Danijel Galun

Quality of life of patients with advanced pancreatic cancer during treatment with mistletoe: a randomized controlled trial.

BACKGROUND The treatment of cancer patients with mistletoe extract is said to prolong their survival and, above all, improve their quality of life. We studied whether the quality of life of patients with advanced pancreatic cancer could be improved by mistletoe extract. METHOD An open, single-center, group-sequential, randomized phase III trial (ISRCTN70760582) was conducted. From January 2009 to December 2010, 220 patients with locally advanced or metastatic pancreatic cancer who were receiving no further treatment for pancreatic cancer other than best supportive care were included in this trial. They were stratified by prognosis and randomly allocated either to a group that received mistletoe treatment or to one that did not. Mistletoe extract was given in escalating doses by subcutaneous injection three times a week. The planned interim evaluation of data from 220 patients indicated that mistletoe treatment was associated with longer overall survival, and the trial was terminated prematurely. After termination of the study, the results with respect to quality of life (assessed with the QLO-C30 scales of the European Organisation for Research and Treatment of Cancer) and trends in body weight were evaluated. RESULTS Data on quality of life and body weight were obtained from 96 patients treated with mistletoe and 72 control patients. Those treated with mistletoe did better on all 6 functional scales and on 7 of 9 symptom scales, including pain (95% confidence interval [CI] -29 to -17), fatigue (95% CI -36.1 to -25.0), appetite loss (95% CI -51 to -36.7), and insomnia (95% CI -45.8 to -28.6). This is reflected by the trend in body weight during the trial. CONCLUSION In patients with locally advanced or metastatic pancreatic carcinoma, mistletoe treatment significantly improves the quality of life in comparison to best supportive care alone. Mistletoe is an effective second-line treatment for this disease.The recent advances in oncology are plainly evident: more than half of all persons with cancer in Germany now survive their illness and are considered cured (1). Many types of cancer can be kept under control for a long period and converted into a disease with a chronic course and an acceptable quality of life (2). Unfortunately, some cancers still regularly lead to the death of the patient within a short time. Superficially considered, these diseases may seem to be a matter of fate that cannot be influenced by any type of treatment. In fact, however, physicians have many options at hand when treating patients nearing their lifes end, and there are many medical decisions to be taken. Pancreatic carcinoma is nearly always fatal; yet, even for this disease, further treatments have recently become available. New therapeutic approaches prolong survival and improve the manifestations of the disease and the patients? overall quality of life (3).

A radiofrequency-assisted minimal blood loss liver parenchyma dissection technique.

Background/Aims: Intraoperative blood loss is still a major concern for surgeons operating on the liver since it is associated with a significantly higher rate of postoperative complications and shorter long-term survival. An original radiofrequency (RF)-assisted minimal blood loss technique for transecting liver parenchyma is presented. Methods: In a prospective study, starting November 2001 and ending December 2005, a total of 90 RF-assisted liver resections were done. Pre-cut coagulative desiccation was produced by the Cool-tip™ (Valleylab, Tyco) water-cooled, single, RF tumor ablation electrode connected to a 480-kHz 200 W generator (Valleylab Cool-tip™ RF System). Vascular occlusion techniques and low central venous pressure anesthesia were not used. Results: Only 14 (15.5%) patients received blood transfusion (mean transfused blood volume 397 ml; mode 310 ml) and 10 of 14 patients received <310 ml of blood. There was no statistical difference between the patients who underwent major and minor liver resection in frequency of blood transfusion. Blood loss was associated with dense adhesions and difficult liver mobilization and not with liver transection. Conclusion: The ‘sequential coagulate-cut’ RF-assisted liver resection technique is a safe liver transection technique associated with minimal blood loss and it has facilitated tissue-sparing liver resection.

Hepatocellular carcinoma: From clinical practice to evidence-based treatment protocols

Hepatocellular carcinoma (HCC) is one of the major malignant diseases in many healthcare systems. The growing number of new cases diagnosed each year is nearly equal to the number of deaths from this cancer. Worldwide, HCC is a leading cause of cancer-related deaths, as it is the fifth most common cancer and the third most important cause of cancer related death in men. Among various risk factors the two are prevailing: viral hepatitis, namely chronic hepatitis C virus is a well-established risk factor contributing to the rising incidence of HCC. The epidemic of obesity and the metabolic syndrome, not only in the United States but also in Asia, tend to become the leading cause of the long-term rise in the HCC incidence. Today, the diagnosis of HCC is established within the national surveillance programs in developed countries while the diagnosis of symptomatic, advanced stage disease still remains the characteristic of underdeveloped countries. Although many different staging systems have been developed and evaluated the Barcelona-Clinic Liver Cancer staging system has emerged as the most useful to guide HCC treatment. Treatment allocation should be decided by a multidisciplinary board involving hepatologists, pathologists, radiologists, liver surgeons and oncologists guided by personalized -based medicine. This approach is important not only to balance between different oncologic treatments strategies but also due to the complexity of the disease (chronic liver disease and the cancer) and due to the large number of potentially efficient therapies. Careful patient selection and a tailored treatment modality for every patient, either potentially curative (surgical treatment and tumor ablation) or palliative (transarterial therapy, radioembolization and medical treatment, i.e., sorafenib) is mandatory to achieve the best treatment outcome.

