Pressurised Intraperitoneal Aerosolised Chemotherapy-Results from the First Hundred Consecutive Procedures.

PIPAC is a new and promising technique for the intraperitoneal administration of chemotherapy. It can be used in patients with various peritoneal cancer metastases. It is mainly a palliative treatment, but there is some neoadjuvant treatment potential. We have operated on 41 patients with various intra-abdominal cancers. PIPAC was performed every 6 weeks. The indication was extension of peritoneal carcinomatosis beyond the criteria for cytoreductive surgery and HIPEC. The effect was evaluated according to the peritoneal cancer index, the peritoneal regression grading score and the amount of ascites. Complications were classified according to the Clavien-Dindo system. We have performed 100 PIPAC procedures. There were two major complications, classified as Clavien Dindo III (2%). The number of procedures varied from 1 to 6. Five patients switched to cytoreductive surgery and HIPEC, and one was indicated for the watch and wait strategy due to total regression according to PRGS. Three patients are still continuing treatment. The others stopped treatment mainly because of progression of the disease and loss of metastases. We observed a reduction in ascites production soon after PIPAC application. PIPAC is a safe and well-tolerated treatment modality. It is mainly a palliative treatment that can improve the quality of life by reducing the production of ascites, but in about 10% of cases, it can reduce the extent of the disease and allow for further radical treatment.

Diagnosis and Surgical Management of Insulinomas-A 23-Year Single-Center Experience.

Background and Objectives: Insulinoma is a rare tumor of the Langerhans islets of the pancreas. It produces insulin and causes severe hypoglycemia with neuroglycopenic symptoms. The incidence is low, at about 1-2 per 1 million inhabitants per year. The diagnosis is based on the presence of Whipple's triad and the result of a fasting test. Surgery is the treatment of choice. Objectives: A retrospective observational study of patients operated on for insulinoma in our hospital focused on the diagnosis, the type of surgery, and complications. Materials and Methods: We retrospectively reviewed patients operated on due to insulinoma. There were 116 surgeries between 2000 and 2022. There were 79 females and 37 males in this group. A fasting test and a CT examination were performed on all the patients. Results: The average duration of the fasting test was 18 h. Insulinoma was found in the body and tail of the pancreas in more than half of the patients. Enucleation was the most frequent type of surgery. Complications that were Clavien Dindo grade III or more occurred in 18% of the patients. The most frequent complications were abscesses and pancreatic fistula. Five patients had malignant insulinoma. Conclusions: Surgery is the treatment of choice in the case of insulinomas. The enucleation of the tumor is a sufficient treatment for benign insulinomas, which are not in contact with the main pancreatic duct. Due to the low incidence of the condition, the centralization of patients is recommended.

TET protein inhibitors: Potential and limitations.

TET proteins (methylcytosine dioxygenases) play an important role in the regulation of gene expression. Dysregulation of their activity is associated with many serious pathogenic states such as oncological diseases. Regulation of their activity by specific inhibitors could represent a promising therapeutic strategy. Therefore, this review describes various types of TET protein inhibitors in terms of their inhibitory mechanism and possible applicability. The potential and possible limitations of this approach are thoroughly discussed in the context of TET protein functionality in living systems. Furthermore, possible therapeutic strategies based on the inhibition of TET proteins are presented and evaluated, especially in the field of oncological diseases.

Therapeutic potential and limitations of curcumin as antimetastatic agent.

Treatment of metastatic cancer is one of the biggest challenges in anticancer therapy. Curcumin is interesting nature polyphenolic compound with unique biological and medicinal effects, including repression of metastases. High impact studies imply that curcumin can modulate the immune system, independently target various metastatic signalling pathways, and repress migration and invasiveness of cancer cells. This review discusses the potential of curcumin as an antimetastatic agent and describes potential mechanisms of its antimetastatic activity. In addition, possible strategies (curcumin formulation, optimization of the method of administration and modification of its structure motif) to overcome its limitation such as low solubility and bioactivity are also presented. These strategies are discussed in the context of clinical trials and relevant biological studies.

Influence of opioid analgesia type on circulating tumor cells in open colorectal cancer surgery (POACC-1): study protocol for a prospective randomized multicenter controlled trial.

