Navigating Intraductal Papillary Mucinous Neoplasm Management through Fukuoka Consensus vs. European Evidence-Based Guidelines on Pancreatic Cystic Neoplasms-A Study on Two European Centers.

This study addresses the critical need for the accurate diagnosis and management of intraductal papillary mucinous neoplasms (IPMNs), which are pancreatic cystic neoplasm types holding a substantial potential for malignancy. It evaluates the diagnostic effectiveness of the Fukuoka consensus guidelines and the European evidence-based guidelines in detecting high-grade dysplasia/invasive carcinoma in IPMNs, utilizing a retrospective analysis of 113 patients from two European medical centers. The methods include a comparative analysis of clinical, radiological, and endoscopic ultrasonography data, alongside an assessment of guideline-driven diagnostic performance. The results demonstrate that both guidelines offer similar accuracy in identifying severe disease stages in IPMNs, with certain clinical markers-such as jaundice, solid mass presence, and an increase in CA 19-9 levels-being pivotal in predicting the need for surgical intervention. This study concludes that while both guidelines provide valuable frameworks for IPMN management, there is an inherent need for further research to refine these protocols and improve patient-specific treatment strategies. This research contributes to the ongoing discourse on optimizing diagnostic and treatment paradigms for pancreatic cystic neoplasms, aiming to enhance clinical outcomes and patient care in this challenging medical field.

Safety and Efficacy of IL-12 Plasmid DNA Transfection into Pig Skin: Supportive Data for Human Clinical Trials on Gene Therapy and Vaccination.

Gene electrotransfer (GET) of plasmids encoding interleukin 12 (IL-12) has already been used for the treatment of various types of tumors in human oncology and as an adjuvant in DNA vaccines. In recent years, we have developed a plasmid encoding human IL-12 (phIL12) that is currently in a phase I clinical study. The aim was to confirm the results of a non-clinical study in mice on pharmacokinetic characteristics and safety in a porcine model that better resembled human skin. The GET of phIL12 in the skin was performed on nine pigs using different concentrations of plasmid phIL12 and invasive (needle) or noninvasive (plate) types of electrodes. The results of our study demonstrate that the GET of phIL-12 with needle electrodes induced the highest expression of IL-12 at the protein level on day 7 after the procedure. The plasmid was distributed to all tested organs; however, its amount decreased over time and was at a minimum 28 days after GET. Based on plasmid copy number and expression results, together with blood analysis, we showed that IL-12 GET is safe in a porcine animal model. Furthermore, we demonstrated that pigs are a valuable model for human gene therapy safety studies.

Intraoperative electrochemotherapy of the posterior resection surface after pancreaticoduodenectomy: Preliminary results of a hybrid approach treatment of pancreatic cancer.

BACKGROUND: Despite extensive research in recent decades, pancreatic cancer continues to be among the most lethal forms of cancer, with no substantial increase in survival rates. Local recurrences account for approximately 30 per cent of all disease recurrences. With the intent to improve survival, we designed a novel, hybrid treatment strategy consisting of surgical resection and additional intraoperative electrochemotherapy of the posterior resection surface. We present the study protocols and preliminary findings of a prospective pilot study investigating this treatment approach. METHODS: Consenting patients with resectable pancreatic head ductal adenocarcinoma who met the inclusion criteria were enrolled in the study. After surgical resection, electrochemotherapy with bleomycin was performed using plate electrodes to cover the area between anatomical landmarks. RESULTS: Electrochemotherapy of the posterior resection surface was feasible in all 7 patients. We observed pancreatic fistula grade B in only one patient; all other noted complications were Clavien-Dindo grade 2 or less. The hospital mortality was 0%. CONCLUSIONS: Our preliminary results suggest that a hybrid approach combining surgery with intraoperative electrochemotherapy is safe and feasible.

Electrochemotherapy combined with immunotherapy - a promising potential in the treatment of cancer.