European Viscum album: a potent phytotherapeutic agent with multifarious phytochemicals, pharmacological properties and clinical evidence

Viscum album L. or European mistletoe (Loranthaceae), a semi-parasitic shrub, has been used as a traditional medicine in Europe for centuries to treat various diseases like cancer, cardiovascular disorder, epilepsy, infertility, hypertension and arthritis. V. album contains diverse phytochemicals, which exert a large number of biological and pharmacological activities. The aim of this review is to compile the developments in the domain of V. album and research trends, with a focus on ethnopharmacology, phytochemistry and pharmacological properties, to illustrate the potential of this phytotherapeutic as an attractive commercial herbal medicine. Crude extracts and isolated chemical constituents from V. album have exhibited significant medicinal effects in experimental models and in patients with cancer, autoimmune and inflammatory conditions. Importantly, recent randomized clinical trials have suggested improved overall survival and quality of life in cancer patients treated with different mistletoe preparations. The current phytochemical studies have shown that lectins, hetero-dimeric glycoproteins, polysaccharides, viscotoxins, alkaloids, lipids, triterpenes, peptides, vesicles, flavonoids, cyclitols and amines are principal bioactive phytochemicals of V. album. Clinical studies and experimental models have revealed that V. album exhibits several pharmacological functions such as immunomodulatory, anti-hypertensive, anti-oxidant, cytotoxicity, anti-tumor, anti-inflammation, anti-diabetic, anti-microbial and sedative activities. It is conceivable that the heterogenous profile of biochemical compounds provides the basis for the broad diversity of pharmacological activities of mistletoe, as each single component contributes diverse modes of action in addition to imparting a synergistic beneficial action in conjunction with other molecules.

Sensitization of K562 Leukemia Cells to Doxorubicin by the Viscum album Extract

Toxicity of conventional chemotherapeutics highlights the requirement for complementary or alternative medicines that would reduce side effects and improve their anticancer effectiveness. European mistletoe (Viscum album) has long been used as a complementary and alternative medicine supporting cancer therapy. The aim of this study was to investigate synergistic antitumor action of V. album extract and doxorubicin during co‐treatment of chemoresistant chronic myelogenic leukemia K562 cells. Combined treatment of leukemia cells led to inhibitory synergism at sub‐apoptotic doxorubicin concentrations and multifold reduction of cytotoxic effects in healthy control cells. Prolonged co‐treatment was associated with reduced G2/M accumulation and increased expression of early and late apoptotic markers. Our data indicate that V. album extract increases antileukemic effectiveness of doxorubicin against resistant K562 cells by preventing G2/M arrest and inducing apoptosis. Copyright

Sclerosing Mesenteritis Presenting as a Pseudotumor of the Greater Omentum

Objective: The aim was to demonstrate a diagnostic challenge of sclerosing mesenteritis initially considered as liposarcoma. Clinical Presentation and Intervention: A 45-year-old man was admitted with a painful abdominal mass. Abdominal computed tomography demonstrated a well- demarcated tumor in his left hemiabdomen, with a large fat component and areas of soft tissue attenuation suggestive of liposarcoma. Intraoperative findings showed a tumor arising from the greater omentum. The tumor was completely removed, and histopathology confirmed a pseudotumorous type of sclerosing mesenteritis with dominant mesenteric lipodystrophy. Conclusion: This case showed that a pseudotumorous type of sclerosing mesenteritis should be considered in the differential diagnosis of the mesenteric tumors.

Monoclonal immunoscintigraphy for detection of metastasis and recurrence of colorectal cancer

AIM To assess the clinical role of monoclonal immunoscintigraphy for the detection of metastasis and recurrence of colorectal cancer. METHODS Monoclonal immunoscintigraphy was performed in patients operated on for colorectal adenocarcinoma suspected of local recurrence and metastatic disease. The results were compared with conventional diagnostics. RESULTS Immunoscintigraphic investigation was done in 53 patients. Tumor recurrence occurred in 38 patients, and was confirmed by other diagnostic modalities in 35. In 15 patients, immunoscintigraphic findings were negative, and confirmed in 14 with other diagnostic methods. Comparative analysis confirmed good correlation of immunoscintigraphic findings and the results of conventional diagnostics and the level of tumor marker carcinoembryonic antigen. Statistical analysis of parameters of radiopharmaceutical groups imacis, indimacis and oncoscint presented homogenous characteristics all of three radiopharmaceuticals. The analysis of immunoscintigraphic target focus was clearly improved using tomography. CONCLUSION Immunoscintigraphy is highly specific and has a good predictive value in local recurrence of colorectal cancer.