BACKGROUND: Opioids and epidural analgesia are a mainstay of perioperative analgesia but their influence on cancer recurrence remains unclear. Based on retrospective data, we found that cancer recurrence following colorectal cancer surgery correlates with the number of circulating tumor cells (CTCs) in the early postoperative period. Also, morphine- but not piritramide-based postoperative analgesia increases the presence of CTCs and shortens cancer-specific survival. The influence of epidural analgesia on CTCs has not been studied yet. METHODS: We intend to enroll 120 patients in four centers in this prospective randomized controlled trial. The study protocol has been approved by Ethics Committees in all participating centers. Patients undergoing radical open colorectal cancer surgery are randomized into epidural, morphine, and piritramide groups for perioperative analgesia. The primary outcome is the difference in the number of CTCs in the peripheral blood before surgery, on the second postoperative day, and 2-4 weeks after surgery. The number of CTCs is measured using molecular biology methods. Perioperative care is standardized, and relevant data is recorded. A secondary outcome, if feasible, would be the expression and activity of various receptor subtypes in cancer tissue. We intend to perform a 5-year follow-up with regard to metastasis development. DISCUSSION: The mode of perioperative analgesia favorably affecting cancer recurrence would decrease morbidity/mortality. To identify such techniques, trials with long-term follow-up periods seem suboptimal. Given complex oncological therapeutic strategies, such trials likely disable the separation of perioperative analgesia effects from other factors. We believe that early postoperative CTCs presence/dynamics may serve as a sensitive marker of various perioperative interventions´ influences on cancer recurrence. Importantly, it is unbiased to the influence of long-term factors and minimally invasive. Analysis of opioid/cannabinoid receptor subtypes in cancer tissue would improve understanding of underlying mechanisms and promote personalization of treatment. We are not aware of any similar ongoing studies. TRIAL REGISTRATION NUMBER: NCT03700411, registration date: October 3, 2018. STUDY STATUS: recruiting.

Circulating Tumour Cells (CTCs) in NSCLC: From Prognosis to Therapy Design.

Designing optimal (neo)adjuvant therapy is a crucial aspect of the treatment of non-small-cell lung carcinoma (NSCLC). Standard methods of chemotherapy, radiotherapy, and immunotherapy represent effective strategies for treatment. However, in some cases with high metastatic activity and high levels of circulating tumour cells (CTCs), the efficacy of standard treatment methods is insufficient and results in treatment failure and reduced patient survival. CTCs are seen not only as an isolated phenomenon but also a key inherent part of the formation of metastasis and a key factor in cancer death. This review discusses the impact of NSCLC therapy strategies based on a meta-analysis of clinical studies. In addition, possible therapeutic strategies for repression when standard methods fail, such as the administration of low-toxicity natural anticancer agents targeting these phenomena (curcumin and flavonoids), are also discussed. These strategies are presented in the context of key mechanisms of tumour biology with a strong influence on CTC spread and metastasis (mechanisms related to tumour-associated and -infiltrating cells, epithelial-mesenchymal transition, and migration of cancer cells).

Spectroscopic study of in situ-formed metallocomplexes of proton pump inhibitors in water.

Proton pump inhibitors, such as omeprazole, pantoprazole and lansoprazole, are an important group of clinically used drugs. Generally, they are considered safe without direct toxicity. Nevertheless, their long-term use can be associated with a higher risk of some serious pathological states (e.g. amnesia and oncological and neurodegenerative states). It is well known that dysregulation of the metabolism of transition metals (especially iron ions) plays a significant role in these pathological states and that the above drugs can form complexes with metal ions. However, to the best of our knowledge, this phenomenon has not yet been described in water systems. Therefore, we studied the interaction between these drugs and transition metal ions in the surrounding water environment (water/DMSO, 99:1, v/v) by absorption spectroscopy. In the presence of Fe(III), a strong redshift was observed, and more importantly, the affinities of the drugs (represented as binding constants) were strong enough, especially in the case of omeprazole, so that the formation of a metallocomplex cannot be excluded during the explanation of their side effects.

Malignant Peritoneal Tumors - Introduction.

This article provides an introduction to peritoneal tumors, which are the subject of a series of review papers published in Issue 5 (2019) of Klinicka onkologie. Many malignant peritoneal tumors are characterized by production of mucinous and gelatinous masses, multiple peritoneal disability, so-called peritoneal carcinomatosis, and various grades of malignancy depending on their origin, staging, and histological type. Malignant peritoneal tumors are rare and their clinical symptomatology is nonspecific and varies according to the extent of disability. Diagnosis, particularly in the initial asymptomatic stages, is very complicated and often impossible, and tumors are often diagnosed by chance during other operations. Malignant peritoneal tumors were regarded as incurable and lethal for a long time; however, this view has changed over the past three decades. The Sugarbaker method, a combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, was introduced in the 1990s. Postoperative cytostatic lavage is usually performed in specific cases. Classifications for the extent of disease and completeness of cytoreduction were established. Studies repeatedly confirmed the efficacy of this treatment for peritoneal malignancy. The combination of an aggressive surgical approach and intraperitoneal chemotherapy not only enhances quality of life, but also prolongs progression-free survival and overall survival in selected patients. Specialized centers for treatment of peritoneal malignancy were established based on results from the Czech Republic and around the world. These centers provide complex care, including specific surgical interventions and follow-up, for selected patients with primary and secondary peritoneal malignancy.

Peritoneal Carcinomatosis of Gastric Origin - Treatment Possibilities.