Electrochemotherapy is a novel, locoregional therapy that is used to treat cutaneous and deep-seated tumors. The electric pulses used in electrochemotherapy increase the permeability of the cell membranes of the target lesion and thus enhance the delivery of low-permeant cytotoxic drugs to the cells, leading to their death. It has also been postulated that electrochemotherapy acts as an in situ vaccination by inducing immunogenic cell death. This in turn leads to an enhanced systemic antitumor response, which could be further exploited by immunotherapy. However, only a few clinical studies have investigated the role of combined treatment in patients with melanoma, breast cancer, hepatocellular carcinoma, and cutaneous squamous cell carcinoma. In this review, we therefore aim to review the published preclinical evidence on combined treatment and to review clinical studies that have investigated the combined role of electrochemotherapy and immunotherapy.

Laparoscopic electrochemotherapy for the treatment of hepatocellular carcinoma: Technological advancement.

Electrochemotherapy is an effective treatment modality for hepatocellular carcinoma (HCC). Electrochemotherapy for HCC was initially used in the setting of open surgery. Recently, with the development of newer electrodes, percutaneous approaches have also been performed. However, laparoscopic application of electrochemotherapy for HCC has not yet been described. Two patients with unresectable HCC were enrolled in the study. The first patient was not suitable for the percutaneous approach because the tumor was located close to the gallbladder. He also had symptomatic gallstones. The second patient had HCC in close proximity to the stomach and was therefore not suitable for percutaneous access or any other ablative technique. Thus, the laparoscopic approach was chosen, using newly developed Stinger electrodes for the application of electric pulses. After intravenous administration of bleomycin, several sets of electric pulses were delivered to the whole tumor mass in both patients. Ultrasonographically, the coverage of the whole tumor was verified, as described previously. Cholecystectomy was also performed in the first patient. Follow-up abdominal computed tomography showed a complete response of the treated lesions in both patients. Minimally invasive laparoscopic electrochemotherapy is safe, feasible and effective method for the treatment of HCC. It could be used in patients in whom the percutaneous approach is unsafe (proximity to other organs) and in patients with concomitant symptomatic gallstones in whom cholecystectomy is already indicated. This technological approach thus allows broader and minimally invasive clinical applicability of electrochemotherapy.

Neuroendocrine Tumor Arising within Mature Cystic Teratoma of the Pancreas: Literature Review and Case Report.

Cystic teratomas are germ cell tumors most commonly found in the ovaries and testes. The pancreas, however, is very rare as a site of occurrence. Moreover, only two cases of cystic teratoma with concomitant neuroendocrine tumor have been reported to date. We report the case of a 33-year-old female who presented with abdominal pain. Computed tomography and magnetic resonance imaging of the upper abdomen revealed an 85 mm cystic tumor in the head of the pancreas. Cystic teratoma and mucinous cystadenoma were suggested as differential diagnoses. Cytopathologic analysis of endoscopic ultrasound-guided fine needle aspiration was consistent with mucinous cystadenoma. Therefore, the patient underwent surgical resection. Histologic analysis revealed a mature cystic teratoma of the pancreas with a concomitant neuroendocrine tumor. The patient is in great condition at 8 months follow-up. Cystic teratoma of the pancreas with a concomitant neuroendocrine tumor is an extremely rare condition. Surgical resection remains the mainstay of treatment as it provides a definitive diagnosis and no recurrences have been reported to date.

Preliminary study of reliability of transcutaneous sensors in measuring intraabdominal pressure.

