of this report is to alert to a possible underestimated, late consequence of colorectal carbon-based marker tattooing, namely pronounced fibrosis at the site of the injection that could lead to a blurring and misinterpretation of changes evaluated by radiological techniques. We describe a case of cT stage overestimation due to fibrosis of the rectal wall and perirectal fat, induced by carbon-based dye injection in a 66-year-old patient. In our case it was an overestimation of MR evaluation in the case of early invasive carcinoma. Although there have been some studies on tissue effect of carbon-based dyes, the possible scenario consequence of cancer stage overestimation due to fibrosis has not yet been described. Such a mistake could lead to inappropriate overtreatment. Clinicians must be aware of the possible consequences of dye injection and resultant overestimation of T stage of colorectal cancer. More histological studies concerning histological changes after carbon-based marker tattooing are needed to establish the extent of its significance.

Due to a lack of data on predictors of electroporation-based treatment outcomes, we investigated the potential predictive role of contrast-enhanced harmonic ultrasound (CEUS) in mice B16F10 melanoma treated by gene electrotransfer (GET) to silence melanoma cell adhesion molecule (MCAM) and radiotherapy, which has not been evaluated yet. CEUS evaluation was verified by tumor histological analysis. Mice bearing subcutaneous tumors were treated with GET to silence MCAM, irradiation or the combination of GET to silence MCAM and irradiation (combined treatment). CEUS of the tumors used to evaluate tumor perfusion was performed before and up to 10 days after the beginning of the experiment, and the CEUS results were compared with tumor growth and the number of blood vessels analyzed in the histological tumor sections. CEUS revealed a decrease in tumor perfusion in the combined therapy groups compared with the control groups and correlated with tumor histological analyses, which showed a decreased vascular density. In this study a trend of inverse correlation was observed between tumor perfusion and treatment efficacy. The greater the perfusion of the tumor, the shorter the expected doubling time. Furthermore, decreased perfusion showed a trend to correlate with higher antitumor efficacy. Thus, CEUS could be used to predict tumoral vascular density and treatment effectiveness.

Background Radiologic findings after electrochemotherapy of large hepatic blood vessels and healthy hepatic parenchyma have not yet been described. Materials and methods We performed a prospective animal model study with regulatory approval, including nine grower pigs. In each animal, four ultrasound-guided electroporated regions were created; in three regions, electrodes were inserted into the lumen of large hepatic vessels. Two types of electrodes were tested; variable linear- and fixed hexagonal-geometry electrodes. Ultrasonographic examinations were performed immediately and up to 20 minutes after the procedure. Dynamic computed tomography was performed before and at 60 to 90 minutes and one week after the procedure. Results Radiologic examinations of the treated areas showed intact vessel walls and patency; no hemorrhage or thrombi were noted. Ultrasonographic findings were dynamic and evolved from hyperechogenic microbubbles along electrode tracks to hypoechogenicity of treated parenchyma, diffusion of hyperechogenic microbubbles, and hypoechogenicity fading. Contrast-enhanced ultrasound showed decreased perfusion of the treated area. Dynamic computed tomography at 60 to 90 minutes after the procedure showed hypoenhancing areas. The total hypoenhancing area was smaller after treatment with fixed hexagonal electrodes than after treatment with variable linear geometry electrodes. Conclusions Radiologic findings of porcine liver after electrochemotherapy with bleomycin did not show clinically significant damage to the liver, even if a hazardous treatment strategy, such as large vessel intraluminal electrode insertion, was employed, and thus further support safety and clinical use of electrochemotherapy for treatment of hepatic neoplasia.

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.

Rak debelega črevesa in danke (RDČD) je najpogostejši rak v Sloveniji. Po podatkih Registra raka Slovenije za leto 2008 je v Sloveniji zbolelo 1.450 ljudi(1). Z naraščajočo incidenco narašča tudi umrljivost bolnikov, saj bolezen pri polovici bolnikov še vedno ugotovimo v napredovali obliki. Razsejana bolezen je neozdravljiva bolezen, sta se pa prognoza in preživetje teh bolnikov močno izboljšala, saj zadnjih deset let z uporabo novih zdravil, to je kombinacijo citostatikov (kapecitabin, irinotekan, oksaliplatin) in tarčnih zdravil (cetuksimab, bevacizumab, panitumumab), dosegamo srednja preživetja, ki so daljša od 30 mesecev(2). Kadar kombiniramo sistemsko in kirurško zdravljenje pri bolnikih s samo jetrnimi zasevki, še posebej, če gre za solitarne zasevke, pa 5-letno preživetje lahko presega 50 %. V tem prispevku opisujemo primer bolnice s primarno razsejanim karcinomom danke z zasevki v jetrih, kjer smo v okviru multidisciplinarnega pristopa, s kombinacijo sistemske terapije in večkratne operacije jetrnih zasevkov ter tudi drugimi terapevtskimi pristopi dosegli preživetje, daljše od 50 mesecev. Colorectal cancer (CC) is the most common cancer in Slovenia. According to the Cancer Registry of the Republic of Slovenia, a total of 1,450 people were diagnosed with colorectal cancer in Slovenia in 2008(1). The increasing incidence also means increasing morbidity, as in half of the patients, the disease is diagnosed when already at an advanced stage. Metastatic disease is incurable, but the prognosis and the survival of these patients have improved considerably, as in the last decade, with the use of new drugs, namely a combination of cytostatics (capecitabine, irinotecan, oxaliplatin) and target drugs (cetuximab, bevacizumab, panitumumab) we have achieved a median survival of more than 30 months(2). When combining systemic and surgical treatment in patients with liver metastases, in particular if these are solitary metastases, the 5-year survival can exceed 50%. In this paper, we present a case of a patient with primary metastatic rectal carcinoma with metastases in the liver. Within the framework of a multidisciplinary approach with a combination of systemic therapy and multiple surgeries of liver metastases, and using also other therapeutic approaches, we have achieved a survival of more than 50 months.