Histopathology of Hepatic Sinusoidal Obstruction Syndrome After Neoadjuvant Oxaliplatin-Based Chemotherapy

Abstract Sinusoidal obstruction syndrome („blue liver syndrome“) has been frequently associated with oxaliplatin-based neoadjuvant chemotherapy in patients with colorectal liver metastasis. Hepatotoxic vascular lesions in the nontumourous liver parenchyma result in hypoperfusion and tissue hypoxia leading to lower tumour response to oncologic treatment and to increase the risk of liver metastasectomies. Furthermore, hepatic parenchyma injuries could be aggravated by hepatic resection itself. Contrary to standard surgical techniques, radiofrequency assisted liver resection significantly reduce harmful intraoperative blood loss and perfusion-reperfusion effects. We compared histological alterations in 59 specimens of bloodless radiofrequency-assisted liver recetions made for colorectal metastases to those in 38 specimens of standard liver resections. In general, the main histologic alterations in both examined groups related to oxaliplatin include SOS lesions (69.35%), fibrosis (50.95%) and steatosis (38%). After scoring of histopathological parameters based on modified criteria according to Rubbia-Brandt et al., they were statistically insignificant between both groups for portal and/or porto-portal fibrosis (59.3% vs 47.4%, respectively) and moderate/severe macrovacuolar steatosis (10.2% vs 26.3%). Similar distribution between groups was shown for surgical hepatitis with „borderline“ statistical significance (23,7% vs 42,1%, p= 0.05). However, there were significant differencies in vascular lesions, particularly for hemorrhagic centrilobular necrosis (10,2% vs 31,5%, p= 0.01) and peliosis (15,2% vs 36,8%, p= 0.04), but were not significant for sinusoidal dilatation and congestion as well as surgical necrosis. Highgrade vascular lesions such as hemorrhagic centrilobular necrosis and peliosis are less frequent in cases of radiofrequency-assisted liver recetions and might be associated with better clinical outcome in these patients.

Preoperative neutrophil-to-lymphocyte ratio as a prognostic predictor after curative-intent surgery for hepatocellular carcinoma: experience from a developing country

Purpose The aim of the study was to evaluate a prognostic value of preoperative neutrophil-to-lymphocyte ratio (NLR) on long-term survival of cirrhotic and noncirrhotic hepatocellular cancer (HCC) patients managed by a curative-intent liver surgery in a developing country. Patients and methods During the study period between November 1, 2001, and December 31, 2012, 109 patients underwent potentially curative hepatectomy for HCC. Data were retrospectively reviewed from the prospectively collected database. The median follow-up was 25 months. NLR was estimated by dividing an absolute neutrophil count by an absolute lymphocyte count from the differential blood count. Receiver operating characteristic curve was constructed to assess the ability of NLR to predict long-term outcomes and to determine an optimal cutoff value for all patients group, the subgroup with cirrhosis, and the subgroup without cirrhosis. The optimal cutoff values were 1.28, 1.28, and 2.09, respectively. Results The overall 3- and 5-year survival rates were 49% and 45%, respectively, for low NLR group and 38% and 26%, respectively, for high NLR group. The difference was statistically significant (p=0.015). Overall survival was similar between low and high NLR groups in patients with cirrhosis; no difference was found between the groups (p=0.124). In patients without cirrhosis, low NLR group had longer overall survival compared with high NLR group (p=0.015). Univariate analysis identified four factors as significant predictors of long-term survival: cirrhosis, Child-Pugh score, platelet count, and NLR. On multivariate analysis, only platelet count and NLR were independent prognostic factors of long-term survival. Conclusion Prognostic value of NLR was confirmed in noncirrhotic HCC patients who underwent curative-intent liver surgery. In HCC patients with cirrhosis, the prognostic role of NLR was not confirmed.

Radiofrequency ablation for hepatocellular carcinoma - analysis of the clinical outcome

Introduction/Objective Radiofrequency ablation (RFA) is a minimally invasive treatment modality for primary and metastatic liver tumors. It can be performed percutaneously or as a laparoscopic or open surgical procedure under ultrasound or computerized tomography guidance. The objective of the study was to evaluate the clinical outcome of the initial 16 patients with hepatocellular carcinoma (HCC) managed by percutaneous RFA at a tertiary institution and to assess the efficacy of this procedure in the management of selected patients with HCC. Method From June 2011 until December 2013, 16 patients with early-stage HCC were managed by percutaneous radiofrequency ablation at the Clinic for Digestive Surgery, Clinical Center of Serbia, Belgrade. All the patients were treated by the same team composed of an interventional radiologist and a liver surgeon. We analyzed the clinical outcome and the biologic effect of this treatment by comparing the preand post-treatment levels of alpha-fetoprotein (AFP). Results Post-treatment values of liver transaminase levels returned to the pre-treatment values from Day 3. Post-treatment hospital stay was two days. Post-procedural complications included mild pain in all patients, skin necrosis at the site of the electrode puncture in five patients, and transient hepatic decompensation in one patient. In all the patients the AFP level correlated with the findings of liver imaging (ultrasound and/or magnetic resonance imaging with liver-specific contrast agent) indicating viability of the treated tumor. Conclusion RFA is a feasible and effective procedure providing favorable clinical outcome in patients with early-stage HCC.