Early recognition of elevated intraabdominal pressure (IAP) in critically ill patients is essential, since it can result in abdominal compartment syndrome, which is a life-threatening condition. The measurement of intravesical pressure is currently considered the gold standard for IAP assessment. Alternative methods have been proposed, where IAP assessment is based on measuring abdominal wall tension, which reflects the pressure in the abdominal cavity. The aim of this study was to evaluate the feasibility of using patch-like transcutaneous sensors to estimate changes in IAP, which could facilitate the monitoring of IAP in clinical practice. This study was performed with 30 patients during early postoperative care. All patients still had an indwelling urinary catheter postoperatively. Four wearable sensors were attached to the outer surface of the abdominal region to detect the changes in abdominal wall tension. Additionally, surface EMG was used to monitor the activity of the abdominal muscles. The thickness of the subcutaneous tissue was measured with ultrasound. Patients performed 4 cycles of the Valsalva manoeuvre, with a resting period in between (the minimal resting period was 30 s, with a prolongation as necessary to ensure that the fluid level in the measuring system had equilibrated). The IAP was estimated with intravesical pressure measurements during all resting periods and all Valsalva manoeuvres, while the sensors continuously measured changes in abdominal wall tension. The association between the subcutaneous thickness and tension changes on the surface and the intraabdominal pressure was statistically significant, but a large part of the variability was explained by individual patient factors. As a consequence, the predictions of IAP using transcutaneous sensors were not biased, but they were quite variable. The specificity of detecting intraabdominal pressure of 20 mmHg and above is 88%, with an NPV of 96%, while its sensitivity and PPV are currently far lower. There are inherent limitations of the chosen preliminary study design that directly caused the low sensitivity of our method as well as the poor agreement with the gold standard method; in spite of that, we have shown that these sensors have the potential to be used to monitor intraabdominal pressure. We are planning a study that would more closely resemble the intended clinical use and expect it to show more consistent results with a far smaller error.

Primary Hepatic Leiomyoma in a Healthy Middle-Aged Woman: Literature Review and Case Report.

Introduction: Primary hepatic leiomyoma (PHL) is a rare benign hepatic tumor with unclear pathogenesis. It more commonly occurs in immunosuppressed patients, while only 24 cases have been described among immunocompetent individuals. To date, only one successful preoperative diagnosis of PHL has been achieved. Case Presentation: Here we report a case of PHL in a middle-aged woman with no history of immunosuppression. Preoperative diagnosis of PHL was established using ultrasound-guided fine needle trucut biopsy (FNTB). Nevertheless, due to the growing nature of tumor and patient's symptoms, we proceeded with surgical resection, which confirmed the diagnosis of PHL. At 6-month follow up, the patient is in good condition with no evidence of tumor recurrence. Conclusions: PHL is an uncommon tumor that should be considered in the differential diagnosis of rare liver tumors. Image guided FNTB appears to be effective in achieving preoperative diagnosis of PHL. Surgical resection, however, remains both diagnostic and curative in the management of PHL.

New era of electrochemotherapy in treatment of liver tumors in conjunction with immunotherapies.

Electrochemotherapy is a local ablative therapy that increases the cytotoxicity of either bleomycin or cisplatin by applying electric pulses (electroporation) to tumors. It has already been widely used throughout Europe for the treatment of various types of human and veterinary cutaneous tumors, with an objective response rate ranging from 70%-90%, depending on the tumor histotype. Recently, electrochemotherapy was introduced for the treatment of primary liver tumors, such as hepatocellular carcinoma (HCC). The complete response rate was 85% per treated lesion, with a durable response. Therefore, electrochemotherapy could become a treatment of choice for HCC, especially after achieving a transition from an open surgery approach to a percutaneous approach that uses dedicated electrodes. Electrochemotherapy elicits a local immune response and can be considered an in situ vaccination. HCC, among others, is a potentially immunogenic tumor; thus, electrochemotherapy could boost adjuvant immunotherapy to achieve a better and longer-lasting antitumor response. Therefore, therapeutic strategies that combine electrochemotherapy with immune checkpoint inhibitors or adjuvant treatment with cytokines are indicated for HCC. Immunogene therapy using electroporation as a delivery system for plasmid DNA coding for interleukin-12 is a highly promising approach. This electroporation approach has shown efficacy in preclinical settings and veterinary oncology and is awaiting translation for the treatment of liver tumors, i.e., HCC.

A Prospective Phase II Study Evaluating Intraoperative Electrochemotherapy of Hepatocellular Carcinoma.