The introduction of stent grafts for thoracic and abdominal aorta (T / EVAR) has raised the demand for percutaneous closure devices for larger femoral arterial access sites. The aim of our study was to evaluate the success and complication rate of completely percutaneous T / EVAR with Prostar XL® and surgical haemostasis over a 50- month period.Between December 16th 2005 and February 17th 2010 T / EVAR was performed in 306 patients with 568 arterial access sites with diameters of 12 to 24 Fr. The exclusion criteria for percutaneous haemostasis were a calcified anterior wall at the puncture site and / or a stenotic common femoral artery, seen on computed tomographic angiography.Surgical haemostasis was performed in 184 (32.4 %, o-T / EVAR group) while percutaneous haemostasis was attempted at 384 sites (67.6 %, p-T / / EVAR group). Most of the procedures were elective; five of twelve emergency patients had percutaneous haemostasis that was successful in all. Percutaneous haemostasis failed at 23 sites. No data about follow-up was recorded for 54 sites (9,5 %). The technical success rate of percutaneous haemostasis was 93.6 % (338 / 361 sites). A larger size of the access site resulted in significantly more complications of haemostasis in both groups (p-T / EVAR group p = 0.019; o-T / EVAR group p = 0.003). p-T / EVAR caused more mild complications compared to o-T / EVAR (p = 0.03). No deaths as consequence of failed haemostasis were recorded.Complete percutaneous T / EVAR is technically feasible and safe in a majority of patients. Good patient selection based on adequate pre-procedural imaging and technical expertise of the operators are key to success. Surgical back-up is strongly recommended to assist in those patients in whom p-T / EVAR fails.Hintergrund: Die Einführung von Stent-Grafts für die thorakale Aorta und die Bauchaorta (T / EVAR) hat die Nachfrage nach perkutanen Gefäßverschlussystemen für größere arterielle Öffnungen erhöht. Das Ziel unserer Studie war es, den Erfolg und die Komplikationsrate von vollständig perkutanen T / EVAR mit Prostar XL® und chirurgischer Hämostase während eines 50-monatigen-Zeitraumes zu bewerten. Patienten und Methoden: Zwischen dem 16. Dezember 2005 und dem 17. Februar 2010 wurde T / EVAR in 306 Patienten mit 568 arteriellen Zugängen für 12 bis 24 Fr durchgeführt. Die Ausschlusskriterien für die perkutane Hämostase waren Vorderwandverkalkungen an der Einstichstelle und / oder eine verengte A. femoralis communis gemäß computertomographischer Angiographie. Ergebnisse: Chirurgische Hämostase wurde in 184 Patienten (32,4 %, o-T / EVAR Gruppe) durchgeführt, während eine perkutane Hämostase an 384 Einstichstellen (67,6 %, p-T / EVAR Gruppe) versucht wurde. Die meisten Interventionen waren elektiv; fünf von zwölf Notfallpatienten hatten eine perkutane Hämostase, die in allen Fällen erfolgreich war. Die perkutane Hämostase scheiterte an 23 Einstichstellen (f-T / EVAR Gruppe). Keine Daten zum Follow-up wurden für 54 Einstichstellen (9,5 %) verzeichnet. Die technische Erfolgsrate der perkutanen Hämostase betrug 93,6 % (338 / 361 Einstichstellen). Der größere Öffnungsumfang war ein Prädiktor für Komplikationen. Es waren keine Todesfälle als Folge der gescheiterten Hämostase zu verzeichnen. Schlussfolgerungen: Komplette perkutane T / EVAR ist technisch und in der Mehrzahl der Patienten machbar. Gute Auswahl der Patienten basierend auf einer entsprechenden präoperativen Bildgebung und technisches Know-how des Operateurs stellten den Schlüssel zum Erfolg dar. Chirurgisches back-up wird dringend empfohlen bei Patienten, bei denen p-T / EVAR scheitert.