BACKGROUND: Peritoneal carcinomatosis of gastric origin is challenging to diagnose and treat. This disease is often misdiagnosed in the early stages using a non-invasive technique. Conventional surgery is unsuitable for treatment of patients with peritoneal seeding and positive peritoneal cytology. Peritoneal recurrence is the most frequent cause of therapeutic failure. The effectiveness of chemotherapy is low due to the plasma-peritoneal barrier. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is the standard treatment for pseudomyxoma peritonei and mesothelioma and improves overall survival and disease-free survival. This approach is also widely used to prevent and treat peritoneal carcinomatosis of gastric origin. PURPOSE: This article aims to provide a short summary of the contemporary role of cytoreductive surgery and HIPEC for treatment of gastric cancer patients. Theoretically, there are four possible applications and indications. First, palliative application to improve quality of life without prolongation of overall survival. This application mainly affects malignant ascites. Second, therapeutic application using a combination of gastrectomy/cytoreductive surgery and HIPEC to treat advanced disease including peritoneal metastases. Localized peritoneal seeding is the only indication for this application (maximum peritoneal cancer index of 10-12 or Cy+). Third, adjuvant/prophylactic application in patients at high risk of peritoneal recurrence, typically those with T3, T4, N+ disease (without peritoneal seeding). Fourth, neoadjuvant application using a combination of repeated HIPEC and chemotherapy with the aim of decreasing peritoneal seeding and enabling radical surgery. In this indication, HIPEC is often replaced by pressurized intraperitoneal aerosol chemotherapy.

Strategy for improved therapeutic efficiency of curcumin in the treatment of gastric cancer.

Gastric cancer is a common oncological disease. Although enormous efforts have been expended, possible therapeutic modalities are still limited. For this reason, new therapeutic approaches and agents are highly requested and intensively developed. One strategy is the application of natural agents, such as curcumin, with proven anticancer effects and low toxicity for patients. Therefore, this review discusses the potential application of curcumin in the therapy of gastric cancer and its potential incorporation in therapeutic regimens. Because one of the largest impediments for widespread curcumin application is its limited bioavailability (caused mainly by its very low water solubility), studied strategies (drug delivery systems and curcumin derivatization) aimed to solve this obstacle are discussed in more detail.

Peritoneal lavage examination as a prognostic tool in cases of gastric cancer.

INTRODUCTION: Peritoneal tumor seeding is a common form of recurrence after gastric cancer surgery. The finding of free tumor cells and/or elevation of tumor markers in the peritoneal fluid could predict intraperitoneal tumor recurrence. The results of these examination can be used for indication of aggressive treatment modalities such as hyperthermic intraperitoneal chemotherapy (HIPEC). MATERIAL AND METHODS: We have operated on 105 patients suffering from gastric cancer. The control group consisted of 12 patients without malignant disease. Peritoneal lavage fluid or ascites was collected immediately after laparotomy and examined by cytology and biochemistry (levels of carcinoembryonic antigen (CEA) and Ca 19-9). Sensitivity, specificity, stage correlation and overall survival were observed. RESULTS: Elevation of tumor markers or the finding of free intraperitoneal tumor cells predicts recurrence. The prognosis of these patients is same as in stage IV TNM classification with median survival time less than 1 year (p = 0.713). Patients with negative cytology have median survival time 5 years contrary to them with positive cytology (p < 0.001). Sensitivity of the cytology was 34% and specificity was 85%. Sensitivity of biochemistry was 53% (combination of both markers) and specificity was 100%. CONCLUSIONS: This study confirms the importance of peritoneal fluid examination for the prognosis. We cannot recommend routine use as an indicator for HIPEC due to low sensitivity, but the result of cytological examination is an independent factor for patient survival.

Fast-track in open intestinal surgery: prospective randomized study (Clinical Trials Gov Identifier no. NCT00123456).

BACKGROUND: Studies have shown the value of using fast-track postoperative recovery. Standard procedures (non-fast-track strategies) remain in common use for perioperative care. Few prospective reports exist on the outcome of fast-tracking in Central Europe. The aim of our study was to assess the effect and safety of our own fast-track protocol with regard to the postoperative period after open bowel resection. PATIENTS AND METHODS: One hundred and five patients with ASA score I-II scheduled for open intestinal resection in the period April 2005-December 2007 were randomly selected for the fast-track group (FT) and non-fast-track group (non-FT). A designed protocol was used in the FT group with the emphasis on an interdisciplinary approach. The control group (non-FT) was treated by standard established procedures. Postoperative pain, rehabilitation, gastrointestinal functions, postoperative complications, and post-op length of stay were recorded. RESULTS: Of 105 patients, 103 were statistically analyzed. Patients in the FT group (n=51) and non-FT group (n=52) did not differ in age, surgical diagnosis, or procedure. The fast-track procedure led to significantly better control of postoperative pain and faster restoration of GI functions (bowel movement after 1.3 days vs. 3.1, p<0.001). Food tolerance was significantly better in the FT group and rehabilitation was also faster. Hospital stay was shorter in the FT group - median seven days (95% CI 7.0-7.7) versus ten days (95% CI 9.5-11.3) in non-FT (p<0.001). Postoperative complications within 30 postoperative days were also significantly lower in the FT group (21.6 vs. 48.1%, p=0.003). There were no deaths and no patients were readmitted within 30 days. CONCLUSIONS: Following the FT protocol helped to reduce frequency of postoperative complications and reduced hospital stay. We conclude that the FT strategy is safe and effective in improving postoperative outcomes.