The aim of this clinical study was to investigate the effectiveness and long-term safety of electrochemotherapy as an emerging treatment for HCC in patients not suitable for other treatment options. A prospective phase II clinical study was conducted in patients with primary HCC who were not suitable for other treatment options according to the Barcelona Clinic Liver Cancer classification. A total of 24 patients with 32 tumors were treated by electrochemotherapy. The procedure was effective, feasible, and safe with some procedure-related side effects. The responses of the 32 treated nodules were: 84.4% complete response (CR), 12.5% partial response (PR), and 3.1% stable disease (SD). The treatment was equally effective for nodules located centrally and peripherally. Electrochemotherapy provided a durable response with local tumor control over 50 months of observation in 78.0% of nodules. The patient responses were: 79.2% CR and 16.6% PR. The median progression-free survival was 12 months (range 2.7-50), and the overall survival over 5 years of observation was 72.0%. This prospective phase II clinical study showed that electrochemotherapy was an effective, feasible, and safe option for treating HCC in patients not suitable for other treatment options.

Safety and Feasibility of Electrochemotherapy of the Pancreas in a Porcine Model.

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 an 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 ECT with 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.

Percutaneous image guided electrochemotherapy of hepatocellular carcinoma: technological advancement.

Background Electrochemotherapy is an effective treatment of colorectal liver metastases and hepatocellular carcinoma (HCC) during open surgery. The minimally invasive percutaneous approach of electrochemotherapy has already been performed but not on HCC. The aim of this study was to demonstrate the feasibility, safety and effectiveness of electrochemotherapy with percutaneous approach on HCC. Patient and methods The patient had undergone the transarterial chemoembolization and microwave ablation of multifocal HCC in segments III, V and VI. In follow-up a new lesion was identified in segment III, and recognized by multidisciplinary team to be suitable for minimally invasive percutaneous electrochemotherapy. The treatment was performed with long needle electrodes inserted by the aid of image guidance. Results The insertion of electrodes was feasible, and the treatment proved safe and effective, as demonstrated by control magnetic resonance imaging. Conclusions Minimally invasive, image guided percutaneous electrochemotherapy is feasible, safe and effective in treatment of HCC.

Intraoperative electrochemotherapy of colorectal liver metastases: A prospective phase II study.

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.

Ultrasonographic changes in the liver tumors as indicators of adequate tumor coverage with electric field for effective electrochemotherapy.

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.

Electrochemotherapy as treatment option for hepatocellular carcinoma, a prospective pilot study.

BACKGROUND AND OBJECTIVES: Electrochemotherapy provides non-thermal ablation of cutaneous as well as deep seated tumors. Based on positive results of the treatment of colorectal liver metastases, we conducted a prospective pilot study on hepatocellular carcinomas with the aim of testing the feasibility, safety and effectiveness of electrochemotherapy. PATIENTS AND METHODS: Electrochemotherapy with bleomycin was performed on 17 hepatocellular carcinomas in 10 patients using a previously established protocol. The procedure was performed during open surgery and the patients were followed for median 20.5 months. RESULTS: Electrochemotherapy was feasible for all 17 lesions, and no treatment-related adverse events or major post-operative complications were observed. The median size of the treated lesions was 24 mm (range 8-41 mm), located either centrally, i.e., near the major hepatic vessels, or peripherally. The complete response rate at 3-6 months was 80% per patient and 88% per treated lesion. CONCLUSIONS: Electrochemotherapy of hepatocellular carcinoma proved to be a feasible and safe treatment in all 10 patients included in this study. To evaluate the effectiveness of this method, longer observation period is needed; however the results at medium observation time of 20.5 months after treatment are encouraging, in 15 out of 17 lesions complete response was obtained. Electrochemotherapy is predominantly applicable in patients with impaired liver function due to liver cirrhosis and/or with lesions where a high-risk operation is needed to achieve curative intent, given the intra/perioperative risk for high morbidity and mortality.

Variation in dielectric properties due to pathological changes in human liver.

Dielectric properties of freshly excised human liver tissues (in vitro) with several pathological conditions including cancer were obtained in frequency range 100 MHz-5 GHz. Differences in dielectric behavior of normal and pathological tissues at microwave frequencies are discussed based on histological information for each tissue. Data presented are useful for many medical applications, in particular nanosecond pulsed electroporation techniques. Knowledge of dielectric properties is vital for mathematical calculations of local electric field distribution inside electroporated tissues and can be used to optimize the process of electroporation for treatment planning procedures.